Allergen Immunotherapy and Asthma
Asthma is a chronic inflammatory disease of the airways associated with hyperresponsiveness, that leads to recurrent episodes of wheezing, dyspnoea, chest tightness and cough, as well as variable airflow obstruction that with time may become permanent due to airway remodelling.
Allergic asthma is frequently characterized by an abnormally polarized Th2-type immune response against specific allergens, leading to inflammatory responses. The consequent activation of the epithelial mesenchymal trophic unit has been hypothesized to be responsible for the observed persistent changes of airway remodelling.
Currently, the pharmacological treatment of asthma is aimed at controlling the clinical manifestations of the disease, by suppressing airways inflammation and relieving the bronchospasm. So far, none of the available drugs has been demonstrated to be capable of modifying the progression of the disease, which invariably relapses on ceasing the treatment. AIT may represent a curative approach for allergic asthma due to its immuno-modulatory properties that yield sustained disease-modifying effects. SCIT has been shown to provide a protective or less harmful Th1 response and the induction of regulatory T cells causing anergy or tolerance of allergen-specific T lymphocytes. The induction of a population of IL-10/TGF-β-producing CD4+ CD25+ regulatory cells is usually associated with an increase in serum allergen-specific immunoglobulin G (IgG) and IgG4 levels, exhibiting some functional inhibition of mast cell degranulation.
AIT has long been regarded as a controversial treatment for asthma and although beneficial effects on clinically relevant outcomes have been observed in randomized controlled trials, the recommendations of several professional bodies have ranged from cautious acceptance to complete refusal, likely because of the potential risk of severe, and sometimes fatal anaphylaxis. For instance, despite recognizing the clinical efficacy and the long lasting and preventive effects of AIT, GINA (Global Initiative for Asthma) guidelines state that the role of AIT in adult asthma is limited (and considered only after environmental measures and failure of pharmacological treatment), owing to the modest benefit compared with other treatment options, weighed against the risk of adverse events and the inconvenience of a prolonged course of injections for SCIT. On the other hand, almost all the large surveys conducted in the United States indicated that severe or uncontrolled asthma is the most important and independent risk factor for both nonfatal and fatal adverse reactions to SCIT. The comprehensive Cochrane systematic review by Abramson et al., including 88 randomized controlled trials, concluded that the possibility of local or systemic adverse effects due to SCIT (such as anaphylaxis and very rarely fatal reactions) must be considered. If 16 patients are treated with SCIT, one would be expected to develop a local adverse reaction (wheal and itching at the injection site), and if nine patients are treated, one would be expected to develop a systemic reaction of any severity (rash, wheezing and breathlessness). The implication is that patients must be observed long enough to deal with any major systemic reactions (typically within 30–45 min) and adequate resuscitation equipment and medications must be promptly available. Importantly, this Cochrane review reported an overall clinical efficacy, that is reductions in asthma symptom scores, medication usage and allergen-specific bronchial hyperreactivity (BHR), with some reduction in nonspecific BHR as well. The number of patients needed to treat in order to avoid asthma symptoms deterioration or increase in medications were estimated as three and five, respectively. The effects on lung function were not consistent among trials. In addition to the small size of most trials and some methodological limitations, a significant inter-study heterogeneity was present, thus downgrading the overall quality of the evidence. Unfortunately, this meta-analysis provided limited information concerning the extent of benefit provided by SCIT in comparison to other standard therapies.
No paediatric meta-analyses are available for SCIT, and in children with perennial asthma a benefit has been less easy to demonstrate, while small studies have demonstrated some benefit in pollen and animal dander allergy.
SLIT has been shown to work differently from SCIT, the extract being captured by dendritic cells in the oral mucosa (expressing high levels of Fc[epsilon]RI receptors, major histocompatibility complex class I and II and costimulatory molecules compared with their skin counterparts) and migrating to draining lymph nodes, wherein regulatory or suppressive T cells secreting interferon-γ (IFN-γ) and/or IL-10 are stimulated and blocking IgG1 and IgG4 antibodies are generated.
Recent meta-analyses suggested the clinical efficacy of SLIT in allergic rhinitis and asthma, both in adults and in children. One of them, including 25 open or blind controlled trials in more than 1000 patients, showed a significant benefit of SLIT on the explored outcomes (i.e. symptoms and medications and lung function) while symptoms alone failed to reach statistical significance. A more recent meta-analysis restricted to the paediatric population reported a moderate effectiveness on asthma symptoms and medication intake. However, some reasonable concerns were raised about shortcomings in the robustness of these systematic reviews, mainly explained by the substantial inter-study heterogeneity and by the fact that older randomized controlled trials had limitations in adequate sample size and methodology.
It is important to establish if SLIT can exacerbate asthma as a side-effect and if asthma itself represents a risk factor for adverse events with SLIT. Concerning the first point, SLIT has been shown to be safer than SCIT and so far no fatalities have been reported. The side-effects of SLIT, occurring with an incidence of 30–70% in clinical trials and in less than 10% in postmarketing surveys, are mainly local (oral itching/swelling, throat irritation, nausea and stomach ache) and self-resolving, with a general agreement that asthma worsening is exceptional. Concerning the second point, there is no formal demonstration that asthmatic patients more frequently experience adverse reactions, including asthma exacerbations, than patients with only allergic rhinitis. In none of the total of 11 cases with anaphylaxis reported in the literature following SLIT was asthma identified as a possible risk factor; however, as a prudential choice, SLIT is not recommended to be administered in uncontrolled disease.
Up to June 2009, The World Allergy Organization position paper on SLIT pointed out that only eight out of more than 60 randomized double-blind placebo-controlled trials were specifically designed to evaluate its efficacy on asthma. In the same year, one large pivotal trial has assessed the effect of grass pollen tablets in asthmatic children, demonstrating a significant reduction of symptoms and a positive trend for less intake of rescue medication. In 2011, a proof of concept trial including 602 individuals to determine if treatment of asthmatic patients allergic to house dust mite (HDM) with sublingual tablet can reduce the need of inhaled corticosteroids (ICSs) revealed very promising preliminary results: a positive therapeutic effect on asthma control was demonstrated by a reduction in the dose of inhaled budesonide (mean: >80 μg/day) for the active group compared with the placebo after 1 year of daily treatment. Overall, SLIT treatment was well tolerated, and only mild-to-moderate local reactions were reported. An ongoing study will be able to establish whether HDM SLIT can reduce the frequency and the time to first exacerbation after ICSs reduction.
A matter of debate is related to the fact that isolated allergic asthma without allergic rhinitis is rare, whereas asthma is present in more than 30% of rhinitics. This is the reason why the majority of the clinical trials have been conducted in allergic rhinitis with or without asthma, and very few trials were specifically designed to address the effect of AIT in asthma. As a consequence, none of the trials evaluating asthma symptoms have been adequately powered on this primary outcome or specifically designed to avoid biases. Moreover, no consensus exists on the optimal endpoints to be used, that is, asthma symptoms, the use of medications, the number of asthma exacerbations, asthma-free days and/or lung function. As a consequence, objective measurements were only rarely recorded. Hence, it is not possible to provide fully evidence-based answers on the role of AIT in asthma alone.
Beyond these considerations, AIT remains a valid approach for treating patients with allergic rhinitis and asthma. Its potentially complementary value to pharmacological treatment consists of the sustained disease-modifying effects and preventive effects on the natural progression of the allergic disease, that is, from allergic rhinitis to the development of full-blown asthma. In randomized open trials, both pollen SCIT and SLIT were associated with a reduction in the risk of developing BHR or asthma in children and adults with allergic rhinitis. Head-to-head open randomized trials versus ICSs in mild asthmatic patients showed in the long-term an overall superiority of AIT, suggesting that this option may be more cost-effective, providing a benefit after discontinuation and a steroid-sparing effect. A summary of the potential expected effect of AIT in asthma is proposed in Fig. 1.
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Figure 1.
Potential effects of allergen immunotherapy on asthma.