Holistic View on Asthma

In the past 15 years, striking progress has been made in our understanding of the mechanisms underlying chronic inflammatory airway disease as well as the predisposing and interfering factors. These insights have resulted in a more holistic and personalised approach to the diagnosis and management of chronic inflammatory airway diseases including their comorbidities. At the annual congress of the European Respiratory Society (ERS), held in Madrid from 28 September–2 October, several novel data on different topics within the respiratory field have been presented in a variety of lectures, hot topic sessions, and special symposia. This review will focus on the latest developments in the field of asthma and its management including some highlights of ERS 2019.

In- and outdoor air pollution: respiratory health concern

The effects of air pollution and subsequent climate change on human health are increasingly worrisome. Undoubtedly, the expanding urbanisation, industrialisation, (air) traffic, and other human outdoor activities account for the massive emission of particulate matter (PM) and several pollutants, such as carbon dioxide, methane, nitrous oxide, as major causes of the greenhouse effect, global warming, and climate change [1]. Specifically, air pollution and global working may both directly and indirectly affect the respiratory system, while the allergenicity of some plants is being promoted; for example, due to changed allergen composition or longer pollen seasons [2].

Apart from the harmful outdoor substances, indoor pollutants should not be overlooked. The latter include household cleaning products [3], tobacco smoke (including e-cigarettes vaping), gas cooking, open fireplaces, wood-burning stoves, and waste-incinerators. Apart from inflicting serious respiratory diseases including COPD, lung cancer, and upper respiratory tract diseases, constituents of tobacco smoke can also induce or worsen asthma at young age [4,5]. Based on their negative health effects addressed by an ERS task force [6], the ERS recently denounced e-cigarettes in an official statement.

Furthermore, the ERS 2019 dedicated a large session—including 77 posters—to air pollution. Several research groups across the world reported on various aspects and components of air pollution on respiratory health in both paediatric [7,8] and adult populations [9]. Specifically, there were several reports on detrimental effects of PM and wood stoves on the airways [10,11]. Using different statistical approaches, Dr Alicia Guillien (Université Grenoble Alpes, France) and colleagues studied the association of several aspects of the exposome (i.e. totality of human environmental and lifestyle exposures) on lung function parameters in adults with asthma (who participated in the EGEA2 study 2003–2006) [9]. They found that some urban and air pollutant factors are associated with lower lung function. Interestingly, a Portuguese study investigated the effects of an inflammatory diet (assessed by the dietary inflammatory index [DII]) on asthma characteristics and outcomes in association with indoor pollution in children [12]. They found that an inflammatory diet increases the risk of asthma for both PM2.5 (OR 1.67; 95% CI 1.03–2.73) and PM10 (OR 1.75; 95% CI 1.07–2.87) levels, highlighting the role of the diet’s inflammatory characteristics in modulating the effects of indoor pollution on asthma risk.

In addition to a plethora of reports on detrimental health effects associated with air pollution, there were also presentations on initiatives and programmes to educate stakeholders and raise awareness to improve the environment and promote fresh air [13].

The bottom line is that nationwide programmes are needed to attract and keep the attention of all stakeholders on this burning matter in the joint effort to try and revert the devastating effects of air pollution and climate change on the environment and human health.

Microbiome: macro-impact

The importance of a well-balanced microbiome to warrant a good health status is increasingly recognised. Recently, Dr Pirkka Kirjavainen (National Institute for Health and Welfare, Finland) and colleagues published on the impact of both the external and internal microbiome and their major role in the modulation of asthma, allergy, and associated conditions: i.e. disease-promoting or disease-protecting [14]. At the ERS 2019, Prof. Markus Ege (Ludwig-Maximilians-University of Munich, Germany) reported on the environmental microbiome and its links to allergies, and Dr Hermelijn Smits (Leiden University, the Netherlands) commented on the links between exposure to helminth parasites and asthma development [15]. Interesting new data came from a study investigating severe asthma phenotypes using induced sputum microbiome profiles of a subset of patients from the U-BIOPRED adult cohort, and cluster-wise stability was assessed after 12–18 months of a prospective follow-up [16]. Based on the microbiome from induced sputum, the researchers were able to identify 2 distinct severe asthma phenotypes. In addition, they found a relative stability of the microbiome-driven phenotypic clusters over time underscoring its potential for precision medicine approaches.

Fundamental changes in GINA2019

Risk reduction and prevention

The recently updated GINA guidelines include some fundamental changes focusing on risk reduction and prevention (i.e. reducing exacerbations associated with accelerated lung function decline and prevention of adverse events associated with overuse of corticosteroids), as well as further implementation of precision medicine guided by biomarkers [17].

Based on emerging evidence that severe exacerbations can also occur in patients with milder disease, GINA2019 now recommends symptom-triggered controller therapy to be combined with rescue medication in treatment steps 1 and 2. This recommendation is based on data coming from large clinical studies (e.g. SYGMA, START) showing superior disease control with inhaled corticosteroids (ICS) added to as-needed relievers (short-acting beta-agonists [SABA]) or combinations with ICS/LABA as needed compared with SABA only in patients with mild asthma [18,19]. This may implicate that, for example, in cases of seasonal house dust mite (HDM)-driven (intermittent or mild persistent) asthma, patients should no longer be prescribed as-needed relievers only [17]. Potentially, this “prevention-focused approach” might shift the place of allergen immunotherapy (presently on step 4 for eligible patients) to earlier treatment steps; however, this is still a point of debate.

Based on increased awareness of the (serious) side effects of corticosteroids, GINA2019 advocates lower doses of ICS as preferred regimen across all treatment steps, while implementing add-on controllers or biologics at the distinct treatment steps in selected patient populations.

At the ERS2019, some post-hoc analyses of the SYGMA studies were presented, underscoring the benefits of as-needed budesonide/formoterol treatment versus terbutaline prn only on several clinical outcomes in patients with mild asthma [20,21]. In addition, several studies of targeted therapies with biologicals (e.g. mepolizumab and dupilumab) showed corticosteroid-sparing effects in selected patients with severe asthma in addition to improving disease control and/or lung function [22-24].

Towards precision medicine

GINA2019 continues to recognise that asthma, in many cases, may appear to be “difficult-to-treat” because of a wrong diagnosis or the presence of modifiable factors (or: treatable traits) including poor adherence, incorrect inhaler technique, smoking, or comorbidities, which should be pro-actively assessed [17].

In line with the advocacy for the implementation of precision medicine into clinical practice [25]—which more recently has been further extended with treatable mechanisms [26]—these principles are now increasingly being incorporated into the concurrent guidelines [17].

Indeed, GINA2019 underscores the presence of several clinical phenotypes (i.e. asthma with late-onset, allergic, and non-allergic asthma, asthma with obesity, and asthma with persistent airway flow limitation) that might require a different approach. Despite not recognising a strong relationship between specific pathological features and particular clinical patterns or treatment responses, GINA2019 proposes treatment algorithms (based on composite biomarkers) to assess and manage difficult-to-treat and purely refractory (i.e. severe) asthma and to predict the response to type2-targeted treatment options for uncontrolled severe asthma (step 5) with or without comorbidities such as allergy, atopic dermatitis, and/or nasal polyps [17]. At the ERS2019, a session was dedicated to the management of severe asthma with highlights from the recently published ERS/ATS guideline including (GRADE) evidence-based treatment algorithms –some of which slightly differ from those presented in GINA2019 due to different methodologies and a different expert panel [17,27].

mHealth supports adherence and self-monitoring

Despite several innovative treatment options, patient education and treatment adherence continue to call for attention. At the ERS2019, several insightful reports on treatment adherence have been presented showing an overall low adherence to inhaled controlled–according to some studies as low as 43% [28]. In contrast, combining data from 10 key studies on the topic, Culling and Dennison found conflicting associations between adherence to inhaled therapy and clinical outcomes in adult patients with severe asthma [29]. Over a follow-up period of 12 years, Dr Iida Vähätalo (Seinäjoki Central Hospital, Finland) and colleagues concluded that better adherence to ICS was associated with clinical features of more severe disease but not with symptoms or inflammatory markers [30]. Clearly, these outcomes need further investigation.

Alternatively, the rapidly evolving mobile health (mHealth) technology may help to improve adherence through patients’ empowerment based on self-monitoring, personalised feedback, and education. Currently, there are several mobile applications (apps) available through digital distribution platforms but only few qualify for applicability in daily clinical care [31,32].

In line with this trend, Uddhav Vaghela (Imperial College London, United Kingdom) and colleagues investigated the feasibility and viability of personalised asthma action plans (PAAPs) by primary and secondary healthcare professionals and patients (18–65 years). Besides anticipated drawbacks such as data overload, quality issues, and overdependence on technology, it was concluded that digital PAAPs, if a validated algorithm is used in close collaboration with key stakeholders, could help improve self-management for patients [33].

Another closely associated topic is the emerging development of smart inhalers connected to a smartphone aimed to improve inhalation technique and/or adherence. These e-modules (i.e. sensors, chips) are either attached externally (as add-on tools) or integrated in the inhaler and can monitor its use in real-life setting. They offer potential health and economic benefits (i.e. reducing health care consumption by decreasing severe exacerbations and prescriptions of expensive medications), but their added value needs to be confirmed in health-economic analyses [34].

One airway concept revived: asthma and upper airways comorbidities

In parallel with the development of biologicals targeting the underlying mechanisms, there has been a revival in appreciating the type2-conditions associated with and/or affecting concomitant asthma, including atopic dermatitis, allergic rhinitis (AR), and chronic rhinosinusitis (CRS) with and without nasal polyps (CRSwNP; CRSsNP) [17,35-37]. Indeed, several biologicals targeting type2-pathways (IL-5 and IL-4/13) showed clinical benefits in patients with CRSwNP with or without concomitant asthma [38-40], underscoring the urge to treat all parts of the respiratory system to optimise control in patients with type2-chronic inflammatory airway disease [17,37,41].

The multi-facetted association between the different airway compartments has been highlighted in a unique ENT session during the ERS 2019. Prof. Peter Hellings (UZ Leuven, Belgium) stressed the importance to differentiate between anatomical and mucosal abnormalities in nasal obstruction [42]. The latter being often associated with chronic inflammation requiring further investigation beyond the upper airway compartment [36]. Thought-generating data came from a study by Dr Plamena Novakova (Medical University of Sofia, Bulgaria) and colleagues showing no association between blood eosinophil count and disease control (measured by CAT score) in their cohort of AR patients [43]. A recent comprehensive review of remodelling of the upper airways highlights some striking differences in structural changes between patients with AR and patients with CRS [44]. While only modest structural changes were observed in AR, CRS phenotypes demonstrated epithelial hyperplasia, increased matrix deposition, and degradation along with accumulation of plasma proteins, consistent with more extensive remodelling. Future studies need to establish if long-term treatment with targeted treatments can, at least partly, revert the structural changes within the upper (and lower) airways.

Targeted treatment options: something old – something new…

In a recent review, Dr Jonathan Corren (UCLA Medical Center, USA) discusses several currently available treatment options for uncontrolled (severe) asthma. In summary, for type2 uncontrolled (severe) asthma, which is currently the best defined pheno/endotype in terms of underlying mechanisms, biomarkers, and targets, 3 types of targeted biologicals are currently available: i.e. anti-IgE (if allergy-driven), anti-IL-5 (if eosinophilic), and anti-IL-4/13 (a broader type2 indication) (Figure 1) [45].

Figure 1: Pathways underlying type2- asthma [45]

A, allergic asthma; B, nonallergic T2 asthma.
B, B cell; BM, basement membrane; CRTH2, chemoattractant receptor-homologous molecule expressed on TH2 cells (or prostaglandin D2[DP2] receptor); DC, dendritic cell; DR3, death receptor 3; E, eosinophil; EC, epithelial cell; GATA3, GATA3 transcription factor; KIT, stem cell receptor; GC, goblet cell; IL, interleukin; ILC2, innate lymphoid cell2; MC, mast cell; OX40L, OX40 ligand; PGD2, prostaglandin D2; SM, smooth muscle cell; ST2, IL-33 receptor; T, naïve T helper cell; TSLP, thymic stromal lymphopoietin.
Reprinted from Corren J. J Allergy Clin Immunol Pract. 2019;7:1394-403. Copyright © 2019, with permission from Elsevier.

In a topical symposium, Dr Mario Castro (University of Kansas Medical Center, USA) presented the most recent data derived from the large, phase 3 Liberty Asthma QUEST and VENTURE studies of dupilumab, a fully human monoclonal antibody (MoAb) directed at the IL-4 receptor alpha (IL-4Rα) blocking the IL-4/IL-13 axis. In these placebo-controlled studies, dupilumab showed substantial improvements in asthma control and lung function in combination with a reduction in type2-biomarkers and OCS-sparing effects in patients with moderate-to-severe and severe asthma [23,24,46]. Interestingly, despite its indication for type2 uncontrolled severe asthma characterised by increased blood eosinophils and/or FeNO levels, several of the reported beneficial effects were achieved irrespective of the level of type2 biomarkers before commencing treatment [47]. The most commonly reported adverse event consisted of injection-site reaction.

A novel approach to blocking this dual inflammatory pathway by an inhaled anti-IL-4Rα MoAb was presented by Prof. Mark FitzGerald (University of British Columbia, Canada) showing efficacy by reducing FeNO in patients with mild asthma across all tested doses; subsequent clinical studies are being awaited [48].

Further upstream approaches, e.g. with anti-alarmins, are anticipated to have still a broader clinical effectiveness (blocking both the type2 and non-type2 pathways). Presently, phase 3 studies with tezepelumab (anti-thymic stromal lymphopoietin) in severe uncontrolled asthma are ongoing [45].

Apart from biologicals, other promising pharmacotherapeutic approaches targeting type2 pathways include prostaglandin D2 receptor (DP2, also referred to as chemo-attractant receptor, homologous molecule expressed by Th2 cells [CRTH2]) antagonists [45,49]. At the ERS2019, several mechanistic studies on these novel drugs were presented, while phase 3 results are expected in 2020.

Apart from type2 asthma, approximately 50% of adult patients present with non-type2 or type2-low asthma, associated with (viral) infections, occupational irritants, and oxidative stress, which is usually unresponsive to ICS [50]. Non-type2 asthma represents a heterogeneous group including paucigranulocytic and neutrophilic inflammatory phenotypes with less defined underlying mechanisms, biomarkers, and (targeted) therapeutic options [51].

In a recent publication based on animal observations, Dr Omar Tliba and colleagues describe potential mechanisms underlying paucigranulocytic asthma (PGA) where environmental triggers interact with structural cells (including neurons and airway smooth muscle cells) to produce the pathobiology of asthma characterised by fixed bronchoconstriction and increased airway hyperresponsiveness (Figure 2). As PGA usually does not respond well to ICS, alternative therapies including combined bronchodilators (beta2-agonists and M2 antagonists), mast cell-stabilisers, or bronchial thermoplasty (BT) could be of clinical benefit [52]. At the ERS2019, data from the BT global registry have been presented showing sustained clinical effectiveness of BT in patients with severe asthma uncontrolled by standard therapy in real-life settings [53].

Figure 2: Model of the Mechanisms Underlying Paucigranulocytic Asthma [52]

ACh, acetylcholine; ECM, extracellular matrix; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; M₂R, muscarinic receptor 2; M₃R, muscarinic receptor 3; TGF-β, transforming growth factor beta.
Reprinted from Tliba O, et al. JACI 2019;143:1287-94. Copyright © 2019, Elsevier.

Future directions

So far, significant progress has been made in our understanding of the heterogeneous nature and underlying mechanisms of asthma, which has allowed for the development of targeted treatments and subsequent implementation of precision medicine in clinical practice. However, several questions remain unanswered.

Today, asthma is still a chronic, incurable disease, affecting over 350 million individuals worldwide, which may still cause death as reported by the World Health Organization (WHO).

The long-term safety, clinical effectiveness, and disease-modifying properties of the newly introduced targeted treatment options are being awaited, while mechanisms underlying type2-low asthma including applicable biomarkers and effective therapies are still an unmet need.

About the author: Apart from academic affiliations, Zuzana Diamant acts as Executive Medical and Scientific Director of Respiratory & Allergy at QPS-NL, a CRO that conducts early phase clinical studies for biotech and pharma companies. In the past 3 years, she received honoraria/consultancy fees from ALK, Aquilon, Acucort, AstraZeneca, Boehringer-Ingelheim, Gilead, HAL Allergy, MSD, and Sanofi-Genzyme

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