The spread of respiratory allergies is increasing in parallel with the alarm of the scientific community. Evidently, our knowledge of the onset mechanisms of these diseases and, as a consequence, of the available remedies is inadequate. This review provides a brief, general description of current therapeutic resources and the state of research with regard to both drugs and medical devices in order to highlight their limits and the urgent need for progress. Increasing the amount of basic biochemical research will improve our knowledge of such onset mechanisms and the potential efficacy of therapeutic preparations.
It is known that allergic rhinitis (AR) is mainly induced by an IgE-mediated response and shares many features with allergic asthma (AA). AR is often associated with sinusitis or other comorbidities such as conjunctivitis [
The IgE-mediated response is not a unique mechanism of allergic reaction onset; other less known mechanisms exist. In fact, five years ago, the ARIA group of experts wrote [
At present, we know somewhat more [
As a consequence, the need to make progress is increasingly evident. In the last two years, several proposals/requests have been presented with respect to research, the development, regulation, and utilization of therapeutic resources for respiratory allergies [
It is known that besides the basic, obvious, but, in some circumstances, difficult-to-follow rule of “avoid contact with allergens,” guidelines suggest many different treatments for adults, while there are tables for disease diagnostic classification and control assessment. However, treatments for children and for women during pregnancy and when breastfeeding are only sometimes described. Remedies are available in both systemic and topical form; they can be preventive as well as curative but are more often symptomatic.
Existing therapeutic preparations can essentially be divided into the following three groups, in which drugs for inflammation reduction belong to the second, while drugs for the recovery of the immune balance belong to the other two: preparations for allergen specific immunotherapy, traditional symptomatic drugs, and anti-IgE biological agents.
Unfortunately, none of these treatments ensure a full recovery from the illness, the causes of which are still partly unknown.
A patient’s hypersensitivity can be reduced by a desensitization or hyposensitization treatment known as allergen specific immunotherapy (SIT), which consists of gradual vaccination with progressively larger doses of an allergen. It relies on the progressive skewing of IgG4 antibody production, which is known as a “blocking antibody” due to its ability to compete for the same epitopes as IgE, thus preventing IgE-dependent allergic responses [
SIT, in its subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) forms, is recognized as an effective treatment for respiratory allergies [
SLIT is an orally administered therapy that takes advantage of oral immune tolerance to nonpathogenic antigens such as foods and resident bacteria. While SCIT [
Currently available medication options for the treatment of symptoms of respiratory allergies are summarized in Table
Treatment of respiratory allergies: drug categories and their targets [
Category | Target organ | Target symptom/function | Improvement |
---|---|---|---|
Drugs taken daily for the reduction of symptoms and disease control | |||
Antihistamines | Nose | Sneezing, rhinorrhoea, itching, obstruction | Medium |
Lungs | Coughing, wheezing, shortness of breath | Medium | |
Eyes | Itching, watering | High | |
Corticosteroids | Nose | Sneezing, rhinorrhoea, itching, obstruction | High |
Lungs | Coughing, wheezing, shortness of breath | High | |
Eyes | Itching, watering | Medium | |
Leukotriene inhibitors | Nose | Rhinorrhoea, obstruction | Low |
Lungs | Coughing, wheezing, shortness of breath | Medium | |
Eyes | Watering | Low | |
Anticholinergics | Nose | Rhinorrhoea | Medium |
as relievers for asthma (second-line therapy) | Lungs | Coughing, wheezing, shortness of breath | Medium |
Cromones | Nose | Sneezing, rhinorrhoea, itching, obstruction | Low |
Lungs | Coughing, wheezing, shortness of breath | Low | |
Eyes | Itching, watering | Medium | |
Decongestants (for not more than 10 days) | Nose | Obstruction | Very high |
Inhaled long-acting bronchodilators (LABAs) | Lungs | Coughing, wheezing, shortness of breath | High |
Combinations LABA + corticosteroid | Lungs | Coughing, wheezing, shortness of breath | High |
Long-acting muscarinic antagonists (LAMAs) | Lungs | Lung function | Medium |
Theophylline | Lungs | Coughing, wheezing, shortness of breath | Medium |
Anti-IgE monoclonal antibodies | Lungs | Coughing, wheezing, shortness of breath | High |
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Drugs taken on demand for quick relief of asthma exacerbations | |||
Rapid-acting inhaled |
Lungs | Bronchoconstriction, coughing, wheezing | High |
Combinations corticosteroid + formoterol | Lungs | Bronchoconstriction, coughing, wheezing | High |
Systemic corticosteroids | Lungs | Bronchoconstriction, coughing, wheezing | High |
Traditional drug therapy is indispensable in reducing and preventing symptoms and is extremely important in acute, critical cases. Nevertheless, it is rarely useful in the first phase of AR and is unlikely to modify the natural history of the disease, which can become chronic in nature. Medications are classified according to their use, contents, and route of administration.
It is known that, generally, six classes of drug and nasal saline are used to treat AR [
The second- and third-generation antihistamines (acrivastine, bilastine, cetirizine, desloratadine, ebastine, epinastine, fexofenadine, loratadine, levocetirizine, mizolastine, olopatadine, and rupatadine) are more selective than their first generation counterparts, because they cross with difficulty the blood-brain barrier to bind central H1 receptors. As a result, sedation is reduced [
Several antihistaminic preparations are available on the market: oral antihistamines (tablets and drops), nasal sprays that can act more rapidly than oral preparations, and eye drops. They are often produced in combination with other drugs such as mast cell stabilizers and decongestants.
According to Sastre and Mosges [
In addition to intranasal preparations, other formulations of corticosteroid are the eye drops used for the treatment of severe ocular, allergic symptoms.
Intranasal decongestants (oxymetazoline, xylometazoline, hydrocodone, and phenylephrine) are often associated with a corticosteroid or an antihistamine to improve the delivery of these drugs [
Drugs for the treatment of asthma are generally classified as either “controllers,” which are taken daily on a long-term basis to prevent exacerbations by keeping a check on allergic inflammation, or “rapid relievers,” which are taken on demand for rapid relief in cases of abrupt worsening of symptoms [
The following description of medications for asthma has been updated in accordance with the GINA guidelines, 2012 ed. [
Since ICSs do not “cure” asthma, most patients will require long-term, if not life-long, ICS treatment. When ICS therapy is unsuccessful in achieving asthma control, add-on therapy with another class of controllers is preferred over increasing the ICS dose. Systemic adverse effects can be associated with higher doses of ICSs, as described below in the reliever medication section. The most common local adverse events associated with ICS therapy are oropharyngeal candidiasis and dysphonia. Mouth washing after each inhalation and/or the use of a spacer device can, however, help to reduce the risk of these side effects [
Anti-IgE therapy, which is a recent and very promising form of biological therapy, involves the subcutaneous or intravenous injection of monoclonal anti-IgE antibodies. The therapy can be considered a cure in the complete sense of the term, because it counteracts the development of the disease, even before symptoms. Ideally, it should be administered at the first onset of AR to as many patients as possible to reduce AR development and its evolution toward AA. At present, omalizumab is the only approved monoclonal antibody. Omalizumab is a recombinant, humanized, expensive antibody that binds to free and B-cell associated IgE, thus blocking the interaction between IgE and effector cells (Figure
Anti-IgE therapy by monoclonal antibodies (modification of Sari Sabban’s image [
For now, the use of omalizumab is reserved for patients with severe allergic asthma and elevated serum levels of IgE (but not more than 1500 UI/mL, versus normal value <100 UI/mL), whose symptoms remain uncontrolled despite ICS therapy [
Omalizumab reduces symptoms and the frequency of asthma exacerbations by approximately 50%. It has a significantly decreased risk of the hospitalization of patients with uncontrolled severe asthma. The growing interest in anti-IgE therapy in asthma treatment has been highlighted in the PRACTALL guidelines [
This very good, but limited, effect of anti-IgE therapy is consistent with the fact that it only prevents IgE mediated stimuli. As the allergic response is triggered by both IgE mediated and non-IgE mediated stimuli, a new therapeutic agent against the latter is required to achieve complete protection. Alternatively, the search for a new therapeutic agent against the totality of stimuli would be an even more ambitious challenge. To achieve such results, pharmaceutical research should identify the possible biochemical steps that are common to the different triggering mechanisms of an allergic response. The existence of such common biochemical steps seems to be highly probable when considering the fact that different stimuli produce, for some aspects, the same final response.
In addition to available medications, several new molecular entities are in an advanced phase of clinical study or are in development. Most of them are anti-IL monoclonal antibodies [
A number of genome-wide association studies (GWAS) have investigated asthma- and allergy-related phenotypes. Results suggest a need to increase pharmacogenetic studies for a better definition of the disease and identification of nonresponder patients [
It is evident that modern molecules are increasingly specific. This narrow approach of pharmacologists presupposes deep and complete knowledge of the complex onset pathway of respiratory allergic diseases in order to achieve the exact identification of the best target for a good pharmacological response. Since this knowledge is unfortunately still incomplete, research is now moving in several different directions in an attempt to identify the best pharmacological target, thus risking a waste of resources.
In order to find the possible biochemical steps common to the different triggering mechanisms of the allergic response, research should take more careful consideration of cytosolic
The most common routes of administration of respiratory antiallergic drugs include the preferred oral, transmucosal (nasal, buccal/sublingual, ocular) and inhalation routes, as well as the more invasive injection routes. The drugs come in different pharmaceutical forms such as: tablets, capsules, solutions, suspensions, powders for inhalation and insufflation, solutions for instillation, and injection.
Delivery systems include nebulizers, propellant-based oral and nasal metered-dose inhalers, dry powder inhalers, soft mist inhalers, devices for premetered and device-metered nasal sprays, insufflators, devices for ocular drop instillation, syringes, and accessories such as spacers, facemasks, and needles. This wide variety of dosage forms and devices represents an ambitious challenge for pharmaceutical scientists. Inhalers and sprays in particular have undergone a process of chaotic development in recent years and are continuously evolving. Delivery systems have been reviewed recently [
Delivery systems for respiratory antiallergic drugs.
Devices for respiratory antiallergic drugs delivery | ||
---|---|---|
Device use | Category | Type |
Pulmonary | Nebulizers | Jet |
Ultrasonic | ||
Mesh | ||
Inhalers | Propellant-based metered-dose inhalers (pMDIs) | |
Dry powder inhalers (DPIs) | ||
Soft mist inhalers | ||
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Nasal | Nebulizers | Similar to pulmonary nebulizers |
Sprayers | Metered spray pumps | |
Propellant-based nasal sprayers | ||
Powder based devices | Similar to pulmonary DPIs |
Pulmonary devices fall into two main categories: nebulizers and inhalers, which can be divided into three subcategories:
propellant-based metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and soft mist inhalers (SMIs).
Nebulizers are the oldest inhalation devices. They can be utilized by all patients, including those with weak or slow inhalation capacities or coordination problems like the elderly and children. Nebulizers deliver a cloud of droplets of a drug solution or watery drug suspension. The cloud can be produced in three different ways: air jet, ultrasounds, or, more recently, through a membrane with microholes (mesh). In conventional systems, the cloud is delivered constantly. Nevertheless, the three different principles yield different aerosols with different densities and size distributions at different output rates. Mesh nebulizers have been shown to be more efficient than ultrasound and jet types. In recent years, to reduce environmental aerosol dispersion and increase delivery to patients, jet nebulizers have evolved towards four different subcategories: those with a reservoir tube, those with a collection bag, breath-enhanced jet nebulizers, and breath-actuated jet nebulizers. The breath-enhanced type has two one-way valves to reduce dispersion, while the breath-actuated version only generates aerosol during inspiration. The four subcategories can have consistent differences in delivery, with the reservoir tube type generally being the least efficient and the breath-actuated version the most efficient.
In addition, mesh nebulizers are changing; the last generation models are battery-powered, very light, and silent and give a minimal residual volume. The breath-controlled aerosol delivery (Akita) system, which is an evolution of the adaptive aerosol delivery (AAD) system, is a portable, electronic, vibrating mesh nebulizer that monitors breathing and delivers aerosol only during inhalation. It can be operated in two different breathing modes: normal and slow. A consistent reduction in treatment times is achievable with good deposition by selecting the second operation mode that guides the patient toward deep and slow breathing.
Nebulizers are regulated as medical devices, while the liquid formulations are approved separately and have an “advisable use with” label. For example, suspensions should not be used with ultrasound devices. Nebulizers can be coupled with a facemask or a mouthpiece, with a consequent possible increase in the delivered dose. Mouthpieces are preferable to facemasks because they eliminate losses in the nose and increase deposition in the lungs. Facemasks for nebulizers should have vent holes to reduce deposition on the face and in the eyes.
In conclusion, nebulizers are suitable for all patients, delivering variable doses of a broad range of drugs and not releasing any propellant. Nevertheless, given the high variability in the performance of the different systems, particular attention should be paid to the manufacturer’s instructions and the drug label, particularly, when delivering drugs with narrow therapeutic indices. Moreover, nebulizers are often bulky, expensive, require preparation, have a long treatment time (ranging from five to 25 min), and need proper cleaning to avoid contamination.
Inhalers are typically single-patient-use, portable devices that are available in combination with a specific formulation and dose of drug. They have a shelf life of at least 12–24 months and are disposed of when depleted. Unlike nebulizers, inhalers must be developed and approved as drug and device combinations.
In conclusion, pMDIs are portable, robust, cheap, and easy-to-use and are therefore indispensable for disabled patients. However, they are often inefficient and a nonnegligible source of environmental pollution.
DPIs do not have propellant and are small, portable, cheap, and breath-actuated. However, the variability of the effective dose with the required medium-high force of inspiration limits their use to patients over five years of age [
Spacers, valved holding chambers, facemasks, and mouthpieces are common accessories for nebulizers and inhalers. Often, they are dedicated to a particular device. Since spacer devices or facemasks differ in how they deliver a drug, they may not be interchangeable. Moreover, for effective asthma therapy, different age groups require different inhalers [
Nasal devices fall into three main categories: nebulizers, sprayers,
metered spray pumps and propellant-based nasal sprayers, and powder based devices.
There are relatively few nebulizers specifically designed for intranasal delivery. They work like pulmonary nebulizers but have a nosepiece as an add-on instead of a facemask. A description of them has recently been provided [
The powder form is ideal for active principles that are unstable in liquid formulations, do not need preservatives, and can produce longer nasal retention times than liquids. Powder based nasal devices for the treatment of allergies are “snort-actuated” inhalers, similar to DPIs.
Another type of powder device, known as an insufflator, is in development. This device establishes an external, tubular connection between the nostrils according to the principles of Breath-powered Bi-DirectionalTM technology, so that exhalation from one nostril blows the drug into the other and vice versa [
In addition to improving the efficacy of active principles, formulations, and devices, another important objective of pharmaceutical research is improving the relationship between in vitro test data and in vivo behavior. In this direction, the constructive dialogue between industry, regulators, and academic researchers, which started with workshops concerning bioequivalence, is continuing. Some recent, important documents have been published in the last two years. These reflect the official positions of those involved in orally inhaled and nasal drug product (OINDPs) development, with particular attention being paid to their design and analytical control.
With reference to design, physicians complain that, due to the great number of existing devices with different characteristics/instructions, errors are frequent among patients. Clearly, the role of the physician is fundamental in motivating and addressing patients towards the choice of the better device that is compatible with possible individual limitations [
The view that, by using the same inhaler, a patient can achieve better control of his/her asthma is emerging [
On July 19, 2012, the association of manufacturers, known as the International Pharmaceutical Aerosol Consortium of Regulation and Sciences (IPAC-RS), presented the IPAC-RS Human Factors webinar [
With reference to analytical controls, three major issues are attracting attention: acceptance criteria for materials, incorporation of AIM-EDA in the development cycle of orally inhaled products (OIPs), and revision of USP.
With reference to the acceptance criteria for materials, in a quality by design approach (QbD), the IPAC-RS last year promoted a series of webinars, the most important [
With respect to AIM-EDA, there is a proposal by manufacturers to include in pharmacopoeias abbreviated impactor measurement (AIM) and efficient data analysis (EDA) as an alternative approach to the current cascade impaction (CI) for the measurement of aerodynamic particle size distribution (APSD) in product quality assessments [
On the other hand, the same presentation confirmed the authorities’ position on delivered dose uniformity (DDU), which is also a matter of debate. Indeed, in June 2011, the Pharmacopeial Forum published an in-process revision of Chapter
This general, concise overview of the pharmacotherapy of respiratory allergies has highlighted that, in spite of the availability of new drugs and several specialized devices, in some cases AR, AA, and related comorbidities continue to be uncontrolled diseases that can evolve towards chronicity. Moreover, the levels of these diseases are increasing worldwide.
For this reason, many publications, initiatives, and reports continue to be produced and are a clear expression of the general need to make progress. Some sources containing explicit proposals/requests have been cited above [
These explicit proposals/requests are briefly recalled here with regard to the three main directions of outstanding issues: therapy, regulation, and research.
Therapy improvement is invoked through a better use of existing drugs/devices and the better treatment of the comorbidities that negatively influence the control of asthma. A recent review [ improvement of the treatment strategy with respect to specific patient phenotypes in pediatric [ better patient education and control to achieve optimal adherence to therapy and a health-related quality of life [ better human factor testing and the improved usability of devices to reduce using errors and injuries from medical devices [ prescription of the same device for both ICS and reliever therapy to increase asthma control [ improvement of asthma comorbidity treatment not only for AR or rhinosinusitis but also for other conditions like obesity, heart disease, and COPD (in smokers). For a more complete list of comorbidities, please see Boulet [
Regulation improvement by rationalizing and harmonizing regulatory documents and guidelines includes revising the USP [ updating the regulatory aspects of immunotherapy [ modifying the ARIA two-point classification of AR as “mild” or “moderate/severe” to improve the assessment of AR control [
Research improvement, particularly in diagnostics, device design, analytical control, and basic mechanisms includes new biomarkers and new diagnostic tests for the better characterization of patients and the personalization of treatments in both AR and AA [ further studies about the prevalence of local allergic rhinitis (LAR) and improvement of diagnostic methods to better identify patients affected by LAR [ improvement of device design and development [ better analytical controls by incorporation of AIM-EDA in the development cycle of OIPs [ efforts to unveil the basic mechanisms of allergies [
Several of the proposals/requests referred to the above can find an answer in pharmaceutical research. This is especially true for device design improvements, device analytical controls, new biomarkers, and new diagnostic tests. Physicians and health authorities can provide other fruitful answers. Great, foreseeable benefits could be achieved: the better personalization/efficacy of treatments, improved adherence to treatment, and a better quality of life. Nevertheless, it is unlikely that recovery from illness will only be achieved in these ways.
On the other hand, the current therapeutic treatments, which are preventive, curative, and often only symptomatic, display the previously described evident limits in terms of efficacy and/or adverse effects. Indeed, only two of the available treatments have been shown to have the capability to both prevent new allergic sensitization and arrest the progression of these diseases: SIT and anti-IgE, the best of which seems to be anti-IgE therapy, with an approximately 50% level of improvement. Anti-IgE is, however, also the more expensive treatment, and its prescription is therefore limited.
This therapeutic offer, which is not yet completely adequate, and the increase in the spread of respiratory allergies fully justify the alarm of the scientific community. We should undoubtedly enhance our knowledge of these diseases, and especially their first steps, to counteract their spread and to increase the availability and efficacy of specific therapeutic offers.
For this reason, the EAACI/EFA position paper [
Accordingly, an improvement in basic biochemical research should be hoped for regarding the early phase of effector cell activation and allergic signal reception and transduction, with particular reference to intracellular reactions and the cytosolic
Allergic rhinitis
Allergic asthma
Local allergic rhinitis
Immunoglobulin E
Immunoglobulin G
Allergic rhinitis and its impact on asthma
Global initiative for asthma
Inositol triphosphate
Allergen specific immunotherapy
Intranasal corticosteroids
Inhaled corticosteroids
Long-acting
Long-acting muscarinic antagonists
Rapid-acting
Pressurized metered-dose inhalers
Dry powder inhalers
Orally inhaled and nasal drug products
Abbreviated impactor measurement
Efficient data analysis.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors wish to thank Prof. Ferdinando Giordano, Torre d’Isola, Italy, for his assistance in preparing and completing this work.