Asthma pathogenesis and new drugs for treatment - BMJ State of the Art Review

Asthma affects more than 300 million people worldwide. Of these, 10-15% have severe asthma, which is refractory to commonly available drugs. New drugs are needed because those that are currently available cannot control symptoms and exacerbations in all patients and can cause adverse reactions.

In the past 10 years, advances in asthma genetics, airway biology, and immune cell signaling have led to the development of small molecule therapeutics and biologic agents.

Several new classes of asthma drugs have been evaluated in randomized controlled trials:

- ultra long acting beta agonists
- modulators of the interleukin 4 (IL-4), IL-5, IL-13, and IL-17 pathways

Other new drug classes remain in earlier phases of development:

- dissociated corticosteroids
- CXC chemokine receptor 2 antagonists
- toll-like receptor 9 agonists
- and tyrosine kinase inhibitors

Despite some preliminary efficacy data, there is insufficient evidence to make strong recommendations about the use of these newer agents. Future research will focus on:

- clinical efficacy of the biologic agents
- effect of newer agents on severe asthma in pediatric patients
- biology of non-eosinophilic and corticosteroid resistant asthma

References:

Asthma: pathogenesis and novel drugs for treatment. BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g5517 (Published 24 November 2014)
Cite this as: BMJ 2014;349:g5517
http://www.bmj.com/content/349/bmj.g5517.long

Image source: Lungs, Wikipedia, public domain.

Lung Sound Analysis Predicts Airway Inflammation in Patients with Asymptomatic Asthma

The expiratory-inspiratory ratios of sound power in the low-frequency range (E-I LF) from 36 patients with asymptomatic asthma were compared with those of 14 healthy controls (here is the study link).

The mean E-I LF was higher in the patients with asthma and with increased sputum eosinophils than in those patients without increased sputum eosinophils (0.45 vs 0.20) or in the healthy controls (0.25). Sputum eosinophil ratio and exhaled nitric oxide were independently correlated with E-I LF.

For the prediction of increased sputum eosinophils and increased fractional exhaled nitric oxide levels, the E-I LF thresholds of 0.29 and 0.30 showed sensitivities of 0.80 and 0.74 and specificities of 0.83 and 0.77, respectively.

Lung sound analysis (LSA) could predict airway inflammation of patients with asymptomatic asthma.

References:

Prediction of Airway Inflammation in Patients with Asymptomatic Asthma by Using Lung Sound Analysis - The Journal of Allergy and Clinical Immunology: In Practice http://buff.ly/1zJK0CX

Questionnaire-based tool to recognize small airways dysfunction in asthma (SADT) is in development

In this preliminary research from The Netherlands, the authors aimed to develop a small airways dysfunction tool (SADT) to identify asthma patients having small airways dysfunction. SADT was based on interviews and pulmonary function tests.

Asthma patients with and without SAD were interviewed (10 interviews, 2 focus groups). Patients were selected to participate in this study based on FEF50% and R5-R20 values from spirometry and impulse oscillometry.

Patients with small airways dysfunction reported to wheeze easily, were unable to breathe in deeply, mentioned more symptoms related to bronchial hyperresponsiveness, experienced more pronounced exercise-induced symptoms and more frequently had allergic respiratory symptoms after exposure to cats and birds. 63 items will be further explored for the SADT in the future. The authors will attempt to validate all 63 items in order to retain the most relevant ones and create a shorter, simple tool to identify asthma patients with small airways dysfunction.

References:

Development of a tool to recognize small airways dysfunction in asthma (SADT).
Schiphof-Godart L, van der Wiel E, Ten Hacken N, van den Berge M, Postma DS, van der Molen T. Health Qual Life Outcomes. 2014 Nov 22;12(1):155. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253607/

Allergic conjunctivitis: What are the new treatments?

Even Higher Concentration Olopatadine (Pataday (TM))

A newer higher concentration (0.77%) version of topical olopatadine is investigated vs. legacy versions of lower concentrations (0.2% and 0.1%) of olopatadine. Ocular itch was reduced for the higher concentration.

Currently, most drugs are marketed as lasting up to 16 hours. By increasing the bioavailability of olopatadine, the new version of this drug could extend to 24 hours (the original marketting for Pata-DAY was supposed to imply once a DAY efficacy) .



Treatment options for allergic conjunctivitis (eye drops) (click here to enlarge the image).

Cetirizine eye drops

Zyrtec Itchy Eye Drops currently available on the US market actually do not contain Zyrtec (cetirizine), they contain ketotifen. This could change in the future. Cetirizine is a popular over-the-counter oral antihistamine that had already been assessed for a potential ocular allergy treatment in the past. As an oral agent, it may induce dry eyes.

Ophthalmic cetirizine (0.24%) significantly reduced ocular itch up to 8 hours. The drying effect of antihistamines is a conundrum. For nasal sprays, drying effects are highly desirable. For the ocular surface, drying effects can cause havoc. Tear volume can have the effect of increasing the concentration of inflammatory mediators on the eye. With artificial tears, an opposite effect can be seen: increased volume of tears dilute the inflammatory mediators.

Third-Generation H1 and H4 Antihistamines

The H1 receptor was first described more than 40 years ago. The most recently discovered histamine receptor, the H4 receptor, was found in 1994. Current topical antihistamine therapy for allergic conjunctivitis still focuses on H1 receptors. The addition of H4 receptor antagonism may increase efficacy and reduce dosing intervals.

Dry eyes reported more commonly than watery eyes

In Australian Ocular Allergy Study, patients had more frequent symptoms of dry eyes (61%–74%) and itchy or burning eyes (50%–59%) than red eyes, watery eyes, or swollen/puffy eyes.

Artificial tears increase volume of tears and dilute the inflammatory mediators, thus bringing relief of symptoms.

If the comorbidity of allergic conjunctivitis and dry eyes is so high, should an allergist be treating dry eyes?

Treatment options for dry eyes:

1. artificial tears, if not better, add:
2. topical cyclosporine, if not better, add:
3. topical corticosteroid - intraocular pressure must be monitored

References:

Allergy and immunology interfaces with ophthalmology and optometry - Annals of Allergy, Asthma & Immunology, 2014 http://buff.ly/1D6SR1v

Urticaria Activity Score (UAS)

Consensus guidelines from the European Academy of Allergology and Clinical Immunology, Global Allergy and Asthma European Network, European Dermatology Forum, and World Allergy Organization (EAACI/GA2LEN/EDF/WAO) recommend using a direct well-established scale such as the Urticaria Activity Score (UAS), which evaluates the main disease characteristics (itch, presence, and number of wheals) on a Likert-type symptom intensity scale (0 to 3), with a total daily score ranging from 0 to 6.

 The UAS has been used in numerous controlled clinical trials and in daily clinical practice. It was recently validated specifically for the follow-up and monitoring of CU activity, with the explicit recommendation that it would be used for at least 4 consecutive days or, preferably, for 1 week (UAS 7).

Score -- Wheals or hives -- Itch

0 -- None -- None
1 -- Mild (less than 20 wheals/24 h) -- Mild
2 -- Moderate (21-50 wheals/24 h) -- Moderate
3 -- Intense or severe (>50 wheals/24 h -- Intense or large confluent areas of wheals) or severe

The UAS assigns a score from 0 (no disease activity) to 3 (intense activity) for each of the 2 key urticaria symptoms, wheals and pruritus. The sum of the scores represents disease severity on a scale from 0 (minimum) to 6 (maximum).



Chronic Urticaria Treatment Options in 6 Steps (click to enlarge the image). En Español.



References:

Assessment of Severity and Quality of Life in Chronic Urticaria. J Investig Allergol Clin Immunol 2014; Vol. 24(2): 80-86.
http://www.jiaci.org/issues/vol24issue2/2.pdf

How to assess disease activity in patients with chronic urticaria? - Młynek - 2008 - Allergy - Wiley Online Library http://buff.ly/1qm49Pr

Image source: Urticaria, Wikipedia, public domain.
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