In the strategies to prevent asthma exacerbations, allergic asthma needs specific treatment

Abstract

No generally accepted definition of asthma exacerbation is thus far available, though in 2012 an expert committee endorsed by the National Institute of Health proposed such definition as “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome”. Graham and Eid reviewed the impact of asthma exacerbations, and noted that, analysing the outcomes with existing treatments, many patients with asthma remain symptomatic and experience exacerbations. This requires the introduction of new strategies to more effectively reduce the exacerbation risk, based on correct diagnosis, stopping smoking, correct inhaler technique, consistent adherence, weight management, and gaining control with the addition of medication”. Indeed, as allergic asthma is the most common form, a specific approach by allergen immunotherapy should receive more attention. Actually, the efficacy of immunotherapy in allergic asthma, by the subcutaneous or the sublingual route, is supported by robust meta-analyses. The most important allergen source causing asthma is the house dust mite, but an increasing role for molds is apparent due to the ongoing climate change.

Keywords: :

• Allergic asthma
• Asthma exacerbation
• GINA guidelines
• Omalizumab
• Allergen immunotherapy

Thus far, there is no generally accepted definition of asthma exacerbation. In 2012, an expert committee endorsed by the National Institute of Health (NIH) reviewed all the available literature and found no dominant definition of exacerbation. The most widely used definitions included three components, all related to treatment rather than symptoms, based on systemic use of corticosteroids, asthma-specific emergency department visits or hospitalization, and use of short-acting β-agonists (SABAs) as quick-relief medications, respectively. The working group participants proposed that the definition of ‘asthma exacerbation’ be “a worsening of asthma requiring the use of systemic corticosteroids to prevent a serious outcome”. As core outcomes, they proposed inclusion and separate reporting of several essential variables of an exacerbation and the development of a standardized, component-based definition of ‘exacerbation’ with clear thresholds of severity for each component1. In addition, it was suggested that the term ‘exacerbation’ should be distinguished from the terms ‘not well controlled asthma’ or ‘uncontrolled asthma’, which are measures of chronic disease activity. Indeed, according to the Global Initiative on Asthma (GINA) “Poor asthma control itself substantially increases the risk of exacerbations. However, several additional independent risk factors have been identified, i.e. factors that, when present, increase the patient’s risk of exacerbation even if symptoms are few”2.

The article by Graham and Eid in the present issue reviews the impact of asthma exacerbations, and the current and future treatment strategies to establish asthma control and reduce the risk of future exacerbations3. The authors analyse the outcomes with existing treatments, concluding that many patients with asthma remain symptomatic and experience exacerbations regardless of disease severity. This requires the introduction of new strategies to more effectively reduce the exacerbation risk. As far as limiting environmental factors is concerned, the authors correctly state that “while exposure to environmental risk factors should be minimized where practical, removing them fully is not feasible without imposing severe restriction on patients”. In addition, even considering the results from controlled trials, where such severe restrictions are performed, the evidence of effectiveness is weak4. The authors conclude that “Consequently, the viable measures that can be employed to improve asthma control and reduce exacerbation risk include correct diagnosis, stopping smoking, correct inhaler technique, consistent adherence, weight management, and gaining control with the addition of medication”. However, concerning the latter issue they review the approaches to nonallergic asthma, while the only treatment considered for managing allergic asthma is the anti-IgE antibody omalizumab.

Actually, omalizumab is an efficacious agent in patients with allergic asthma uncontrolled by standard drug treatment, and its immunologic effect may define the treatment as ‘nonspecific immunotherapy’5. Indeed, a pivotal role in allergic asthma is played by specific allergen immunotherapy, which is overlooked in the article by Graham and Eid. On the other hand, this treatment is also poorly considered in GINA guidelines2. This is quite surprising because its efficacy is supported by several meta-analyses, the most recent including 88 double-blind, placebo-controlled trials and concluding for a clear capacity to reduce asthma symptoms and use of asthma medications and to improve bronchial hyper-reactivity6. Allergen immunotherapy (AIT) was accurately defined in a document endorsed by the World Health Organization in 1998 that reviewed the scientific literature and the rationale for its appropriate use to treat allergic diseases, the crucial characteristic of AIT being the ability, not shared by any other treatment, to work on the causes of allergy7. The traditional, subcutaneous route of administration has a drawback in the possible occurrence of systemic, sometimes severe, adverse reactions to the specific allergen, but the sublingual route of administration, introduced more recently and defined in a document from the World Allergy Organization, is much safer while maintaining clinical efficacy8.

As far as the use of AIT in asthma is concerned, the attention received by guidelines on management of asthma, as stated above, is negligible. A number of factors may account for such neglect, but most of them are related to misconceptions9. For the purpose of our analysis, we will highlight two misconceptions, concerning AIT in patients with severe asthma and in polysensitized subjects. For the first issue, guidelines on AIT suggest that patients with severe asthma should be excluded from this treatment. The major reason for this exclusion is that most fatal reactions to subcutaneous immunotherapy (SCIT) actually occurred in patients with uncontrolled asthma at the time of the injection of the allergen extract7. Concerning sublingual immunotherapy (SLIT), to date no fatal reaction has been reported, but the indication to start the treatment only in conditions of asthma control remains valid8. However, it must be understood that a history of severe asthma is not by itself a contraindication to perform AIT, because achieving disease control by adequate drug treatment makes AIT feasible. When severe asthma is not controlled despite full standard drug treatment, omalizumab has been suggested since 2003 to serve as an effective combination therapy with AIT10, and recent data confirm that by pre-treating children and young adults with severe asthma with omalizumab, AIT can be safely performed11.

The other misconception is polysensitization. In fact, respiratory allergy usually starts with a sensitization to only one allergen source, but the natural history of the disease develops by adding further sensitizations over time, and in patients with asthma, that in most cases is preceded by rhinitis, polysensitization is common. The approach to the issue by administering extracts containing all the allergens to which the patient is sensitized was found to be ineffective12, but recent studies demonstrated that by treating polysensitized patients with SLIT, based on the two most clinically relevant allergens, the majority of patients achieved good control of the respiratory disease and significantly improved their quality of life13^,14.

Another important indicator is provided by data showing that AIT is able to influence the parameters commonly used in the assessment of asthma severity. This is true for the steroid-sparing effect, reported with both SCIT15 and SLIT16, and for the ability of SLIT to induce a stepdown of asthma17.

As argued by Custovic et al., high-level exposure to sensitizing allergens is an important factor in increasing the risk of exacerbation of asthma, especially when combined with respiratory virus infections, which are related to the risk of severe exacerbations resulting in hospital admission, both in adults and children18. Next to the well known house dust mites and animal epithelia, molds are playing an increasingly important role as a cause of asthma exacerbations. Epidemiological studies and meta-analyses highlighted a positive association between moulds and indoor dampness and increase of diagnosis of asthma, wheeze and cough and asthma exacerbation19. Nowadays the presence of dampness and moulds in the human environment is frequent, being traced in 18% to 50% of buildings, and the risk is much higher in damp dwellings20. Moreover, in the near future fungal spore production is likely to be enhanced by the increased occurrence of extreme events like cyclones and floods, caused by climate changes. Despite this, the diagnosis of mold allergy, including the most clinically relevant species such as Alternaria, Aspergillum and Cladosporium, is still neglected21.

Considering the whole outcome of drug treatment on asthma exacerbations, the survey from Rank et al. provided data of great interest. This survey estimated the change in asthma controller medication use according to guidelines and its association with changes in asthma exacerbation rates between the 1997–1998 and 2004–2005 periods. The proportion of individuals with a controller-to-total asthma medication ratio greater than 0.5, when adjusted for other demographic factors, has improved by 16.1% (95% CI: 10.8%, 21.3%) for all individuals from 1997–1998 to 2004–2005, but the annual asthma exacerbation rates did not change significantly in any group from 1997–1998 to 2004–200522.

This finding clearly shows that drug treatment alone is unlikely to effectively prevent allergic asthma exacerbations. Thus, the appropriate use of a disease-modifying treatment such as AIT deserves to be considered to meet this need.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

C.I. is a scientific consultant for Stallergenes Italy s.r.l. E.R. has no significant relationships with or financial interest in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.