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Asthma Research

Why we need research.

Asthma research helps us understand how the disease is caused, how it develops and how it is best treated. Research can also help us understand who is at high risk for developing asthma, certain triggers, and ways to avoid getting asthma. 

Our Asthma Research Program

The American Lung Association is committed to funding asthma research. Our Awards and Grants Program funds top-notch researchers at important career crossroads to gain long-term commitment to lung health and disease research. Without the life-long dedication of lung researchers, important and much-needed discoveries would not be possible. In addition to the Awards and Grants Program, the Lung Association funds the Airways Clinical Research Centers (ACRC) Network , which implements patient-centered clinical trials, and has helped to change the nature of asthma patient care since its inception in 2000. 

What Research Is Being Done?

Some of the current topics American Lung Association funded researchers are investigating include understanding the immune system’s role in asthma, using mobile technology to reach young African Americans with asthma, and better defining subtypes of asthma. Together, studies like these lead to improved therapy, quality of life, and access to care for all people with asthma.

Thanks to the medical breakthroughs led by Lung Association researchers and their colleagues, we have made significant contributions to improve our understanding of asthma. 

Currently funded Lung Association researchers are:  

  • Studying asthma that is resistant to steroid treatments 
  • Boosting the immune system to reduce allergic inflammation in airways  
  • Understanding which genes are responsible for severe asthma 
  • Finding new genetic targets in lung tissue for new asthma therapy and prevention
  • Improve our understanding of the challenges in access to asthma medication in schools 
  • Evaluating asthma management policy in Chicago schools 
  • Providing asthma education to children in the hospital and at home 

Asthma Researchers

Visit our Meet the Researchers section to view our asthma researchers and their studies.

Asthma Clinical Trials

  • See our Lung Association  listing of current trials . 
  • View ACRC clinical trials that are currently recruiting as well as outcomes from completed studies.

Airways Clinical Research Centers (ACRC) Network

The ACRC is the nation's largest not-for-profit network of clinical research centers dedicated to asthma and chronic obstructive pulmonary disease (COPD) treatment research, attracting some of the best investigators nationwide. The ACRC Network conducts large clinical trials that will directly impact patient care for COPD and asthma. 

Meet our Principal Investigators, see where our centers are located and learn more about some of the important research findings at Lung.org/acrc .

Page last updated: April 19, 2023

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Advances and recent developments in asthma in 2020

Affiliations.

  • 1 Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
  • 2 Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland.
  • 3 Department of Medical Immunology, Institute of Health Sciences, Bursa Uludag University, Bursa, Turkey.
  • 4 Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.
  • 5 Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
  • 6 Swiss Institute for Bioinformatics (SIB), Davos, Switzerland.
  • 7 Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China.
  • 8 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 9 Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Bialystok, Poland.
  • 10 Faculty of Medicine, Transylvania University, Brasov, Romania.
  • PMID: 32997808
  • DOI: 10.1111/all.14607

In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19.

Keywords: COVID-19; asthma biomarkers; asthma phenotypes; biological therapeutics; comorbidities.

© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Publication types

  • Asthma / diagnosis
  • Asthma / epidemiology*
  • Asthma / therapy
  • Comorbidity
  • Hypersensitivity / diagnosis
  • Hypersensitivity / epidemiology*
  • Hypersensitivity / therapy
  • Precision Medicine
  • Risk Factors

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  • Open access
  • Published: 17 June 2020

Improving primary care management of asthma: do we know what really works?

  • Monica J. Fletcher 1 ,
  • Ioanna Tsiligianni 2 ,
  • Janwillem W. H. Kocks   ORCID: orcid.org/0000-0002-2760-0693 3 , 4 , 5 ,
  • Andrew Cave 6 ,
  • Chi Chunhua 7 ,
  • Jaime Correia de Sousa   ORCID: orcid.org/0000-0001-6459-7908 8 , 9 ,
  • Miguel Román-Rodríguez 10 ,
  • Mike Thomas   ORCID: orcid.org/0000-0001-5939-1155 11 ,
  • Peter Kardos   ORCID: orcid.org/0000-0002-4725-4820 12 ,
  • Carol Stonham 13 ,
  • Ee Ming Khoo   ORCID: orcid.org/0000-0003-3191-1264 14 ,
  • David Leather 15 &
  • Thys van der Molen 16  

npj Primary Care Respiratory Medicine volume  30 , Article number:  29 ( 2020 ) Cite this article

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  • Health policy

Asthma imposes a substantial burden on individuals and societies. Patients with asthma need high-quality primary care management; however, evidence suggests the quality of this care can be highly variable. Here we identify and report factors contributing to high-quality management. Twelve primary care global asthma experts, representing nine countries, identified key factors. A literature review (past 10 years) was performed to validate or refute the expert viewpoint. Key driving factors identified were: policy, clinical guidelines, rewards for performance, practice organisation and workforce. Further analysis established the relevant factor components. Review evidence supported the validity of each driver; however, impact on patient outcomes was uncertain. Single interventions (e.g. healthcare practitioner education) showed little effect; interventions driven by national policy (e.g. incentive schemes and teamworking) were more effective. The panel’s opinion, supported by literature review, concluded that multiple primary care interventions offer greater benefit than any single intervention in asthma management.

Introduction

Asthma is a common chronic condition that is estimated to affect 339 million people worldwide 1 , 2 . Despite major advances in asthma treatment and the availability of both global 2 and national guidance, asthma continues to cause a substantial burden in terms of both direct and indirect costs 1 . In 2016, estimated worldwide asthma deaths were 420,000 1 and although there have been falls in some countries over the last decade, significant numbers of avoidable deaths still occur 3 . Mortality rates vary widely, with low- and middle-income countries faring worse 4 . For example, Uganda’s reported mortality rate is almost 50% higher 5 than that reported globally (0.19/100,000) 6 , although inter-country comparisons using different data sources and epidemiological methodologies have limitations. The World Health Organisation (WHO) has a global ambition for universal healthcare coverage by 2030 as millions of people worldwide do not have accessible affordable medical care 7 . The WHO moreover recognises that health systems with strong primary care have the utmost potential to deliver improved health outcomes, greater efficiency and high-quality care 7 . Perversely the availability of good quality primary and social care tends to vary inversely, those having the greatest needs being least likely to receive it 8 .

In addition to the issues of access and the quality of care, both under- and over-diagnosis of asthma is common in all healthcare settings, but the issue is of particular concern in primary care, where most initial diagnoses are made 9 , 10 .

For people with asthma, high-quality, local and accessible primary care could be a solution to poor control 11 . Our aim was to identify the factors that experts believe enable the delivery of high-quality asthma care and to review the evidence that confirms that these factors do indeed have positive outcomes in primary care.

Key drivers and their underpinning components

The expert panel identified five key drivers for the delivery of quality respiratory care in primary care and a number of components underpinning each of these drivers. These are summarised in Table 1 .

Of the 50 articles selected from the review, there were comparatively smaller numbers of publications relating to the impact of National Health Policy and Guidelines. However, there was more substantial evidence relating to the other three key drivers, which is summarised in tabular format (Tables 2 – 4 ).

National Health Policy

The expert panel reached an agreement that the political will to prioritise asthma and to support both primary care and respiratory disease were fundamental elements for the achievement of a sustainable change. In their opinion this required national and local programmes supporting the improvements. There was however little evidence published to support this opinion with respect to patient outcome as it is not the area of research that is commonly undertaken. A review of seven national European asthma programmes to support strategies to reduce asthma mortality and morbidity concluded that national/regional asthma programmes are more effective than conventional treatment guidelines 12 . One of the most well-known and successful national programmes in Europe, which has resulted in reduced morbidity and mortality and decreased costs, is the Finnish National Asthma Programme 13 . Programmes outside of Europe have also demonstrated the impact that prioritisation of primary care can have on respiratory outcomes. Changing structures and policies in South Africa and in Brazil may start to impact on primary care 13 , 14 .

Few studies have explored the extent of adherence to guidelines for asthma management based on data provided directly by GPs. One study aimed to evaluate adherence to GINA guidelines and its relationship with disease control in real life. According to GINA guideline asthma classification, the results indicated overtreatment of intermittent and mild persistent asthma, as well as a general poor adherence to GINA treatment recommendations, despite its confirmed role in achieving a good asthma control 15 . In the US, nationally representative data showed that agreement with and adherence to asthma guidelines was higher for specialists than for primary care clinicians, but was low in both groups for several key recommendations 16 .

Reward for performance

Pay-for-performance (P4p) schemes are those that remunerate physicians for achieving pre-defined clinical targets and quality measures—so based on value—that contrasts to schemes that are simply a fee-for-service payment, which pay for volume of activity (Data from Review Table 2 ). In the UK, primary care has moved towards group practices with P4p compensation in which performance is measured using several defined quality indicators 17 , 18 . A systematic review of 94 studies showed increased practice activity but only limited evidence of improvements in the quality of primary care or cost-effectiveness, despite modest reductions in mortality and hospital admissions in some domains 18 . In another review of seven studies from the US and UK, the effects of financial incentive schemes were found to improve patient’s well-being, whilst the effects on the quality of primary healthcare were found to be modest and variable 19 .

An evaluation of three primary care incentive models, namely a traditional fee-for-service model, a blended fee-for-service model and a blended capitation model, demonstrated that the quality of asthma care improved over time within each of the primary care models 20 . The model that combined blended fee-for-service with capitation appears to provide better quality care compared to the traditional fee-for-service model in terms of outcome indicators such as a lower rate of emergency department visits.

A P4p programme in the Netherlands containing indicators for chronic care, prevention, practice management and patient experience was designed by target users 21 . A study of 65 practices that implemented the programme showed a significant improvement in the mean asthma score after 1 year. It showed that a bottom-up developed P4p programme might lead to improvements in both clinical care and patient experience.

Practice resources and organisation

Optimal patient care requires targeted and tailored management (Data from Review Table 3 ). The experts felt that the organisation of both the GP practice and the local healthcare system had an influence on the provision of high-quality care. Registered patient lists and fully integrated computer systems were its foundation. An approach called SIMPLES—developed in the UK, incorporated into a desktop reference tool by the International Primary Care Respiratory Group and adapted for use in the Netherlands 22 , 23 —identifies patients who have uncontrolled symptoms or difficult-to-manage disease and addresses preventable or treatable factors to guide their management. Electronic alerts in patient records have also been used to identify those at increased risk of an exacerbation, in order to modify care and treatment 24 , 25 , 26 .

A systematic review of the effectiveness of computerised clinical decision systems (CCDS) in the care of patients with asthma demonstrated improvements in healthcare process measures and patient outcomes 27 . Conversely another systematic review focussing on their implementation in practice concluded that the limiting factors were the lack of their regular use by healthcare practitioners (HCPs) and adherence to the advice offered 28 . These reviews both concluded that CCDS have the potential to improve patient outcomes, practice efficiency and produce cost-saving benefits if implemented 27 , 28 .

Computerised systems linked with internet programmes to monitor asthma control can also afford benefits for patients. One study identified that the use of both weekly internet-based self-monitoring using the Asthma Control Questionnaire (ACQ) and treatment adjustment using an online management tool resulted in significant improvements in ACQ 29 .

Clinical prediction models could theoretically aid the diagnosis of asthma in primary care but supportive evidence is currently lacking 30 . However, there is strong evidence that service models aimed at supporting primary care practitioners with the diagnosis or ongoing monitoring of patients result in improved accuracy and patient outcomes 31 , 32 , 33 .

The expert panel felt that having access to dedicated and appropriately trained personnel preferably as part of multidisciplinary teams was essential (Data from Review Table 4 ). This need was accentuated because of increasing GP workloads and a shortage of primary care physicians in many countries.

There was extensive evidence 34 , 35 , 36 , 37 , 38 , 39 , 40 that a variety of models involving a range of healthcare practitioners within both the core primary healthcare team and extended community teams improve patient outcomes and healthcare process measures—such as an increased use of asthma action plans, improved medication adherence 36 , 39 —and reduces the use of emergency care 34 , 38 .

One approach in Canada is based on using primary care networks, in which additional non-physician healthcare providers are funded to help provide coordinated healthcare 34 . In these networks patients were shown to be less likely to visit the ED than patients in practices that were not part of the network.

Evidence from a range of countries supports the beneficial role of pharmacists, working alone or in teams 36 , 37 , 38 . In a study utilising community pharmacists to review patients with either poorly controlled asthma or no recent asthma review, there were benefits in terms of asthma control, inhaler technique, action plan ownership, asthma-related QOL and medication adherence 36 . The pharmacists were able to recruit patients and incorporate this as part of daily practice. Availability of referral to a physician was an important component of the service.

Evidence also indicates that education delivered by a variety of methods enhances the quality of care delivered and improves patient outcomes 41 , 42 , 43 , 44 , 45 . Approaches integrating education with other interventions, such as the Colorado Asthma Toolkit Programme (CATP) that combines education with decision support tools, electronic patient records and other online support materials, have been shown to have positive outcomes 41 , 42 . Another team-based approach that combined an educational intervention with the integration of an electronic clinical quality management system with a reminder system found that the number of action plans increased significantly 39 .

Patient education is an important factor for the improvement of self-management and asthma control. An educational programme from Australia demonstrated that patients who received person-centred education had improved asthma outcomes compared to those receiving a brochure only 46 . One review paper 47 about patient enablement concluded that HCPs need to develop their understanding of this concept to integrate this into practice as the level of this is linked to better patient outcomes.

Primary care is pivotal to any health system; however, there is no universal definition of what we mean by primary care and certainly not one standardised model of care. Without focussing on a single model, we have attempted to bring together expert opinion and the most recent evidence on strategies that improve outcomes in asthma patients in primary care. To our knowledge the methodology used in this project has not been used before. The panel of experts who identified the key drivers were knowledgeable of asthma in primary care at a national level in their respective countries and globally. A literature search to investigate the individual key drivers and their underpinning components was undertaken using a keyword search. This identified many publications but very few measured the effect on patient outcome and those that did reported conflicting results. Furthermore, we found a paucity of research relating to the components relating to national healthcare policy and guidelines.

The evidence suggests that health systems that have primary care as a cornerstone and place asthma as a healthcare priority improve asthma care and improve outcome on patient level. The highly regarded Finnish asthma initiative carried out more than 25 years ago not only identified asthma as a national priority, but also placed primary care at the centre of the programme, recognising the key role of General Practitioners and nurses and greatly reduced asthma mortality and morbidity 48 . After the successful implementation of the Finnish asthma plan, many other countries and regions have attempted to implement similar initiatives 13 , 14 . For example, in Poland and Brazil, asthma burden was reduced utilising such a strategy 49 .

Poor health outcomes in asthma patients have been attributed in primary care to gaps between evidence-based recommendations and practice 50 , 51 . Studies show that adherence to clinical guidelines is poor, whatever the clinical setting, with the main barriers being time pressures and limited resources 52 , reflecting that it is not the guidelines per se that improve care, but it is the implementation of the recommendations.

Most guidelines are complex, lengthy and generally biased towards a secondary care perspective. The Global Initiative for Asthma (GINA) committee acknowledges the difficulty of implementing their recommendations in primary care, but they are almost exclusively developed by tertiary care physicians 2 . In the Netherlands, the Dutch Royal Society of General Practitioners writes its own guidelines, which are all presented in the same recognisable brief format. Their asthma guidelines were first published in 1986 with revisions every 4 years and are relatively well followed 53 . However, there are now 194 different clinical guidelines in the Netherlands, illustrating just how difficult it is for General Practitioners to adopt all the recommendations of each clinical guideline and its update.

A survival analysis of guidelines has concluded that 86% are still up to date 3 years after their publication and yet the median lifespan of a clinical guideline is about 60 months 54 . New evidence is continually emerging and this implies that regular updates of clinical guidelines are necessary 55 , 56 . It is therefore important that all guidelines have a process for regular scrutiny 57 and are updated for contemporary applicability. Indeed, asthma and COPD guidelines published by the Association of Scientific Medical Societies in Germany and the Asthma Guidelines of the German Respiratory Society are regularly updated, at least every 5 years (more frequently as necessary); if not they are deleted from the website.

The proliferation of guidelines and their asynchronicity can result in conflicting recommendations. For example, in the UK, four asthma guidelines could be followed (the GINA Report, British Thoracic Society and Scottish Intercollegiate Guidelines (BTS) and the NICE recommendations next to local guidelines) 2 , 58 , 59 , none of which are fully aligned. A review of three contemporaneous international guidelines updated in 2012 (The Canadian Thoracic Society (CTS), BTS and GINA) also revealed significant inconsistency arising from varying approaches to evidence interpretation and recommendation formulation 60 .

Globally, there is a move away from pure fee-for-service payments towards primary care payment schemes linked to performance, which recognise and reward good practice to improve quality and reduce costs 61 . These schemes combine quality standards and targets but still tend to be process driven, not outcome based. The evidence for the effectiveness of such schemes in general on improving quality of care is both inconclusive and inconsistent 62 .

The UK quality and outcomes framework (QOF), which includes asthma, is the world’s largest primary care payment for performance (P4p) scheme 63 . Evidence however shows that improved patient outcomes may not be sustained, cost reduction is unproven 18 and leads to increased GP activity, but this does not necessarily correlate with improved individual patient benefit 64 , 65 . Furthermore, in Portugal, the recording of asthma and COPD prevalence as performance indicators in pay-for-performance contracts showed a modest but steady increase over time in physician’s diagnosis and ICPC-2 coding of these two conditions, but no direct patient benefits 66 .

Disease-specific schemes are usually aligned to clinical guidelines and some focus on prescribing. In Norway, under such a scheme, combination asthma medications were only reimbursed for patients diagnosed with asthma. As a result, asthma diagnosis significantly increased 67 .

The effect on health inequalities has also been studied. The results from UK QOF have shown that the gap between achievements from practices in the most deprived and least deprived areas narrowed 68 . Nevertheless, inequalities in morbidity and premature mortality persisted 69 , 70 . Additionally incentives can increase inequalities because those conditions that are ‘incentivised’ are afforded greater priority and resource allocation, to the detriment of those that are not 71 .

It would appear that simplistic fee-for-service schemes based purely on an activity—such as performing spirometry tests—which are not part of reimbursement of a more comprehensive assessment, have the potential to inadvertently lead to an increase in unnecessary tests. Pay-for-performance schemes have the potential to improve asthma care, but will be reliant on the specifics of the scheme and the quality indicators applied. They can be useful as part of a wider programme to raise quality and afford benefits over rewarding fee-for-service activity.

Appropriate practice organisation and systems focussing on the identification, diagnosis and treatment are pivotal for quality asthma care. There was compelling evidence to indicate that integrated, multi-faceted practice-based approaches for the management of patients improves outcomes and reduces the need for referral to secondary care 22 , 25 , 72 . Coordinated practice systems that combine several interventions such as decision support tools, flagging of electronic records, use of care pathways, staff training and structured approaches to patient education, if consistently implemented, afford the greatest benefits. Implementation of practice schemes is likely to be enhanced where there is dedicated clinical and administrative leadership.

Intuitively an accurate diagnosis should lead to better patient outcomes, although we found conflicting evidence that access to proper diagnosis has an impact on patient outcomes 33 , 73 . Nevertheless, an accurate diagnosis remains the fulcrum on which optimal asthma management depends. Indeed programmes in which an expanded medical team improved the quality of asthma care within the primary care setting (such as a diagnostic and management support organisation) show clear benefit on patient outcome 32 .

Spirometry combined with an assessment of reversibility has been set as gold standard for asthma diagnosis 2 . However, standards on quality of spirometry such as those set by the ERS and ATS are often not achieved 74 , 75 , 76 and impose an unnecessarily high and potentially unachievable threshold in primary care 73 . Nevertheless, some studies have demonstrated that primary care office spirometry can meet the acceptability criteria 77 , 78 , 79 . Although such standards are laudable particularly in a specialist setting, their practicability in primary care, where patients commonly have mild–moderate, intermittent disease, is debatable. The latest ATS-ERS spirometry guidelines (published in October 2019) may address some of these issues. 80 However, the use of spirometry in the diagnosis of asthma remains beyond reach in primary care around the world.

In many countries primary care physicians have limited or no access to tests of lung function or airway inflammation. The creation of diagnostic hubs in the community may open access to these tests 32 . A structured approach to diagnosis including applicability and feasibility for primary care is currently under development by an ERS taskforce; its outcome not available at the time of writing.

With rising clinical workloads, increasing clinical complexity and in many countries a shortage of trained primary care physicians, multi-professional teamworking is increasingly important. 81 , 82 This is accentuated by the expectation for primary care to manage patients with chronic illness.

In many parts of the world, appropriately asthma-trained personnel, such as primary care nurses, are key to the delivery of high-quality asthma care. Dedicated nursing staff can offer continuity to patients, providing education and routine follow-up 35 . Evidence supports the concept that pharmacists working alone or in teams in collaboration with GPs are an accessible asset for the effective management of asthma and can positively influence asthma outcomes 36 .

Healthcare practitioner education is pivotal and the need for guideline-focused training in primary care is well established 82 . The literature seems to support this viewpoint but in many studies the effect on outcome has not been adequately considered, highlighting a need for more outcome-focussed research. Healthcare systems faced with the challenge of moving the care of people with long-term conditions such as asthma from established specialist services to primary care should consider implementing collaborative educational strategies 44 . Matrix-support collaborative care that includes training and support for primary care physicians/nurses from specialists, including joint consultations, case discussions and tailored education, has been shown to be well-accepted by primary care professionals and was associated with improved knowledge and reduced respiratory secondary care referrals 44 . A scoping exercise and literature review of the effectiveness of educational interventions in either changing health professional practice or in improving health outcomes was commissioned by The International Primary Care Respiratory Group (IPCRG) 83 . The impact of education interventions on their own was inconclusive, although there was some evidence of effectiveness when they are combined with other quality improvement strategies or incentives 83 .

Asthma continues to be a substantial cause of morbidity and mortality worldwide and there is need for a coordinated effort to improve care. A well-resourced primary care service is central to the provision of accessible and effective asthma care. An expert team identified the drivers that could enable improvements in both clinical management and patient outcomes, and a literature search showed that each of these individual drivers is supported by varying degrees of evidence. Objectively assessing the outcomes of such interventions is challenging because studies in this area are inherently complex, difficult to undertake and resource intensive, and so definitive research is seldom undertaken. In contrast single interventions studies are easier to conduct but frequently methodologically less robust and therefore tend to be inconclusive. Nevertheless, if substantial improvements in the management of asthma in primary care at a global level are to be achieved, combinations of interventions appear to be most effective. Well-supported holistic interventions involving the entire healthcare system and including the patient voice appear to provide the best outcomes.

Expert panel

An expert panel of 12 primary care global asthma experts—ten General Practitioners and two specialist nurses—was convened in Amsterdam. An initial teleconference between the panel preceded the meeting to gather ideas. The expert panel undertook a brainstorming exercise as part of a force-field analysis in order to reveal their ideas and experience regarding drivers of successful management of asthma in primary care 84 . A force-field analysis can be used to determine the forces (factors) that may prevent change from occurring and to identify those that cultivate change. During the brainstorming session, the experts were divided into facilitated groups to discuss the relative importance of the drivers and identify the factors which underpin each of them. Results were analysed thematically and circulated after the meeting for comment and agreement.

Literature review

To identify whether evidence existed for the drivers and factors identified by the expert panel, literature was searched from PUBMED using the terms asthma and primary care in combination with other terms listed in Table 5 . Proposed search terms were combined using Boolean operators. The initial search was limited to papers published in English over the last 10 years and studies in adults aged over 18 years old. The experts were also asked for additional papers and in addition, more articles were identified from the references from the selected papers. Papers identified were subsequently screened for eligibility by MF and TM (Fig. 1 ). A total of 171 were included in the summary table of which 50 papers were identified as having evidence for the factors identified by the panel.

figure 1

Process by which papers identified by literature review were subsequently screened for eligibility and the different stages in this process. This highlights the number of articles that were selected at each stage of the process, as well as the number of articles excluded and the reasons for exclusion. n number of articles.

Data availability

Anonymised individual participant data from this study and its associated documents can be requested for further research from www.clinicalstudydatarequest.com .

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Acknowledgements

The authors gratefully acknowledge the Expert Panel contributions of Tan Tze Lee (Singapore). Editorial support (in the form of writing assistance, collating author comments, assembling tables/figures, grammatical editing, fact checking, and referencing) was provided by Diana Jones, Ph.D., of Cambrian Clinical Associates Ltd. (UK) and was funded by GlaxoSmithKline plc. The expert panel meeting was funded by GlaxoSmithKline plc.

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Monica J. Fletcher

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Ioanna Tsiligianni

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D.L. is an employee of GlaxoSmithKline plc., and holds stocks in GlaxoSmithKline plc. M.F. and T.v.d.M. are former employees of GlaxoSmithKline plc., and M.F. holds stocks in GlaxoSmithKline plc. I.T. reports advisory boards from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc. and Novartis and a grant from GlaxoSmithKline Greece, outside the submitted work. J.K. reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants from Chiesi, grants and personal fees from GlaxoSmithKline plc., grants and personal fees from Novartis, grants from Mundipharma, grants from TEVA, outside the submitted work. A.C. reports a grant from AstraZeneca for an asthma study. C.C. reports grants from Pfizer China, outside of the submitted work. M.T. reports the following conflicts of interest: neither M.T. nor any member of his close family has any shares in pharmaceutical companies; receipt in the last 3 years of speaker’s honoraria for speaking at sponsored meetings or satellite symposia at conferences from GlaxoSmithKline plc. and Novartis, companies marketing respiratory and allergy products; receipt of honoraria for attending advisory panels with Boehringer Inglehiem, GlaxoSmithKline plc. and Novartis; membership of the BTS SIGN Asthma guideline steering group and the NICE Asthma Diagnosis and Monitoring guideline development group. P.K. reports personal fees from AstraZeneca, GlaxoSmithKline plc., Chiesi, Menarini, Novartis, Klosterfrau, Bionorica, Willmar Schwabe and MSD, and other support (for a phase 3 investigator cough study) from MSD, all outside the submitted work. C.S. has no shares in any pharmaceutical companies, she has received consultant agreements and honoraria for presentations from several pharmaceutical companies that market inhaled medication including AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline plc., Napp Pharmaceuticals and Teva. J.C.d.S. reports personal fees and speaker’s honoraria from Boheringer Ingelheim, personal fees and speaker’s honoraria from GlaxoSmithKline plc., personal fees and speaker’s honoraria from AstraZeneca, personal fees and speaker’s honoraria from Mundipharma outside the submitted work. M.R.R. reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, grants and personal fees from GlaxoSmithKline plc., personal fees from Menarini, personal fees from Mundipharma, personal fees from Novartis, personal fees from Pfizer, personal fees from Teva, personal fees from Bial, outside the submitted work. E.M.K. received honoraria for attending advisory board meeting from GlaxoSmithKline plc., Boehringer Inglehiem and grant from Novartis outside the submitted work.

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Fletcher, M.J., Tsiligianni, I., Kocks, J.W.H. et al. Improving primary care management of asthma: do we know what really works?. npj Prim. Care Respir. Med. 30 , 29 (2020). https://doi.org/10.1038/s41533-020-0184-0

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DOI : https://doi.org/10.1038/s41533-020-0184-0

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Personalizing treatment for severe asthma

3d rendered medically accurate illustration of the bronchi

Through an adaptive research trial, doctors and patients from 30 U.S. study locations are working together to study if five new medications can help patients with severe asthma by altering the underlying biology of this airway disease.   

As Erin Routh prepares to walk in winter weather, she does more than put on a jacket, hat, and gloves. The 46-year-old North Carolina resident often “pretreats” her asthma to prepare for her biggest trigger: changing temperatures. Otherwise, her chest tightens. Her airways constrict. It becomes hard to breathe.    

Routh’s winter routine may include using two different types of asthma inhalers before she walks outside, keeping medications and a rescue inhaler handy, and covering her mouth and nose to help her body regulate temperature. In the best-case scenario, Routh experiences mild discomfort as cold air seeps into her airways and lungs. Oftentimes, she must wait a few minutes before medications, if needed, take effect. In the worst-case scenario, which, fortunately, hasn’t happened recently, it could mean rushing to the emergency room for treatment.      

Routh, who was diagnosed with asthma when she was 6-months old, is one of about 25 million Americans living with asthma. She is also one of 75,000 to 2,500,000 people, 3-10% of all asthma patients, with a severe case. This frequently causes symptoms that are difficult to control. To help researchers identify ways to help patients like herself, she is participating in an asthma study led by researchers across the U.S., which is funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.  

The adaptive research trial, the Precision Interventions for Severe and/or Exacerbation-Prone Asthma Network (PrecISE), started in 2019 and is enrolling up to 600 teenagers and adults at 30 locations throughout 2023 to test how two novel and three existing treatments used for other inflammatory conditions may help treat severe or uncontrolled asthma.    

Personalizing asthma research    

“Many different types of people can be classified as having severe asthma,” explained Patricia Noel, Ph.D. , a program director in NHLBI’s Division of Lung Diseases . “This may be because there are different biological mechanisms in their body that are actually causing their severe asthma.” A unique aspect of PrecISE is matching patients who fit into a variety of severe asthma subtypes with medications that may alter the underlying biology of their airway disease. Upon enrolling in the study , participants engage in different tests to characterize these pathways – which helps the researchers match participants with treatments, while also testing their predictions about which treatments may work best.    

“We’re testing everything from injectable medications to dietary supplements,” Noel explained. “It’s really important for these patients, who don’t respond well to treatment or for whom asthma has had such a huge impact on their life, that we continue to push forward and find novel treatments that can be tested efficiently,” she said.    

The medications studied in PrecISE include an injectable medication that alters inflammatory pathways in arthritis and cardiovascular disease ; a dietary supplement that changes how the body breaks down and uses energy, which is used to support brain and cardiovascular health; an oral medication used to treat certain types of cancer; and two other oral medications developed to treat other respiratory conditions.  

Asthma health diagnosis as a diagram with a healthy and unhealthy bronchial tube with a constricted breathing problem caused by respiratory muscle tightening with 3D illustration elements.

“We don’t understand all of the biology of severe asthma,” said Noel. That’s where the adaptive nature of the trial comes in. Researchers can quickly evaluate if the predictions they are making about “matched” treatments improve asthma symptoms in patients. They are also evaluating if the same treatments could help people who don’t share the same underlying asthma biology.     

Throughout each intervention, which lasts for four months, researchers will study potential changes in airway and lung function among patients. Patients will share asthma diaries and complete asthma self-assessments. This includes answering questions about how well they slept each night, how often they used medications, symptoms they experienced, like wheezing or having an asthma attack, and if they needed emergency treatment.    

If a treatment proves effective, it could advance to larger trials. The goal of this Phase 2 study is to first evaluate treatment efficacy with hundreds of patients. Then, pending results, a medication could proceed to a Phase 3 trial, where it would be studied for its ability to treat severe asthma within a larger population. Following success in those trials, paired with rigorous safety reviews, a treatment could then be considered for approval by the Food and Drug Administration (FDA) for its use in treating severe asthma.   

But, for now, it’s too early to predict which treatments, if any, may have this effect .    

Studying “outside-in” inflammation    

One treatment approach that researchers are studying in PreCISE is the ability to control inflammation that may start outside of the lungs, referred to as “outside-in” inflammation.    

To assesses indicators of this type of inflammation, researchers analyze levels of interleukin-6 (IL-6) from blood samples they receive from patients.  

“The IL-6 story began probably close to 10 years ago now,” explained Sally Wenzel, M.D. , a PrecISE researcher and the director of the Asthma and Environmental Lung Health Institute at the University of Pittsburgh.      

Patients with asthma who had higher levels of IL-6 often had worse symptoms. This includes lower lung function, more asthma exacerbations, more asthma symptoms, and a slightly higher need for anti-inflammatory medications, like steroids. In some cases, IL-6 levels proportionately increased with metabolic conditions, like obesity or having a higher body mass index.    

Systemic inflammation, the kind associated with obesity, diabetes, and cardiovascular disease, may create a “second hit” of inflammation and make asthma symptoms worse, Wenzel explained. “You have some underlying problem in the lungs that perhaps starts the process but is relatively mild,” she said. “Then you put the systemic inflammation on top of it as your second hit and then you develop more severe disease. So, blocking IL-6 seemed to be a natural target.”    

Clazakizumab, a monoclonal antibody, inhibits IL-6 and is currently used to help patients with cardiovascular disease and arthritis. Wenzel and the PrecISE researchers are seeing if the treatment may also help patients with severe asthma. “Biologically, we know it does the right thing,” Wenzel said. However, like other interventions, they will see who responds, if at all, to the treatment.    

For example, about one-third of patients with severe asthma have elevated IL-6 levels. However, not all asthma patients have cardiovascular disease risk factors, like obesity or diabetes, that could further exacerbate airway inflammation.    

There is also room built into the trial to enable researchers to expand on early observations, such as enrolling more patients with slightly higher or lower elevated IL-6 levels. This would help if one group shows a more beneficial response to the treatment.  

“The focus is bringing the right treatment to the right patient,” Wenzel explained.    

Making a childhood wish come true    

Routh, the North Carolina study participant, has participated in clinical research studies at Wake Forest University over the past 10-12 years to see if she can find that right treatment.    

She fits into a “type 2 inflammation” subtype of severe asthma, which is characteristic of experiencing a greater number of asthma attacks and characteristic of other factors, like having increased levels of eosinophils, a pro-inflammatory white blood cell. Wenzel explains that several approved drugs targeting those pathways can be “game changers” for some patients.    

After participating in a two-year study to test the biologic Tezspire, Routh had that experience.    

“There were times I forgot I had asthma,” she said.    

While she was in that study that meant no longer keeping an inhaler in her pocketbook, not worrying about pretreating her airways before stepping outside, and not having to think about avoiding other triggers, like being around cats or dogs while visiting friends or family members.    

“When I had those realizations, it was wonderful,” Routh said. She plans to take the biologic, which was recently approved by the FDA, again in the future.    

Routh’s journey to find another asthma treatment started at the height of severe exacerbations she experienced while she was pregnant in 2008. “It was just the worst it had ever been,” she said. She took a daily dose of prednisone, an oral steroid, but the medication required her to take short-term disability leave during her pregnancy.    

After her daughter was born, she started looking for an oral steroid replacement.    

This is what led her to asthma studies, like PrecISE.    

In 2019, she enrolled in the treatment arm for clazakizumab, the IL-6 inhibitor. At the time, she wasn’t sure if she was receiving the treatment or a placebo.    

A placebo is a medical “duplicate” that looks just like treatment, but it contains no medicine and serves as a control. The goal is to enable researchers to compare an equal number of patients receiving treatment to those receiving none but who share similar characteristics. To preserve the integrity of the study, the trial is double blinded – meaning neither patients nor researchers know who is receiving the treatment until the intervention ends.    

“For things like this to be created and to actually work for me, it’s magical,” she said, noting her previous experience with asthma trials, including Tezspire, and her willingness to try other biologics through future studies if she’s a good match.     

Like the researchers, she’s looking for a treatment to control severe asthma instead of alleviating its symptoms. And she hopes that through ongoing research, scientists can identify the right treatment strategies to help patients like herself.    

“When I was growing up, I had so many health issues,” she said. “I always used to think, wouldn’t it be nice if people could have wishes granted.”    

“It sounds so simple and kind of hokey,” she added. “But I would always think, my first wish would be to not have asthma. Not to have to struggle so much.”    

Like Routh, the researchers hope that these types of trials can help make those types of wishes come true.     

To learn more about asthma, visit https://www.nhlbi.nih.gov/LMBBasthma .    

To learn more about PrecISE, visit https://preciseasthma.org/preciseweb/ .  

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  • Open access
  • Published: 15 August 2020

Treatment strategies for asthma: reshaping the concept of asthma management

  • Alberto Papi 1 , 7 ,
  • Francesco Blasi 2 , 3 ,
  • Giorgio Walter Canonica 4 ,
  • Luca Morandi 1 , 7 ,
  • Luca Richeldi 5 &
  • Andrea Rossi 6  

Allergy, Asthma & Clinical Immunology volume  16 , Article number:  75 ( 2020 ) Cite this article

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Asthma is a common chronic disease characterized by episodic or persistent respiratory symptoms and airflow limitation. Asthma treatment is based on a stepwise and control-based approach that involves an iterative cycle of assessment, adjustment of the treatment and review of the response aimed to minimize symptom burden and risk of exacerbations. Anti-inflammatory treatment is the mainstay of asthma management. In this review we will discuss the rationale and barriers to the treatment of asthma that may result in poor outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life conditions and how these led to the GINA 2019 guidelines for asthma treatment and prevention will also be discussed.

Asthma, a major global health problem affecting as many as 235 million people worldwide [ 1 ], is a common, non-communicable, and variable chronic disease that can result in episodic or persistent respiratory symptoms (e.g. shortness of breath, wheezing, chest tightness, cough) and airflow limitation, the latter being due to bronchoconstriction, airway wall thickening, and increased mucus.

The pathophysiology of the disease is complex and heterogeneous, involving various host-environment interactions occurring at various scales, from genes to organ [ 2 ].

Asthma is a chronic disease requiring ongoing and comprehensive treatment aimed to reduce the symptom burden (i.e. good symptom control while maintaining normal activity levels), and minimize the risk of adverse events such as exacerbations, fixed airflow limitation and treatment side effects [ 3 , 4 ].

Asthma treatment is based on a stepwise approach. The management of the patient is control-based; that is, it involves an iterative cycle of assessment (e.g. symptoms, risk factors, etc.), adjustment of treatment (i.e. pharmacological, non-pharmacological and treatment of modifiable risk factors) and review of the response (e.g. symptoms, side effects, exacerbations, etc.). Patients’ preferences should be taken into account and effective asthma management should be the result of a partnership between the health care provider and the person with asthma, particularly when considering that patients and clinicians might aim for different goals [ 4 ].

This review will discuss the rationale and barriers to the treatment of asthma, that may result in poor patient outcomes. The benefits of currently available treatments and the possible strategies to overcome the barriers that limit the achievement of asthma control in real-life situations will also be discussed.

The treatment of asthma: where are we? Evolution of a concept

Asthma control medications reduce airway inflammation and help to prevent asthma symptoms; among these, inhaled corticosteroids (ICS) are the mainstay in the treatment of asthma, whereas quick-relief (reliever) or rescue medicines quickly ease symptoms that may arise acutely. Among these, short-acting beta-agonists (SABAs) rapidly reduce airway bronchoconstriction (causing relaxation of airway smooth muscles).

National and international guidelines have recommended SABAs as first-line treatment for patients with mild asthma, since the Global Initiative for Asthma guidelines (GINA) were first published in 1995, adopting an approach aimed to control the symptoms rather than the underlying condition; a SABA has been the recommended rescue medication for rapid symptom relief. This approach stems from the dated idea that asthma symptoms are related to bronchial smooth muscle contraction (bronchoconstriction) rather than a condition concomitantly caused by airway inflammation. In 2019, the GINA guidelines review (GINA 2019) [ 4 ] introduced substantial changes overcoming some of the limitations and “weaknesses” of the previously proposed stepwise approach to adjusting asthma treatment for individual patients. The concept of an anti-inflammatory reliever has been adopted at all degrees of severity as a crucial component in the management of the disease, increasing the efficacy of the treatment while lowering SABA risks associated with patients’ tendency to rely or over-rely on the as-needed medication.

Until 2017, the GINA strategy proposed a pharmacological approach based on a controller treatment (an anti-inflammatory, the pillar of asthma treatment), with a SABA as an additional rescue intervention. The reliever, a short-acting bronc hodilator, was merely an addendum , a medication to be used in case the real treatment (the controller) failed to maintain disease control: SABAs effectively induce rapid symptom relief but are ineffective on the underlying inflammatory process. Based on the requirement to achieve control, the intensity of the controller treatment was related to the severity of the disease, varying from low-dose ICS to combination low-dose ICS/long-acting beta-agonist (LABA), medium-dose ICS/LABA, up to high-dose ICS/LABA, as preferred controller choice, with a SABA as the rescue medication. As a result, milder patients were left without any anti-inflammatory treatment and could only rely on SABA rescue treatment.

Poor adherence to therapy is a major limitation of a treatment strategy based on the early introduction of the regular use of controller therapy [ 5 ]. Indeed, a number of surveys have highlighted a common pattern in the use of inhaled medication [ 6 ], in which treatment is administered only when asthma symptoms occur; in the absence of symptoms, treatment is avoided as patients perceive it as unnecessary. When symptoms worsen, patients prefer to use reliever therapies, which may result in the overuse of SABAs [ 7 ]. Indirect evidence suggests that the overuse of beta-agonists alone is associated with increased risk of death from asthma [ 8 ].

In patients with mild persistent disease, low-dose ICS decreases the risk of severe exacerbations leading to hospitalization and improves asthma control [ 9 ]. When low-dose ICS are ineffective in controlling the disease (Step 3 of the stepwise approach), a combination of low-dose ICS with LABA maintenance was the recommended first-choice treatment, plus as-needed SABA [ 3 , 10 ]. Alternatively, the combination low-dose ICS/LABA (formoterol) was to be used as single maintenance and reliever treatment (SMART). The SMART strategy containing the rapid-acting formoterol was recommended throughout GINA Steps 3 to 5 based on solid clinical-data evidence [ 3 ].

The addition of a LABA to ICS treatment reduces both severe and mild asthma exacerbation rates, as shown in the one-year, randomized, double-blind, parallel-group FACET study [ 11 ]. This study focused on patients with persistent asthma symptoms despite receiving ICS and investigated the efficacy of the addition of formoterol to two dose levels of budesonide (100 and 400 µg bid ) in decreasing the incidence of both severe and mild asthma exacerbations. Adding formoterol decreased the incidence of both severe and mild asthma exacerbations, independent of ICS dose. Severe and mild exacerbation rates were reduced by 26% and 40%, respectively, with the addition of formoterol to the lower dose of budesonide; the corresponding reductions were 63% and 62%, respectively, when formoterol was added to budesonide at the higher dose.

The efficacy of the ICS/LABA combination was confirmed in the post hoc analysis of the FACET study, in which patients were exposed to a combination of formoterol and low-dose budesonide [ 12 ]. However, such high levels of asthma control are not achieved in real life [ 5 ]. An explanation for this is that asthma is a variable condition and this variability might include the exposure of patients to factors which may cause a transient steroid insensitivity in the inflammatory process. This, in turn, may lead to an uncontrolled inflammatory response and to exacerbations, despite optimal controller treatment. A typical example of this mechanism is given by viral infections, the most frequent triggers of asthma exacerbations. Rhinoviruses, the most common viruses found in patients with asthma exacerbations, interfere with the mechanism of action of corticosteroids making the anti-inflammatory treatment transiently ineffective. A transient increase in the anti-inflammatory dose would overcome the trigger-induced anti-inflammatory resistance, avoiding uncontrolled inflammation leading to an exacerbation episode [ 13 , 14 , 15 ].

Indeed, symptoms are associated with worsening inflammation and not only with bronchoconstriction. Romagnoli et al. showed that inflammation, as evidenced by sputum eosinophilia and eosinophilic markers, is associated with symptomatic asthma [ 16 ]. A transient escalation of the ICS dose would prevent loss of control over inflammation and decrease the risk of progression toward an acute episode. In real life, when experiencing a deterioration of asthma control, patients self-treat by substantially increasing their SABA medication (Fig.  1 ); it is only subsequently that they (modestly) increase the maintenance treatment [ 17 ].

figure 1

Mean use of SABA at different stages of asthma worsening. Patients have been grouped according to maintenance therapy shown in the legend. From [ 17 ], modified

As bronchodilators, SABAs do not control the underlying inflammation associated with increased symptoms. The “as required” use of SABAs is not the most effective therapeutic option in controlling a worsening of inflammation, as signaled by the occurrence of symptoms; instead, an anti-inflammatory therapy included in the rescue medication along with a rapid-acting bronchodilator could provide both rapid symptom relief and control over the underlying inflammation. Thus, there is a need for a paradigm shift, a new therapeutic approach based on the rescue use of an inhaled rapid-acting beta-agonist combined with an ICS: an anti-inflammatory reliever strategy [ 18 ].

The symptoms of an exacerbation episode, as reported by Tattersfield and colleagues in their extension of the FACET study, increase gradually before the peak of the exacerbation (Fig.  2 ); and the best marker of worsening asthma is the increased use of rescue beta-agonist treatment that follows exactly the pattern of worsening symptomatology [ 19 ]. When an ICS is administered with the rescue bronchodilator, the patient would receive anti-inflammatory therapy when it is required; that is, when the inflammation is uncontrolled, thus increasing the efficiency of the anti-inflammatory treatment.

figure 2

(From [ 19 ])

Percent variation in symptoms, rescue beta-agonist use and peak expiratory flow (PEF) during an exacerbation. In order to allow comparison over time, data have been standardized (Day-14 = 0%; maximum change = 100%)

Barriers and paradoxes of asthma management

A number of barriers and controversies in the pharmacological treatment of asthma have prevented the achievement of effective disease management [ 20 ]. O’Byrne and colleagues described several such controversies in a commentary published in 2017, including: (1) the recommendation in Step 1 of earlier guidelines for SABA bronchodilator use alone, despite asthma being a chronic inflammatory condition; and (2) the autonomy given to patients over perception of need and disease control at Step 1, as opposed to the recommendation of a fixed-dose approach with treatment-step increase, regardless of the level of symptoms [ 20 ]. Other controversies outlined were: (3) a difficulty for patients in understanding the recommendation to minimize SABA use at Step 2 and switch to a fixed-dose ICS regimen, when they perceive SABA use as more effective; (4) apparent conflicting safety messages within the guidelines that patient-administered SABA monotherapy is safe, but patient-administered LABA monotherapy is not; and (5) a discrepancy as to patients’ understanding of “controlled asthma” and their symptom frequency, impact and severity [ 20 ].

Controversies (1) and (2) can both establish an early over-dependence on SABAs. Indeed, asthma patients freely use (and possibly overuse) SABAs as rescue medication. UK registry data have recently suggested SABA overuse or overreliance may be linked to asthma-related deaths: among 165 patients on short-acting relievers at the time of death, 56%, 39%, and 4% had been prescribed > 6, > 12, and > 50 SABA inhalers respectively in the previous year [ 21 ]. Registry studies have shown the number of SABA canisters used per year to be directly related to the risk of death in patients with asthma. Conversely, the number of ICS canisters used per year is inversely related to the rate of death from asthma, when compared with non-users of ICS [ 8 , 22 ]. Furthermore, low-dose ICS used regularly are associated with a decreased risk of asthma death, with discontinuation of these agents possibly detrimental [ 22 ].

Other barriers to asthma pharmacotherapy have included the suggestion that prolonged treatment with LABAs may mask airway inflammation or promote tolerance to their effects. Investigating this, Pauwels and colleagues found that in patients with asthma symptoms that were persistent despite taking inhaled glucocorticoids, the addition of regular treatment with formoterol to budesonide for a 12-month period did not decrease asthma control, and improved asthma symptoms and lung function [ 11 ].

Treatment strategies across all levels of asthma severity

Focusing on risk reduction, the 2014 update of the GINA guidelines recommended as-needed SABA for Step 1 of the stepwise treatment approach, with low-dose ICS maintenance therapy as an alternative approach for long-term anti-inflammatory treatment [ 23 ]. Such a strategy was only supported by the evidence from a post hoc efficacy analysis of the START study in patients with recently diagnosed mild asthma [ 24 ]. The authors showed that low-dose budesonide reduced the decline of lung-function over 3 years and consistently reduced severe exacerbations, regardless of symptom frequency at baseline, even in subjects with symptoms below the then-threshold of eligibility for ICS [ 24 ]. However, as for all post hoc analyses, the study by Reddel and colleagues does not provide conclusive evidence and, even so, their results could have questionable clinical significance for the management of patients with early mild asthma. To be effective, this approach would require patients to be compliant to regular twice-daily ICS for 10 years to have the number of exacerbations reduce by one. In real life, it is highly unlikely that patients with mild asthma would adhere to such a regular regimen [ 25 ].

The 2016 update to the GINA guidelines lowered the threshold for the use of low-dose ICS (GINA Step 2) to two episodes of asthma symptoms per month (in the absence of any supportive evidence for the previous cut-off). The objective was to effectively increase the asthma population eligible to receive regular ICS treatment and reduce the population treated with a SABA only, given the lack of robust evidence of the latter’s efficacy and safety and the fact that asthma is a variable condition characterized by acute exacerbations [ 26 ]. Similarly, UK authorities recommended low-dose ICS treatment in mild asthma, even for patients with suspected asthma, rather than treatment with a SABA alone [ 10 ]. However, these patients are unlikely to have good adherence to the regular use of an ICS. It is well known that poor adherence to treatment is a major problem in asthma management, even for patients with severe asthma. In their prospective study of 2004, Krishnan and colleagues evaluated the adherence to ICS and oral corticosteroids (OCS) in a cohort of patients hospitalized for asthma exacerbations [ 27 ]. The trend in the data showed that adherence to ICS and OCS treatment in patients dropped rapidly to reach nearly 50% within 7 days of hospital discharge, with the rate of OCS discontinuation per day nearly double the rate of ICS discontinuation per day (− 5.2% vs. − 2.7%; p < 0.0001 respectively, Fig.  3 ), thus showing that even after a severe event, patients’ adherence to treatment is suboptimal [ 27 ].

figure 3

(From [ 27 ])

Use of inhaled (ICS) and oral (OCS) corticosteroids in patients after hospital discharge among high-risk adult patients with asthma. The corticosteroid use was monitored electronically. Error bars represent the standard errors of the measured ICS and OCS use

Guidelines set criteria with the aim of achieving optimal control of asthma; however, the attitude of patients towards asthma management is suboptimal. Partridge and colleagues were the first in 2006 to evaluate the level of asthma control and the attitude of patients towards asthma management. Patients self-managed their condition using their medication as and when they felt the need, and adjusted their treatment by increasing their intake of SABA, aiming for an immediate relief from symptoms [ 17 ]. The authors concluded that the adoption of a patient-centered approach in asthma management could be advantageous to improve asthma control.

The concomitant administration of an as-needed bronchodilator and ICS would provide rapid relief while administering anti-inflammatory therapy. This concept is not new: in the maintenance and reliever approach, patients are treated with ICS/formoterol (fast-acting, long-acting bronchodilator) combinations for both maintenance and reliever therapy. An effective example of this therapeutic approach is provided in the SMILE study in which symptomatic patients with moderate to severe asthma and treated with budesonide/formoterol as maintenance therapy were exposed to three different as-needed options: SABA (terbutaline), rapid-onset LABA (formoterol) and a combination of LABA and ICS (budesonide/formoterol) [ 28 ]. When compared with formoterol, budesonide/formoterol as reliever therapy significantly reduced the risk of severe exacerbations, indicating the efficacy of ICS as rescue medication and the importance of the as-needed use of the anti-inflammatory reliever.

The combination of an ICS and a LABA (budesonide/formoterol) in one inhaler for both maintenance and reliever therapy is even more effective than higher doses of maintenance ICS and LABA, as evidenced by Kuna and colleagues and Bousquet and colleagues (Fig.  4 ) [ 29 , 30 ].

figure 4

(Data from [ 29 , 30 ])

Comparison between the improvements in daily asthma control resulting from the use of budesonide/formoterol maintenance and reliever therapy vs. higher dose of ICS/LABA + SABAZ and steroid load for the two regimens

The effects of single maintenance and reliever therapy versus ICS with or without LABA (controller therapy) and SABA (reliever therapy) have been recently addressed in the meta-analysis by Sobieraj and colleagues, who analysed 16 randomized clinical trials involving patients with persistent asthma [ 31 ]. The systematic review supported the use of single maintenance and reliever therapy, which reduces the risk of exacerbations requiring systemic corticosteroids and/or hospitalization when compared with various strategies using SABA as rescue medication [ 31 ].

This concept was applied to mild asthma by the BEST study group, who were the first to challenge the regular use of ICS. A pilot study by Papi and colleagues evaluated the efficacy of the symptom-driven use of beclomethasone dipropionate plus albuterol in a single inhaler versus maintenance with inhaled beclomethasone and as-needed albuterol. In this six-month, double-blind, double-dummy, randomized, parallel-group trial, 455 patients with mild asthma were randomized to one of four treatment groups: an as-needed combination therapy of placebo bid plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler; an as-needed albuterol combination therapy consisting of placebo bid plus 100 μg of albuterol; regular beclomethasone therapy, comprising beclomethasone 250 μg bid and 100 μg albuterol as needed); and regular combination therapy with beclomethasone 250 μg and albuterol 100 μg in a single inhaler bid plus albuterol 100 μg as needed.

The rescue use of beclomethasone/albuterol in a single inhaler was as efficacious as the regular use of inhaled beclomethasone (250 μg bid ) and it was associated with a lower 6-month cumulative dose of the ICS [ 32 ].

The time to first exacerbation differed significantly among groups ( p  = 0.003), with the shortest in the as-needed albuterol and placebo group (Fig.  5 ). Figure  5 also shows equivalence between the as-needed combination therapy and the regular beclomethasone therapy. However, these results were not conclusive since the study was not powered to evaluate the effect of the treatment on exacerbations. In conclusion, as suggested by the study findings, mild asthma patients may require the use of an as-needed ICS and an inhaled bronchodilator rather than a regular treatment with ICS [ 32 ].

figure 5

(From [ 32 ])

Kaplan Meier analysis of the time to first exacerbation (modified intention-to-treat population). First asthma exacerbations are shown as thick marks. As-needed albuterol therapy = placebo bid plus 100 μg of albuterol as needed; regular combination therapy = 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler bid plus 100 μg of albuterol as needed; regular beclomethasone therapy = 250 μg of beclomethasone bid and 100 μg of albuterol as needed; as-needed combination therapy = placebo bid plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed

Moving forward: a new approach to the management of asthma patients

Nearly a decade after the publication of the BEST study in 2007, the use of this alternative therapeutic strategy was addressed in the SYGMA 1 and SYGMA 2 trials. These double-blind, randomized, parallel-group, 52-week phase III trials evaluated the efficacy of as-needed use of combination formoterol (LABA) and the ICS budesonide as an anti-inflammatory reliever in patients requiring GINA Step 2 treatment, with the current reliever therapy (e.g. as-needed SABA) or with low-dose maintenance ICS (inhaled budesonide bid ) plus as-needed SABA, administered as regular controller therapy [ 33 , 34 ].

The SYGMA 1 trial, which enrolled 3849 patients, aimed to demonstrate the superiority of the as-needed use of the combination budesonide/formoterol over as-needed terbutaline, as measured by the electronically-recorded proportion of weeks with well-controlled asthma [ 34 ]. The more pragmatic SYGMA 2 trial enrolled 4215 patients with the aim to demonstrate that the budesonide/formoterol combination is non-inferior to budesonide plus as-needed terbutaline in reducing the relative rate of annual severe asthma exacerbations [ 33 ]. Both trials met their primary efficacy outcomes. In particular, as-needed budesonide/formoterol was superior to as-needed SABA in controlling asthma symptoms (34.4% versus 31.1%) and preventing exacerbations, achieving a 64% reduction in exacerbations. In both trials, budesonide/formoterol as-needed was similar to budesonide maintenance bid at preventing severe exacerbations, with a substantial reduction of the inhaled steroid load over the study period (83% in the SYGMA 1 trial and 75% in the SYGMA 2 trial). The time to first exacerbation did not differ significantly between the two regimens; however, budesonide/formoterol was superior to SABA in prolonging the time to first severe exacerbation [ 33 , 34 ].

The double-blind, placebo-controlled design of the SYGMA trials does not fully address the advantages of anti-inflammatory reliever strategy in patients who often rely on SABAs for symptom relief, so to what extent the study findings could apply to real-life practice settings was unclear.

These limitations were overcome by the results of the Novel START study, an open-label, randomized, parallel-group, controlled trial designed to reflect real-world practice, which demonstrated the effectiveness in mild asthma of budesonide/formoterol as an anti-inflammatory reliever therapy [ 35 ].

In real-world practice, mild asthma patients are treated with an as-needed SABA reliever or with daily low-dose ICS maintenance therapy plus a SABA reliever. In the Novel START study, 668 patients with mild asthma were randomized to receive either as-needed albuterol 100 µg, two inhalations (SABA reliever as a continuation of the Step 1 treatment according to the 2017 GINA guidelines), budesonide 200 µg (ICS maintenance treatment) plus as-needed albuterol (Step 2 therapy of the GINA 2017 guidelines), or 200 µg/6 µg budesonide/formoterol as anti-inflammatory reliever therapy taken as-needed for a 52-week study period.

In this study, the rate of asthma exacerbations for budesonide/formoterol was lower compared with albuterol (51%) and similar to the twice-daily maintenance budesonide plus albuterol, despite a 52% reduction in the mean steroid dose with the single combination inhaler treatment [ 35 ]. In addition, severe exacerbation rate was lower with budesonide/formoterol as compared with as-needed albuterol and regular twice-daily budesonide. These data support the findings of the SYGMA 1 and 2 trials, highlighting the need for a critical re-examination of current clinical practice. Along with the results of the SYGMA trials, they provide convincing evidence of the advantages of the anti-inflammatory reliever strategy, particularly in real-life settings.

The SYGMA 1, SYGMA 2 and the novel START studies complete the picture of the treatment strategies for asthma at any degree of severity, including mild asthma. A growing body of evidence shows that an anti-inflammatory reliever strategy, when compared with all other strategies with SABA reliever, consistently reduces the rate of exacerbations across all levels of asthma severity (Fig.  6 ) [ 28 , 29 , 34 , 36 , 37 , 38 , 39 ].

figure 6

(Data source: [ 39 ])

Risk reduction of severe asthma attack of anti-inflammatory reliever versus SABA across all levels of asthma severity. Bud = budesonide; form = formoterol; TBH = turbohaler. Data from: 1: [ 36 ]; 2: [ 37 ]; 3: [ 38 ]; 4: [ 28 ]; 5: [ 29 ]; 6: [ 30 ]; 7: [ 34 ]

This evidence set the ground (Fig.  7 ) for the release of the 2019 GINA strategy updates. The document provides a consistent approach towards the management of the disease and aims to avoid the overreliance and overuse of SABAs, even in the early course of the disease. The 2019 GINA has introduced key changes in the treatment of mild asthma: for safety reasons, asthmatic adults and adolescents should receive ICS-containing controller treatment instead of the SABA-only treatment, which is no longer recommended.

figure 7

Timeline of key randomized controlled trials and meta-analyses providing the supporting evidence base leading to the Global Initiative for Asthma (GINA) 2019 guidelines. GINA global initiative for asthma, MART maintenance and reliever therapy, SMART single inhaler maintenance and reliever therapy

In Step 1 of the stepwise approach to adjusting asthma treatment, the preferred controller option for patients with fewer than two symptoms/month and no exacerbation risk factors is low-dose ICS/formoterol as needed. This strategy is indirectly supported by the results of the SYGMA 1 study which evaluated the efficacy and safety of budesonide/formoterol as needed, compared with as-needed terbutaline and budesonide bid plus as-needed terbutaline (see above). In patients with mild asthma, the use of an ICS/LABA (budesonide/formoterol) combination as needed provided superior symptom control to as-needed SABA, resulting in a 64% lower rate of exacerbations (p = 0.07) with a lower steroid dose (17% of the budesonide maintenance dose) [ 34 ]. The changes extend to the other controller options as well. In the 2017 GINA guidelines, the preferred treatment was as-needed SABA with the option to consider adding a regular low-dose ICS to the reliever. In order to overcome the poor adherence with the ICS regimen, and with the aim to reduce the risk of severe exacerbations, the 2019 GINA document recommends taking low-dose ICS whenever SABA is taken, with the daily ICS option no longer listed.

Previous studies including the TREXA study in children and adolescents [ 40 ], the BASALT study [ 41 ] and research conducted by the BEST study group [ 32 ] have already added to the evidence that a low-dose ICS with a bronchodilator is an effective strategy for symptom control in patients with mild asthma. A recently published study in African-American children with mild asthma found that the use of as-needed ICS with SABA provides similar asthma control, exacerbation rates and lung function measures at 1 year, compared with daily ICS controller therapy [ 42 ], adding support to TREXA findings that in children with well controlled, mild asthma, ICS used as rescue medication with SABA may be an efficacious step-down strategy [ 40 ].

In Step 2 of the stepwise approach, there are now two preferred controller options: (a) a daily low-dose ICS plus an as-needed SABA; and (b) as-needed low-dose ICS/formoterol. Recommendation (a) is supported by a large body of evidence from randomized controlled trials and observations showing a substantial reduction of exacerbation, hospitalization, and death with regular low-dose ICS [ 7 , 8 , 9 , 24 , 43 ], whereas recommendation (b) stems from evidence on the reduction or non-inferiority for severe exacerbations when as-needed low-dose ICS/formoterol is compared with regular ICS [ 33 , 34 ].

The new GINA document also suggests low-dose ICS is taken whenever SABA is taken, either as separate inhalers or in combination. This recommendation is supported by studies showing reduced exacerbation rates compared with taking a SABA only [ 32 , 40 ], or similar rates compared with regular ICS [ 32 , 40 , 41 ]. Low-dose theophylline, suggested as an alternative controller in the 2017 GINA guidelines, is no longer recommended.

Airway inflammation is present in the majority of patients with asthma, and although patients with mild asthma may have only infrequent symptoms, they face ongoing chronic inflammation of the lower airways and risk acute exacerbations. The GINA 2019 strategy recognizes the importance of reducing the risk of asthma exacerbations, even in patients with mild asthma (Steps 1 and 2) [ 4 ]. In this regard, the new recommendations note that SABA alone for symptomatic treatment is non-protective against severe exacerbation and may actually increase exacerbation risk if used regularly or frequently [ 4 ].

The reluctance by patients to regularly use an ICS controller means they may instead try and manage their asthma symptoms by increasing their SABA reliever use. This can result in SABA overuse and increased prescribing, and increased risk of exacerbations.

As part of the global SABINA (SABA use IN Asthma) observational study programme, a UK study examined primary care records to describe the pattern of SABA and ICS use over a 10-year period in 373,256 patients with mild asthma [ 44 ]. Results showed that year-to-year SABA prescribing was more variable than that of ICS indicating that, in response to fluctuations in asthma symptom control, SABA use was increased in preference to ICS use. Furthermore, more than 33% of patients were prescribed SABA inhalers at a level equivalent to around ≥ 3 puffs per week which, according to GINA, suggests inadequate asthma control.

The problem of SABA overuse is further highlighted by two studies [ 45 , 46 ], also as part of the SABINA programme. These analysed data from 365,324 patients in a Swedish cohort prescribed two medications for obstructive lung disease in any 12-month period (HERA).

The first study identified SABA overuse (defined as ≥ 3 SABA canisters a year) in 30% of patients, irrespective of their ICS use; 21% of patients were collecting 3–5 canisters annually, 7% were collecting 6–10, and 2% more than 11 [ 45 ]. Those patients who were overusing SABA had significantly more asthma exacerbations relative to those using < 3 canisters (20.0 versus 12.5 per 100 patient years; relative risk 1.60, 95% CI 1.57–1.63, p < 0.001). Moreover, patients overusing SABA and whose asthma was more severe (GINA Steps 3 and 4) had greater exacerbation risk compared with overusing patients whose asthma was milder (GINA Steps 1 and 2).

The second study found those patients using three or more SABA reliever canisters a year had an increased all-cause mortality risk relative to patients using fewer SABA canisters: hazard ratios after adjustment were 1.26 (95% CI 1.14–1.39) for 3–5 canisters annually, 1.67 (1.49–1.87) for 6–10 canisters, and 2.35 (2.02–2.72) for > 11 canisters, relative to patients collecting < 3 canisters annually [ 46 ].

The recently published PRACTICAL study lends further support to as-needed low-dose ICS/formoterol as an alternative option to daily low-dose ICS plus as-needed SABA, outlined in Step 2 of the guidelines [ 47 ]. In their one-year, open-label, multicentre, randomized, superiority trial in 890 patients with mild to moderate asthma, Hardy and colleagues found that the rate of severe exacerbations per patient per year (the primary outcome) was lower in patients who received as-needed budesonide/formoterol than in patients who received controller budesonide plus as-needed terbutaline (relative rate 0.69, 95% CI 0.48–1.00; p < 0.05). Indeed, they suggest that of these two treatment options, as-needed low-dose ICS/formoterol may be preferred over controller low-dose ICS plus as-needed SABA for the prevention of severe exacerbations in this patient population.

Step 3 recommendations have been left unchanged from 2017, whereas Step 4 treatment has changed from recommending medium/high-dose ICS/LABA [ 3 ] to medium-dose ICS/LABA; the high-dose recommendation has been escalated to Step 5. Patients who have asthma that remains uncontrolled after Step 4 treatment should be referred for phenotypic assessment with or without add-on therapy.

To summarise, the use of ICS medications is of paramount importance for optimal asthma control. The onset and increase of symptoms are indicative of a worsening inflammation leading to severe exacerbations, the risk of which is reduced by a maintenance plus as-needed ICS/LABA combination therapy. The inhaled ICS/bronchodilator combination is as effective as the regular use of inhaled steroids.

The efficacy of anti-inflammatory reliever therapy (budesonide/formoterol) versus current standard-of-care therapies in mild asthma (e.g. reliever therapy with a SABA as needed and regular maintenance controller therapy plus a SABA as-needed) has been evaluated in two randomized, phase III trials which confirmed that, with respect to as-needed SABA, the anti-inflammatory reliever as needed is superior in controlling asthma and reduces exacerbation rates, exposing the patients to a substantially lower glucocorticoid dose.

Conclusions

A growing body of evidence shows that anti-inflammatory reliever strategy is more effective than other strategies with SABA reliever in controlling asthma and reducing exacerbations across all levels of asthma severity. A budesonide/formoterol therapy exposes asthma patients to a substantially lower glucocorticoid dose while cutting the need for adherence to scheduled therapy.

Availability of data and materials

Not applicable.

Abbreviations

Global Initiative for Asthma

Inhaled corticosteroids

Long-acting beta-agonists

Oral corticosteroids

Short-acting beta-agonists

Single inhaler maintenance and reliever treatment

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Acknowledgements

The Authors thank Maurizio Tarzia and Gayle Robins, independent medical writers who provided editorial assistance on behalf of Springer Healthcare Communications. The editorial assistance was funded by AstraZeneca.

No funding was received for this study. The editorial assistance was funded by AstraZeneca.

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Giorgio Walter Canonica

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Papi, A., Blasi, F., Canonica, G.W. et al. Treatment strategies for asthma: reshaping the concept of asthma management. Allergy Asthma Clin Immunol 16 , 75 (2020). https://doi.org/10.1186/s13223-020-00472-8

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Assessment and management of adults with asthma during the covid-19 pandemic

Read our latest coverage of the coronavirus pandemic.

  • Related content
  • Peer review
  • Thomas Beaney , academic clinical fellow in primary care 1 ,
  • David Salman , academic clinical fellow in primary care 1 ,
  • Tahseen Samee , specialist registrar in emergency medicine 2 ,
  • Vincent Mak , consultant in respiratory community integrated care 3
  • 1 Department of Primary Care and Public Health, Imperial College London, London, UK
  • 2 Barts Health NHS Trust, London, UK
  • 3 Imperial College Healthcare NHS Trust, London, UK
  • Correspondence to: T Beaney Thomas.beaney{at}imperial.ac.uk

What you need to know

In patients with pre-existing asthma, a thorough history and structured review can help distinguish an asthma exacerbation from covid-19 and guide management

In those with symptoms of acute asthma, corticosteroids can and should be used if indicated and not withheld on the basis of suspected covid-19 as a trigger

Assessment can be carried out remotely, ideally via video, but have a low threshold for face-to-face assessment, according to local arrangements

A 35 year old man contacts his general practice reporting a dry cough and increased shortness of breath for the past three days. He has a history of asthma, for which he uses an inhaled corticosteroid twice daily and is now using his salbutamol four times a day. Because of the covid-19 outbreak, he is booked in for a telephone consultation with a general practitioner that morning.

Asthma is a condition commonly encountered in primary care, with over five million people in the UK prescribed active treatment. 1 While seemingly a routine part of general practice, asthma assessment is a particular challenge in the context of the covid-19 pandemic, given the overlap in respiratory symptoms between the two conditions and the need to minimise face-to-face assessment. Over 1400 people died from asthma in 2018 in England and Wales, 2 while analyses of non-covid-19 deaths during the covid-19 outbreak have shown an increase in deaths due to asthma, 31 highlighting the need to distinguish the symptoms of acute asthma from those of covid-19 and manage them accordingly.

This article outlines how to assess and manage adults with exacerbations of asthma in the context of the covid-19 outbreak ( box 1 ). We focus on the features differentiating acute asthma from covid-19, the challenges of remote assessment, and the importance of corticosteroids in patients with an asthma exacerbation.

Asthma and covid-19: what does the evidence tell us?

Are patients with asthma at higher risk from covid-19.

Some studies, mostly from China, found lower than expected numbers of patients with asthma admitted to hospital, suggesting they are not at increased risk of developing severe covid-19. 3 4 5 However, these reports should be viewed cautiously, as confounding by demographic, behavioural, or lifestyle factors may explain the lower than expected numbers. Recent pre-print data from the UK suggest that patients with asthma, and particularly severe asthma, are at higher risk of in-hospital mortality from covid-19. 6 In the absence of more conclusive evidence to indicate otherwise, those with asthma, particularly severe asthma, should be regarded as at higher risk of developing complications from covid-19. 7

Can SARS-CoV-2 virus cause asthma exacerbations?

Some mild seasonal coronaviruses are associated with exacerbations of asthma, but the coronaviruses causing the SARS and MERS outbreaks were not found to be. 8 9 In the case of SARS-CoV-2 virus, causing covid-19, data from hospitalised patients in China did not report symptoms of bronchospasm such as wheeze, but the number of patients with pre-existing asthma was not reported. 10 More recent pre-print data from hospitalised patients in the UK identified wheeze in a minority of patients with Covid-19. 11 Given the overlap of symptoms, such as cough and shortness of breath, until further published data emerges, SARS-CoV-2 may be considered as a possible viral trigger in patients with an asthma attack.

What you should cover

Challenges of remote consultations.

Primary care services have moved towards telephone triage and remote care wherever possible to minimise the risk of covid-19 transmission. This brings challenges to assessment as visual cues are missing, and, unless the patient has their own equipment, tests involving objective measurement, such as oxygen saturation and peak expiratory flow, are not possible. In mild cases, assessment via telephone may be adequate, but, whenever possible, we recommend augmenting the consultation with video for additional visual cues and examination. 12 However, many patients, particularly the elderly, may not have a phone with video capability. If you are relying on telephone consultation alone, a lower threshold may be needed for face-to-face assessment.

Presenting symptoms

Start by asking the patient to describe their symptoms in their own words. Note whether they sound breathless or struggle to complete sentences and, if so, determine whether immediate action is required. If not, explore what has changed, and why the patient has called now. The three questions recommended by the Royal College of Physicians—asking about impact on sleep, daytime symptoms, and impact on activity—are a useful screening tool for uncontrolled asthma. 13 Alternative validated scores, such as the Asthma Control Questionnaire and Asthma Control Test, which include reliever use, are also recommended. 14 In assessing breathlessness, the NHS 111 symptom checker contains three questions—the answers may arise organically from the consultation, but are a useful aide memoire:

Are you so breathless that you are unable to speak more than a few words?

Are you breathing harder or faster than usual when doing nothing at all?

Are you so ill that you’ve stopped doing all of your usual daily activities?

Consider whether an exacerbation of asthma or covid-19 is more likely. Both can present with cough and breathlessness, but specific features may indicate one over the other (see box 2 ). Do the patient’s current symptoms feel like an asthma attack they have had before? Do symptoms improve with their reliever inhaler? Do they also have symptoms of allergic rhinitis? Pollen may be a trigger for some people with asthma during hay fever season.

History and examination features helping distinguish asthma exacerbation from covid-19 10 11 14 15 16

Exacerbation of asthma*.

Improvement in symptoms with reliever inhaler

Diurnal variation

Absence of fever

Coexisting hay fever symptoms

Examination:

Reduced peak expiratory flow

Close contact of known or suspected case

Dry continuous cough

Onset of dyspnoea 4-8 days into illness

Flu-like symptoms including fatigue, myalgia, headache

Symptoms not relieved by inhaler

Absence of wheeze

Peak expiratory flow may be normal

*Note SARS-CoV-2 infection may be a trigger for an asthma exacerbation

Risk factors and medications

To assess the risk of deterioration, ask specifically about any previous hospital admissions for asthma and about oral corticosteroid use over the past 12 months. Does the patient have any other high risk conditions or are they taking immunosuppressive drugs? Ask the patient if they smoke and take the opportunity to offer support to quit.

Are they prescribed an inhaled corticosteroid (ICS) or a long acting β agonist (LABA) and ICS combination inhaler? Are they using this regularly? Are they using a spacer device, and do they have a personal asthma action plan to guide management?

Psychosocial factors

Taking a psychosocial history can be more challenging over the telephone, where cues are harder to spot. Lessons from asthma deaths have shown that adverse psychosocial factors are strongly associated with mortality. 14 17 These include a history of mental health problems, lack of engagement with healthcare services, and alcohol or drug misuse, along with employment and income problems. Social isolation is also a risk factor, which may be exacerbated during social distancing measures. 17 The covid-19 outbreak is an anxious time for many patients, and symptoms of anxiety can contribute to the overall presentation.

Examination

In remote assessment, video can help guide decision making, and we recommend its use in asthmatic patients presenting with acute symptoms. First, assess the general appearance of the patient. A fatigued patient sitting up in bed, visibly breathless, and anchoring their chest will raise immediate concerns, as opposed to someone who is walking around while talking. Vocal tone and behaviour may indicate any contributing anxiety. Observe if the patient can speak in complete sentences, listen for audible wheeze, and count the respiratory rate. Assess the work of breathing, including the use of accessory muscles, and consider the use of a chaperone where appropriate. The Roth score is not advocated for assessment of covid-19 or asthma. 18

Further objective assessment can be made, such as measuring peak expiratory flow (PEF). If the patient does not have a PEF device at home, one can be prescribed, though this may not be feasible in an acute scenario. We recommend that PEF technique be witnessed via video to assess reliability. Silent hypoxia may be a feature of covid-19, and oxygen saturations should be measured if this is a concern. 19 In some regions, oxygen saturation probe delivery services are being implemented, which may facilitate this. Heart rate can also be provided by the patient if they use conventional “wearable” technology, although, given the potential inaccuracies with different devices, the results should not be relied on. 20 If time allows, inhaler technique can also be checked.

What you should do

Determine the most likely diagnosis.

Decide on the most likely diagnosis on the basis of the history and clinical features (see box 2 and fig 1 ) or consider whether an alternative or coexisting diagnosis is likely, such as a bacterial pneumonia or pulmonary embolus. If you suspect covid-19 without asthmatic features, manage the patient as per local covid-19 guidance.

Fig 1

Assessment and management of patients with known asthma during the covid-19 outbreak 14

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Determine severity and decide if face-to-face assessment is necessary

If asthmatic features are predominant, determine severity and treat according to Scottish Intercollegiate Guidelines Network (SIGN) and British Thoracic Society (BTS) guidance ( fig 1 ). 14 If the patient cannot complete sentences or has a respiratory rate ≥25 breaths/min, treat the case as severe or life threatening asthma and organise emergency admission. A peak expiratory flow (PEF) <50% of best or predicted or a heart rate ≥110 beats/min also indicate severe or life threatening asthma. If the patient does not meet these criteria, treat as a moderate asthma attack—a PEF of 50-75% of best or predicted helps confirm this. If they do not have a PEF meter, or if you are unsure as to severity, brief face-to-face assessment to auscultate for wheeze and assess oxygen saturations can help confirm the degree of severity and determine if the patient may be suitable for treatment at home with follow-up. Do not rely solely on objective tests and use clinical judgment to decide on the need for face-to-face assessment, based on knowledge of the patient, risk factors, and any adverse psychosocial circumstances.

Wheeze has been reported as a presenting symptom in a minority of patients with confirmed covid-19, and it may be difficult to rule out the presence of SARS-CoV-2 via remote assessment. 11 We recommend that, when a face-to-face assessment is needed, it should take place via local pathways in place to safely assess patients with suspected or possible covid-19—for example, at a local “hot” clinic. At present, performing a peak flow test is not considered to be an aerosol generating procedure, but the cough it may produce could be, so individual risk assessment is advised. 21 Consider performing PEF in an open space or remotely in another room via video link. Any PEF meter should be single-patient use only and can be given to the patient for future use.

Initial management when face-to-face assessment is not required

For moderate asthma exacerbations, advise up to 10 puffs of a short acting β agonist (SABA) inhaler via a spacer, administered one puff at a time. There is no evidence that nebulisers are more effective: 4-6 puffs of salbutamol via a spacer is as effective as 2.5 mg via a nebuliser. 22 Alternatively, if the patient takes a combined inhaled corticosteroid and long acting β agonist (LABA) preparation, then maintenance and reliever therapy (MART) can be used according to their action plan. 14 Management of an acute exacerbation should not rely solely on SABA monotherapy, so advise patients to follow their personal asthma action plan and continue corticosteroid treatment (or start it if they were not taking it previously) unless advised otherwise ( box 3 ). Antibiotics are not routinely recommended in asthma exacerbations.

Risks and benefits of inhaled and oral corticosteroids in asthma and covid-19

There is substantial evidence for the benefits of steroids in asthma. Regular use of inhaled steroids reduces severe exacerbations of asthma 23 and the need for bronchodilators, 24 while the prompt use of systemic corticosteroids during an exacerbation reduces the need for hospital admissions, use of β agonists, 25 and relapses. 26

The evidence for corticosteroid use in early covid-19 is still emerging. A systematic review of steroid use in SARS reported on 29 studies, 25 of which were inconclusive and four of which suggested possible harm (diabetes, osteoporosis, and avascular necrosis) but no reported effects on mortality. 27 WHO have cautioned against the use of systemic corticosteroids for the treatment of covid-19 unless indicated for other diseases. 28

In light of the strong evidence of benefits in patients with asthma, inhaled and oral corticosteroids should be prescribed if indicated in patients with symptoms of bronchoconstriction. Steroids should not be withheld on the theoretical risk of covid-19 infection, in line with guidance from the Primary Care Respiratory Society (PCRS), British Thoracic Society (BTS), and Global Initiative for Asthma (GINA). 15 22 29

Response to initial SABA or MART treatment can be assessed with a follow-up call at 20 minutes. If there is no improvement, further treatment may be necessary at a local hot clinic for reviewing possible covid-19, emergency department, or direct admission to an acute medical or respiratory unit depending on local pathways. For those who do respond, BTS-SIGN and GINA advise starting oral corticosteroids in patients presenting with an acute asthma exacerbation (such as prednisolone 40-50 mg for 5-7 days). 14 15 There is an increasing move in personalised asthma action plans to early quadrupling of the inhaled corticosteroid dose in patients with deteriorating control for up to 14 days to reduce the risk of severe exacerbations and the need for oral steroids. 15 30 However, there may be a ceiling effect on those who are already on a high dose of inhaled corticosteroid (see BTS table 14 ), so quadrupling the dose may not be effective in this group of patients. A personalised asthma action plan is an extremely helpful guide to treatment and should be completed or updated for all patients.

Follow-up and safety-netting

We recommend that all patients with moderate symptoms are followed up via remote assessment within 24 hours. Asthma attacks requiring hospital admission tend to develop relatively slowly over 6-48 hours. 14 However, deterioration can be more rapid, and symptoms can worsen overnight. Patients should be advised to look out for any worsening breathing or wheeze, lack of response to their inhalers, or worsening PEF. They should receive clear advice on what to do, including use of their reliever, and who to contact (such as the local out-of-hours GP provider, 111, or 999). With potential long waits for remote assessment, particularly out of hours, they should be advised to have a low threshold to call 999 if their symptoms deteriorate. If covid-19 infection is also suspected, advise them to isolate for seven days from onset of symptoms and arrange testing, according to the latest guidance. 7

How this article was created

We performed a literature search using Ovid, Medline, and Global Health databases using the search terms (asthma OR lung disease OR respiratory disease) AND (coronavirus OR covid-19)). Articles from 2019-20 were screened. We also searched for specific guidelines, including NICE, British Thoracic Society, Scottish Intercollegiate Guidelines Network, Primary Care Respiratory Society, European Respiratory Society, International Primary Care Respiratory Group, Global Initiative for Asthma, and the American Academy of Allergy, Asthma and Immunology.

Education into practice

Do you feel confident in completing personalised asthma plans in collaboration with patients?

How often do you start or increase inhaled corticosteroids in patients at initial presentation with an exacerbation of asthma?

If you manage a patient with acute asthma remotely, what safety netting advice would you give and how could you check understanding?

How patients were involved in the creation of this article

No patients were involved in the creation of this article.

This is part of a series of occasional articles on common problems in primary care. The BMJ welcomes contributions from GPs.

Contributors: TB and TS conceived the article. TB, DS, and TS carried out the literature review and wrote the initial drafts. All four authors contributed to editing and revision, and VM provided expert advice as a respiratory specialist. All authors are guarantors of the work.

Competing interests: We have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

Provenance and peer review: Commissioned, based on an idea from the author; externally peer reviewed.

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  • ↵ Primary Care Respiratory Society. PCRS Pragmatic Guidance: Diagnosing and managing asthma attacks and people with COPD presenting in crisis during the UK Covid 19 epidemic. 2020. https://www.pcrs-uk.org/sites/pcrs-uk.org/files/resources/COVID19/PCRS-Covid-19-Pragmatic-Guidance-v2-02-April-2020.pdf .
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  • ↵ British Thoracic Society. Advice for healthcare professionals treating people with asthma (adults) in relation to COVID-19. 2020. https://www.brit-thoracic.org.uk/about-us/covid-19-information-for-the-respiratory-community/ .
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  • ↵ Office for National Statistics. Analysis of death registrations not involving coronavirus (COVID-19), England and Wales: 28 December 2019 to 1 May 2020. Release date: 5 June 2020. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/articles/analysisofdeathregistrationsnotinvolvingcoronaviruscovid19englandandwales28december2019to1may2020/technicalannex .

research on asthma patients

  • Open access
  • Published: 19 December 2022

Health literacy in asthma and chronic obstructive pulmonary disease (COPD) care: a narrative review and future directions

  • Iraj Poureslami   ORCID: orcid.org/0000-0003-2878-7776 1 , 2 ,
  • J. Mark FitzGerald 1   na1 ,
  • Noah Tregobov 1 , 3 ,
  • Roger S. Goldstein 4 , 5 , 6 ,
  • M. Diane Lougheed 7 , 8 &
  • Samir Gupta 9 , 10  

Respiratory Research volume  23 , Article number:  361 ( 2022 ) Cite this article

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Respiratory self-care places considerable demands on patients with chronic airways disease (AD), as they must obtain, understand and apply information required to follow their complex treatment plans. If clinical and lifestyle information overwhelms patients’ HL capacities, it reduces their ability to self-manage. This review outlines important societal, individual, and healthcare system factors that influence disease management and outcomes among patients with asthma and chronic obstructive pulmonary disease (COPD)—the two most common ADs. For this review, we undertook a comprehensive literature search, conducted reference list searches from prior HL-related publications, and added insights from international researchers and scientists with an interest in HL. We identified methodological limitations in currently available HL measurement tools in respiratory care. We also summarized the issues contributing to low HL and system-level cultural incompetency that continue to be under-recognized in AD management and contribute to suboptimal patient outcomes. Given that impaired HL is not commonly recognized as an important factor in AD care, we propose a three-level patient-centered model (strategies) designed to integrate HL considerations, with the goal of enabling health systems to enhance service delivery to meet the needs of all AD patients.

As the prevalence of chronic diseases continues to increase, along with their burden on health systems and patients [ 1 , 2 ], there is an increasing awareness that patients will benefit from being empowered to actively engage in disease self-management [ 3 , 4 ]. This has led to patient-centered care models [ 5 , 6 , 7 ], which include collaboration between patients and their healthcare providers, and enhanced respect for patient values, preferences and expressed needs [ 5 ]. Although a patient-centered approach relies on improving patients’ disease-related knowledge through educational interventions [ 6 , 7 ], knowledge alone may not sufficiently motivate or enable patients to become active participants in self-management [ 8 , 9 ]. Patient engagement can be hindered by many factors, including difficulty navigating the healthcare system, misunderstanding information, non-adherence to instructions, and lack of regular, ongoing provider contacts [ 10 , 11 , 12 ]. Health literacy (HL) has increasingly become recognized as both a cause of and a solution to this problem, as it is a determinant of patient empowerment [ 13 , 14 ] and disease management success [ 8 , 15 , 16 , 17 ]. Studies among patients with diabetes, cancer, arthritis, cardiovascular disease, and stroke have all shown associations between low HL and worse health outcomes [ 18 , 19 , 20 ]. Unfortunately, despite the importance of HL in self-management of chronic airway diseases (ADs) such as asthma and chronic obstructive pulmonary disease (COPD), its application in empowering AD patients to make informed decisions about their health remains limited [ 11 , 16 , 21 ].

Herein, we describe a model for respiratory patient-centered care that is culturally and HL-competent and explore the potential impact of these competencies on care delivery, individuals, and communities. Our goal was to provide a framework and practical approaches that can be applied to improve patient-centered care through HL. To achieve this, we applied insights from the literature and our own practical experiences (including work with national and international HL-focused groups) [ 22 , 23 ] to suggest strategies to integrate of HL and cultural competency at a system level.

Overview of health literacy

In 2000, Ratzan and Parker [ 24 ] defined HL as: “ The degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. ” The Canadian Expert Panel on Health Literacy (CEPHL) [ 25 ] and the Calgary Charter on Health Literacy [ 26 ] developed a model of HL which included five main domains (Table 1 ) and defined HL as a person’s capability to obtain, understand, communicate, evaluate, and use health information to make appropriate health-related decisions ”. The importance of HL for each of these domains has been well established individually [ 27 , 28 ], and the “five-domain model of HL” has been endorsed and approved by different HL researchers and experts, as essential skills that a person may require to effectively navigate and obtain health information and care services related to their health issues [ 29 , 30 ]. In addition, an individual’s ability to understand and calculate numerical information (“numeracy”) (Table 1 ) [ 31 ] is a necessary skill for an individual to understand and apply information provided in the health care system. Historically, researchers have considered numeracy to be a HL skill individually [ 32 ], however, since numeracy is a variable that is applicable to all core 5 HL domains [ 33 ], many researchers assess it across the domains rather than independently [ 33 , 34 ]. HL is now considered a major determinant of overall health [ 27 , 35 , 36 , 37 , 38 ], and an essential life skill [ 37 , 39 , 40 , 41 ]. HL is also viewed through a population health lens, as health literate individuals improve the overall health of a community [ 42 , 43 ]; and as a component of social capital , with low HL contributing to health inequalities [ 44 ]. Finally, low HL is associated with increased health care costs [ 45 , 46 ].

This recognition of the importance of HL has since led to development and testing of several HL measurement tools [ 47 , 48 , 49 ] for use in healthcare settings:

the Rapid Estimate of Adult Literacy in Medicine (REALM)—a word-recognition assessment [ 50 ];

the Test of Functional Health Literacy in Adults (TOFHLA)—involving reading appointment slips, interpreting prescriptions, and filling in missing words on a consent form [ 51 ];

the Wide Range Achievement Test (WRAT)—assessing reading recognition, spelling and basic math skills [ 52 ]; and

the Newest Vital Sign (NVS)—assessing reading and numeracy skills through nutrition labels [ 53 ].

These tools are brief and relatively easy to administer [ 54 , 55 ], and previous authors have demonstrated relationships between HL scores on these instruments and outcomes such as disease knowledge, health prevention behaviors, and quality of life, across population groups [ 56 , 57 , 58 , 59 , 60 ]. Accordingly, some have encouraged their use in practice [ 61 , 62 ]. However, these tools have also been criticized [ 17 , 48 , 54 , 55 ] for their focus on general literacy skills [ 27 , 35 ] rather than skills that define a health literate individual, including navigation, comprehension, motivation and activation, and self-efficacy [ 16 , 63 ]. In addition, these instruments were developed for the general population, rather than for specific disease groups (which may have disparate needs), and with little or no patient input [ 48 , 64 ]. Accordingly, many have argued that these existing HL measurement tools have limited validity and applicability in real-world healthcare settings [ 26 , 34 , 65 , 66 , 67 ] and emphasized the need for tailored approaches to measuring HL in specific disease populations [ 28 , 36 , 37 , 38 , 39 ]. Although various such function-based HL measures have since emerged [ 68 , 69 , 70 , 71 , 72 ], their use has not yet been reported in patients with AD. To address this, we brought together patients, HL researchers, and respiratory care clinicians to develop a new function-based HL measurement tool (using realistic case scenarios) exclusively for asthma and COPD patients [ 68 , 73 , 74 , 75 , 76 , 77 ], which is currently being validated [ 78 ].

Health literacy in respiratory care—an under-recognized problem

Asthma and COPD are among the most common chronic diseases, presenting a major and growing strain on global healthcare resources [ 21 , 46 , 79 , 80 ]. Patients with these conditions should be empowered to act as informed decision-makers, develop partnerships with care providers, and self-manage their condition [ 3 , 13 , 81 ]. This requires a high degree of self-efficacy, achieved by obtaining and comprehending information and instructions about their health condition and its treatment [ 82 , 83 , 84 , 85 ]. However, patient engagement in such decision-making is dependent on the social determinants of health, including health beliefs and practices, attitudes, cultural norms, socio-economic status (SES), and baseline HL ([ 39 , 40 , 41 , 86 ], Fig.  1 ).

figure 1

Three-level model strategies to promote health literacy and culturally competency in respiratory care

Accordingly, providers can motivate and empower their patients to engage in disease management by improving their HL skills [ 83 , 86 , 87 , 88 , 89 ]. The impact of improved HL skills could include slowing disease progression and improving patient-relevant health outcomes [ 74 , 90 , 91 , 92 ]. Although respiratory organizations around the world have recognized the importance of addressing low HL [ 93 , 94 , 95 , 96 , 97 , 98 , 99 ] and several AD studies have administered HL measurement instruments, most of these tools focused merely on patient capabilities [ 8 , 15 , 16 , 46 , 100 , 101 ], and were not specific to AD populations [ 16 , 64 , 72 , 76 , 100 ], thereby, limiting understanding of the impact of low HL on AD health outcomes [ 14 , 15 , 67 , 102 ]. Prior investigators have suggested strategies to improve care for patients with low health literacy in clinical settings [ 5 , 22 , 37 , 103 ] and some approaches have shown positive results in observational studies [ 104 , 105 ], but, most of existing studies focus narrowly on educational interventions and corresponding outcomes related to comprehension, inhaler technique, and/or disease knowledge [ 106 , 107 , 108 , 109 ]. A previous systematic review [ 64 ] did not identify a single AD study that applied all five components of HL as part of an intervention. To gauge the existing state of interest and knowledge surrounding HL in AD, we sought to identify prior experimental and observational studies in ADs that assessed one or more specific component of HL (accessing, communicating, understanding, evaluating, and/or using information to improve disease outcome). These results are summarized in Table 2 a–c, demonstrating the characteristics of each reviewed article.

Overall, we summarize 31 articles in this narrative review. None used a disease-specific HL assessment tool, and no single study applied more than three HL domains. The ‘understand’ aspect of HL and improving disease ‘knowledge’ (using knowledge questionnaires) were assessed in all 31 reviewed articles (100%). The ‘use’ domain of HL was identified in 25 articles (81%) of the articles. Use was simply assessed by directly assessing if participants applied the intervention in question (e.g., education) in managing their disease, improving medication adherence, and preventing exacerbations, or by indirectly assessing the impact of the intervention in improving the outcome of interest. ‘Communication’ was the least assessed HL domain, which was identified in only 17 (55%) of the reviewed articles, assessed by measuring the impact of communicating with a health care provider on outcomes of interest. The ‘numeracy’ domain was applied in only two studies (6%), which assessed understanding of numerical concepts such as dose change instructions for self-management of asthma or COPD. Lastly, ‘access’ and ‘evaluation’ domains of HL were each assessed by only one article (3%). Access was assessed by evaluating access barriers to healthcare services and relevant disease management education, and ‘evaluation’ was assessed by measuring patients’ ability to judge the severity of disease symptoms required to initiate needed treatment according to their action plan.

Even when HL was assessed, measurements in individual studies were limited to associations between baseline HL and trial outcomes (e.g., behavioural, healthcare services utilization, and health outcomes) among asthma and COPD patients [ 90 , 91 , 92 ]. No trial design attempted to improve HL skills through an intervention in order to measure the impact of changes in HL on patient or health system outcomes. For instance, in Azkan Ture et al. study, [ 110 ] inadequate HL was more common in patients with severe COPD than those with milder disease. Similarly, several studies demonstrated significant associations between HL and improved self- efficacy (Fan et al. [ 62 ]; Martin et al. [ 82 ]), and disease control (Wilson et al. [ 111 ]; Janson et al. [ 112 ]). Others reported correlations between baseline HL and quality of life (Goeman et al. [ 113 ]) and Thomas et al. [ 114 ]); medication adherence and use (Apter et al. [ 91 ]) and (Khdour et al. [ 115 ]); hospitalization (Wang et al. [ 116 ]), emergency department (ED) visits (Pur Ozyigit et al. [ 117 ]), and appropriate response to symptom worsening (Poureslami et al. [ 84 ]). Overall, findings consistently showed that patients with low HL skills had lower adherence to their medications and treatment plan, visited the ED more frequently, and had more asthma/COPD-related hospital admissions/re-admissions, and more symptom flare-ups than patients with higher HL skills. Studies also showed that HL was positively correlated with improved non-medical determinants of health. For instance, Eikelenboom et al. [ 118 ] found a link between HL levels and adopting healthier nutrition and having improved patient activation levels. Other researchers found significant associations between HL skills and exercise capacity (Wang et al. [ 116 ]), smoking cessation (Efraimsson et al. [ 119 ], and medical decision making (Wang et al. [ 90 ]. Despite these promising results, the mechanisms behind the reported associations between HL and respiratory outcomes remain unclear, as we did not identify any interventional studies that sought to enhance HL and measure impact on outcomes (e.g. inhaler technique, awareness and control of symptoms, management of acute exacerbation, and proper use of healthcare services). Accordingly, the causal relationship between HL and health outcomes requires further investigation [ 23 , 101 , 120 ].

Patient HL challenges and potential respiratory care system responses

In the following section, we highlight challenges faced by patients with AD and low HL in actively engaging in disease management, and practice- and system-level changes required to address these barriers and drive improvements in HL.

Accessing health information and services

Limited access includes both the availability and attainability of information and services [ 121 , 122 ]. Disadvantaged individuals experience inadequate access for several reasons [ 58 , 104 ]; (1) they have less regular primary care visits [ 11 , 118 , 123 ]; (2) they are more prone to accessing healthcare information from unreliable sources outside of the medical system (e.g. a friend with a "similar" health condition, family members, neighbors, or the internet) [ 10 , 23 , 84 , 102 ]; (3) even when referred to specialty clinics (including respiratory clinics), these settings are particularly poorly suited to offering culturally sensitive and/or same-language care to patients of diverse backgrounds [ 123 , 124 , 125 , 126 , 127 , 128 ].

Given that culturally matched patient-provider interactions have been shown to augment patient engagement in disease management and to improve health outcomes [ 125 , 126 , 129 , 130 ], healthcare systems must invest in improving competencies and diversity of personnel (language and cultural) in order to render all care services attainable to all members of the community [ 2 , 30 , 102 , 105 ]. This can be supplemented by provision of multi-lingual health information (written and/or electronic) that is also easily understandable and relevant across ethnicities and cultures.

Processing and understanding information and instructions

Respiratory care providers often overestimate patients’ HL skills, assuming that complex instructions have been understood [ 32 , 132 ]. This issue is compounded by the fact that many patients with limited HL also overestimate their own ability to process and understand medical instructions [ 61 , 111 , 133 ]. In addition to verbal communication, printed disease-related educational materials are often inaccessible to low HL patients due to an inappropriately high reading grade requirement for comprehension [ 23 , 93 , 97 , 128 , 134 ] (low HL and low literacy and reading skills are closely associated [ 8 , 9 , 135 , 136 ]).

To address these issues, both care and accompanying educational materials must be tailored to the diverse needs and abilities of patients across different ethnic and cultural communities, ages, and socioeconomic classes [ 90 , 137 , 138 ]. A suggested approach to foster open, interactive patient-provider communication is to compliment plain language resources [ 56 , 132 , 139 , 140 ] with a “teach back” approach (asking the patient to repeat back what was understood), to ensure that patients have understood information correctly [ 141 , 142 ], stimulating dialogue and question-asking [ 143 ]. This approach has been shown to improve medication adherence and inhaler technique in AD patients [ 133 , 144 , 145 ]. Patient input in material development can help to ensure that reading levels and content are properly matched to the target audience, and optimize both content and layout, thereby enhancing understanding and uptake [ 118 , 137 , 144 , 146 ]. Specifically, incorporation of patient input in self-management tools for asthma and COPD augments self-management behaviors and improves outcomes, particularly in older patients [ 92 , 113 , 145 , 147 ].

Appraising the quality of information and care services

To optimize health outcomes, AD patients must assess the quality and credibility of health information they encounter, and its relevance to their personal health needs [ 23 , 87 , 148 ].

Lacking corresponding critical appraisal and evaluation skills has emerged as a central issue in HL research in recent years [ 149 , 150 ], but has barely been studied in respiratory research [ 66 , 87 , 149 ]. Accurate measurement of evaluation skills could help to identify the differences between patients’ expectations and their perceptions of the services and information received [ 61 ]. This evaluation skill component of HL is understudied, particularly in AD [ 68 , 78 ].

Applying information to make health-related decisions

Most attention in HL research has been focused on information availability, accessibility, and comprehension (readiness, attainability, readability, and comprehensibility of health-related information) [ 48 , 58 , 63 ]. However, maintaining health requires a series of practical acts, and obtaining and understanding relevant information does not equate to using it [ 114 , 151 ]. Although all aspects of HL are important, the effectiveness of health information and services in changing behavior is what ultimately determines impact [ 17 , 25 ]. Many patients with airways diseases have high levels of knowledge about their health condition [ 23 , 120 , 137 , 148 ], but struggle to apply that knowledge in the disease management process [ 11 , 12 , 27 , 107 , 125 , 135 ]. A person’s behaviours are also influenced by internal and external motivations, as well as their ability, readiness, and willingness to use the information received from care providers [ 19 , 60 , 102 , 140 , 147 ]. Additionally, factors such as beliefs and worldviews, the perceived trustworthiness and practicability/relevance of the information, and previous experiences all effects a person’s intention to apply the information [ 77 , 78 , 92 , 152 ]. Accordingly, patient-provider interactions must go beyond information “transfer”, to facilitate behavior change [ 133 , 140 ]. Improving patient educational materials to include personalized instructions (both related to the behaviour itself and how to achieve the behaviour change) may empower patients with the skills needed to change [ 90 , 117 , 139 , 153 ]. Additionally, when appropriate, providers may augment this process by having patients practice relevant actions and procedures (and offer feedback) to compliment and reinforce verbal and written information [ 56 , 132 , 154 ].

A model for health literacy and culturally competent respiratory care

Both cultural and social factors deeply influence the way people access and navigate health information and services [ 2 , 41 , 127 , 155 ]. Culturally competent care systems understand and respect the health beliefs and practices of their patients, appreciate language barriers, and apply such understanding in practice [ 126 , 134 , 156 , 157 , 158 ]. Accordingly, HL competent care facilitates equity of essential healthcare services for all community members [ 14 , 37 , 38 , 39 , 40 , 41 , 103 ]. Increasing diversity in healthcare providers themselves (including in leadership and governance) and use of patient navigators (trained health workers) to assist vulnerable patients with language and/or literacy barriers may help to address system inequities [ 102 , 159 ]. However, implementation of these strategies may be hindered by various countries’ population structures (i.e. a lack of sufficient representatives to play these roles across diverse cultural and language groups) [ 134 , 160 ].

A three-level model

Patients with AD, particularly older patients and COPD patients are among population groups with the lowest HL levels [ 92 , 145 , 147 ]. To achieve the goal of creating a responsive, patient-centered system of care for AD patients, we propose new strategies, in a three-level model format (Fig.  1 ), with special focus on training and empowering healthcare professionals to excel in roles as change agents for bridging cultural and HL gaps in their own patients [ 161 ]. The change agents can also leverage rapidly accelerating virtual care and communication technologies to address inequitable access to health information and care; and the last is to broaden the healthcare services team by building partnerships with (culturally competent) community stakeholders [ 162 , 163 ]. We applied the three-level model strategies in our recent research projects [ 10 , 15 , 68 , 84 , 125 , 128 , 130 , 146 , 164 , 165 ]. The results of our studies demonstrated potential efficacy of the proposed strategies and the need for further prospective validation. These strategies and their expected outcomes are outlined below.

Firstly, respiratory clinics should train providers to recognize the heterogeneity in patients’ beliefs, preferences, limits, and needs, and consider these in their communication style and clinical practices [ 102 , 157 , 162 , 163 ]. There is evidence that improved provider communication skills and awareness of social determinants of health mitigate impacts of limited HL and cultural mismatch [ 86 , 157 , 166 ]. With appropriate training (in university for future health professionals and through ongoing/continued education for current staff), respiratory health professionals can acquire the skills required to act as change agents [ 167 ], by engaging in patient questions, explaining treatment instructions while avoiding medical jargon, and using strategies such as the teach-back method [ 108 , 140 , 166 ]. The focus of a change agent is to improve a patient's capacity and motivation to engage in self-management (one of the foundational components of AD management). Given the impact of social determinants of health [ 161 ], this role may extend beyond medical practice to a global assessment and support of financial and social factors impacting adherence, motivation, and treatment response [ 102 , 168 ]. This approach has been shown to improve self-management and outcomes in this population [ 3 , 88 , 89 , 92 , 145 , 154 ]. However, a sustainable model will require advocacy regarding the importance of non-medical determinants of health in respiratory disease management [ 169 ] to ensure that these aspects are included in future curricula and programming, and receive sufficient funding.

Secondly, to address disparate and inequitable access to health information and services, respiratory care providers must espouse emerging technology, in the form of virtual communication and care strategies . The goal is to overcome care access barriers related specifically to patients living in remote or rural areas and/or having difficulties securing time away from work for appointments during normal office hours [ 121 , 164 , 170 , 171 , 172 , 173 ]. With technological advancements as well as increased provider and patient acceptance of and access to remote communication models driven by the COVID-19 pandemic [ 174 , 175 ] (even among lower socioeconomic class groups), telehealth can now be used to address essential healthcare services across patient populations [ 173 ]. It can also facilitate health education for patients and communication between primary care physicians and specialists [ 176 , 177 ]. Although telehealth-based interventions improved knowledge [ 176 ], emotional and mental health [ 173 ], quality of life [ 172 ], medication adherence [ 178 ], hospitalization and emergency department (ED) visits [ 179 ], and self-monitoring [ 176 , 178 ] across chronic diseases, there are no high-quality studies evaluating this in AD [ 177 ]. Ideas such as an electronically accessible action plan with weekly text message reminders to assess one’s asthma control [ 165 ], and virtual pulmonary rehabilitation (PR) (telerehab) [ 172 , 180 ] hold promise [ 181 ]. For example, a telerehab program can provide educational materials online, with the patient attending practical sessions (e.g., exercise, breathing/cough control training) via interactive video conferencing [ 180 , 181 ]. Such a program was shown to improve exercise capacity, health related quality of life, and psychological status [ 180 , 181 ]. This approach also enables access for those living in remote locations and whose physical limitations and/or capacity to secure transit impairs in-person attendance [ 180 ]. In fact, virtual care is often favored by patients and providers alike due to convenience and flexibility [ 174 ].

Finally, a successful model must build partnerships with community stakeholders (patients, community leaders, and opinion leaders). Partnerships lead to allyship—through insights into the challenges faced by community members in accessing and navigating health services [ 82 , 118 ]. This can occur as part of community care, or, for example, community AD patients might be involved in participatory research (from the beginning of the research process) and/or in developing educational material [ 82 , 118 , 131 , 164 ]. For example, we successfully gauged AD patients’ research priorities through a series of focus groups across Canada [ 10 , 73 , 84 , 146 , 182 ] and applied these in the Canadian Respiratory Research Network’s research prioritization exercise ( https://respiratoryresearchnetwork.ca/ ). We also engaged patients, community healthcare providers, and clinicians in developing audio-visual educational materials on AD topics in seven different languages [ 125 , 128 , 130 , 163 , 183 ]. This work enabled us to establish a peer-support network [ 127 ] that offers newly diagnosed patients with AD the opportunity to gain insights from those with lived experience in managing AD [ 184 , 185 ]. These groups also provided an opportunity for individuals of diverse cultural backgrounds and HL levels to interact with others in a familiar language and at a comparable level of sophistication. Such peer support and patient networks have been shown to reduce patients’ feelings of isolation and fear, to enhance their mental capacity to cope with their condition, and to build the confidence needed to engage in self-management [ 132 , 184 , 185 , 186 ]. Care system-community collaboration has also been shown to facilitate delivery of effective education to disadvantaged patients [ 1 , 11 , 68 , 111 , 185 , 187 , 188 ].

Conclusions

As patients with AD are increasingly expected to actively engage in disease self-management, we must acknowledge the responsibility of the health system to ensure that they have the capacity to execute such complex tasks, by addressing their HL [ 30 , 37 , 41 , 105 , 171 ]. A respiratory care system that reinforces HL in a culturally competent way will improve health outcomes through patient engagement, clearer communication, and improved patient-provider interactions. Key components of system change include training healthcare providers to become change agents, accelerating adoption of evidence-based virtual communication and care strategies, and building partnerships with community stakeholders. These changes will reduce socio-cultural and socio-economic disparities in care access and quality, yielding enormous benefits for patient outcomes, possibly with reductions in healthcare costs [ 46 ].

There are exciting research opportunities to design and evaluate novel strategies to both measure HL and to address cultural competency and HL in patients with AD. Longitudinal research is particularly needed to evaluate which health outcomes are improved by addressing HL in a culturally competent way, including the sustainability of observed effects. As communication technologies continually advance, research is also needed to determine the most efficient and effective strategies to enable virtual care. Ultimately, our common goal should be to realize a patient-centered respiratory care system that engages willing patients not only in decision-making around their own care, but also in the development of the very educational material that is presented to them and the very research, which establishes their therapy.

Availability of data and materials

The authors have made readily reproducible materials described in the manuscript, including the software used, databases and all relevant raw data, and made them freely available to any scientist wishing to use them, without breaching participant confidentiality .

Abbreviations

  • Health literacy

Chronic obstructive pulmonary disease

Airway disease

Pulmonary rehabilitation

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Acknowledgements

We would like to thank Dr. Celine Bergeron, Alizeh Akhtar, Jessica Shum and Sarah Chae for their contributions to the research program mentioned in this review. We would also like to thank the many patients and health care providers who participated in the many focus groups etc., which provided the basis for much of the material presented here.

Our health literacy research program has been funded by the Canadian Institute for Health Research (CIHR) (project fund #20R24515), The funding agency has no roles in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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J. Mark Fitzgerald—Deceased

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Division of Respiratory Medicine, Centre for Lung Health, Vancouver Coastal Health Research Institute, University of British Columbia, 716-828 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada

Iraj Poureslami, J. Mark FitzGerald & Noah Tregobov

Canadian Multicultural Health Promotion Society (CMHPS), Vancouver, BC, Canada

Iraj Poureslami

Faculty of Medicine, Vancouver-Fraser Medical Program, University of British Columbia, Vancouver, BC, Canada

Noah Tregobov

Department of Physical Therapy, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada

Roger S. Goldstein

Respiratory Medicine, Westpark Healthcare Centre, Toronto, Canada

Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

Asthma Research Unit, Department of Medicine, Kingston Health Sciences Centre, Queen’s University, Kingston, ON, Canada

M. Diane Lougheed

Institute for Clinical Evaluative Sciences, Toronto, ON, Canada

Unity Health, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, ON, Canada

Samir Gupta

Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON, Canada

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Each author has made substantial contributions to writing, editing, and preparing the manuscript. IP and JMF conceived the idea for this review article. IP initially drafted the manuscript and JMF, NT, SG, RG, and DL critically revised the manuscript and had the final approval for submission. All authors read and approved of the final submitted version of manuscript and agree to be accountable for their own contributions. The authors agreed to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. All authors read and approved the final manuscript.

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Poureslami, I., FitzGerald, J.M., Tregobov, N. et al. Health literacy in asthma and chronic obstructive pulmonary disease (COPD) care: a narrative review and future directions. Respir Res 23 , 361 (2022). https://doi.org/10.1186/s12931-022-02290-5

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February 15, 2024

In a Real-World Study, Most Patients with Severe Asthma Had Good Response to Biologics

David J. Amrol, MD , reviewing Hansen S et al. Chest 2024 Feb

And 24% achieved clinical remission.

Asthma biologics are an effective, but very expensive, treatment for patients with severe asthma. Danish researchers used a national registry to see how many patients achieve “remission” and which patient characteristics predict better responses.

About 500 patients who were starting biologic agents (targeting IgE, interleukin-5, or IL-4/13) for severe asthma were included. Clinical response was defined as a ≥50% reduction in annualized exacerbation rate and ≥50% reduction in maintenance oral corticosteroid doses. Clinical remission was defined as no exacerbations, no maintenance oral steroids, normal lung function, and good asthma control based on questionnaires.

After 12 months, 79% of patients had clinical response, and 24% of those patients achieved clinical remission. Nonresponders were more likely to be obese and to have been taking maintenance oral steroids at baseline. Responders were more likely to be male and to have better baseline lung function, higher levels of type 2 markers of inflammation (i.e., eosinophil counts, IgE levels, and exhaled nitric oxide levels), shorter duration of disease, and more acute exacerbations before starting biologics.

Six biologic agents currently are available in the U.S. Most primary care providers don't start biologics in their asthma patients, but knowing this information will help with counseling. Most patients have good responses to biologics, and about one fifth will achieve complete control of their asthma. Because these medications are very expensive, understanding the characteristics that predict response is important.

Hansen S et al. Clinical response and remission in patients with severe asthma treated with biologic therapies. Chest 2024 Feb; 165:253. ( https://doi.org/10.1016/j.chest.2023.10.046 . opens in new tab )

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Decreased TLR7 expression was associated with airway eosinophilic inflammation and lung function in asthma: evidence from machine learning approaches and experimental validation

  • Kemin Yan 1 &
  • Yuxia Liang 2 , 3  

European Journal of Medical Research volume  29 , Article number:  116 ( 2024 ) Cite this article

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Asthma is a global public health concern. The underlying pathogenetic mechanisms of asthma were poorly understood. This study aims to explore potential biomarkers associated with asthma and analyze the pathological role of immune cell infiltration in the disease.

The gene expression profiles of induced sputum were obtained from Gene Expression Omnibus datasets (GSE76262 and GSE137268) and were combined for analysis. Toll-like receptor 7 (TLR7) was identified as the core gene by the intersection of two different machine learning algorithms, namely, least absolute shrinkage and selector operation (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE), and the top 10 core networks based on Cytohubba. CIBERSORT algorithm was used to analyze the difference of immune cell infiltration between asthma and healthy control groups. Finally, the expression level of TLR7 was validated in induced sputum samples of patients with asthma.

A total of 320 differential expression genes between the asthma and healthy control groups were screened, including 184 upregulated genes and 136 downregulated genes. TLR7 was identified as the core gene after combining the results of LASSO regression, SVM-RFE algorithm, and top 10 hub genes. Significant differences were observed in the distribution of 13 out of 22 infiltrating immune cells in asthma. TLR7 was found to be closely related to the level of several infiltrating immune cells. TLR7 mRNA levels were downregulated in asthmatic patients compared with healthy controls ( p  = 0.0049). The area under the curve of TLR7 for the diagnosis of asthma was 0.7674 (95% CI 0.631–0.904, p  = 0.006). Moreover, TLR7 mRNA levels were negatively correlated with exhaled nitric oxide fraction ( r  = − 0.3268, p  = 0.0347) and the percentage of peripheral blood eosinophils (%) ( r  = − 0.3472, p  = 0.041), and positively correlated with forced expiratory volume in the first second (FEV1) (% predicted) ( r  = 0.3960, p  = 0.0071) and FEV 1 /forced vital capacity ( r  = 0.3213, p  = 0.0314) in asthmatic patients.

Conclusions

Decreased TLR7 in the induced sputum of eosinophilic asthmatic patients was involved in immune cell infiltration and airway inflammation, which may serve as a new biomarker for the diagnosis of eosinophilic asthma.

Asthma is a common chronic disease in which airways become inflamed and narrow, causing airflow obstruction [ 1 , 2 , 3 ]. Asthma is a heterogeneous clinical syndrome that affects more than 300 million people worldwide [ 4 ]. The common symptoms of asthma in the acute phase include wheezing, coughing, chest tightness, and shortness of breath [ 1 , 2 ]. Asthma is a complex and heterogenous respiratory diseases. The underlying pathogenetic mechanisms of asthma were poorly understood [ 5 ].

Induced sputum has several desirable characteristics as a noninvasive marker of airway inflammation [ 6 ]. In patients with asthma, sputum induction is generally a well-tolerated and safe method, and sputum can be used to measure various soluble mediators, including eosinophilic-derived proteins, cytokines, and remodeling-related proteins [ 6 , 7 , 8 , 9 , 10 , 11 ]. Induced sputum may be used to discover inflammatory cell profiles in patients with asthma and other airway diseases, and these profiles may be related to the patient’s response to treatment [ 12 ]. The gene expression profile of induced sputum cells is altered in patients with asthma [ 13 ].

Microarray technology and integrated bioinformatics analysis have been used in recent years to identify novel genes associated with various diseases that may serve as biomarkers for diagnosis and prognosis [ 14 , 15 ]. Bioinformatics analysis has also been performed to identify the underlying mechanisms and hub genes of asthma [ 16 , 17 ]. Studies have also shown that immune cell infiltration plays an increasingly important role in the occurrence and development of various diseases [ 18 , 19 , 20 , 21 ]. Previous studies demonstrated that the Th1/Th2-mediated immune imbalance is the main mechanism of asthmatic airway inflammatory response, and various immune cells are involved in the pathogenesis of asthma [ 22 ].

CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles, has been widely used to evaluate the relative content of 22 kinds of immune cells [ 23 ]. CIBERSORT method has also been applied to study the immune cell infiltration and candidate diagnostic markers in asthma. It has been reported by Yang et al. that autophagy-related genes are involved in the progression and prognosis of asthma and regulate the immune microenvironment [ 24 ]. Least absolute shrinkage and selector operation (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) are two machine learning algorithms. LASSO is a dimension-reduction algorithm that can analyze high-dimensional data compared with regression analysis [ 25 ]. SVM-RFE is a machine learning algorithm used to identify the best variables through classification method [ 26 ]. The combination of LASSO and SVM-RFE has been applied in previous research to identify diagnostic markers [ 20 , 27 , 28 ].

In the present study, bioinformatics analysis and experimental validation were performed to investigate the change of immune cell infiltration in asthma, and screen the biomarker for the diagnosis and treatment of asthma. Two datasets from Gene Expression Omnibus (GEO) database were combined, and differential expression gene (DEG) analysis, machine learning algorithms and CIBERSORT were performed. Toll-like receptor 7 (TLR7), a candidate gene that was found to be closely associated with immune infiltration in asthma, was also validated in another GEO dataset and induced sputum samples of asthmatic patients.

Material and methods

We recruited 12 healthy controls and 36 newly diagnosed asthma patients with untreated asthma. The asthmatic patients included in this study and the control group were non-smokers, and the asthmatic patients were newly diagnosed and untreated. The asthmatic patients were from outpatients and were diagnosed with asthma by specialists. The characteristics of the subjects are summarized in Table  1 . No significant differences were observed in terms of age, sex, and body mass index between the two groups. All subjects provided written informed consent. The study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (2021071).

Dataset acquisition and processing

The study design is shown in Additional file 1 : Fig S1. The datasets GSE76262 and GSE137268 were downloaded from the GEO database ( http://www.ncbi.nlm.nih.gov/geo ). GSE76262 dataset, which is based on GPL13158 platform, included induced sputum samples from 118 asthmatic patients and 21 healthy controls. GSE137268 dataset, which is based on GPL6104 platform, included induced sputum samples from 54 asthmatic patients and 15 healthy controls. The series matrix files were annotated to the official gene symbols, and the two gene expression files were merged. The batch normalization was then conducted using combat method in “sva” R package. Finally, a merged file with 15,043 genes was prepared for the subsequent analysis.

Identification of DEGs and enrichment analysis

The “limma” R package was used to identify DEGs, and the |log2FC|> 0.5 and adjusted p value < 0.05 were filtered as statistically significant. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were then performed using “clusterProfiler” R package. Gene Set Enrichment Analysis (GSEA) was conducted to analyze the associated biological functions and pathways in asthma. Disease Ontology (DO) was also conducted using “DOSE” R package.

Identification of the core gene

First, two distinct machine learning algorithms, namely, least absolute shrinkage and selector operation (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE), were utilized in DEGs to screen the gene signatures. The LASSO is a regression analysis algorithm that uses regularization to improve the prediction accuracy. The LASSO analysis was undertaken using “glmnet” R package; the response type was set as binomial, and the alpha was set as 1. SVM is a supervised machine-learning technique widely utilized for both classification and regression. To avoid overfitting, an RFE algorithm was employed to select the optimal genes from the meta-data cohort. Therefore, to identify the set of genes with the highest discriminative power, SVM-RFE was applied to select the appropriate features. The SVM-RFE was performed using “e1071” and “caret” R package. Second, STRING database was used to construct the protein–protein interaction (PPI) network, and a core network was obtained through Cytoscape software and CytoHubba plugin. The top 10 hub genes were screened according to Degree algorithm. Finally, the results of LASSO regression, SVM-RFE algorithm, and hub genes were incorporated, and the overlapping gene (TLR7) was identified as the core gene.

Analysis of immune cell infiltration

The CIBERSORT algorithm was used to evaluate the percentage of 22 immune cell types in each sample. The fraction of 22 immune cells was compared between the asthma and healthy control groups, and the violin plot was drawn by “vioplot” R package. The correlation coefficient between immune cells was calculated using “corrplot” R package. Spearman correlation analysis was also performed to investigate the correlation of TLR7 and infiltrating immune cells.

Validation of TLR7 in a GEO dataset

The expression level of TLR7 in the merge dataset was visualized, and receiver operating characteristic (ROC) curve was applied to evaluate the diagnostic value of TLR7 for asthma. Furthermore, the GEO dataset GSE147878 with endobronchial biopsy samples from 60 asthmatic patients and 13 healthy controls was used to validate the expression level and diagnostic effectiveness of TLR7 in asthma.

Collection of induced sputum from subjects

A total of 48 subjects from First Affiliated Hospital of Sun Yat-sen University (Guangzhou, Guangdong, China) were enrolled in this study, including 12 healthy controls and 36 asthmatic patients. Patients with asthma met the diagnostic criteria for Global Asthma Initiative (GINA) guidelines [ 29 ] and were free of other respiratory diseases. People with normal lung function test results and no history of pulmonary disease, allergic disease, and autoimmune disease were included in the healthy control group. Sputum samples were collected from the participants. Participants were induced to cough by hypertonic saline. The above steps are completed by ultrasonic atomizer (Yuyue, Jiangsu, China). Sputum cell pellet was selected, weighed, and dissolved by adding 0.1% dithiothreitol (DTT) that is 4 times the weight. The pellet was then filtered through cell sieving [ 30 , 31 , 32 ]. After centrifugation, sputum cells were added with 1 ml TRIzol for subsequent RNA extraction. Additional clinical information was collected for each subject, including lung function, exhaled nitric oxide fraction (FeNO), and peripheral blood eosinophil percentage.

Quantitative real‐time polymerase chain reaction (qRT-PCR)

Total RNA was extracted from induced sputum cells using TRIzol reagent following the manufacturer’s instructions. Evo M-MLV RT Premix kit (AG, Hunan, China) was used for reverse transcription. The reaction conditions were 37 ℃ for 15 min and 85 ℃ for 5 s. Candidate gene expression was quantified using Biosystems Light Cycler 480 (Applied Biosystems, Massachusetts, USA) as standard procedure. The primers used were TLR7: forward, 5′- TCCTTGGGGCTAGATGGTTTC-3′, reverse, 5′- TCCACGATCACATGGTTCTTTG-3′ and GAPDH: forward, 5ʹ-ACCCAGAAGACTGTGGATGG-3ʹ, reverse, 5ʹ-TTCTAGACGGCAGGTCAGGT-3ʹ.

Statistical analysis

All data in this study were analyzed through GraphPad Prism 8. 0 (GraphPad, San Diego, California, USA). Normally distributed data were obtained through unpaired t-test and expressed as mean ± standard deviation. For non-normally distributed data, the results were obtained via a nonparametric test (i.e., Kruskal–Wallis test) and expressed as median (interquartile spacing). Fisher’s exact test was used to analyze classified data, and Spearman rank correlation was used for correlation analysis. ROC was generated to determine the diagnostic value of TLR7. P  < 0.05 was considered statistically significant.

The inclusion criteria of the DEGs were |log2FC|> 0.5 and adjusted p value < 0.05. A total of 320 DEGs between the asthma and healthy control groups were screened, including 184 upregulated genes and 136 downregulated genes. The expressions of the DEGs in each sample are shown in the heatmap (Additional file 1 : Fig S2A), and the distribution of the DEGs is illustrated through a volcano plot (Additional file 1 : Fig S2B).

GO, KEGG, GSEA, and DO analyses were performed to further investigate the DEGs’ functions. GO enrichment analysis was conducted to analyze the gene function in terms of biological processes (BP), cellular component (CC), and molecular function (MF). The GO analysis results showed that BP is mainly enriched in the regulation of immune effector process, CC is mainly enriched in tertiary granule, and MF is mainly enriched in immune receptor activity (Additional file 1 : Fig S3A). The KEGG pathway enrichment analysis demonstrated that the DEGs were mainly involved in cytokine–cytokine receptor interaction, tumor necrosis factor (TNF) signaling pathway, and nuclear factor (NF)-kappa B signaling pathway (Additional file 1 : Fig S3B). As shown in Fig.  1 A, GSEA also showed that the significantly enriched hallmark terms associated with asthma included chemokine signaling pathway, cytokine–cytokine receptor interaction, Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and neuroactive ligand receptor interaction. Furthermore, DO analysis revealed that the DEGs were mainly related to lung disease and obstructive lung disease (Fig.  1 B).

figure 1

GSEA and DO enrichment analyses. A Illustration of several important enrichment hallmark terms in asthma obtained through GSEA. B Top 20 terms in the DO enrichment analysis

Identification of TLR7 as the core gene

To explore the biomarkers of asthma, two distinct machine learning algorithms, namely, the LASSO regression and SVM-RFE, were performed. The LASSO regression analysis identified 46 DEGs as signature genes in asthma (Fig.  2 A). The SVM-RFE algorithm screened 28 DEGs as characteristic genes in asthma (Fig.  2 B). In addition, a PPI network of DEGs was constructed using the STRING database. A core network was then obtained through Degree algorithm in the Cytohubba plugin, and 10 hub genes were identified (Fig.  2 C). After combining the results of LASSO regression, SVM-RFE algorithm, and hub genes by Venn diagram, only an intersection gene was identified, i.e., TLR7 (Fig.  2 D). TLR7 was thus identified as the core gene for the subsequent research.

figure 2

Two machine learning algorithms and PPI network were performed for core gene selection. A LASSO regression analysis. B SVM-RFE algorithm. C Hub genes based on the Degree algorithm in the Cytohubba plugin. D Venn diagram showing the overlapping gene of LASSO regression, SVM-RFE algorithm, and hub genes

Immune infiltration analyses

CIBERSORT algorithm was used to analyze the difference of immune cell infiltration between the asthma and healthy control groups in 22 subpopulations of immune cells. The total value of all immune cells in each sample was set at 100%, and the proportion of each immune cell in these samples is presented in Fig.  3 A. The interaction between the immune cells was also analyzed. Average linkage clustering revealed that M1 macrophages and activated memory CD4 T cells have a significant positive correlation, whereas neutrophils and M0 macrophages are significantly negatively correlated (Fig.  3 B). The violin plot showed marked differences in the distribution of 13 out of 22 immune cells (Fig.  3 C). The fractions of naive CD4 T cells ( p  = 0.027), resting dendritic cells ( p  = 0.018), activated dendritic cells ( p  < 0.001), and eosinophils ( p  = 0.006) in the asthma group were remarkably higher compared with those of the healthy controls, while the fractions of memory B cells ( p  = 0.018), CD8 T cells ( p  = 0.015), activated memory CD4 T cells ( p  = 0.043), follicular helper T cells ( p  < 0.001), gamma delta T cells ( p  = 0.018), monocytes ( p  = 0.021), M0 macrophages ( p  = 0.006), M1 macrophages ( p  = 0.029), and M2 macrophages ( p  < 0.001) were lower in asthma. Taken together, these results suggest that the heterogeneity of infiltrating immune cells in asthma is evident and may play a role in the pathogenesis of asthma.

figure 3

Landscape of immune infiltration between the asthma and healthy control groups. A The box plot diagram indicates the relative percentage of different types of immune cells in each sample. B The heatmap shows the correlation of infiltrating immune cells. C The violin plot shows the differences of immune infiltration between the asthma (red) and healthy control (blue) groups. D The lollipop chart presents the correlation of TLR7 and infiltrating immune cells on the basis of Spearman correlation analysis results. ( p value < 0.05 indicated statistical significance)

To further investigate the correlation of TLR7 and infiltrating immune cells, Spearman correlation was performed (Table  2 ) and plotted in a lollipop chart (Fig.  3 D) and several scatter charts (Additional file 1 : Fig S4). The results demonstrated that TLR7 was positively correlated with M2 macrophages ( r  = 0.59, p  < 0.001), follicular helper T cells ( r  = 0.46, p  < 0.001), memory B cells ( r  = 0.36, p  < 0.001), CD8 T cells ( r  = 0.32, p  < 0.001), M0 macrophages (r = 0.32, p  < 0.001), M1 macrophages ( r  = 0.28, p  < 0.001), resting memory CD4 T cells ( r  = 0.24, p  < 0.001), and monocytes ( r  = 0.21, p  < 0.01). Meanwhile, TLR7 was negatively correlated with activated dendritic cells ( r  = − 0.52, p  < 0.001), naive CD4 T cells ( r  = − 0.40, p  < 0.001), plasma cells ( r  = − 0.25, p  < 0.001), eosinophils ( r  = − 0.22, p  < 0.01), resting dendritic cells ( r  = − 0.20, p  < 0.01), activated mast cells ( r  = − 0.19, p  < 0.01), activated memory CD4 T cells ( r  = − 0.18, p  < 0.05), and resting NK cells ( r  = − 0.17, p  < 0.05). These results indicate that the core gene TLR7 is closely related to the level of immune cell infiltration and plays a crucial role in the immune microenvironment of asthma.

Validation of TLR7 in a GEO dataset and the diagnostic value of TLR7 for asthma

In the merged dataset, the expression level of TLR7 in the asthma group significantly decreased compared with that of the healthy control group ( p  < 0.001, Fig.  4 A). ROC curve analysis was conducted to evaluate the sensitivity and specificity of TLR7 for the diagnosis of asthma. As shown in Fig.  4 B, the area under curve (AUC) value of TLR7 was 0.799 (95% CI 0.719–0.874). Moreover, the GSE147878 dataset was used to validate the expression and diagnostic effectiveness of TLR7 in asthma. Consistently, the TLR7 expression level in the asthma group of the GSE147878 dataset also significantly decreased ( p  < 0.01, Fig.  5 A), and the AUC value of TLR7 was 0.783 (95% CI 0.645–0.897, Fig.  5 B).

figure 4

TLR7 expression level and its diagnostic value in asthma. A The expression level of TLR7 in the asthma (red) and healthy control (blue) groups in the merged dataset. ( p value < 0.05 indicated statistical significance). B ROC curve analysis of TLR7 in the merged dataset

figure 5

Validation of the expression and diagnostic value of TLR7 in the GSE147878 dataset. A The expression level of TLR7 in the asthma (red) and healthy control (blue) groups in the GSE147878 dataset. ( p value < 0.05 indicated statistical significance). B The ROC curve analysis of TLR7 in the GSE147878 dataset

Validation of TLR7 mRNA expression in induced sputum cells of asthmatic patients

Detection of TLR7 mRNA levels via qRT-PCR showed that TLR7 mRNA levels were significantly downregulated in asthmatic patients compared with those in healthy controls ( p  = 0.0049, Fig.  6 A). The AUC value was 0.7674 (95% CI 0.631–0.904, p  = 0.006) (Fig.  6 B). Our test results are thus consistent with those of the GEO dataset, and TLR7 has a satisfactory diagnostic ability for asthma.

figure 6

Validation of the expression and diagnostic value of TLR7 in asthmatic patients. A TLR7 mRNA expression level in induced sputum cells of asthma. B ROC curve of TLR7 in induced sputum cells

TLR7 mRNA expression is associated with airway eosinophilic inflammation and lung function

We investigated the correlation between TLR7 mRNA expression and clinical indicators such as FeNO, percentage of peripheral blood eosinophils (%), and lung function. The results showed that TLR7 mRNA expression was significantly negatively correlated with FeNO ( r  = − 0.3268, p  = 0.0347) (Fig.  7 A) and percentage of peripheral blood eosinophils (%) ( r  = − 0.3472, p  = 0.041) (Fig.  7 B), and positively correlated with forced expiratory volume in the first second (FEV1) (% predicted) ( r  = 0.3960, p  = 0.0071) (Fig.  7 C) and FEV 1 /forced vital capacity (FVC) ( r  = 0.3213, p  = 0.0314) (Fig.  7 D). These data suggest that TLR7 is involved in the pathogenesis of eosinophilic inflammation and bronchoconstriction in asthmatic patients.

figure 7

Relationship between TLR7 mRNA expression level and clinical parameters. Relationship between TLR7 mRNA expression level in induced sputum cells and A FeNO, B percentage of peripheral blood eosinophils (%), C FEV1 (% predicted), and D FEV1/FVC (%)

Asthma is a common chronic disease [ 2 ]. Induced sputum may have some characteristics as a noninvasive marker of airway inflammation [ 12 ]. The gene expression profile of induced sputum cells is altered in patients with asthma [ 13 ]. In the current study, two datasets (i.e., GSE76262 and GSE137268), including induced sputum samples of 172 asthmatic patients and 36 healthy controls, were combined for analysis. The combat algorithm in “sva” R package was used to eliminate batch effect [ 33 ]. TLR7 was identified as the core gene through the intersection of two different machine learning algorithms (i.e., LASSO regression and SVM-RFE) and the top 10 core networks based on Cytohubba. The immune infiltration analysis results showed that TLR7 is closely related to the level of numerous infiltrating immune cells. Finally, the decreased TLR7 expression levels were validated in induced sputum samples of patients with asthma. The diagnostic value of TLR7 for eosinophilic asthma was evaluated, and its correlation with related clinical indicators was also analyzed.

In the present study, a total of 320 DEGs between the asthma and healthy control groups were obtained. GO and KEGG analyses revealed that DEGs between the asthma and healthy controls were primarily enriched in cytokine–cytokine receptor interaction and immune-related functions, such as immune effector process and immune receptor activity. GSEA is a threshold-free method that analyzes all genes on the basis of their differential expression rank, or other score, without prior gene filtering [ 34 ]. GSEA results coincided with the GO and KEGG results. Moreover, these DEGs were proven to be related to lung diseases, such as asthma, by DO analysis. Furthermore, two machine learning algorithms, the LASSO regression and SVM-RFE, were performed to identify the biomarkers of asthma. The combination of LASSO and SVM-RFE has been applied in previous research to identify diagnostic markers [ 20 , 27 , 28 ]. The traditional PPI network of DEGs was also constructed to identify hub genes. After combining the results of LASSO, SVM-RFE, and hub genes, decreased TLR7 was finally identified as the core gene of asthma.

Toll-like receptors (TLRs) play crucial roles in the recognition of invading pathogens and the immune system. The role of TLR signatures in asthma has been reported by Wu et al. that TLR2/TLR3/TLR4 pathway, MyD88-dependent/independent TLR pathway, positive regulation of TLR4 pathway and TLR binding signatures were correlated with asthma [ 35 ]. TLR7 is an endosomal receptor that recognizes microbial or self-antigen-derived single-stranded RNA ligands [ 36 ]. Currently, TLR7 has been reported to be involved in the pathogenesis of various immunological diseases [ 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. Research reports that TLR7 agonists reduce Th2-mediated airway inflammation, airway hyperreactivity, and chronic airway remodeling in asthma [ 44 ]. Jha A and coworkers also achieved similar results [ 45 ]. TLR7 agonists can increase the expression of interferon and C-C motif chemokine ligand 13 (CCL13) in nasal mucosa of patients with asthma and allergic rhinitis [ 46 ]. Several research findings also revealed that TLR7 regulates RV1b-induced type I and type III interferon signaling pathways in allergic asthma [ 47 ]. TLR7 may confer predisposition to asthma and related atopic diseases [ 48 ]. A significant correlation was found between TLR7 single nucleotide polymorphism (SNP) and childhood asthma [ 49 ]. Furthermore, the expression of TLR7 in the airway of asthmatic mice was significantly decreased, and upregulation of TLR7 was found to inhibit the activation of NF-κB signaling pathway, reduce airway inflammation, inhibit the proliferation of airway smooth muscle cells (ASMCS), and promote apoptosis in asthmatic mice [ 50 ]. Recently, TLR7-nanoparticle adjuvants have been reported to improve the immune response to viral antigens [ 51 ]. TLR7 plays a key role in the pathogenesis of rosacea by activating the NFκB-mTORC1 axis [ 52 ]. Another study also showed that TLR7 expression is decreased in the lungs of patients with severe asthma [ 53 ]. The GSE147878 dataset confirmed that the TLR7 expression level in asthma is also significantly reduced and has good diagnostic value. The expression trend of our test result was consistent the GEO datasets, that is, TLR mRNA expression is significantly decreased in the induced sputum of asthmatic patients and has satisfactory diagnostic ability. TLR7 mRNA expression was significantly negatively correlated with FeNO and percentage of peripheral blood eosinophils (%) and positively correlated with FEV1 (% predicted) and FEV 1 /FVC. We thus inferred that TLR7 is involved in the pathogenesis of eosinophilic inflammation and bronchoconstriction in asthmatic patients.

In addition, immune infiltration analysis in this study demonstrated that the changes of infiltrating immune cells in asthma are evident. Significant differences were observed in the distribution of 13 out of 22 immune cells in asthma. The fractions of dendritic cells and eosinophils in the asthma group were remarkably higher, whereas the fractions of memory B cells, T cells, monocytes, and macrophages were lower compared with those of the healthy controls. Interestingly, TLR7 was also found to be closely related to the level of immune cell infiltration in the current study. Therefore, it could be concluded that TLR7 may play a critical role in asthma by regulating immune cells.

There are also inherent limitations in this study. First, the size of induced sputum samples was not sufficiently large. Further study should include more samples. Second, our sample size was small and we did not compare TLR7 protein levels across different asthma subtypes. Finally, the mechanism by which TLR7 affects eosinophilic asthma was not thoroughly studied. Therefore, further studies are warranted to confirm this mechanism as potential new therapeutic targets of eosinophilic asthma.

In conclusion, this study proved that decreased TLR7 in the induced sputum of eosinophilic asthmatic patients was involved in immune cell infiltration and airway inflammation, which may serve as a new biomarker for the diagnosis of eosinophilic asthma.

Availability of data and materials

The data that support the findings of this study are available in GEO database ( http://www.ncbi.nlm.nih.gov/geo ), reference number [GSE76262, GSE137268 and GSE147878].

Abbreviations

Gene expression omnibus

Differential expression gene

Toll-like receptor 7

Gene ontology

Kyoto Encyclopedia of Genes and Genomes

Gene set enrichment analysis

Disease Ontology

Least absolute shrinkage and selector operation

Support vector machine-recursive feature elimination

Protein–protein interaction

Receiver operating characteristic

Exhaled nitric oxide fraction

Quantitative real‐time polymerase chain reaction

Biological processes

Cellular component

Molecular function

Tumor necrosis factor

Nuclear factor

Janus kinase/signal transducer and activator of transcription

Mitogen-activated protein kinase

Area under curve

Forced expiratory volume in the first second

Forced vital capacity

C-C motif chemokine ligand 13

Single nucleotide polymorphism

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YL and KY conceived and designed the study. They also drafted and critically revised the manuscript. KY collected and analyzed the data for bioinformatic analysis. YL conducted the experiments, performed statistical analysis, and illustrated the results. All authors approved the manuscript’s final version.

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Additional file 1: figure s1..

Flow chart of the study design. Figure S2. Visualization of differentially expressed genes (DEGs). (A) Heatmap showed the expression of DEGs in each sample. (B) DEGs filtered by thresholds were presented in volcano map. Red dots represent upregulated genes and blue dots represent downregulated genes. Figure S3. Functional enrichment analysis of differentially expressed genes (DEGs). (A) GO analysis of DEGs. (B) KEGG analysis of DEGs. Figure S4. Scatter charts of the correlation of TLR7 and infiltrating immune cells. Spearman correlation of the correlation of TLR7 and infiltrating immune cells was performed. The results were presented in scatter charts.

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Yan, K., Liang, Y. Decreased TLR7 expression was associated with airway eosinophilic inflammation and lung function in asthma: evidence from machine learning approaches and experimental validation. Eur J Med Res 29 , 116 (2024). https://doi.org/10.1186/s40001-023-01622-5

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Using AI to identify high risk patients with asthma and COPD

A sthma and chronic obstructive pulmonary disease (COPD) are two of the most common lung diseases worldwide, and exacerbation of these conditions can negatively impact health and increase health care costs. A new study shows that deep learning, a type of artificial intelligence (AI) that uses large amounts of data to process information, can improve detection of patients with these diseases who are at increased risk for multiple hospitalizations.

The study was published Dec. 13, 2023, in the journal Respiratory Research .

In the study, researchers identified electronic health record (EHR) characteristics of severe asthma and COPD exacerbations. They then evaluated four machine learning models and one deep learning model in predicting hospital readmissions using EHR data. The researchers found that multilayer perceptron, a deep learning method, had the best performance.

The findings show that AI can play a role in helping pulmonologists develop new classifications for asthma, COPD, and other conditions, said Jose Gomez-Villalobos, MD, associate professor of medicine and director of the Center for Precision Pulmonary Medicine (P2MED) in the Section of Pulmonary Critical Care and Sleep Medicine (Yale-PCCSM) at Yale School of Medicine.

"The implementation of these methods can help us identify groups of patients who may benefit from specific treatments or who have characteristics that are not always obvious to the clinician," Gomez-Villalobos said. "If we know which patients have increased needs or can benefit from targeted therapies, we can reduce their likelihood of needing to return to the hospital."

Most importantly, the study highlighted significant racial and ethnic disparities in the burden of these disease exacerbations, Gomez-Villalobos noted. "Minority groups are disproportionately affected by these hospitalizations," he said.

The new tools are an important step in ensuring that patients receive the best care possible, said Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals, Inc. Professor of Medicine and chief of Yale-PCCSM. "Incorporating deep learning and AI into clinical practice can help prioritize care for vulnerable individuals with respiratory disease, and I am proud of the groundbreaking progress our P2MED researchers are making towards this goal," he said.

As pulmonologists work to improve the management of asthma and COPD, Gomez-Villalobos envisions applying computational methods and AI to tailor interventions, improving outcomes for patients from minority and other groups who may be at high risk. The new knowledge will decrease events that cause patients to go to the emergency room or hospital—an expensive and intense use of resources, he said.

"The power of these neural networks—or AI—is that they enable us to synergize and transform what we do as clinicians to achieve better outcomes for all patients," he said.

More information: Kevin Lopez et al, Deep learning prediction of hospital readmissions for asthma and COPD, Respiratory Research (2023). DOI: 10.1186/s12931-023-02628-7

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A Receiver operating characteristic (ROC) curves of four machine learning models and a deep learning model to predict readmissions in the combined cohort (n = 2682) of asthma (n = 777) and COPD (n = 1905). B Precision-recall (PR) curves of five machine learning models implemented in the combined cohort. C SHapley Additive exPlanation (SHAP) values of the top 10 predictive features of the multilayer perceptron (MLP) model implemented in the combined cohort. Credit: Respiratory Research (2023). DOI: 10.1186/s12931-023-02628-7

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Impact of Air Pollution on Asthma Outcomes

Angelica i. tiotiu.

1 Department of Pulmonology, University Hospital of Nancy, 54395 Nancy, France

2 Development of Adaptation and Disadvantage, Cardiorespiratory Regulations and Motor Control (EA 3450 DevAH), University of Lorraine, 54395 Nancy, France

Plamena Novakova

3 Clinic of Clinical Allergy, Medical University, 1000 Sofia, Bulgaria; moc.oohay@anemalpn

Denislava Nedeva

4 Medical University Sofia, 1000 Sofia, Bulgaria; [email protected]

Herberto Jose Chong-Neto

5 Division of Allergy and Immunology, Department of Pediatrics, Federal University of Paraná, Curitiba 80000-000, Brazil; [email protected]

Silviya Novakova

6 Allergy Unit, Internal Consulting Department, University Hospital “St. George”, 4000 Plovdiv, Bulgaria; moc.oohay@66avokavon

Paschalis Steiropoulos

7 Department of Respiratory Medicine, Medical School, Democritus University of Thrace, University General Hospital Dragana, 68100 Alexandroupolis, Greece; moc.oohay@soluoporiets

Krzysztof Kowal

8 Department of Allergology and Internal Medicine, Medical University of Bialystok, 15-037 Bialystok, Poland; lp.ude.bmu@dmklawok

Asthma is a chronic respiratory disease characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Evidence suggests that air pollution has a negative impact on asthma outcomes in both adult and pediatric populations. The aim of this review is to summarize the current knowledge on the effect of various outdoor and indoor pollutants on asthma outcomes, their burden on its management, as well as to highlight the measures that could result in improved asthma outcomes. Traffic-related air pollution, nitrogen dioxide and second-hand smoking (SHS) exposures represent significant risk factors for asthma development in children. Nevertheless, a causal relation between air pollution and development of adult asthma is not clearly established. Exposure to outdoor pollutants can induce asthma symptoms, exacerbations and decreases in lung function. Active tobacco smoking is associated with poorer asthma control, while exposure to SHS increases the risk of asthma exacerbations, respiratory symptoms and healthcare utilization. Other indoor pollutants such as heating sources and molds can also negatively impact the course of asthma. Global measures, that aim to reduce exposure to air pollutants, are highly needed in order to improve the outcomes and management of adult and pediatric asthma in addition to the existing guidelines.

1. Introduction

Air pollution can be defined as the presence in the air of substances harmful to humans and is associated with a high risk for premature deaths due to cardio-vascular diseases (e.g., ischaemic heart disease and strokes), chronic obstructive pulmonary disease, asthma, lower respiratory infections and lung cancer [ 1 , 2 ]. People living in developing and overpopulated countries disproportionately experience the burden of outdoor (ambient) air pollution with 91% of the 4.2 million premature deaths in 2016 occurring in low- and middle-income countries of the South-East Asia, Central Africa and Western Pacific regions where exposure is higher [ 1 , 3 ]. The quality of air has been improving in the developed countries, however air pollution is steadily rising in the developing ones [ 4 ]. In order to quantify air pollution, standards of air quality for different pollutants were developed by the World Health Organization (WHO). The data from WHO indicate that 9 out of 10 people breathe air containing high levels of pollutants. More than 80% of people living in urban areas, where air pollution is monitored, are exposed to air pollutant levels that exceed WHO guideline limits. In addition, approximately 3 billion people are exposed to high levels of indoor (household) air pollution due to the use of biomass, kerosene fuels and coal for cooking and the heating of their homes, inducing a high prevalence of respiratory disorders [ 5 ].

Although there are many natural sources of air pollution such as volcanos or wildfires, it was the industrial revolution that made air pollution a real global problem [ 1 ]. Ambient air pollution affects the quality of indoor air and vice versa. According to the particle size, pollutants can be categorized as gaseous and particulate matter (PM) [ 6 ]. The main gaseous pollutants include inorganic components such as nitrogen dioxide (NO 2 ), sulphur dioxide (SO 2 ), ozone (O 3 ), carbon monoxide (CO), carbon dioxide (CO 2 ) and heavy metals such as lead or chromium (Pb or Cr), as well as volatile organic compounds (VOCs) including polycyclic aromatic hydrocarbons (PAHs). Some of them, for example NO 2 or SO 2 , are directly produced by different pollution sources while others, i.e., O 3 are formed by the interaction of nitric oxides and VOCs with the sunlight. The pollutants with the greatest impact on humans health are PM, which are commonly used as a measure of air quality [ 6 , 7 ]. Traffic-related air pollution (TRAP), a complex mixture rich in PM, exerts a particularly deleterious effect on the function of the respiratory system [ 5 ].

Asthma is a chronic inflammatory airway disease characterized by respiratory symptoms such as wheeze, dyspnoea, cough and chest tightness asssociated with variable expiratory airflow limitation. The prevalence of asthma is estimated at between 1 and 18% of the population in different countries. Evidence suggests that 13% of global incidence of asthma in children could be attributable to TRAP and data showed that air pollution has a negative impact on asthma outcomes in both adult and pediatric populations [ 8 ].

The aim of this review is to summarize the recent data about the effects of various outdoor and indoor pollutants on asthma development, symptoms, exacerbations/hospitalisations, severity, lung function and medication use, as well as to highlight the possible measures that could reduce their impact on asthma outcomes. A better knowledge of the negative impact of air pollution on asthma outcomes could help physicians (e.g., general practitioners, pulmonologists, allergologists, pediatrics, gynecologists, and emergency doctors) to improve their daily practice by adding in the interrogatory specific questions on a possible recent exposure worsening the respiratory symptoms, to educate the patients about how they could minimise the exposure and manage their asthma by an action plan. At the same time, the global awareness of air pollution effects on asthma should stimulate public health authorities and governments to take more efficient measures to limit the exposure to air pollutants.

2. Search Strategy, Data Sources and Selection Criteria

This review examines the literature linking air pollution and asthma across PubMed and Medline databases from January 1, 2010 and June 30, 2020. The search terms used were: “air pollution”, “outdoor air pollutants”, “indoor air pollutants”, “environmental risk factors”, “ambient sources of pollution”, “household sources of pollution”, “smoking”, and “preventive measures to reduce air pollution” associated with “asthma”. We prioritized cross-sectional and observational studies, followed by meta-analyses, systematic reviews, and general reviews. A preference was given to more recent articles published the last five years in order to have the most up-to-date evidence. Results were limited to publications in English.

3. Air Pollution and Risk of Asthma

The effect of air pollution on the development of asthma has been studied for many years. Increasing evidence indicates that both outdoor and indoor air pollution contributes to asthma development. Numerous cross-sectional studies provided evidence for an association between poor air quality and the incidence of asthma [ 9 , 10 , 11 , 12 , 13 ]. One of those studies, conducted in an urban population, demonstrated that the association between asthma morbidity and air pollutions was stronger in children than in adolescents and adults [ 10 ]. The important role of increased exposure to TRAP, particularly to its components PM 2.5 , PM 10 , NO 2 and black carbon, in asthma development was demonstrated in a recent meta-analysis of 41 publications [ 14 ]. Those observations are supported by longitudinal studies evaluating the relationship between early childhood exposure to ambient air pollution and future asthma incidence. A meta-analysis of published birth cohort studies reported significant associations between long-term exposure to black carbon and PM 2.5 and the risk of asthma in childhood up to 12 years of age [ 13 ]. The interaction between air pollution exposure in early life and asthma development was demonstrated in a prospective study on the cohort Prevention and Incidence of Asthma and Mite Allergy (PIAMA). Both early and recent exposures to PM 2.5 , PM 10 or NO 2 , especially TRAP, were associated with a higher incidence of asthma until age of 20 years [ 15 ]. Another large population-based birth cohort study found a positive association between perinatal exposure to air pollution and asthma incidence during preschool years [ 16 ]. A recently published birth cohort study including 184,604 children born between 2004 and 2011 in Taiwan demonstrated that both prenatal and postnatal exposures to air pollutants, in particular PM 2.5 , were associated with later development of asthma [ 17 ]. The role of prenatal exposure to air pollutants in childhood asthma development was also shown in two independent meta-analyses [ 18 , 19 ]. The long-term effects of air pollution on asthma have been summarized in an American Thoracic Society Workshop Report, which indicates that the available evidence indicates that long-term exposure to air pollution was a cause of childhood asthma, but the evidence for a similar determinant role for adult asthma remained insufficient [ 20 ]. Some studies also provided evidence for positive associations between indoor air pollution, mainly due to cooking with polluting fuels, and asthma development in children. In a meta-analysis of 41 studies, a positive association between gas cooking, exposure to NO 2 , and childhood asthma or wheeze was found [ 21 ].

Second-hand smoking (SHS) was also reported to play an important role in asthma development. However, it is plausible that gene–environment interaction is also important for the effects of air pollution on asthma development. It has been shown recently that exposure to PM 10 and maternal smoking was associated with a higher susceptibility for infants with an adverse genetic predisposition to asthma that also depended on the infant’s ancestry [ 22 ]. Genetic traits that affect the risk of asthma due to SHS were also demonstrated in American children participants in the Cincinnati Childhood Allergy and Air Pollution Study. Variation in the N-Acetyltransferase 1 (NAT1) gene modified asthma risk in children exposed to SHS [ 23 ]. Systematic reviews and meta-analyses have demonstrated that maternal smoking during pregnancy is a risk factor of wheezing and asthma in children, especially in the first years of life [ 24 , 25 ]. The mechanisms behind the adverse health effects of maternal smoking during pregnancy are still not entirely clear, but epigenetics most likely plays a role [ 26 ]. Associations between deoxyribonucleic acid (DNA) methylation at loci previously linked to in utero tobacco smoke exposure and asthma-related outcomes were observed [ 27 ]. Grandmothers smoking during pregnancy with the mother, increases the risk for asthma in the grandchild, independently of the mother’s smoking status, suggesting a transgenerational impact of prenatal tobacco smoke exposure on asthma development [ 28 , 29 ]. Prenatal paternal smoking exposure was also associated with childhood asthma development at 6 years of age, presumably mediated by an IgE-independent mechanism. Prenatal paternal smoking led to epigenetic modifications in certain genes as such as LIM Domain Only 2 (LMO 2 ) and interleukin-10 (IL-10) via cytosine-phosphate-guanine (CpG) methylation, and these modifications are correlated to childhood asthma development [ 30 ].

Postnatal exposure to maternal and paternal smoking is also associated with wheezing in infants and pre-school children, while the data for school-aged children and adolescents are contradictory [ 24 ]. One of the limitations related to the investigation of the effect of postnatal exposure is the fact that most of the parents smoke during both the prenatal and postnatal periods, and studies on solely postnatal exposure lack consistency. A recent study showed that fathers’ smoking before the age of 15 of their children increased the risk of asthma without nasal allergies in their offspring, suggesting an effect of paternal pre-adolescent environment on the next generation [ 29 ].

Less data is available for maternal smoking and adult onset asthma. A recent study found that gestational tobacco smoke exposure is associated with new asthma diagnoses in adult offspring between 31 and 46 years, thus indicating the long-term effect of smoking. The association was accentuated in offspring who reported at age 31 as having past respiratory problems (wheeze) [ 31 ]. In addition, a reduction in forced expiratory volume in the one second (FEV 1 )/forced vital capacity (FVC) ratio was observed at age 31 years in the offspring with gestational smoke exposure [ 29 ]. Several longitudinal studies showed a positive association between active and passive smoking and the incidence of asthma in adults [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Women seem to be more susceptible to the effect of tobacco smoking than men [ 34 , 40 ]. Some of the studies suggested a stronger association between smoking and onset of asthma for non-atopics [ 35 , 37 ]. Other trials did not find any relation between smoking and newly onset asthma in the adult population [ 41 , 42 , 43 ]. A possible explanation of the inconsistencies between the results could be the different definitions of asthma that were used, self-reported questionnaires and evaluation, changes in tobacco smoking habits during the follow-up period and the ‘healthy smoker effect’ (reduces smoking initiation or favors smoking cessation among people more susceptible to the noxious effects of smoking) [ 44 ]. Current evidence is suggestive but not sufficient for a causal relationship between smoking and the incidence of asthma in adults and future research is needed in this domain.

4. Outdoor Air Pollution

The composition of outdoor air pollution is complex and dynamic. It changes from season to season, and is influenced by human activity and meteorological events [ 45 ]. Outdoor air pollutions include both primary pollutants emitted directly into the atmosphere and secondary pollutants formed in the air from chemical transformation of the primary. These chemical reactions depend on temperature and therefore can be influenced by global climate warming. Accumulated evidence suggested that air pollution cannot only aggravate asthma symptoms but might cause new-onset asthma as well. Several mechanisms have been identified and implicated. The respiratory mucosa formed by the airway epithelium represents the first contact between air pollutants and the respiratory system, functioning as a mechanical and immunologic barrier. Airway epithelial cells are connected by tight junctions and secrete mucus, host defense peptides and antioxidants, and express innate immune receptors, which could be activated by inhaled foreign substances and pathogens [ 45 ]. Under conditions of air pollution exposure, the defenses of the airway epithelium are compromised by the disruption of epithelial integrity, uptake of particles, activation of Toll-like and Nucleotid-binding Oligomerization Domain (NOD-receptors), epithelial growth factor receptor and induction of oxidative stress. Activation of these receptors results in (NF)-kB (nuclear factor Kappa B) activation, leading to pro-inflammatory cytokine expression [ 46 ]. Oxidative stress is one of the biological mechanisms proposed to partly explain the association between outdoor air pollution and asthma. Neutrophils attracted into the airways after exposure to certain pollutions produce reactive oxygen species (ROS) that induce epithelial cell inflammation, airway hyperreactivity (AHR) and lung injury. Pollutants can act directly by the production of free ROS and diffusion from the airway surface, or indirectly by inducing inflammation. Ozone (O 3 ) exposure causes ROS production and changes in the expression of claudins, the major components of tight junctions, thus leading to tight junction barrier permeability and AHR [ 47 ].

Importantly, pollutants (e.g., O 3 , SO 2 ) can act as adjuvants and affect the production of some cytokines (e.g., thymic stromal lymphopoetine) in airway epithelial cells, which promote T-helper 2 (Th2) phenotypic differentiation and IgE production. There is evidence for the stimulation of T-helper 17 (Th17) responses as well. Furthermore, repeated exposure to O 3 induces group 2 innate lymphoid cells (ILC2)-mediated airway type 2 immunity and the nonatopic asthma phenotype [ 20 ]. Numerous studies have repeatedly demonstrated epidemiological links between air pollution and increased respiratory tract infections in patients of all ages, which are considered the cause of asthma exacerbations. Changes in receptor expression for pathogens, antiviral mechanisms, or host defense peptide biology could be responsible. Oxidative stress could affect intercellular adhesion molecule-1 (ICAM-1) responses to rhinoviruses in epithelial cells of the respiratory mucosa. Coexposure of airway epithelial cells to rhinoviruses and NO 2 appears to induce a synergistic upregulation of ICAM-1, which could exaggerate the pathogen response. Available data indicated that oxidant pollutants (NO 2 or O 3 ) could amplify the generation of proinflammatory cytokines by rhinovirus-infected cells in epithelial cells of the respiratory mucosa. Oxidative stress has also been linked to a reduction in corticosteroid (CS) responsiveness in asthma patients, an important observation from a practical point of view [ 48 ].

One predisposing factor that contributes to the injury of airways by air pollutants might be atopy. Conversely, air pollutants could increase the risk of sensitization and the responses to inhaled allergen in asthma patients. Such a potential enhancing effect has been studied and demonstrated for O 3 , NO 2 , SO 2 . The mechanisms that could explain the enhanced sensitisation to aeroallergens by air pollutants include the higher deposition of allergen in the airways due to carriage by particles, an increased epithelial permeability due to oxidative stress, a greater antigenicity of proteins, and a possible direct adjuvant effect [ 49 ]. Apparently, the responses to air pollutants are diverse and individual. Genetic variations affect the function and susceptibility of epithelial cells. Specific polymorphisms in antioxidant enzyme genes, such as the glutathione-S-transferase family, especially Glutathione S-Transferase Pi 1 (GSTP1), are associated with differences in susceptibility to the adverse effects of pollutants and can modify the risk of asthmatic responses. Adults and children with Glutathione S-Transferase Mu 1 (GSTM1) null genotypes have reduced glutathione-S-transferase enzyme activity and are at increased risk of developing asthma when exposed to O 3 . The association of tumor necrosis factor (TNF) polymorphisms with asthma and differences in susceptibility to the adverse effects of pollutants has been demonstrated. TNF polymorphisms, thought to affect the expression of pro-inflammatory cytokines, seem to influence the response of the lungs to O 3 , and the risk of developing asthma [ 50 ]. Results from a recent genome-wide interaction study identified gene–NO 2 interactions on asthma and indicated that gene–environment interactions are important for asthma development [ 51 ]. Mucin gene variants contribute to air pollutant responses in asthmatic patients. Their role in air pollution-induced mucin production has been demonstrated [ 52 ].

The impact of air pollution on asthma could by modified by other individual factors like obesity, as reported in most studies. A large cross-sectional study found that the effect of NO 2 and SO 2 on asthma was significantly greater in overweight or obese children. Similarly, the exposure to O 3 is associated with a poorer lung function for obese adults when compared to people with a normal weight [ 53 ].

In the troposphere, O 3 is a secondary pollutant generated through a chemical reaction between oxides of nitrogen and Volatile Organic Compounds (VOCs) released by natural sources or following anthropogenic activities in the presence of sunlight. Other involved elements are CO and methane [ 54 ]. The combustion of fossil fuels, emissions from industrial facilities and electric utilities, gasoline vapors, motor vehicle exhaust and chemical solvents are among the main sources of O 3 precursors. Anthropogenic emissions were responsible for 37% of O 3 impacts in 2015 globally [ 55 ]. Due to its low water-solubility, O 3 is not effectively removed by the upper respiratory tract and has the capacity to penetrate deeply into the lungs [ 7 ].

It is well established that inhaled O 3 first interacts with antioxidants in the airway epithelial cells. Surfactant protein D in particular has been shown to modulate the response to O 3 and appears to have important genetic variability that influences personal susceptibility [ 56 ]. When the dose of O 3 in the respiratory tract exceeds the protective capacity of antioxidants, adverse health effects are likely to occur. The oxidative stress induced by the secondary oxidation results in airway inflammation, AHR, and decrements in lung function in asthmatic adults. As a highly reactive gaseous pollutant, O 3 exerts inflammatory effects on the respiratory system. The oxygen radicals evoke oxidative stress and airway inflammation, more pronounced among allergic subjects [ 57 ].

Personal short-term exposure to O 3 increases the risk of current asthma with persistent evidence that it could directly cause asthma exacerbation [ 58 , 59 ]. Increased rates of asthma hospital admissions and emergency department visits following days of elevated ambient O 3 concentrations have been reported in some epidemiology studies. The consequences of short-term O 3 exposure have been evaluated in meta-analysis of 47 eligible studies published recently, which confirmed the association between O 3 exposure and asthma exacerbations measured as emergency room visits or hospitalizations. The association was significant during the warm season and in the areas where ambient O 3 concentrations were higher [ 60 ]. As estimated recently, 9–23 million annual asthma emergency room visits globally in 2015 could be attributable to O 3 , representing 8–20% of the annual number of global visits [ 53 ]. Children appeared to be more susceptible to O 3 . This may be due to children’s higher breathing rate, narrower airways, lungs and immune system still being in development, and more frequent outdoor activities. Results from time series analysis of asthma hospital admissions and daily 8-h maximum O 3 concentrations established significant relationships for all ages with the highest risk for children [ 61 ].

Strong evidence of a relationship between long-term O 3 exposure and respiratory morbidity is provided by studies focused on asthma development in children and on increased respiratory symptoms in asthmatics. It was demonstrated that exposure to O 3 in early life was significantly and positively associated with a detrimental effect on the lung function development in children, larger in boys. Nevertheless, no clear and consistent findings have been reported for the long-term effects on lung function [ 54 ]. Prenatal exposure to O 3 has not been associated with subsequent childhood asthma [ 18 ]. O 3 might be an important risk factor affecting the progression of asthma to chronic obstructive pulmonary disease (COPD), defining the asthma–COPD overlap (ACO) syndrome. It was established that individuals with asthma exposed to higher levels of O 3 had greater odds of developing ACO [ 62 ]. Long-term O 3 exposure is significantly associated with the risk of death, especially for cardiovascular and respiratory diseases. A study compared daily O 3 concentrations to the daily number of deaths in an urban European population during 3-years. An increase in O 3 concentration was observed during the warm period of the year, and was associated with an increase in the daily number of deaths (0.33%), notably respiratory deaths (1.13%). No effect was observed during wintertime [ 7 ].

4.2. Nitrogen Dioxide

NO 2 is a traffic-related pollutant, as it is emitted from automobile motor engines. Transportation can contribute up to 80% of ambient NO 2 , so it is a convenient marker of primary pollutant. NO 2 is an irritant of the respiratory system, which penetrates deep into the lung, inducing coughing, wheezing, dyspnea, bronchospasm, and even pulmonary edema when inhaled at high levels. It seems that concentrations of over 0.2 parts per billion (ppb) produce these adverse effects in humans, while concentrations higher than 2.0 ppb affect T-lymphocytes, particularly the CD8+ cells and natural killer (NK) cells involved in different immune responses [ 7 ]. It can augment the degree of allergic airway inflammation and prolong allergen-induced AHR. Compared with its direct effects on the airways, NO 2 might play a more prominent role as a sensitizing agent to inhaled allergen. Exposure to 0.4 ppm NO 2 for 4 h enhances both immediate- and late-phase responses to inhaled allergen, and can activate NF-κB, and develop allergen sensitization. High exposure to NO 2 during the first year of life was associated with increased risk of sensitization to pollens at age 4 years [ 63 ]. Meta-analysis provided evidence for association between NO 2 exposure during pregnancy and differential offspring DNA methylation in mitochondria-related genes. Exposure to NO 2 was also linked to differential methylation as well as the expression of genes involved in antioxidant defense pathways [ 64 ].

NO 2 is associated with significant morbidity in asthmatic individuals and might be a cause of incident asthma. Consistent with other studies that found associations between prior pollution exposure and future asthma risk, a recent study revealed that the odds of future asthma diagnosis for children exposed to a high concentration of NO 2 in early life were 1.25 times greater than those for children exposed to a low concentration of NO 2 [ 65 ]. A recent estimation on the basis of data from 194 countries concluded that, each year, 4.0 million (95% CI 1.8–5.2) new cases of paediatric asthma might be attributable to NO 2 pollution, accounting for 13% (5.8–16) of global incidence. This contribution exceeded 20% of new asthma cases. The European analysis subset reported in the same paper estimated that 17% of the burden in Western Europe, 14% in Central Europe and 17% in Eastern Europe was attributable to NO 2 . About 92% of paediatric asthma incidence attributable to NO 2 exposure occurred in areas with annual average NO 2 concentrations lower than the WHO guideline of 21 ppb [ 66 ]. The longest longitudinal study of the health of school-aged children in Canada with >17 years of follow-up found that exposure to total oxidants (O 3 and NO 2 ) at birth increased the risk of developing asthma by 17% [ 67 ]. A recent meta-analysis, using observational data from five European birth cohorts, found no evidence suggesting that long-term air pollution levels including NO 2 were associated with the prevalence of current pediatric asthma up to age eight years [ 68 ]. Compliance with the NO 2 WHO air quality guidelines was estimated to prevent 2434 (0.4% of total cases) incident childhood asthma cases per year across eighteen European countries [ 11 ].

Studies in children and adults have identified associations between even low-levels of NO 2 and symptoms of asthma, reduced lung function, and exacerbation of asthma. Data from several cross-sectional studies and from a meta-analysis of published studies evaluated the association between air pollution and lung function in children. NO 2 exposure was correlated with an increase of fractional exhaled nitric oxide (FeNO) and a delayed increase in both FEV 1 and FVC [ 69 , 70 ]. Even during pregnancy, NO 2 exposure could impair lung function in early life [ 71 ]. A systematic review showed a significant association between NO 2 exposure and moderate/severe asthma exacerbations in children and adults (OR: 1.024; 95% CI [1.005, 1.043]) [ 72 ].

4.3. Carbon Monoxide and Carbon Dioxide

CO and CO 2 are produced by fossil fuel when combustion is incomplete. Higher temperatures and amounts of CO 2 in the atmosphere are major factors that have been linked to an increased duration of pollen seasons, quantity of pollen produced by plants, and possibly allergenicity of pollen. It has been demonstrated that birch pollen extracts from trees grown in warmer temperatures had stronger IgE binding intensity. Enhanced ragweed pollen production as a function of increasing CO 2 levels has also been established. The growth of Alternaria species can become more abundant and produce more allergens in an enhanced CO 2 environment. These changes could affect allergic asthma. A potential link with thunderstorm-related asthma epidemics could be suspected [ 73 ].

Evidence suggests an association between exposure to CO and moderate or severe asthma exacerbations in adults (OR: 1.045; 95% CI: [1.005, 1.086]), but the link was not confirmed in children. Significant associations were observed between decreasing death rates of asthma and lower CO levels [ 72 ].

4.4. Sulfur Dioxide

SO 2 is released primarily from the combustion of sulfur-containing coal and oil. People prone to allergies, especially allergic asthma, can be extremely sensitive to inhaled SO 2 . The major health problems associated with SO 2 are bronchitis, mucus production, and bronchospasm. It is an irritant that penetrates deep into the lung where is converted into bisulfite and interacts with sensory receptors, causing bronchoconstriction [ 5 ]. In response to SO 2 , asthmatic subjects experience increased symptoms and a greater decrease in lung function at lower concentrations compared with non-asthmatics, who are often unresponsive at concentrations of less than 5 ppm. Considerable individual variations in the spirometric response to inhaled SO 2 have been noticed, suggesting a potential genetic link. Children with a particular polymorphism in the TNF-α gene had more significant reductions in lung function after SO 2 exposure [ 74 , 75 ].

A significant association between SO 2 and both asthma prevalence and current symptoms among children, especially in those with atopy, has already been established. Decreased lung function and increased hospital admissions with enhanced SO 2 exposure have been documented in pediatric populations. Even the low-dose SO 2 exposure is associated with a decline in lung function (FEV 1 and FVC) among the general population [ 76 ]. A systematic review showed a significant relationship between SO 2 and moderate/severe asthma exacerbations in children aged 0 to 18 years (OR: 1.047; 95% CI: [1.009, 1.086]) but not in adults [ 72 ].

4.5. Particulate Matter

PM is a complex heterogeneous mixture of dirt, soot, smoke and liquid droplets from both natural and man-made sources. PM ambient air pollution is responsible for approximately 0.8 million premature deaths per year and 6.4 million years of life lost [ 77 ]. It was also estimated that PM 2.5 was responsible for around 16 million incident cases of childhood asthma every year. Although particles are detected in many organs, the respiratory system is usually the first line of entry into the body. PM penetrates deeply into the lungs and increases the frequency and severity of asthma attacks, exacerbating bronchitis and other lung diseases [ 55 ].

Sources of PM could be natural or anthropogenic. The former include wind-blown dust, sea salt, volcanic ash, pollens, fungal spores, soil particles, the products of forest fires and the oxidation of biogenic reactive gases. Anthropogenic emissions of PM derive from industrial processes, construction work, mining, cigarette smoking, fossil fuel combustion and wood stove burning. The main sources of PM in the urban areas are road traffic as well as the burning of fossil fuels in power stations [ 74 , 78 ].

Depending on the way it is released into the environment, PM could be primary or secondary. Primary particles are introduced into the atmosphere directly from their sources (road transport, combustion as well as the land and sea through soils carried by the wind), whereas secondary PM is a product of chemical reactions among different primary particulates. The difference between these two types of PM is the length of stay in the atmosphere—it takes more time for the secondary PM to be formed and therefore its persistence is prolonged [ 78 ].

The size of PM is of vital importance since it determines, to a great extent, its impact on respiratory health and the penetration degree in the human respiratory system. According to its diameter, PM could be divided into three categories: coarse PM 10 (from 2.5 to 10 μm), fine PM 2.5 (from 0.1 to 2.5 μm), ultrafine PM 0.1 (UFPs) (less than 0.1 μm). Coarse PM deposits primarily in the nasopharynx or primary bronchi; fine PM in the alveoli and terminal bronchioles; UFPs cross cell membranes and interact directly with cellular structures. The greatest number of particles fall into the ultrafine size range. UFPs have a detrimental effect on human health because their small size allows the greatest lung penetration and passage across the air–blood barrier [ 6 , 7 , 78 ].

Inhaled PM has the capacity to elicit lung oxidative stress as well as to interact with different components of the immune system and enhance allergic inflammatory response. What is more, not only do the particles infiltrate the circulatory system through layers of alveolar obstruction, but they can also absorb many airborne toxic substances on their surface, such as heavy metals, PAHs and organic/inorganic ions. It has been suggested that PM induces oxidative stress through several different mechanisms. Firstly, the redox cycle of some components of the particle’s surface, like iron or quinones, leads to the formation of ROS, hydrogen peroxide and the damaging hydroxyl radical in the lungs. Secondly, bacterial endotoxins associated with the particle surface can trigger inflammation. The particle surface itself has also been found to cause oxidative stress in vivo but this effect is not well defined yet [ 78 ]. PM enhances airway inflammation by interacting with the innate and adaptive immune system. It was suggested that PM activates neutrophils and eosinophils through increased levels of proinflammatory cytokines. PM induces antigen-presenting cell-mediated inflammatory responses as well as an imbalance of Th cells with an increase in Th2 and Th17 cells and downregulation of T-helper 1 (Th1). Exposure to PM could also lead to apoptosis and autophagy in lung epithelial cells in asthma. What is more, UFPs cross cell membranes and directly interact with cellular structures. UFPs escape the mucociliary clearance and the ingestion by alveolar macrophage scavenging [ 79 ]. A study of Mills et al. demonstrated that UFPs were detected in the blood immediately after inhalation and remained in the lungs for up to 6h after installation. Therefore, UFPs can induce severe eosinophilic inflammation, alveolar macrophage chemotaxis and epithelial damage in asthma [ 80 ].

The respiratory health effects of short-term exposure to air pollution include worsening of asthma symptoms, school absences, emergency department visits, hospitalizations and decreased lung function. Despite the limited available data, there is growing evidence about a possible impact of long-term outdoor air pollution exposures and asthma incidence. The American Thoracic Society Workshop Report revealed a strong correlation between childhood asthma and long-term air pollution exposure, especially to TRAP. PM 2.5 was found to induce airway remodeling and an increase in the incidence/severity of asthma-like phenotypes [ 20 ]. Particulate pollution might be a risk factor for the progression of asthma to ACO. The Canadian Community Health Survey found that asthmatics exposed to higher levels of PM 2.5 had nearly three-fold greater odds of ACO [ 62 ]. It was also demonstrated that PM increases the rate of emergency room visits due to asthma exacerbations in both adults and children. A study of Anenberg et al. concluded that 5–10 million annual asthma emergency room visits globally (4–9%) could be attributable to PM 2.5 [ 55 ]. A significant correlation was found between increased asthma emergency room visits in adults and high PM 2.5 concentrations, especially in the warm seasons [ 81 ]. It was also demonstrated that PM 10 was a statistically significant risk factor for a 2% increase in the number of asthma-related emergency visits in children [ 82 ]. A recent meta-analysis revealed that UFP exposure increased the number of asthma exacerbations, subsequent emergency room visits and hospital admissions in children [ 83 ]. In contrast, the exposure to PM attributable to landscape fire smoke (PM LFS ) seems to be associated with a higher risk for emergency department visits for the elderly compared to children. A meta-analysis showed that emergency department attendance increases with a 10μg/m 3 PM 2.5LFS of 15% for elderly (95% CI [1.1–1.2]) vs 4% (95% CI [1–1.08]) for children [ 84 ]. The risk is greatest on the day of exposure to PM LFS (an increase in emergence department attendances for asthma by 1.96% [95% CI: 0.02, 3.94]) and for women 20 years and older (5.08% 95% CI [1.76, 8.51]). [ 85 , 86 ].

There is growing evidence that PM exposure could be associated with impaired asthma control. A study found a correlation between poor asthma control, elevated PM 2.5 and pollen severity in a pediatric population [ 87 ]. A cohort study of 32 asthmatic adult patients revealed that a 10 mg/m 3 increase in PM 10 personal exposure was associated with an increase in Saint George Respiratory Questionnaire scores and a decrease in Asthma Control Test scores [ 88 ].

PM exposure might be an important risk factor for lung function deterioration in both children and adults with asthma. An association between the fall of the FEV 1 /FVC ratio and air pollution was found in a cohort study by Yu et al. Acute exposure to PM 10 in non-smoking adults with refractory asthma correlated with a 0.4% drop in the FEV 1 /FVC ratio in the spring [ 89 ]. A longitudinal analysis showed that an increase in PM 10 concentration was associated with increased peak expiratory flow (PEF) variability of >20% and a decrease in the mean PEF among 64 adults with asthma [ 90 ]. It was also found that an increase of 10 μg/m 3 in 24-h mean PM was associated with a drop of 3 L/min in PEF in children hospitalized for severe asthma exacerbations [ 91 ].

4.6. Outdoor Air Pollution and Asthma Outcomes

Many studies have demonstrated so far a clear association between short-term exposure to outdoor air pollutants and different asthma outcomes including asthma control [ 87 ], lung function [ 92 ], consumption of asthma medications [ 93 , 94 ], outpatient visits [ 95 , 96 ], asthma exacerbations [ 97 , 98 ], emergency room visits [ 99 ], hospitalizations [ 100 , 101 ], length of stay in the hospital [ 102 ] and deaths [ 2 ]. Several air pollutants have been implicated in the loss of asthma control. It seems that TRAP plays a particular role in this process because associations of asthma outcomes with outdoor air pollution were enhanced among subjects living in homes with high TRAP [ 9 ]. A study found that TRAP was associated with increased risk of hospitalizations due to asthma exacerbations in a population of 0–14 years of age children in California [ 100 ].

On the other hand, some air pollutants are associated with asthma morbidity independent of their source. In one study, exposure to outdoor PM 2.5 was significantly associated with an increased number of emergency room visits due to asthma and the effect was independent of the source of PM 2.5 [ 99 ]. An analysis of 3520 cases of acute asthma exacerbation indicated a positive association with the concentration of PM 2.5 in the outdoor air and the association remained significant after adjusting for gaseous co-pollutants [ 97 ]. Several meta-analyses have been performed in order to single out those components responsible for asthma exacerbations. A meta-analysis of 26 studies conducted worldwide found a 4.8% increase in the risk of asthma-associated emergency department visits and admissions among children exposed to short-term increases in PM 2.5 of 10 μg/m 3 , with greater effects in Europe and North America than in Asia [ 103 ]. In children, the association between NO 2 , SO 2 , and PM 2.5 exposures and asthma exacerbations, as well between all outdoor pollutants and hospital admissions, were confirmed by two meta-analyses [ 72 , 104 ].

The effect of outdoor air pollution may change with time within the same population. In a longitudinal study, it was demonstrated that each 6.8 μg/m 3 increase in PM 2.5 on the same day was associated with 0.4% (0.0%, 0.8%), 0.3% (−0.2%, 0.7%), and 2.7% (1.9%, 3.5%) increases in the rate of asthma emergency department visits in the 2005–2007, 2008–2013, and 2014–2016 periods, suggesting that the toxicity from PM 2.5 increased with the time [ 105 ].

Although the relation between exposure to outdoor air pollution and exacerbations of childhood asthma has been well documented, there is less evidence on exposure to indoor air pollution from incomplete combustion of polluting fuels. However, in a recent study, coexposure to elevated concentrations of indoor and outdoor pollutants was synergistically associated with increased emergency room visits for asthma [ 106 ].

It has been estimated that the combined effects of outdoor and indoor air pollution are responsible for approximately seven million premature deaths every year, mainly due to respiratory and cardiovascular diseases. Annually, around 500,000 deaths of children under 5 years of age and 50,000 deaths of children aged 5–15 years were attributable to air pollution. The burden of disease attributable to air pollution is not evenly distributed is greater in low- and middle-income countries than in high-income countries [ 107 ].

Table 1 shows the legal concentrations of outdoor air pollutants according to WHO guidelines and summarizes their negative impact on asthma outcomes.

Effects of outdoor air pollutants on asthma outcomes if legal concentrations are exceeded.

4.7. Outdoor Air Pollution and Asthma Management

Several risk reduction measures have been recommended. These include personal strategies, community and government interventions, as well as the use of effect modifiers, which could reduce the risk factors [ 108 ]. Patients’ education to minimise their exposure to air pollutants represents an important step in asthma management. Several measures could be beneficial, like the use of close-fitting N95 facemasks when air pollution levels are high, shifting from motorised to active travel (e.g., cycling, walking), selecting low-traffic routes or those with open spaces, driving with windows closed, maintaining car air filtration systems and internal circulation, and being informed of local air pollution levels [ 108 ]. For that purpose, alerts on the occurrence of peaks of pollution, freely available online for the general population, could be helpful. This exclusion of outdoor activities during the period of poor air quality could be added to the asthma action plan. Moreover, peak pollution levels could be concomitant with exposure to seasonal aeroallergens, with an additive negative impact on asthma outcomes [ 109 ]. It was also suggested that patients with asthma ought to live at least 300 m from major roadways to reduce the impact of pollutant exposure on their asthma [ 49 ]. Community-level interventions such as urban planning of “smart” cities with more green space at distance from major traffic arteries and industrial areas, as well as the development of walking and cycling paths separated from motorised streets, may reduce respiratory morbidity [ 108 ]. Governments must monitor air pollution, inform the population about the risks when air pollution levels are high and take measures in controlling the release of PM, like considering alternative fuels such as gas, fuel-cleaning options such as coal washing as well as alternative production processes and technologies [ 49 ]. For example, an European pediatric study showed that compliance with the WHO air quality guidelines for PM 2.5 could prevent 11% of all incident asthma cases, while the minimum air pollution levels for NO 2 (1.5 µg·m −3 ) and PM 2.5 (0.4 µg·m −3 ) were estimated to prevent 23% and 33% of incident cases, respectively [ 11 ].

The treatment of asthma exacerbations related to air pollution is not different from the usual clinical practice. All asthmatic patients must have a controller asthma treatment as recommended by current guidelines [ 8 ]. Inhaled corticosteroids (ICSs), the first choice treatment as a controller of asthma, proved to be beneficial in decreasing adverse responses to pollutant exposures [ 46 ]. Dietary supplements such as carotenoids, vitamin D and vitamin E are suggested to protect against airway inflammation and damage induced by pollutants that can trigger asthma initiation. Vitamin C, curcumin, choline and omega-3 fatty acids may also play a role [ 46 , 110 ]. Previous data showed that dietary intake of fruits and vegetables (e.g., Mediterranean diet) was associated with a better lung function, particularly among children exposed to O 3 [ 46 ]. However, this protective effect of dietary antioxidant intake seems more evident in children with low levels of outdoor air pollution exposure, but may be insufficient for the children exposed to higher amounts of air pollutants [ 111 ].

Most of enumerated measures to reduce the impact of air pollutants on asthma outcomes are easier to apply in developed countries with adapted economical resources than in low- or middle-income countries. Poor countries often lack the technology and resources to fight pollution because their economies are still growing, so their citizens are more at risk of respiratory and cardiovascular diseases related to high levels of air pollution. Energy production is one of the most polluting activites because much of this energy comes from coal. While developed countries are more likely to invest in cleaner fuel sources, and technologies that limit emissions, governments of developing nations just want to ensure energy for their citizens at competitive and accessible prices. Even the monitoring of air pollution is sometimes difficult in developing countries; it must be encouraged, and the use of mobile devices is a less expensive solution [ 1 , 5 ]. In addition, evidence suggests that asthma is underdiagnosed and undertreated in low-income countries [ 112 ]. However, access to proper diagnosis and treatment with controller medications for asthma (e.g., ICSs) is feasible and cost-effective even in low-resource settings by reducing symptoms, health care utilization, mortality and improving quality of life [ 112 ]. Actions by cities and national governments are needed in developing counties to minimize the impact of air pollution on their populations’ health. Monitoring of air quality, education for health, development of healthcare systems, active and public transport infrastructure, use of better methods of energy production (e.g., renewable energy sources) and technologies to reduce emissions are efficient measures that improve air quality and consequently life expectancy and worker productivity. It is important for developing nations to find a balance between economic growth and air quality to protect the health and standard of living of their citizens [ 50 , 113 ].

The effects of various air pollutants on asthma outcomes and their socio-economic impact are represented in Figure 1 .

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Burden of air pollutants on asthma outcomes and socio-economic impact.

5. Indoor Air Pollution

5.1. tobacco smoke.

Tobacco smoking is the inhalation of smoke produced during the burning of tobacco leaves. Currently, more than 1.1 billion people are smokers and, additionally, another part of population is exposed to SHS. Tobacco smoke is a complex and dynamic mixture containing more than 7000 chemicals, of which at least 250 are known to be harmful and at least 69 are known to cause cancer [ 114 ]. Mainstream smoke is the aerosol drawn and inhaled directly by a smoker from a cigarette, cigar, or pipe, while sidestream smoke is the aerosol emitted in the surrounding air from a smoldering tobacco product [ 115 ]. Sidestream smoke is the main part of the SHS. The other main contributor to SHS is the exhaled portion of mainstream smoke. SHS is also known as passive smoking or environmental tobacco smoke. The aerosol of mainstream smoke is complex and consists of vapor and particulate phase. The main component of the vapor phase is the CO, but it also contains acetaldehyde, formaldehyde, acrolein, nitrogen oxides and CO 2 . Tar and nicotine form the particulate part of the mainstream smoke aerosol [ 116 ]. Tobacco smoking increases the risk of developing cardiovascular disease, stroke, COPD, lung cancer and other cancers [ 117 ]. It has an impact on asthma at various levels and it is a well known modifiable risk factor for symptom control and exacerbation. The prevalence of smoking among asthma patients is comparable to the general population (around 20%) [ 118 ].

Airway inflammation in asthmatic smokers differs from asthmatic non-smokers with higher total sputum cell counts, predominance of activated macrophages and neutrophils in sputum, airways, and lung parenchyma as in early COPD [ 119 , 120 ]. Previous data showed that smokers with asthma have higher sputum matrix metalloproteinase (MMP)-12 concentrations compared to non-smokers and the levels are inversely associated with lung function and positively related to sputum neutrophil counts [ 121 ]. This neutral endopeptidase is primarily responsible for the degradation of extracellular matrix components during the remodelling processes essential for normal tissue growth and repair. The excessive activity of MMPs and the impaired balance between them and their regulators, tissue inhibitors of metalloproteinases (TIMPs), have been implicated in the tissue-destructive processes associated with chronic lung diseases, including COPD and asthma [ 121 ]. In the same line, another study found reduced sputum MMP-9 activity/TIMP ratios in smokers with asthma compared with never-smokers. Low sputum ratios in asthmatic smokers were associated with persistent airflow obstruction and a reduced CT airway lumen area, which may indicate that an imbalance of MMP-9 and TIMPs contributes to structural changes to the airways in this group [ 121 ]. These results suggest that the persistent exposure to cigarette smoke drives additive or synergistic inflammatory and remodelling responses in the asthmatic airways [ 122 ]. In addition, the number of CD83+ mature DCs and B lymphocyte cells in bronchial biopsies are significantly lower in asthmatic smokers in comparison with never-smokers with asthma, which could explain the higher number of lower respiratory tract infections in the group of smokers [ 123 ]. The rhinovirus respiratory infection is an etiologic factor for severe asthma exacerbations necessitating hospitalization, and after adjustment for baseline asthma severity, rhinovirus-positive patients were more likely to be current smokers [ 124 ].

Asthmatic smokers are less sensitive to the therapeutic effects of inhaled and oral CSs in short- to medium term administration [ 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 ]. The impact of smoking in long-term CSs treatment still needs to be investigated, but the data collected showed that impairment in response to smoking was present, even after one year of treatment with ICSs, overruling the suggestion that the insensitivity could be improved with prolonged treatment [ 130 ]. Two main mechanisms explain the CSs insensitivity in smokers with asthma. The first one is the decrease in histone deacetylase-2 (HDAC-2) activity among smokers with increased inflammatory gene expression [ 131 , 132 , 133 , 134 ]. This is the consequence of oxidative stress. There are high levels of nitric oxide in tobacco smoke generating peroxynitrite, which leads to the inactivation of HDAC-2 via nitration and ubiquitination [ 135 , 136 ]. The second mechanism involves glucocorticoid receptor (GR). CSs act through the GR that has two alternative splicing isoforms, the GRα and GRβ. GRα is the classic and the functional isoform, through which the effects of CSs are mediated, while the overexpression of GRβ inhibits the action of the ligand-activated GRα [ 137 , 138 , 139 ]. The ratio of GRα/GRβ isoforms is reduced in peripheral blood mononuclear cells from current-smokers compared with non-smokers, including patients with asthma, which could lead to a lower CS [ 140 ]. These mechanisms could partially explain the poorer asthma outcomes in smokers with asthma.

Smoking patients with asthma form a separate phenotype that requires better understanding of underlying disease mechanisms and specific management.

5.2. Wood-Burning and Unflued Gas Heaters, Cooking Behaviors (Using Wood or Coal), Molds

Biomass combustion is known to be an important contributor to indoor air pollution in developing countries with resultant adverse health effects [ 141 ]. Residential heating devices can be a large contributor to ambient PM, notably in rural communities; the majority of these heating sources are old and inefficient, resulting in high levels of PM emissions [ 142 ]. The Consumer Product Safety Commission estimates that there are nearly 9 million wood stoves currently in use in the US [ 143 ]. Estimates of the contribution of wood-burning to ambient air quality can vary widely [ 144 ], but wood smoke accounts for 80–90% of the PM concentrations in communities with a high proportion of wood-burning households [ 145 ]. In the European Union, it is estimated that domestic woodstoves will be the dominant source of ambient PM 2.5 , accounting for 38% of all emissions by 2020 [ 146 ]. Follow-up of cohorts or panels of asthmatic patients have demonstrated that increases in levels of PM 10 and PM 2.5 in the indoor environment are associated with increases in severe asthma attacks, respiratory symptoms, asthma medication use, and hospital emergency department visits [ 147 , 148 ]. PM exposures have been shown to result in annual lung function growth deficits that are greater than those attributed to SHS exposure in children [ 149 ].

Unflued gas heaters (UFGHs) are a major source of NO 2 , nitrous acid and CO indoors, and they can also emit formaldehyde and produce water vapour [ 150 , 151 ]. Exposure to gas appliances or indoor NO 2 has been associated with a worsening of asthma symptoms in children and adults. A positive association was found between indoor NO 2 exposure and asthma exacerbations [ 152 ]. The effects of UFGHs exposure was studied in seventy-one patients with >55 years of age with mild to moderate asthma. A significant increase in respiratory symptoms was shown (wheeze and dyspnoea) when the people used UFGHs compared with days without exposure. In addition, there were significant increases in the average odds of reported wheeze and dyspnoea per hour of UFGH use. Small but significant reductions in morning to evening PEF and FEV 1 were observed on the days when UFGH was used compared with days when other/no heating was used [ 153 ].

Cooking has been also extensively studied as a source of indoor air pollution. Most people from low- or middle-income countries use, in their homes, biomass fuel (wood, animal dung and crop residues) or coal to cook, producing high levels of indoor pollution (e.g., CO, PM). Using coal and wood as cooking fuels were identified as risk factors of asthma in child and adult populations [ 154 , 155 ].

Indoor sources of molds may also be a risk factor for asthma [ 156 , 157 ]. If more studies showed a causal relationship between indoor mould exposure and the development/exacerbations of asthma in children, a limited level of evidence was found in the adult asthma population [ 157 ]. Several species, such as Aspergillus fumigatus and versicolor, Penicillium spp or Cladosporium sphaerospermum, herbarum and cladosporioides, display a more pronounced indoor tropism [ 158 ]. Exposure to increased daily levels of basidiospores and ascospores in the first 3 months of life were associated with increased odds of wheezing among children under 24 months in a cohort study in California [ 159 ]. Fungal components are biologically active and contribute to asthma development and the severity by IgE- and non-IgE-mediated mechanisms [ 156 ]. Fungal sensitization is associated with earlier onset of asthma and demonstrates a dose-dependent relationship of symptom severity and duration [ 160 ]. The senzitization to Aspergillus fumigatus and Penicillium spp was linked to an increased risk of severe asthma [ 158 ]. Alternaria alternata sensitization is a predictor of epidemic asthma in patients with seasonal asthma and is likely to be an important factor in thunderstorm-related asthma [ 161 ]. These data suggest that indoor mold exposure can initiate asthma and influence asthma outcomes.

5.3. Indoor Air Pollution and Asthma Outcomes

The asthmatics who are active smokers have increased morbidity and mortality, more severe symptoms, difficulties in controlling asthma, higher rates of exacerbations, worse quality of life, and an increased number of life-threatening asthma attacks [ 162 ]. This group of patients have more frequent unscheduled doctor visits and hospital admission, thus leading to the utilization of more health care resources [ 8 , 163 , 164 , 165 ]. The risk of death from asthma is increased in asthmatic patients with a smoking history of more than 20 pack-years [ 166 ]. In a cohort of 147 cases of near-fatal asthma attacks, smoking was associated with a higher in-hospital and post-hospitalization mortality [ 167 ]. Several population-based surveys demonstrate that smoking is strongly associated with poorer asthma control and this seems to be dose-dependent [ 168 ].

Exposure to SHS impacts asthma control and severity in both adults and children. A systematic review and meta-analysis has shown a nearly two-fold increase in the risk of hospitalization for asthma exacerbations in children with asthma and SHS exposure [ 169 ]. Adolescents with asthma exposed to SHS were at increased risk of having a dry cough at night, wheeze and sleep disturbance due to asthma symptoms. Dyspnea and exercise limitations were also more frequent among this population. The risk of having Emergency department/urgent care visits was two times higher in asthmatic adolescents exposed to SHS compared with unexposed adolescents. The group of adolescents with asthma were also 1.5 times more likely to use a rescue medication, nebulizer treatment, or other controlling medication and over 3.5 times more likely to have had an asthma attack that required the use of an oral or injected CS [ 170 ]. A recent study found that SHS in children aggravated the severity of asthma by affecting the balance of Treg/Th17 cells with a higher percentage of Th17 cells, while the percentage of Treg cells was reduced. SHS significantly reduced the levels of FoxP3 and tumor growth factor-β, which were associated with Treg cells, and increased the levels of interleukin-17A and interleukin-23, which were associated with Th17 cells [ 171 ]. Adults with asthma who are exposed to SHS have poor symptom control, worse quality of life, lower lung function and greater healthcare utilization [ 172 ].

Asthma itself is associated with a decline in lung function over time [ 173 ] and this process is more rapid in asthmatic smokers, compared with asthmatic non-smokers [ 174 , 175 , 176 , 177 ]. A smoking history of ≥10 pack-years seems to be a significant predictor factor of accelerated loss of lung function [ 176 ]. Regular/former smoking reduces lung function levels with a dose–response pattern (daily smoking rate and cumulative smoking) by affecting both larger and smaller airways [ 177 ].

Smoking is a predictive factor for ACO development, a term introduced to describe patients who have features of both asthma and COPD [ 8 ]. More than 25% of asthma patients with a smoking history of at least 10 pack-years have ACO [ 178 ]. It is important to actively look for features of ACO in asthmatic smokers because these patients have more frequent exacerbations, a poor quality of life, a more rapid decline in lung function, and high mortality, compared with asthma or COPD alone [ 8 , 179 ].

Exposure to high levels of PM from wood-burning or NO 2 from UFGHs is associated with more symptoms of asthma, a high rate of exacerbations and has a negative impact on lung function [ 147 , 148 , 152 ]. These effects seem more evident in children and older people with asthma [ 147 , 148 , 153 ]. Children exposed to biomass smoke from cooking have more frequent symptoms of severe asthma [ 180 ] and the risk of asthma-related symptoms is greater for males [ 180 ], while those exposed to NO 2 from cooking with natural gas have a higher risk of asthma exacerbations [ 21 ]. A large cross-sectional study performed in China showed that adults using coal for cooking have a higher risk for asthma symptoms than those without such exposure, and they have more asthma symptoms and poorer lung function in winter than in summer [ 181 ].

Several data sources suggested an association between the sensitization to Aspergillus fumigatus or Penicillium spp. and severe asthma [ 158 , 160 ]. A study perfomed in Mexico City including asthmatic patients found an association between the exposure to some molds, particularly Aspergillus fumigatus, Aureobasidium pullulans, Stachybotrys chartarum, Alternaria alternata, Cladosporium cladosporioides, Cladosporium herbarum, and Epicoccum nigrum, and uncontrolled asthma in males, but not in female patients, suggesting a possible gender susceptibility [ 182 ].

The effects of indoor air pollution on asthma are summarized in Table 2 .

Effects of indoor pollution on asthma according to their sources.

SHS: second-hand smoking.

A large cross-sectional Brazilian study including adult asthmatic patients evaluated the impact of smoking, indoor air pollution, and dual exposure on asthma outcomes. Exposure to indoor air pollution was associated with poorer asthma control, a higher proportion of severe asthma, and worsening of lung function in exposed vs. unexposed individuals. These effects were more important for the double-exposure. Exposure to indoor air pollution and double-exposure were predictive factors for uncontrolled and severe asthma in multivariate analysis [ 183 ].

All these findings suggest that indoor pollutants play a negative role on asthma outcomes, but, more importantly, an additive effect if they are associated.

5.4. Indoor Air Pollution and Asthma Management

The management of asthmatics exposed to indoor pollutants must include preventive measures to reduce/avoid exposure, such as smoking cessation, efficient household ventilation, use of clean fuels (e.g., methane, liquid petroleum gas, electricity, solar cookers), portable air cleaners, and pharmacologic interventions to optimize asthma treatment.

Smoking cessation must be encouraged in all possible ways to reduce the exposure of people with asthma. Smoking cessation in patients with asthma leads to better symptom control, less use of rescue medication, improved asthma quality of life score, lung function and AHR [ 184 , 185 ]. However, former-smokers have an accelerated FEV 1 decline for decades after smoking cessation compared to never-smokers, but less important than for current-smokers, suggesting a lasting and progressive lung damage induced by tobacco smoke [ 186 ]. Counseling and first-line medications for smoking cessation (nicotine replacement therapy, bupropion and varenicline) significantly increase quitting rates along with increasing the chance of preventing relapses [ 187 ]. E-cigarettes could be a valid option for asthmatic patients who cannot quit smoking by other methods. A study showed significant improvements in lung function, asthma control and AHR for asthmatic patients who chose this method for smoking cessation [ 188 ]; however, e-cigarettes might generate respiratory toxicants such as acrolein, formaldehyde, and acetaldehyde [ 189 ]. A study found that current e-cigarette use is associated with 39% higher odds of self-reported asthma compared to never e-cigarette users [ 190 ]. Therefore, the recommendation of e-cigarettes as a smoking cessation tool must be balanced against the short- and long-term safety of these products.

In general, it could be suggested that the treatment of asthmatic smokers should follow the international guidelines for asthma treatment [ 8 ], but this could be challenging due to the aforementioned. Although the data shows that asthmatic smokers have decreased sensitivity to ICSs, there are studies demonstrating that long-term ICS treatment may reduce the decline in lung function in smokers with asthma, with a greather benefit for people who have smoked <5 pack-years [ 191 , 192 ]. The combination therapy with ICS and long-acting beta-agonist (LABA) is probably the preferable option, in asthmatic smokers, to increasing the dose of ICS, due to the relative insensitivity and the potential adverse effects of the latter [ 128 , 193 , 194 ]. One of the most significant changes in asthma management was the announcement of the Global Initiative for Asthma (GINA) 2019 recommendations regarding the use of as-required ICS/LABA as rescue medication in symptomatic mild or moderate asthma. Trials investigating this rescue medication option are lacking in asthmatic smokers; it seems reasonable that current or former-smokers should not be excluded from this new GINA recommendation [ 195 ]. Montelukast, a leukotriene receptor antagonist, represents another therapeutic option as a controller of asthma. A study showed a significant benefit of the montelukast treatment (10 mg/day) on asthma control over 6 months compared to placebo in asthmatic patients actively smoking cigarettes. This effect is comparable to the administration of 250 μg of fluticasone propionate twice daily. However, the patients with a smoking history of more than 11 pack-years experienced better benefits with montelukast than with fluticasone. The explanation of these findings is that the more intensive exposure to tobacco smoke induces an increased synthesis of leukotrienes [ 196 ]. The effect of tiotropium, an inhaled long-acting muscarinic antagonist, is comparable in current-smokers and non-smokers with asthma treated by ICSs plus a second controller, with a significant improvement of symptoms and lung function in both groups [ 197 ]. Preliminary findings suggest that biologic therapies, such as omalizumab, mepolizumab, and dupilumab, improve clinical outcomes in smokers with asthma or ACO but current data is limited [ 198 ]. The group of asthmatic smokers forms a distinct asthma phenotype with worse outcomes, altered airway inflammation and changes in the response to pharmacological treatment. Smoking cessation interventions must start as early as possible. More studies investigating the effect of pharmacological treatments in this group of asthma patients are required.

Several studies showed the positive impact of the comprehensive statewide smoke-free indoor air laws on SHS exposure and the improvement of asthma outcomes through a reduction in prevalence, respiratory symptoms and exacerbations/hospitalizations [ 199 , 200 , 201 ]. The respect of smoke-free indoor environments and public areas is beneficial, and smoke-free indoor air laws should be enforced in all states. Several studies of children with asthma in urban environments have targeted the indoor environment to improve health outcomes. Improving household ventilation by opening windows or doors, using chimneys, hoods, or exhaust fans decreased asthma symptoms in children [ 202 , 203 ]. The intervention strategies (e.g., education by a health coach, remediation of the exposure by air cleaners) consistently demonstrated declines in asthma-related symptoms and significant improvements in peak expiratory flow [ 108 ]. However, all of these studies were conducted in urban environments, and the nature of these exposures likely differ from that of exposures in rural environments [ 204 , 205 , 206 ]. A study showed that installing non-polluting, more effective heating (with lower levels of indoor exposure to NO 2 ) in the homes of children with asthma significantly reduced respiratory symptoms, days off school, healthcare utilisation, and visits to a pharmacist [ 207 ]. Similarly, the replacement of UFGHs with high NO 2 emission in the schools by flue gas or electric heaters reduced asthma symptoms in children during 12 weeks following the intervention [ 208 ]. In contrast, household-level interventions, such as improved-technology wood-burning appliances or air-filtration devices did not affect quality-of-life measures among children with asthma and chronic exposure to wood-smoke [ 209 ]. If the avoidance of wood-smoke or UFGHs emission is not possible, several general cautionary measures could be made in practice.

A study found that the removal of indoor molds significantly improved asthma symptoms and reduced medication use at 6 and 12 months compared with the group without this intervention [ 210 ]. The advice of a Medical Indoor Environment Counselor could be also useful to improve the quality of the indoor environment [ 211 ]. This is summarized in the following Table 3 .

Recommendations to minimise indoor air pollution from heating sources.

UFGHs: Unflued gas heaters.

These measures could reduce the exposure but, unfortunately, the complete avoidance of the pollutants is impossible, so the asthma management plan and the controller medication use are mandatory for all asthmatics, as recommended by current guidelines [ 8 ].

Unfortunately, if most of these measures to reduce indoor pollution are feasible and already promoted in developed countries, their application in low- or middle-income countries is more difficult because of limited financial resources. If the use of air cleaners, low-polluting sources for cooking and heating, or personal devices to monitor indoor air pollution are less accessible for people who live in developing countries, government measures promoting health, such as smoking cessation programs and avoidance of SHS, education of people to improve household ventilation by opening windows or doors (at least during cooking periods) and mold removal, are cost-effective methods that could reduce the negative impact of indoor air pollution on asthma, and are feasible worldwide, independent of socioeconomic status.

6. Conclusions

Indoor and outdoor pollution represents a major public health threat with a negative impact on asthma outcomes. Current data showed that not only is the TRAP a risk factor for asthma development in children, but so are the NO 2 and SHS exposures. A causal relation between air pollution and the development of adult asthma is not yet clearly established. The exposure to ourdoor pollutants (O 3 , NO 2 , SO 2, CO, PM) could induce asthma symptoms, exacerbations and hospitalizations. The effects are dose and duration-dependent. A decrease in lung function was more frequently reported for O 3, NO 2 , SO 2 and PM. Active tobacco smoking is associated with poorer asthma control, more frequent exacerbations/hospitalizations, accelerated decline of lung function and a lower response to CS. Exposure to SHS increases the risk of asthma exacerbations, respiratory symptoms, healthcare utilization, and poor lung function. High-level exposures to indoor pollutants (e.g., PM from wood-burning or NO 2 from UFGHs) could induce more symptoms of asthma and higher rates of exacerbation, and have a negative impact on lung function. The sensitization to Aspergillus fumigatus and Penicillium spp seems to be associated with more severe asthma. These negative effects are more evident in children and older people with asthma. Asthma management according to current guidelines could reduce these effects but global measures are mandatory to minimize the exposure to indoor/outdoor pollutants and to improve asthma outcomes. Limited data exists for the effects of dual exposures (e.g., tobacco smoking and other air pollutants or associations between outdoor and indoor air pollutants) on asthma outcomes. Future research is needed on double or multiple exposures, as well as in the identification of a pattern of respiratory disease that increases susceptibility to air pollution.

Acknowledgments

The authors would like to thank the Interasma European Scientific network (INES).

Author Contributions

A.I.T. Conceptualization, writing—original draft preparation, review and editing, visualization, supervision; P.N., D.N., H.J.C.-N., S.N. Writing—original draft preparation, P.S., K.K. Writing—original draft preparation, review and editing. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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    Out of 71 182 patients with asthma, 1006 (1.41%) suffered from COVID-19. Compared to asthmatic individuals without COVID-19, patients with asthma and COVID-19 were significantly older (55 versus 42 years), predominantly female (66% versus 59%), smoked more frequently and had higher prevalence of hypertension, dyslipidaemias, diabetes and obesity.

  24. Decreased TLR7 expression was associated with airway eosinophilic

    Background Asthma is a global public health concern. The underlying pathogenetic mechanisms of asthma were poorly understood. This study aims to explore potential biomarkers associated with asthma and analyze the pathological role of immune cell infiltration in the disease. Methods The gene expression profiles of induced sputum were obtained from Gene Expression Omnibus datasets (GSE76262 and ...

  25. Using AI to identify high risk patients with asthma and COPD

    More information: Kevin Lopez et al, Deep learning prediction of hospital readmissions for asthma and COPD, Respiratory Research (2023). DOI: 10.1186/s12931-023-02628-7 Provided by Yale University

  26. PDF Asthma Clinical Research Network Study Protocol A study to compare the

    Asthma Clinical Research Network Long Acting Beta Agonist Response by Genotype (LARGE) Study Protocol Version 22.0 February 2, 2006 A study to compare the effects of a long acting beta agonist in patients with asthma receiving inhaled corticosteroids who express two distinct polymorphisms of the β 2 -adrenergic receptor.

  27. Impact of Air Pollution on Asthma Outcomes

    Asthma is a chronic respiratory disease characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Evidence suggests that air pollution has a negative impact on asthma outcomes in both adult and pediatric populations.