Manuel J. Rial1*†
Javier Domínguez-Ortega2†- 1Department of Allergy, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
- 2Department of Allergy, Hospital Universitario La Paz, Institute for Health Research, Madrid, Spain
Asthma is the most common chronic respiratory disease, affecting more than 300 million people worldwide (1). The cornerstone of asthma treatment over the past 50 years has been and continues to be, inhaled and in some circumstances, oral glucocorticoids. Corticosteroids are very effective drugs, but their non-specific mechanism of action, based on anti-inflammatory effect, has not been shown to have a significant long-term impact on the course of the disease (2). According to Menzies-Gow et al. (2), clinical remission of asthma implies 12 months or longer without significant symptoms or the use of corticosteroid medications, as well as improved lung function tests. Asthma remission could be split into three major groups: clinical remission, inflammatory remission, and complete remission (Table 1). Although currently no cure is available, it is widely recognized that some asthmatic patients can spontaneously enter in remission later in life, as in allergy sufferers who cease exposure to the causative agent (3). Longitudinal studies conducted in the adult population show a remission rate of around 20% of subjects over a 10-year period, with moderate variations between studies, with a higher percentage of remission among milder patients (4). In adults under 50 years of age, smoking, allergic sensitization, female sex, older age, and high body mass index (BMI) are risk factors for non-remission or inadequate asthma control, without knowledge of the age of onset of asthma (5). Novel therapies emerged in the last years and new ones soon, offers an opportunity to consider clinical and inflammatory asthma remissions as targets to be achieved. The concept of asthma remission has not had a unanimous consensus in recent years and the different results in longitudinal studies are partly due to the different definitions taken into account (4, 5). Subjects in clinical remission continue to have some degree of lung function impairment or bronchial hyperresponsiveness, whereas in complete asthma remission bronchial hyperresponsiveness would no longer be present. In inflammatory remission, airway or serum biomarkers of inflammation (eosinophils, allergen-specific IgE, periostin, FENO...) would be very low or undetectable, but variability of obstruction and hyperresponsiveness would still be present (6). This remission group is the most easily achievable at present in severe asthma with type 2 (T2) inflammation, biologics targeting key mediators of T2 inflammation, including interleukin (IL)-5, IL-4/IL-13, and immunoglobulin (Ig)E. It should be noted that in all three remission groups there is some degree of airway remodeling, therefore it would not formally be a cure of the disease.
Table 1. Types of asthma remission, their definition and implications on lung function.
The concept of remission usually includes freedom from the need for controller medication. In severe uncontrolled asthma treated with a biologic drug, patients can reduce or even eliminate the need for oral corticosteroids and reduce or even eliminate the need for rescue bronchodilators, but complete elimination of the use of inhalers (ICS/LABA, LAMA) is not common (7). The high price of biologic therapies makes them a therapeutic option in the most severe forms of asthma, where bronchial remodeling is more present and lung function is more impaired. In these situations of lung function deterioration, even if the asthma remains stable, there is a lack of evidence to recommend withdrawal of the controller drug. If currently available biologic therapies, or those yet to come, were to result in the patient not needing any treatment at all, it is possible that health systems would force biologic discontinuation in favor of cheaper treatment options. The use of biologics blocks a specific pathway that in some patients may lead to effective control of inflammation if it is the main pathway involved in that case. In some others, there may be alternative or secondary pathways which, after the blockade induced by the prescribed drug, may be over-activated and may not achieve complete remission.
In real life, biologic drug discontinuation has been performed with omalizumab concluding that it can be performed after prolonged use (>2 years) in children with non-active allergic disease, prolonged controlled asthma and no severe exacerbations for at least 1 year (7). A real-life adult study suggest that the effects of 6 years of omalizumab may persist after discontinuation of therapy in 60% of patients for at least 4 years (8). However, in adults, an increased blood eosinophil count at baseline and a significant increase in FeNO from baseline to week 12 after discontinuation of omalizumab were associated with clinical deterioration (9). The COSMOS trial (10) of 592 patients evaluated changes in ACQ-5 score and blood eosinophil counts 12 weeks after discontinuation of mepolizumab. 12 weeks after the last administration of mepolizumab, the mean ACQ-5 score had increased in parallel with the increase in blood eosinophil counts. The mean increase in ACQ-5 score after discontinuation was only 0.35 points, which is not considered clinically significant. Thus, this study indicated that cessation of mepolizumab does not contribute to a significant deterioration in asthma symptoms during the 12 weeks following discontinuation. It is important to bear in mind that averages are normally used so there are patients in whom the deterioration is important. It should also be noted that there are patients in whom the deterioration in control does not occur so early, opening the door to assessing in which types of patients the responses would be more prolonged. According to these studies, the interruption of biological products may be a feasible strategy in suitable patients with severe asthma, although the predictors of success must be analyzed. In the XPORT study, patients who successfully discontinued omalizumab had lower peripheral eosinophil counts than those who failed to discontinue treatment, indicating that suppressed T2 inflammation may be a predictor of successful discontinuation. In the Vennera study, patients who successfully discontinued tended to have fewer asthmatic comorbidities (e.g., sinusitis, nasal polyps). COMET study concluded that mepolizumab cessation led to deterioration in asthma control. This may simply indicate that residual asthma symptoms are associated with worsening asthma. Further research into predictors of sustained well-controlled conditions after discontinuation of biologics is required to identify patients who are suitable candidates for biologics interruption.
Future research should focus on at least two aspects: determining true remission from a histological point of view and performing more thorough analyses of the biological pathways to explore the triggers that cause this phenomenon. The remission of asthma as a treatment objective, allows to advance in its treatment and improve the results obtained, similar to what has been achieved in other chronic inflammatory diseases.
Author Contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the global burden of disease study 2015. Lancet Respir Med. (2017) 5:691–706. doi: 10.1016/S2213-2600(17)30293-X
2. Menzies-Gow A, Bafadhel M, Busse WW, Casale TB, Kocks JWH, Pavord ID, et al. An expert consensus framework for asthma remission as a treatment goal. J Allergy Clin Immunol. (2020) 145:757–65. doi: 10.1016/j.jaci.2019.12.006
3. Dominguez-Ortega J, Navarro A, Delgado Romero J, Dordal T, Habernau A, Rodríguez M, et al. Landscape study group of the SEAIC. Pollen-induced allergic asthma and rhinoconjunctivitis: differences in outcome between seasonal and nonseasonal exposure to allergens under real-life conditions (The landscape study). J Investig Allergol Clin Immunol. (2020) 30:454–56. doi: 10.18176/jiaci.0544
4. De Marco R, Locatelli F, Cerveri I, Bugiani M, Marinoni A, Giammanco G. Italian study on asthma in young adults study group. Incidence and remission of asthma: a retrospective study on the natural history of asthma in Italy. J Allergy Clin Immunol. (2002) 110:228–35. doi: 10.1067/mai.2002.125600
5. Tuomisto LE, Ilmarinen P, Niemelä O, Haanpää J, Kankaanranta T, Kankaanranta H. A 12-year prognosis of adult-onset asthma: Seinäjoki adult asthma study. Respir Med. (2016) 117:223–9 doi: 10.1016/j.rmed.2016.06.017
6. Carpaij OA, Burgess JK, Kerstjens HA, Nawijn MC, van den Berge M. A review on the pathophysiology of asthma remission. Pharmacol Therap. (2019). 201:8–24. doi: 10.1016/j.pharmthera.2019.05.002
7. Deschildre A, Roussel J, Drumez E, Abou-Taam R, Rames C, Le Roux P, et al. Omalizumab discontinuation in children with severe allergic asthma: an observational real-life study. Allergy. (2019) 74:999–1003. doi: 10.1111/all.13678
8. Vennera MDC, Sabadell C, Picado C. Spanish omalizumab registry. Duration of the efficacy of omalizumab after treatment discontinuation in 'real life' severe asthma. Thorax. (2018) 73:782–4. doi: 10.1136/thoraxjnl-2017-210017
9. Ledford D, Busse W, Trzaskoma B, Omachi TA, Rosén K, Chipps BE, et al. Randomized, multicenter study evaluating Xolair® persistency of response after long-term therapy (XPORT). J Allergy Clin Immunol. (2017) 140:162–9. doi: 10.1016/j.jaci.2016.08.054
Keywords: severe asthma, biomarkers, T2 asthma, eosinophils, remission
Citation: Rial MJ and Domínguez-Ortega J (2022) Inflammatory Remission in T2 Severe Asthma. Front. Allergy 3:923083. doi: 10.3389/falgy.2022.923083
Received: 18 April 2022; Accepted: 03 May 2022;
Published: 30 May 2022.
Edited by:
Lisa A. Miller, University of California, Davis, United StatesReviewed by:
Davor Plavec, Children's Hospital Srebrnjak, CroatiaCopyright © 2022 Rial and Domínguez-Ortega. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Manuel J. Rial, TWFudWVsLmpvcmdlLnJpYWwucHJhZG8mI3gwMDA0MDtzZXJnYXMuZXM=
†These authors have contributed equally to this work