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  • Published: 13 August 2021

Biological therapy for severe asthma

  • Silvano Dragonieri   ORCID: orcid.org/0000-0003-1563-6864 1 &
  • Giovanna Elisiana Carpagnano 1  

Asthma Research and Practice volume  7 , Article number:  12 ( 2021 ) Cite this article

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Around 5–10% of the total asthmatic population suffer from severe or uncontrolled asthma, which is associated with increased mortality and hospitalization, increased health care burden and worse quality of life. In the last few years, new drugs have been launched and several asthma phenotypes according to definite biomarkers have been identified. In particular, therapy with biologics has revolutionized the management and the treatment of severe asthma, showing high therapeutic efficacy associated with significant clinical benefits. To date, four types of biologics are licensed for severe asthma, i.e. omalizumab (anti-immunoglobulin E) antibody, mepolizumab and reslizumab (anti-interleukin [IL]-5antibody), benralizumab (anti-IL-5 receptor a antibody) and dupilumab (anti-IL-4 receptor alpha antibody). The aim of this article was to review the biologic therapies currently available for the treatment of severe asthma, in order to help physicians to choose the most suitable biologic agent for their asthmatic patients.

Since the beginning of this millennium, asthma assessment and management have been revolutionized. While some new therapeutic approaches have been suggested for mild asthmatics, the most relevant changes have occurred in severe asthma. Severe asthma accounts for the 5–10% of the global asthma population, with 3 to 5% being uncontrolled despite adherence to therapy and proper use of inhalers [ 1 ]. These subjects cannot achieve symptoms control despite maximal therapy with inhaled corticosteroids (ICS) and, quite often, maintenance oral corticosteroids (OCS) are necessary in an endeavor to avoid life-threatening exacerbations [ 2 ]. Although OCS courses remain essential for the management of acute exacerbations, their recurrent or continuous usage is associated with several complications, such as an increased risk of developing osteoporotic fractures and pneumonia [ 3 ]. Moreover, other conditions including cardiovascular and cerebrovascular events, renal dysfunction, diabetes mellitus type 2, humor alterations, obesity and sleep apneas are known to be associated with systemic corticosteroid exposure [ 3 ]. Additionally, many patients remain poorly controlled and show recurrent exacerbations despite a strict adherence to therapy [ 4 ].

The recent advances in our knowledge of the etiopathological mechanisms of different phenotypes and endotypes of severe asthma gave us very innovative therapies, such as biological drugs for severe asthma. These medications are mostly directed against molecules involved in the type 2 inflammatory pathway, thus modifying the natural course of the disease by reducing airways inflammation without the collateral damage associated with corticosteroids. Based on the above, the aim of this article was to review the biologic therapies currently available for the treatment of severe asthma, in order to help physicians to choose the most suitable biologic agent for their asthmatic patients.

Licensed medications for severe asthma

To date, there are five biologic molecules officially approved for use in selected severe asthmatic patients. The first of these is omalizumab, an anti-IgE monoclonal antibody acting through various mechanisms on allergic pathways (Table 1 ). Three more biologics for asthma, belonging to a different class, have been approved, i.e. mepolizumab, reslizumab and benralizumab. They all target the interleukin-5 (IL-5) pathway with the first two targeting the interleukin itself and the last one its receptor. Finally, dupilumab is a monoclonal antibody against the receptor of interleukin-4 (IL-4) which blocks the signaling pathways of IL-4 and IL-13.

BIOLOGICS TARGETING IgE

Omalizumab was the first targeted biologic therapy developed and licensed for severe asthma, being approved by the Food and Drugs Administration in 2003 [ 5 ]. It is a recombinant monoclonal Antibody which binds to IgE, thereby lowering blood IgE levels of up to 99% [ 6 ]. Moreover, It decreases expression of IgE receptor FCRI on inflammatory cells such as mast cells and basophils, thus helping to both mitigate the allergic response and strengthen the antiviral immune response, finally leading to prevent asthma exacerbations [ 7 ]. Omalizumab is approved in adults and children above 6 years old with IgE-driven moderate-to-severe persistent allergic asthma which remains uncontrolled despite GINA step 4/5 treatment, high levels of blood IgE, and documented sensitization to a perennial allergen [ 8 ]. Its dosage varies according to patient’s bodyweight and circulating IgE levels and it is administered subcutaneously every 14 or 28 days [ 9 ]. Although not necessary from a safety point of view, it is advisable to re-evaluate patients after the initial 16 weeks of treatment to assess the drug efficacy before continuing with omalizumab therapy [ 8 ].

The efficacy and safety of omalizumab are nowadays unquestionably recognized, with numerous studies demonstrating that this biological is generally well-tolerated, with no serious adverse effects reported [ 10 , 11 , 12 , 13 , 14 , 15 ]. Common side effects include injection site or diffuse rash, fever, nose bleeding, joint pain, gastro-intestinal disturbances, headache, dizziness and cold symptoms [ 10 , 11 , 12 , 13 , 14 , 15 ]. A Cochrane systematic review assessing 25 randomized controlled trials in patients with allergic asthma showed the efficacy of omalizumab in reducing asthma exacerbations, hospitalizations, and inhaled corticosteroid dosage [ 10 , 15 , 16 , 17 , 18 , 19 ].

During the last few years, a number of biomarkers for monitoring the efficacy of omalizumab therapy have been proposed, including total and antigen-specific IgE, blood eosinophil count and exhaled nitric oxide (FeNO) [ 20 , 21 ]. Surprisingly, total IgE did not appear to be a reliable predictor of response to omalizumab therapy, evidencing that our knowledge on this field is still limited [ 21 ]. Peripheral blood eosinophil count ≥300 cells/mL are linked to higher asthma severity and to a better response to omalizumab [ 22 , 23 ]. Furthermore, patients under omalizumab with higher blood eosinophil count have a higher chance to suffer from asthma exacerbations in case of omalizumab discontinuation [ 24 ]. Regarding FeNO, elevated values at baseline correlated with a better response to omalizumab with regard to exacerbations decrease [ 20 , 25 ]. Likewise, elevated levels of FeNO after suspension of long-term therapy with omalizumab may be a predictor of successive exacerbations [ 24 ].

Biologics targeting IL-5

IL-5 is a well-known regulator of the activation, differentiation, effector function, migration and survival and effector function of eosinophils [ 26 ]. Eosinophil levels associated with symptoms of asthma correlate with disease severity and increase the risk of asthma exacerbations, evidencing that this granulocyte type plays a key role in the pathophysiololgy of asthma [ 26 ]. Currently, licensed biologics against IL-5 pathways are mepolizumab, reslizumab, and benralizumab.

MEPOLIZUMAB

Mepolizumab is a monoclonal antibody directed against IL-5 which has been approved as an add-on treatment for patients ≥6 years old in Europe and for patients ≥12 years old in the USA. Mepolizumab was the first anti-IL-5 antibody approved for the treatment of severe asthma by the Food and Drugs Administration in 2015. Eligible subjects are those with severe eosinophilic asthma that remains uncontrolled despite GINA step 4/5 therapy, with blood eosinophil count of ≥150 cells/μl during the first administration or ≥ 300 cells/μl in the previous year and with at least 2 asthma exacerbations requiring systemic steroid course in the past year [ 27 , 28 ]. Mepolizumab is administered by a subcutaneous injection at a fixed dose of 100 mg every 28 days.

Several studies evaluating mepolizumab for uncontrolled eosinophilic asthma showed a markedly reduction with regard to number of exacerbations, systemic corticosteroid usage, emergency room accesses and hospital admissions, and a concurrent improvement of asthma controls and lung function parameters [ 29 , 30 , 31 , 32 , 33 ].

Furthermore, a number of studies revealed that mepolizumab has a positive long-term safety profile [ 34 , 35 , 36 ]. No reports of mepolizumab-associated anaphylaxis reactions were documented, as well as parasitic infections [ 34 , 35 , 36 ]. Common side effects include headache, injection site reaction, fatigue, flu symptoms, urinary tract infection, abdominal pain, itching, eczema, and muscle spasms [ 34 , 35 , 36 ].

Additionally, numerous investigations highlighted that the most important markers of response prediction to mepolizumab are the rate of previous exacerbation and baseline peripheral blood eosinophil count [ 29 , 32 , 37 , 38 , 39 ]. Indeed, a better clinical efficacy is directly proportional to a higher eosinophil count and to a higher rate of exacerbations [ 29 , 32 , 37 , 38 , 39 ]. Interestingly, mepolizumab effectiveness was not related to baseline IgE and to atopy [ 40 , 41 ] and earlier treatment with omalizumab is not a predictor for mepolizumab efficacy [ 42 , 43 , 44 ].

There is a lack of consensus about the duration of treatment before evaluating the effectiveness of mepolizumab. Actually, the GINA statement suggests that a 4-month trial may be adequate [ 8 ], whereas the NICE guidelines recommend that mepolizumab should not be discontinued before 12 months of therapy and that drug-responsiveness should be assessed every year [ 45 ].

Reslizumab is monoclonal antibody approved in 2016, which binds with high-affinity to IL-5 [ 46 ]. By an analogous mechanism of action to mepolizumab, reslizumab lowers circulating blood eosinophil levels [ 47 ]. It has been approved for patients ≥18 years old with severe eosinophilic asthma which remains uncontrolled despite therapy with high-doses of ICS plus another inhaler. Reslizumab is indicated in patients with ≥400 eosinophils/μl and history of asthma exacerbations in the previous 12 months [ 48 , 49 ]. Reslizumab is administered intravenously every 28 days at a weight-based dose of 3 mg/kg.

Similarly to mepolizumab, studies assessing reslizumab have shown a decreased number of asthma exacerbations and improved asthma control and lung function parameters in subjects with high blood eosinophil levels [ 47 , 50 ].

The safety profile of reslizumab has been evaluated for up to 24 months, revealing minor adverse effects without any reports of parasitic and opportunistic infections [ 51 ]. Most frequent side effects include cough, dizziness, itching, skin rash and fatigue [ 51 ].

However, despite its proven excellent clinical efficacy, intravenous formulation has a significant impact on the ease of administration compared to mepolizumab and/or benralizumab. Studies using reslizumab showed unsatisfactory results, without significant improvements in terms of acute exacerbations reduction or OCS lowering [ 52 ].

BENRALIZUMAB

Benralizumab is a monoclonal antibody approved in 2017 and directed against IL-5 receptor a (IL-5Ra) which induces eosinophil apoptosis via the antibody-dependent cell-mediated cytotoxicity (ADCC) involving natural killer cells, leading to peripheral blood eosinophil depletion [ 53 , 54 ]. Benralizumab acts like a competitive inhibitor to IL-5, binding with higher affinity to the a-subunit of IL-5Ra, which is expressed on mature (and precursors) eosinophils and basophils [ 55 ].

This biologic drug is licensed as an add-on treatment for uncontrolled severe eosinophilic asthma in patients ≥18 years with ≥300 blood eosinophils/μl [ 56 , 57 ]. A 30 mg dose of benralizumab is injected subcutaneously every 28 days for the first 3 administrations and afterwards every 56 days.

Large studies evaluating benralizumab in patients with moderate to severe asthma have shown a decrease in exacerbations number, improved lung function, and reduced use of OCS [ 53 , 54 , 58 ]. Combined analysis of these investigation have revealed that the best predictors of response to benralizumab are adult-onset asthma, more than 3 exacerbations in the previous year, nasal polyposis and pre-bronchodilator FVC < 65% of predicted [ 53 , 54 , 58 ].. The most common adverse effect were fever after the first injection, headache and pharyngitis [ 53 , 54 , 58 ].

Interestingly, based on its mechanism, benralizumab almost completely depletes blood eosinophils within 24 h of administration and a total depletion of airway eosinophils compared to that caused by mepolizumab [ 59 , 60 ]. Likewise, nasal eosinophils were totally suppressed after 6 months of therapy with benralizumab [ 61 ].

Recently, some concerns have been raised about the theoretical risks following an eosinophil depletion, especially with respect to host defense. However, these warnings were not confirmed, since it appears that there is adequate redundancy within human immune apparatus, which is not impaired by eosinophils depletion [ 62 ].

Biologics targeting IL-4 and IL-13

IL-4 and IL-13 are two interleukins which regulate and drive Type-2 inflammation. IL-4 increases the Th-2 cell population and B-cell isotype rearrangement of IgE as well as promoting eosinophilic transmigration through endothelium, whereas IL-13 plays an important role in asthma by promoting airway hyperresponsiveness, mucus secretion and airway remodeling [ 63 , 64 ]. Thus far, the only licensed drug acting on the two aforementioned ILs is dupilumab.

Dupilumab is a monoclonal antibody approved in 2018 which binds to the IL-4 receptor alpha-subunit, mutual to IL-4 and IL-13 receptors and inhibits both IL-4 and IL-13 pathways. Dupilumab is licensed as an add-on maintenance therapy in asthmatic patients GINA step 4/5 ≥ 12 years with type 2 inflammation characterized by increased blood eosinophils and/or raised FeNO. Dupilumab is administered subcutaneously at a starting dose of two injections of 200 mg each (total 400 mg), followed by one injection of 200 mg every 14 days, or at a starting dose of 600 mg (two injections of 300 mg each) followed by 300 mg every 14 days. The latter regimen is recommended for asthmatic subjects strictly dependent from OCS or with atopic dermatitis [ 65 ]. Dupilumab is also indicated for moderate to severe atopic dermatitis and for nasal polyposis.

A number of studies have demonstrated that therapy with dupilumab in severe asthmatics lowers the number of asthma exacerbations, improves lung function parameters and asthma control test scores, and lowers the use of OCS, irrespective of peripheral blood eosinophil count [ 66 , 67 , 68 , 69 ]. Indeed, a transitory increase of blood eosinophilia at the beginning of treatment with dupilumab has been observed although it may be due to blocked migration into tissues rather than hyperproduction [ 69 ]. Furthermore, reduced levels of T2 inflammation markers, including FeNO, serum levels of eotaxin-3, periostin and thymus and activation regulated chemokine (TARC) and total IgE, may serve as parameters for monitoring the efficacy of therapy with dupilumab [ 66 , 67 , 68 , 69 ]. The most common adverse reactions were injection site reactions, various types of infections, conjunctivitis and related conditions [ 66 , 67 , 68 , 69 ].

Biologics under development

Research for next-generation biologics is ongoing. Currently, other effector molecules are under the spotlight as new targets for perspective biological therapies, particularly the so-called alarmins [ 70 ]. These molecules are released by the airway epithelium against the harmful actions of germs, pollutants, allergens and cigarette smoke.

Tezepelumab is a human monoclonal antibody which binds to thymic stromal lymphopoietin (TSLP), an epithelium-derived alarmin that plays a relevant role in the pathogenesis of asthma, being an upstream effector T2-high pathobiologic pathways [ 71 , 72 , 73 ]. With the presence of tezepelumab, TLSP cannot bind to its receptor [ 74 ] hence inhibiting downstream signaling. A number of phase 2 and 3 trials have clearly shown that patients with severe uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo [ 75 , 76 ]. Concerning its safety profile, neither investigational tezepelumab-related anaphylactic reactions nor the detection of neutralizing antibodies were reported [ 75 , 76 ]. To date, license application for tezepelumab has been accepted and granted Priority Review for the treatment of asthma from the US Food and Drug Administration, whose regulatory decision is expected during the first quarter of 2022.

Ipetekimab is a monoclonal antibody targeting IL-33, another alarmin which associates with TSLP leading to an activation of T2-high inflammatory pathway in asthma [ 77 ]. Phase 2 studies with this biologic are ongoing, however preliminary results did not show adequate efficacy in severe asthmatics when associated with dupilumab or vs dupilumab alone [ 70 ].

Moreover, Tralokinumab and lebrokizumab are monoclonal antibodies both targeting IL-13 alone with disappointing results of phase 3 studies in terms of exacerbations reduction and OCS sparing in severe asthmatics [ 78 ].

Finally, regarding Th2-low asthma, mainly characterized by a neutrophilic airways inflammation, efforts are focusing on its pathogenic cascade involving cytokines such as IL-1beta, IL-17 and IL-23. Several monoclonal antibodies against the aforementioned interleukins such as canakinumab (anti IL-1beta), brodalumab (anti IL-17 receptor) and risankizumab (anti IL-23) are under evaluation with phase 1–2 trials showing controversial results [ 79 , 80 , 81 ].

Which biologic should I choose for my asthmatic patient?

When choosing a biologic medication for their patients with severe uncontrolled asthma, clinicians should always take into account the asthma endotype, clinical biomarkers, and patient-focused aspects (Fig 1 ).

figure 1

Algorithm for Selecting Ideal Biologic Treatment for severe uncontrolled asthma

Omalizumab should always be the first biological option in allergic non-eosinophilic severe asthmatics, with high levels of blood IgE, and with at least a documented positivity to a perennial aeroallergen. Contrariwise, patients with a non-allergic eosinophilic phenotype should be treated with an anti-IL-5 biological drug. Finally, anti- IL-4/IL-13 should be reserved to patients with severe eosinophilic type 2 asthma OCS dependent [ 8 ].

Given to the a lack of comparison studies, to date there are no recommendations about the selection of appropriate anti IL-5 biologic drug among those available. Hence, the choice is empirical and possibly shared between physician and patient.

According to GINA guidelines, a (at least) 4-month trial should be carried to evaluate asthma control. In the event of poor asthma control, a switch to a different biological treatment can be attempted if the patient meets the eligibility criteria.

Nevertheless, the right time and the right modality of switching from one biologic to another and the treatment time are still unknown. Large studies focused on biological drug switch in patients with severe asthma are ongoing and will help physicians to ease therapeutic strategies.

Conclusions

Severe asthma accounts for a small proportion of total asthma cases, but impose a heavy burden on health care system. Recent revelations of the T2 inflammatory pathways and the development of monoclonal antibodies acting on the T2 cascade has completely revolutionized the management of severe asthma, by introducing new, life-improving treatment options for this class of patients. This paves the way for a biomarker-driven personalized medicine. Strictly following GINA recommendations, the categorization of T2 molecular targets has allowed the identification of patients with severe asthma who would likely respond to specific biological molecules. However, the most suitable biological option for severe asthmatics with overlapping phenotypes is still unclear, thus requiring further discriminatory and predicting biomarkers which may allow a better patient selection.

Availability of data and materials

Not applicable.

Abbreviations

interleukin

inhaled corticosteroids

oral corticosteroids

immunoglobulin E

fractional exhaled nitric oxide

forced vital capacity

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

  • Monica J. Fletcher 1 ,
  • Ioanna Tsiligianni 2 ,
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  • 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  

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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.

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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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All authors participated in the expert panel meeting. M.F. and T.v.d.M. were responsible for screening the papers identified in the literature search for suitability for inclusion in the article. All authors developed the manuscript and approved the final version to be submitted.

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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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A significant update was made to both the Global Initiative for Asthma (GINA) in 2019 and the National Heart Lung and Blood Institute (NHLBI) asthma guidelines in 2020 for mild asthma. These groups no longer recommend short-acting beta-agonists (SABA) as monotherapy for mild (GINA) or mild-persistent (NHLBI) asthma. With the lag that can occur between guideline or evidence updates and changes in practice, this study sought to evaluate whether guideline adoption had occurred.

In this retrospective chart review, patient electronic medical records from a large healthcare system were evaluated from July 1 of 2021 to July 1 of 2022 to determine how many patients with mild asthma were prescribed as needed or daily inhaled corticosteroids (ICS) in addition to as needed SABA. The secondary outcome was to evaluate the incidence of exacerbations in patients with mild asthma, comparing those on guideline-directed therapy or not. In addition, we evaluated other patient factors increasing exacerbation risk in mild asthma.

For the primary outcome, of the 1,107 patients meeting inclusion criteria, 284 patients (26%) did not have documentation of guideline-directed therapy for mild asthma during the study period, while 823 (74%) were on guideline-directed therapy (Diff:48.7%; 95% CI:45.1 to 52.3%, p  < 0.001). For the secondary objective, 161 patients had an exacerbation (12% on guideline-directed therapy, 15.4% not on guideline-directed therapy). This difference in incidence of exacerbation between the two treatment groups was not statistically significant (Diff: -3.4%; 95% CI: -8 to 1.1%; p  = 0.133). In addition, being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among our patient population.

Conclusions

Nearly one-fourth of patients with mild persistent asthma were not on guideline-directed therapy, despite updates in asthma guidelines (GINA 2019, NHLBI 2020). Factors such as being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among patients with mild persistent asthma.

Asthma is a chronic respiratory disease characterized by airway inflammation, bronchial hyperresponsiveness, and reversible airflow obstruction [ 1 ]. Asthma is commonly classified as mild, moderate, or severe based on symptom frequency and severity, and these classifications guide treatment with the goals to reduce symptoms and prevent asthma exacerbations. The term mild asthma can be misleading, implying a low risk of serious disease sequelae. Because of this, some organizations have proposed no longer using the term mild to describe asthma [ 2 ]. According to the Centers for Disease Control (CDC), 25 million people in the United States are currently diagnosed with asthma, and a majority (50–75%) classified as having mild asthma [ 3 , 4 ]. Of those diagnosed with asthma, over 41% claimed to have one or more asthma exacerbations in a 12-month period, while nearly 2 million visited the emergency room due to uncontrolled asthma [ 3 ]. In addition, per a systematic review published in 2020, up to 22% of patients with mild asthma had a severe exacerbation in the previous year [ 5 ]. An earlier study published in 2007 found severe exacerbations in mild asthma represent 30–40% of asthma exacerbations requiring emergency consultation [ 6 ], highlighting the need for more effective treatment of mild asthma.

The Global Initiative for Asthma (GINA) and the National Heart Lung and Blood Institute (NHLBI) updated their asthma guidelines in 2019 and 2020, respectively. Both groups included a significant update to the recommended treatment of mild asthma, and the recommendation remains in the latest guideline updates. Before the 2019 GINA update, short-acting beta-agonist (SABA) monotherapy was considered appropriate only for step 1 therapy (mild intermittent asthma or very mild asthma). The fundamental change in the 2019 GINA guideline was the recognition that SABA monotherapy was no longer appropriate for any patient with asthma, regardless of severity classification. The 2020 NHLBI update continued to recommend SABA monotherapy for mild intermittent asthma, but no longer recommended it for mild persistent. Specifically, the use of daily inhaled corticosteroids (ICS) + as needed SABA, as needed ICS-long-acting beta agonist (LABA) or as needed ICS + as needed SABA are recommended over monotherapy with as needed SABA [ 2 , 7 ]. This change was prompted by evidence of ICS-containing treatment markedly reducing asthma hospitalizations, severe exacerbations, and death [ 8 , 9 , 10 ]. As these updates represent fundamental changes to the management of mild asthma, changes in prescribing patterns may lag behind guideline publication.

The purpose of this study was to evaluate how many patients with mild asthma were prescribed as needed or daily ICS in addition to as needed bronchodilator per the updated GINA and NHLBI guidelines. In addition, evaluation of incidence of exacerbations in patients with mild asthma, and examination of patient-specific factors that contribute to exacerbations, included but not limited to guideline-adherence, will also be assessed.

In this retrospective chart review, patient electronic medical records were evaluated from Banner Health, a large healthcare system with 30 hospitals and over 300 clinics across six states in the western part of the United States. This study was approved by Banner Health IRB. Charts were reviewed to determine how many patients with mild asthma were prescribed as needed or daily ICS in addition to as needed SABA. Charts were electronically reviewed from July 1, 2021, to July 1, 2022. Patients were included if they were a primary care patient age 12 years or older with an ICD-10 code(s) for mild or mild persistent asthma {ICD-10 codes: J45.30 (mild persistent asthma, uncomplicated), J45.31 (mild persistent asthma with (acute) exacerbation), J45.32 (Mild persistent asthma with status asthmaticus)}. A patient with a prescription, lab work, and/or encounter generated during study duration was considered an active patient. Patients were excluded if they were less than 12 years of age, had an active diagnosis for moderate persistent asthma or severe persistent asthma, an allergy to ICS-containing medications, or an active prescription for a nebulizer solution. The following data were collected: age, sex, race, payer type, active prescriptions for ICS, SABA, and ICS-LABA medications, prescriber, encounter diagnoses codes, location name, and date. The primary outcome was to evaluate how many patients with mild asthma were prescribed as needed or daily ICS in addition to as needed SABA. The secondary outcome was to evaluate the incidence of exacerbations {ICD-10 code: J45.901(unspecified asthma with (acute) exacerbation)} in patients with mild asthma, comparing those on guideline-directed therapy (daily ICS + as needed SABA, as needed ICS-LABA or as needed ICS + as needed SABA) or not (as needed SABA only). In addition to guideline-adherence, we evaluated other patient factors influencing exacerbation risk in mild asthma.

Statistical and data analysis

Categorical variables were reported as counts and percentages with differences between groups using chi-square, two-proportion, or Fisher’s exact test. Continuous measures were reported with means and standard deviation and/or, medians with interquartile ranges and differences between groups using student t-test. Lastly, a multivariate logistical regression was used to evaluate demographic and clinical characteristics most influencing asthma exacerbations. Minitab v20 was used for all statistical comparisons with alpha = 0.05.

Between July 1, 2021 and July 1, 2022, there were 1,107 patients who met inclusion criteria for this study. In evaluating the primary outcome, of those 1,107 patients, 284 patients (26%) did not have documentation of guideline-directed therapy for mild asthma during the study period, while 823 (74%) were on guideline-directed therapy (Diff:48.7%; 95% CI:45.1 to 52.3%, p  < 0.001). The mean age of those included in the study was 42.4 years for non-guideline-adherent patients and 43.7 years for guideline-adherent patients ( p  = 0.353) (Table  1 ). In addition, most of the population was female and Caucasian/white, with no statistical significance between the primary outcome groups ( p  = 0.781 and p  = 0.524, respectively) (Table  1 ). When examining provider type in respect to the primary objective (non-guideline-adherent versus guideline-adherent), 37% of patients seen in the primary care setting (primary care, family medicine and internal medicine clinics) have no documentation of guideline-directed therapy (Fig.  1 ).

figure 1

Facility/provider type and guideline adherence

*Includes other specialty clinics with a small representation such as Obstetrics/Gynecology., Ophthalmology, Neurology, Urology, Dermatology, Gastrointestinal, etc

Looking at this graph we see provider type and whether or not the patient was on guideline therapy. It may be hard to attribute patients to just one facility because they could be going to 2–3 different providers listed here. The numbers here add up to over 2,500, which is well above our 1,107 patients in our inclusion group

When assessing the secondary objective, 161 patients of the 1107 had an exacerbation during the study period. Of patients not on guideline-directed therapy, 12% experienced an exacerbation. Of patients on guideline-directed therapy, 15.4% had an exacerbation. This difference in incidence of exacerbation between the two treatment groups was not statistically significant (Diff: -3.4%; 95% CI: -8 to 1.1%; p  = 0.133).

The multivariate logistical regression model (see Fig.  2 ) represents those demographic and clinical characteristics most influencing an asthma exacerbation ( p  < 0.001). As shown in the figure, asthma exacerbations decreased incrementally by 1.2% for each additional year of age ( p  = 0.006). Males were about 39% less likely to have an exacerbation when compared to females ( p  = 0.01). Those with gastroesophageal reflux disease (GERD) were 63% more likely to have an asthma exacerbation ( p  = 0.02). Obese patients were 73% more likely to have an asthma exacerbation ( p  = 0.01), while those with bronchitis being about 81% more likely to have an asthma exacerbation, but this was not statistically different ( p  = 0.082). Lastly, three characteristics trended towards increased incidence of exacerbation, but were not statistically significant; patients with documented guideline-directed therapy were 38% more likely to have an asthma exacerbation, with documented history of Covid were 47% more likely, and with bronchitis were 81% more likely ( p  = 0.124, p  = 0.183, and p  = 0.082 respectively). In conclusion, being female, having GERD, and being obese were all statistically significant factors associated with having asthma exacerbations among our patient population. Other factors that were assessed but did not fit the logistical regression model were COPD, pneumonia, influenza, allergic rhinitis or sinusitis, smoking, and heart failure.

figure 2

Logistical regression model ( n  = 1107): Factors associated with at least one asthma exacerbation*

*Multivariate logistical regression including factors creating most parsimonious model. Overall model p  < 0.001, Concordance = 63.8%, R 2  = 3.57%, Hosmer-Lemeshow p  = 0.741

The results of this study indicate that about 3 in 4 (74%) patients with mild asthma did have documentation of guideline-directed therapy. Previously reported adherence rates to asthma guidelines have varied. A 2016 study assessed primary care adherence to the previous 2007 NHLBI asthma guidelines. This study found that 88% of patients had documented guideline adherence for reliever medication and 70.4% had guideline adherence to maintenance medication [ 11 ]. Data on adherence to the more recent guidelines is available from an international study that assessed adherence via provider and patient surveys. This 2021 study examined asthma therapy in four countries (Australia, Canada, China, and the Philippines) and found that 47% of patients were on guideline-directed therapy [ 12 ]. Our study found a greater percentage of patients on guideline-directed therapy (74% compared to 47%). This may be due to the increased amount of time from the updated guidelines release and/or data collection methodology.

Information in Fig.  1 allows an assessment of which facility had the greatest patient population not receiving guideline-directed therapy, which may help target providers with education on guideline updates. As shown in the results and in Fig.  1 , patients seen in the primary care setting (primary care, family medicine and internal medicine clinics) had the highest percentage of patients without guideline-directed therapy. This is valuable information as most patients with mild asthma will often be seen in a primary care setting due to the low severity of their asthma symptoms.

Regarding the secondary objective, patients in this study were found to be at a slightly greater risk for an asthma exacerbation if they were on guideline-directed therapy versus not; however, this objective was not statistically significant. The correlation of the timing of the asthma exacerbation and when the patient was started on guideline-directed therapy was unable to be determined based on the data gathered. During the study period, we assessed if the patient had an asthma exacerbation and if they were on guideline-directed therapy, but we did not assess the time at which these events occurred or in what order they occurred. In other words, during the study period, a patient who was not on guideline-directed therapy may have experienced an asthma exacerbation, and then was subsequently started on guideline-directed therapy. In addition, more acute or critical patients who were at a higher risk of having an asthma exacerbation may have been followed more closely by their practitioner which is why they were started on guideline-directed therapy sooner than other patients. Despite being followed more closely, they still had an asthma exacerbation due to being a higher risk patient. Finally, it is possible that some patients classified as having mild asthma actually have a more severe form of asthma and this may have contributed to the incidence of exacerbations.

Factors that were statistically significant with regards to exacerbation risk include female sex, GERD, and obesity. Previous studies have described morbidity and mortality risk factors for asthma, including high SABA use, increased age, ever smoking, and high blood eosinophils [ 13 ]. Few studies have specifically examined risk factors in patients characterized as having mild asthma. As discussed earlier, patients with mild asthma make up a large proportion of all patients with asthma, and these patients still experience exacerbations, but may not be treated with guideline-directed ICS therapy which is proven to reduce exacerbation risk [ 14 ]. Our study may add new insight into risk factors and treatment goals for patients with mild asthma, particularly optimizing treatment for GERD and obesity.

Limitations

Despite Banner Health having a large patient population, the number of patients meeting our inclusion criteria was low. This may be suggesting a low prevalence of mild persistent asthma, low documentation of patients as having mild asthma, or more severe patients because of the large influence of the academic facilities on excluded patients. The lower than expected number of patients in this study may have limited the results.

Additionally, a limitation to the study was our inability to correlate the timing of patient exacerbations and medication use. As a result, the number of patients on guideline-directed therapy who experienced an asthma exacerbation may have been falsely elevated.

Another limitation to this study was that it was difficult to determine which provider or facility was managing therapy because patients could have been visiting multiple facilities within the institution or even outside the institution. Lastly, we are unable to be certain that each patient had the correct diagnosis code entered on their problem list. This was an assumption that the provider diagnosed the patient correctly and updated their problem list accordingly.

Accurately assessing patients with mild asthma may be a limitation of this study, as patients with more severe disease may have been classified as having mild asthma due to underreporting of symptoms by patients or failure to recognize severity by providers, particularly primary care providers.

Finally, the number of asthma exacerbations experienced by each patient is unknown based on the data gathered. This study only characterized patients as having an exacerbation or not having an exacerbation during the study period. In addition to this, patients seen at an outside facility for asthma exacerbation treatment would not be accounted for in our electronic health record. Patient adherence to medication is something we cannot determine from this study but could have an impact on exacerbations.

Nearly one-fourth of patients with mild asthma in this study population were not on guideline-directed therapy, despite updates in asthma guidelines (GINA 2019 and NHLBI 2020). Factors such as being female, having GERD, and being obese are all statistically significant factors associated with having asthma exacerbations among patients with mild asthma. More work needs to be done to increase provider awareness regarding asthma guideline updates in outpatient and inpatient settings. Lastly, further studies in patients with mild asthma are needed to examine medication adherence, patient satisfaction, and exacerbation rate comparing patients on guideline-directed therapy versus those who are not.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Centers for Disease Control

Global Initiative for Asthma

National Heart Lung and Blood Institute

Short-Acting Beta-Agonists

Inhaled Corticosteroids

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Acknowledgements

We would like to thank the following pharmacists at Banner Health for their contributions to this project: Sophia Galloway, Virginia Boomershine, and Elizabeth Scheffel.

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BZ was involved in study design, literature search, data collection, data analysis, and manuscript preparation. JK was involved in study design, literature search, data collection, data analysis, and manuscript preparation. JG was involved in data collection and data analysis. All authors read and approved the final manuscript.

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Zerr, B.A., Kruse, J.M. & Glover, J.J. Evaluation of adherence to guideline-directed therapy and risk factors for exacerbation in mild asthma: a retrospective chart review. Allergy Asthma Clin Immunol 20 , 27 (2024). https://doi.org/10.1186/s13223-024-00888-6

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  • Inhaled corticosteroids
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March 26, 2024

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Researchers find new way to curb asthma attacks

by Dennis Thompson

Researchers find new way to curb asthma attacks

A protein that shuts down immune cells in the lungs could be key to a new treatment for asthma attacks, a new report says.

The naturally occurring protein , called Piezo1, prevents a type of immune cell called type 2 innate lymphoid cells (ILC2s) from becoming hyperactivated by allergens.

An experimental drug called Yoda1 that switches on Piezo1 reduced the activity of these immune cells in mice , alleviating asthma symptoms, researchers report.

"Given the importance of ILC2s in allergic asthma, there is an urgent need to develop novel mechanism-based approaches to target these critical drivers of inflammation in the lungs," researcher Omid Akbari, a professor at the University of Southern California's Keck School of Medicine, said in a news release.

Once triggered by an allergen, ILC2s drive the inflammatory cascade that cause airways to swell and tighten, making it tough for asthma patients to draw breath.

In mouse research, researchers found that activated ILC2s naturally produce a protein called Piezo1 that limits their activity.

In the absence of Piezo1, mouse ILC2s became more responsive to allergy signals and promoted even more airway inflammation.

On the other hand, Yoda1 caused Piezo1 to kick into action, reducing the activity of ILC2s.

Human ILC2s also produce Piezo1, researchers say, and the drug Yoda1 also worked on lab-engineered mice with the human immune cells .

"Remarkably, treatment of these humanized mice with Yoda1 reduced airway hyperreactivity and lung inflammation, suggesting that Yoda1 may be used as a therapeutic tool to modulate ILC2 function and alleviate the symptoms associated with ILC2-dependent airway inflammation in humans," Akbari said.

He said future research should focus on developing specific drugs to control Piezo1 in humans, which might help control or head off allergic asthma attacks .

The new study appears in the Journal of Experimental Medicine .

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Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters

  • Yuan-Ting Hsu 1 , 2 ,
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DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are “non-atopic”, lacking a clear etiology.

In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman’s rank correlation coefficients, multiple logistic regression, and multinomial logistic regression.

Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified.

The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

Phthalates, recognized as environmental contaminants and endocrine-disrupting chemicals, have demonstrated adverse effects on reproductive and developmental systems [ 1 , 2 , 3 , 4 ]. Recent studies indicate that metabolites of di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, may play a role in immune regulation and are associated with respiratory and allergic diseases [ 5 , 6 ]. Furthermore, DEHP exposure has been linked to an increased prevalence of childhood allergic asthma and adult asthma [ 7 , 8 , 9 ]. However, the connection between DEHP exposure and adult asthma lacks clarity, especially considering that a substantial portion of adult asthma cases is classified as “non-atopic” with an unclear etiology.

In asthma, genetic factors alone cannot account for the heightened morbidity, emphasizing the crucial role of environmental factors in triggering or exacerbating the disease. Given the heterogeneity of asthma as a chronic condition, exploring variations in DEHP exposure across different phenotypes could enhance our understanding of its impact on asthma heterogeneity. Building upon our prior research, we have illustrated diverse exposure risks to ambient air pollutants among current asthma patients with six distinct phenotypes. These phenotypes are defined by 18 demographic and clinical variables, resulting in Cluster A (older non-atopic and non-smoker females with late-onset asthma), Cluster B (primarily older atopic and non-smoker females), Cluster C (older ex-smoking males with second-hand smoke exposure), Cluster D (older non-smoking atopic females with high BMI and poor lung function), Cluster E (young males and current smokers with early onset and low Asthma Control Test (ACT) scores), and Cluster F (young, atopic, non-smoker males with early onset), laying a crucial foundation for unraveling the correlation between the environment and asthma [ 10 , 11 ].

Rodent studies support the notion that phthalates, acting as adjuvants at environmentally relevant doses, can induce respiratory and inflammatory effects in the presence of an allergen [ 12 ]. Cellular studies have shown that phthalates may modify both innate and adaptive immune responses [ 12 ]. Additionally, adult asthma is often associated with comorbidities, and asthma and type 2 diabetes mellitus (T2DM) are two common chronic diseases with an increasing incidence, possibly attributed to low-grade systemic inflammation and the use of corticosteroids and other medications [ 13 ]. However, research on the comorbidity of asthma with other diseases is currently limited. Ongoing efforts by researchers seek to deepen our understanding of the interrelationships between asthma and various illnesses, aiming to facilitate the development of more comprehensive and effective treatment methods and management strategies.

DEHP is widely employed to enhance the plasticity of plastic products, with approximately 97% of DEHP utilized in PVC products. Throughout the manufacturing, usage, and disposal phases, DEHP may be released into the environment due to processes like heating or wear and tear. Exposure to DEHP can arise from various sources, including dietary habits, daily life products, medical procedures, and drug use. In the general population, the primary routes of DEHP exposure are ingestion and inhalation. Significantly, the sources of DEHP exposure vary among different age groups, leading to corresponding differences in exposure concentrations [ 14 ].

In Taiwan, phthalates, including DEHP, have been identified in the human body [ 15 , 16 ], food [ 17 ], and soil [ 18 ]. Nevertheless, a notable gap persists in establishing the threshold for DEHP exposure in the context of asthma disease. This gap is primarily attributed to unclear sources of exposure, individual variations, and the heterogeneity of asthma.

Continuing from our prior research [ 10 , 11 ], this study employed the phenotypic clusters established in the previous investigation to examine variations in DEHP exposure among different phenotypes of asthma patients and further explored DEHP exposure levels across asthma and its comorbidities. This assessment utilized primary and secondary DEHP metabolites, MEHP and MEHHP, respectively, as markers of exposure, along with a panel of physiological biomarkers to investigate associations. The goal is to enhance our understanding of the health effects of DEHP exposure on asthma heterogeneity and its comorbidities.

Study participants

The case-control study comprised 365 individuals with “current asthma” attending clinical visits and 235 healthy controls undergoing routine checkups from Kaohsiung City in Taiwan, recruited between 2011 and 2015 (Figure. A.1 ). Healthy controls were individuals aged between 20 and 65 years without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, and other respiratory and allergic diseases. The cases were selected through simple random sampling from a population of 1,163 asthmatic subjects, who were phenotypically categorized into six clusters (for details, see Wu et al., 2022). To continue from our previous research [ 10 , 11 ], this study employed the phenotypic clusters established in previous study to explore the variations in DEHP exposure among different phenotypes of asthma patients. Cluster A was a group of older non-atopic and non-smoker females with late onset asthma, while Cluster B included primarily older atopic and non-smoker females. Cluster C included older ex-smoking males with second-hand smoke exposure, and Cluster D consisted of older non-smoking atopic females with high BMI and poor lung function. Cluster E included young male and current smokers with early onset and low Asthma Control Test (ACT) scores, while Cluster F consisted of young, atopic, non-smoker males with early onset. The study was approved by the ethics committees of the National Health Research Institutes in Miaoli, Taiwan, and the respective recruiting hospitals. Moreover, consent to participate was obtained from all participants involved in the study.

Data collection

To ensure the consistency and reliability of sample collection, processing, and storage, specific measures were implemented. Standardized procedures were utilized to collect urine and blood samples during a single visit by participants, minimizing potential variability. Venous blood was drawn using vacuum blood collection tubes (BD Vacutainer EDTA Blood Collection Tubes with K2 EDTA, Becton, Dickinson and Company, Franklin Lakes, NJ, US), while urine was collected in sterilized centrifuge tubes (BD Falcon Conical Tubes, Becton, Dickinson and Company, Franklin Lakes, NJ, US). These stringent procedures guaranteed standardized and controlled conditions for subsequent analysis. Following collection, all samples were promptly processed, separated into 15 c.c. sterilized centrifuge tubes for both plasma and urine, and then stored at -80 °C.

DEHP metabolites

The urinary metabolites of di(2-ethylhexyl) phthalate (DEHP), namely Mono(2-ethylhexyl) phthalate (MEHP) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), underwent analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS method utilized for examining DEHP metabolites has been previously published [ 19 , 20 ], with the limit of detection (LOD) for MEHP and MEHHP being 0.7 and 0.3 ng/mL, respectively.

Oxidative stress, sphingolipid metabolites, and inflammatory biomarkers

Urinary concentrations of Nε-(hexanoyl)-lysine (HEL) and 4-hydroxynonenal (4-HNE), an early and a late lipid peroxidation products [ 21 , 22 ], respectively, were measured using the HEL ELISA kit (JaICA, Nikken SEIL Co., Shizuoka, Japan) and the OxiSelect HNE Adduct Competitive ELISA Kit (Cell Biolabs, Inc., CA, USA). The minimum levels assessed for HEL and 4-HNE were 9.63 nmol/L and 0.005 µg/mL, respectively. Plasma concentrations of sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) were analyzed using ELISA kits (MyBiosource, MBS069092 and MBS2601367, respectively; CA, USA) with detection limits of 1 ng/mL and 0.5 ng/mL for S1P and C1P, respectively. In addition, plasma concentrations of inflammatory biomarkers including IL-1β, IL-6, IL-8, IL-10, IL-13, IL-17 A, IFN-γ, MCP-1, and MIP-1β were measured using the Bio-Plex Pro Human Cytokine Assay and Bio-Plex 200 Systems (Bio-Rad) by the service platform of SUU-FLOWER Co., Taiwan. The minimum levels assessed for IL-1β, IL-6, IL-8, IL-10, IL-13, IL-17 A, IFN-γ, MCP-1, and MIP-1β were 0.03, 0.23, 1.33, 0.20, 0.04, 0.06, 0.13, 0.21, and 3.48 ng/mL, respectively. The oxidative stress, sphingolipid metabolites, and inflammatory biomarkers were evaluated in triplicate according to the manufacturers’ provided experimental protocols. These analyses were conducted following the official instructions, demonstrating a coefficient of variation below 10%.

Statistical analysis

Asthma phenotypic clusters were classified using t-SNE (t-distributed Stochastic Neighbor Embedding) and implemented in R version 3.4.2 with the Rtsne package ( https://cran.rproject.org/web/packages/tsne/index.html ), which included 18 clinical and demographic parameters as previously described [ 23 ]. t-SNE is a powerful technique for visualizing and analyzing intricate high-dimensional data. Its strength lies in preserving local data structure, making it ideal for uncovering underlying patterns and clusters within such data. This method transforms complex data into a more manageable, low-dimensional form, facilitating the identification and understanding of data patterns and similarities. Hence, t-SNE is highly valuable for revealing hidden structures and clustering in data. To compare medians and proportions between cases and controls, or among phenotypic clusters and controls, we employed the Mann-Whitney U, Kruskal-Wallis H, and Chi-square tests. These tests assessed differences in continuous variable distributions between two or more groups (Mann-Whitney U and Kruskal-Wallis H) and differences in categorical variable distributions among multiple groups (Chi-square test). After performing the Kruskal–Wallis H test, we adopted to utilize Bonferroni test for post-hoc analysis. Spearman’s rank correlation coefficients were used to evaluate the correlation between the concentrations of urinary DEHP metabolites and oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. After adjusting for potential confounders such as age, BMI, atopy, education, and household income, multiple logistic regression was used to assess the association between urinary DEHP metabolites and the status of asthma. In addition, multinomial logistic regression analysis was used to assess the exposure risk of DEHP among different phenotypic clusters and controls. Statistical analyses were performed using SPSS (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY, USA) software, and P -values less than 0.05 were considered significant.

Table  1 illustrates the demographic differences between the case and control groups. Variables such as age, BMI, education, household income, atopy, asthma severity, FEV 1 %, FEV 1 (L), PEFR%, and various asthma comorbidities showed significant differences. Notably, there were no significant differences in smoking status or exposure to second-hand smoke at home or work. This table was referenced from Wu et al., except for education and household income variables [ 23 ]. Cases had a mean age and BMI of 56.0 and 25.1 kg/m 2 , respectively, whereas controls had a mean age and BMI of 53.6 and 24.3 kg/m 2 , respectively. The results indicated that the education level and household income were higher in the control group compared to the case group. Among cases and controls, the percentage of atopic participants was 78.9% ( n  = 288/365) and 5.1% ( n  = 12/235), respectively. In the case group, 68.5% (250/365) had severe/very severe asthma, while 31.5% (115/365) had mild/moderate severity of the disease. The mean FEV 1 and its %predicted and PEFR %predicted of cases and controls were 2.0 and 2.4 L, 78.2% and 87.6%, and 70.0% and 72.2%, respectively. The proportions of asthma with co-morbid conditions such as T2DM, hypertension, or a combination of T2DM and hypertension, as well as allergic rhinitis, were as follows: 12.3% ( n  = 45/365), 29.3% ( n  = 107/365), 7.4% ( n  = 27/365), and 66.0% ( n  = 241/365), respectively. Additionally, Table  A.1 revealed the frequency of using plastic packaging for both food and drinks. Cluster E exhibited the highest frequency, followed by Clusters C, B, D, A, and F.

Description of DEHP metabolites

The concentrations of MEHP, MEHHP, and MEHP + MEHHP in urine samples, as well as the MEHHP/MEHP ratio, were presented in Table  2 . The median concentration of MEHP (8.74 vs. 5.48 µg/g creatinine), MEHHP (20.63 vs. 11.86 µg/g creatinine), and MEHP + MEHHP (30.73 vs. 18.20 µg/g creatinine) in cases were significantly higher than in controls. However, there were no significant differences in the MEHHP/MEHP ratio between cases and controls (2.49 vs. 2.14). In comparison to controls, Clusters C and D exhibited significantly higher concentrations (median: 11.42 and 104.75, respectively, compared to 5.48). Additionally, Clusters A, C, D, and F demonstrated increased levels of MEHHP (median: 25.93, 20.70, 196.72, and 19.65, respectively, compared to 11.86) and MEHP + MEHHP (median: 39.16, 30.74, 301.47, and 25.01, respectively, compared to 18.20) when compared to the control group. However, no significant differences were observed in the MEHHP/MEHP ratio among these clusters or between the cases and controls.

Relationship between DEHP metabolites and asthma

Table  3 presents the risk of DEHP exposure in both case-control relationships and comparisons among phenotypic clusters and controls. After adjusting for age, BMI, atopy, education, and household income, the odds ratios (ORs) for MEHHP and MEHP + MEHHP in cases were significantly higher than those in controls (ORs = 4.49 and 3.50, respectively). The analysis from multinomial logistic regression revealed significantly higher ORs for MEHHP in various clusters compared to controls. Specifically, Clusters E (comprising young males and current smokers with early onset and low ACT scores), D (consisting of older non-smoking atopic females with high BMI and poor lung function), C (encompassing older ex-smoking males with second-hand smoke exposure), F (including young, atopic, non-smoker males with early onset), and A (comprising older non-atopic and non-smoker females with late-onset asthma) exhibited ORs of 3.42, 3.00, 2.94, 2.92, and 2.86, respectively. The ORs for MEHP + MEHHP were significantly elevated across all clusters compared to controls, with Clusters E, D, C, A, and F having ORs of 3.31, 2.95, 2.92, 2.83, and 2.75, respectively. Furthermore, the ORs for MEHP were notably higher in Clusters C and D compared to controls, with ORs of 1.78 and 1.70, respectively. Importantly, only Cluster B (mainly older atopic and non-smoker females) exhibited no significant association with DEHP exposure risks.

Table  4 presents the relationship between DEHP exposure and different classifications compared to controls, based on asthma severity, atopy, asthma comorbidity with T2DM or hypertension or both, and asthma comorbidity with allergic rhinitis. After adjusting for age, atopy, education, and household income, the ORs for MEHHP and MEHP + MEHHP were significantly higher in the severe/very severe group compared to controls (ORs = 3.85 and 3.19) with similar results being observed in the mild/moderate group (ORs = 3.60 and 2.98). Additionally, after adjusting for age, BMI, education, and household income, the ORs for MEHP, MEHHP, and MEHP + MEHHP were significantly higher in the atopic asthma group compared to controls (ORs = 1.56, 2.81, and 2.69), with similar results observed in the non-atopic asthma group (ORs = 1.61, 3.19, and 3.04). Following adjustments for age, BMI, atopy, education, and household income, asthma patients—whether they had T2DM, hypertension, or both conditions simultaneously—demonstrated significantly lower exposure risks for both MEHHP and MEHP + MEHHP compared to the control group, as detailed in Table  4 . Furthermore, after adjusting for age, BMI, atopy, education, and household income, the ORs for MEHHP and MEHP + MEHHP were significantly higher in the group with comorbidity of allergic rhinitis compared to controls (ORs = 19.98 and 10.47), with similar results being observed in the group without comorbidity of allergic rhinitis (ORs = 10.62 and 6.45).

Correlation between urinary DEHP metabolites to biomarkers

Table  5 (MEHP + MEHHP), Table  6 (MEHP), and Table  7 (MEHHP) show the results from the Spearman’s rank correlation analyses of urinary DEHP metabolites and oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. This study combined the levels of MEHP and MEHHP to explore the differences in exposure to primary and secondary metabolites among different phenotypes and comorbid conditions. The concentration of the sum of primary and secondary metabolites (MEHP + MEHHP) showed a higher correlation with MEHHP than with MEHP, emphasizing the significance of MEHHP exposure among these subgroups.

When stratified by asthma status, the correlation coefficients between MEHP + MEHHP and both MEHP (ρ = 0.84 vs. 0.81) and MEHHP (ρ = 0.92 vs. 0.94) were similar in both cases and controls. Clusters C and F consistently showed higher correlation coefficients between MEHP + MEHHP, MEHP, and MEHHP than Clusters A, B, and D. Specifically, for Cluster C, the correlations were MEHP + MEHHP vs. MEHP (ρ = 0.93), MEHP + MEHHP vs. MEHHP (ρ = 0.95), and MEHP vs. MEHHP (ρ = 0.81). For Cluster F, the correlations were MEHP + MEHHP vs. MEHP (ρ = 0.87), MEHP + MEHHP vs. MEHHP (ρ = 0.97), and MEHP vs. MEHHP (ρ = 0.77). In Cluster E, no significant correlations were observed among urinary DEHP metabolites. The correlation coefficients for MEHP + MEHHP vs. MEHP were ρ = 0.64, for MEHP + MEHHP vs. MEHHP were ρ = 0.64, and for MEHP vs. MEHHP were ρ = 0.26 (data not shown).

In the case group, we consistently observed significantly negative correlations between MEHP + MEHHP, MEHP, and MEHHP and IL-1β (ρ=-0.24, -0.27, and − 0.17), IL-6 (ρ=-0.31, -0.34, and − 0.20), IL-8 (ρ=-0.22, -0.25, and − 0.16), IL-13 (ρ=-0.20, -0.20, and − 0.17), and IL-17 A (ρ=-0.22, -0.22, and − 0.16). However, we found no significant correlation between these urinary DEHP metabolites and cytokines, except for the significantly positive correlation between MEHHP and IL-17 A (ρ = 0.14). Moreover, in Cluster B, we observed a significantly negative correlation between MEHP + MEHHP and MEHP to IL-1β (ρ=-0.32 and − 0.36), IL-8 (ρ=-0.30 and − 0.35), and IL-10 (ρ=-0.35 and − 0.29), respectively. Additionally, we found a significantly negative correlation between MEHP and IL-10 (ρ=-0.34).

We consistently observed significant positive correlations between the early lipid peroxidation product HEL and MEHP + MEHHP in both the case and control groups, as well as in the atopic group, asthma without T2DM group, asthma without hypertension group, and asthma without T2DM and hypertension group (ρ ranging from 0.17 to 0.27). Additionally, in the control group, we found a significant positive correlation between the late lipid peroxidation product 4-HNE and MEHP + MEHHP, MEHP, and MEHHP (ρ = 0.27, 0.22, and 0.23, respectively).

Table A.2 shows the Spearman’s rank correlation coefficients between urinary DEHP metabolites and total IgE levels. However, no significant positive or negative correlations were observed between urinary DEHP metabolites and total IgE levels.

DEHP is a widely utilized plasticizer in plastic products. Research indicated that exposure to DEHP might have influenced asthma heterogeneity and associated comorbidities. To address this concern, our aim was to examine variations in DEHP exposure among different asthma phenotypes and comorbidities, utilizing primary and secondary DEHP metabolites. This investigation included the integration of a panel of physiological biomarkers to explore these associations. Emphasizing the impact of DEHP on asthma heterogeneity and related comorbidities, including potential alterations at the biological and molecular levels, suggested a new research direction distinct from previous studies.

Exposure to DEHP stratified by asthma status

Numerous research findings indicate that the presence of urinary phthalate metabolite levels can serve as indicators of recent exposure to phthalates. However, these measurements may not accurately reflect long-term exposure due to the relatively brief half-lives associated with these chemical compounds [ 24 , 25 ]. Nonetheless, given the practically continuous exposure, these chemicals are considered pseudo-persistent [ 24 ]. In the Taiwan study led by Tsai and colleagues, children’s urine revealed MEHP and MEHHP levels of 12.2 µg/g creatinine and 55.3 µg/g creatinine (baseline median) [ 26 ]. In contrast, a study by Zhang et al. in China found the geometric mean of MEHP in adult urine was 1.97 µg/g creatinine, and MEHHP was 6.44 µg/g creatinine [ 27 ]. In South Korea, Yoon et al.’s research showed the MEHHP level in the urine of the elderly was 25.93 µg/g creatinine [ 28 ]. Additionally, adults with current asthma in this study had median urinary levels of 8.74 for MEHP and 20.63 for MEHHP, while healthy controls had levels of 5.48 and 11.86 µg/g creatinine, respectively. These results highlighted higher plasticizer exposure in Taiwan compared to other countries.

The study results indicated that in various subgroups, the exposure risk of DEHP’s secondary metabolite, MEHHP, was higher than the sum of primary and secondary metabolites (MEHP + MEHHP). We found that the DEHP exposure risk in asthma patients (all asthma patients) was significantly higher than that in the phenotypic clusters (Clusters A to F). We also observed significant but varying levels of exposure differences among different asthma phenotypes. In these asthma phenotypes, the ORs of MEHHP consistently exceeded those of MEHP + MEHHP. MEHP showed the highest exposure risk in Cluster C, followed by D among different phenotypes. These results underscored DEHP exposure in Clusters E, C, and D.

Existing data suggested that differences in food packaging and individual variations may contribute to exposure variations among different asthma phenotypes. Moreover, alternative exposure routes, such as skin exposure (resulting from the use of medical and household products) and inhalation exposure (due to air pollution), could also contribute to variations in DEHP exposure among phenotypic clusters. Regarding food and drinks with plastic packaging, according to the results of the questionnaire survey, participants from Cluster E had the highest frequency of using plastic packaging for both food and drinks, followed by Clusters C, D, B, A, and F. Regarding individual variations, it is widely recognized that the ratio of MEHHP to MEHP (MEHHP/MEHP) serves as an indicator of the efficiency of DEHP’s secondary and primary metabolites. Although no significant differences were found between cases and controls or among different phenotypes and controls, we still observed that the median and mean of MEHHP/MEHP in asthma patients were slightly higher than those in the control group. The comparison between cases and controls showed marginal significance.

When stratified by asthma severity (severe/very severe vs. mild/moderate), we observed higher exposure risks of MEHHP and MEHP + MEHHP in the severe/very severe groups compared to the mild/moderate groups. However, after evaluating asthma control using the Asthma Control Test (ACT), we found no significant correlation between DEHP exposure and asthma control. When considering disease comorbidity, the ORs for asthma alone were higher than those for asthma comorbid with T2DM, hypertension, or the combination of T2DM and hypertension. However, in cases where asthma was comorbid with T2DM or hypertension, we observed that MEHP exposure was not associated with asthma. Additionally, we observed significantly higher exposure risks of MEHP, MEHHP, and MEHP + MEHHP in non-atopic asthma compared to atopic asthma. Notably, this was the only grouping where the exposure risk of MEHP reached statistical significance. In the grouping of asthma comorbid with rhinitis (yes vs. no), we observed very high ORs, particularly in asthma comorbid with rhinitis, where the ORs for MEHHP and MEHP + MEHHP exceeded 10, and the ORs for asthma alone were also significantly higher than in other groups.

The significant and varying levels of DEHP exposures in the results highlight an increased risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, underscoring the complex relationship with asthma, especially concerning health effects. Notably, rodent studies provided evidence that phthalates, functioning as adjuvants at environmentally relevant doses, can induce respiratory and inflammatory reactions when combined with an allergen [ 12 ]. Cellular investigations have revealed that phthalates have the potential to modify both innate and adaptive immune responses [ 12 ]. Additionally, adult asthma often accompanied with other health conditions. Asthma and T2DM were prevalent chronic diseases on the rise, potentially linked to mild systemic inflammation and the use of corticosteroids and other medications [ 13 ]. The current study results supported an association between DEHP exposure and asthma or immune responses, aligning with the findings of the referenced studies on the risk of DEHP exposure and asthma status. We acknowledge the limitation of measuring only one primary metabolite, MEHP, and one secondary metabolite, MEHHP. Importantly, we observed that the concentration of the combined primary and secondary metabolites (MEHP + MEHHP) exhibited a stronger correlation with MEHHP than with MEHP alone, emphasizing the significance of MEHHP exposure within these subgroups.

DEHP exposures and a panel of physiological indicators in asthma patients

Interestingly, we observed a consistent and negative correlation between DEHP metabolites and the selected cytokines when examining multiple physiological indicators. However, it is crucial to note that this finding may be influenced by factors such as peripheral blood collection, other prominent environmental health factors, or the medication habits of current asthma patients, all of which could potentially impact their physiological regulation. This observation may also suggest exploring a new direction in understanding the relationship between DEHP exposure and physiological markers, potentially diverging from previous interpretations. To confirm these results, more studies of various types and larger sample sizes are required.

Despite using different classifications for asthma conditions, no significant correlation was found between total IgE levels and the levels of DEHP metabolites in urine. While the link between DEHP and total IgE was not significant, noteworthy associations emerged with asthma severity and specificity. As asthma is a heterogeneous disease, based on a comprehensive consideration of 18 demographic and clinical parameters, we categorized asthma patients into six different phenotypes. We observed that among asthma patients with different phenotypes, Clusters D (value of 25th, 50th, and 75th percentiles: 41.3, 138.5, and 298.0 U/mL) and F (36.8, 103.0, and 301.0 U/mL) exhibited relatively higher total IgE levels, indicating higher DEHP exposure risks, surpassed only by Cluster E of current smokers and Cluster C of ex-smokers. These results highlight the complex interplay between environmental exposure and asthma immunology.

It was also perplexing to note that most cytokines presented a significant negative correlation with DEHP concentration. Specifically, IL-1β, IL-6, IL-8, IL-13, and IL-17 in the case group showed consistent results. The reason for these findings is, at present, unclear. It could be that the circulating levels of cytokines may not be indicative of those at sites of tissue mucosa, or it might be that under certain circumstance, DEHP exposure may cause immune cell death, thereby reducing the levels of immune cell-derived cytokines. It is also likely that the primary DEHP metabolite, MEHP, known to activate PPARγ (peroxisome proliferator-activated receptor gamma), differentially regulate the immune response in the context- and cell-dependent manner. While these possibilities could not be discerned at this time, our recent research has revealed that environmental pollutants played a role in the development of allergic asthma and interact with innate immunity, holding significant importance [ 6 ]. Long-term exposure to DEHP promoted allergic lung inflammation, partly through the alteration of CD8α + dendritic cells (DCs) differentiation via the MEHP-PPARγ axis. When mice were exposed to DEHP at a human tolerable daily intake dose, it led to changes in DCs in the spleen, DC progenitors in the bone marrow, decreased IL-12 production in splenic DCs, and increased T helper 2 polarization, it exacerbated allergic lung inflammation in mice. The upregulation of PPARγ enhanced the migration and Th2-priming capacity of lung DCs, indicating a pro-inflammatory role for PPARγ in Th2-mediated allergic lung inflammation [ 5 ]. Furthermore, systemic treatment with a pharmacological PPARγ agonist has shown to reduce inflammation, partly by inhibiting DC function in various inflammatory diseases, including asthma [ 29 ]. These findings supported the notion that PPARγ undergoes immune suppression following DEHP exposure, potentially altering the immune response in the body.

It was reasonable to explain that DEHP exposure in the participants of this study did not significantly worsen asthma symptoms (stratified by severity) or elicited an immediate response (correlation between DEHP exposure and a panel of inflammatory markers). It was also possible that their levels of DEHP exposure were not accurately reflected in total IgE levels. Our findings reveal a statistically significant negative correlation between urinary DEHP metabolites—whether MEHP, MEHHP, or MEHP + MEHHP—and various sphingolipids and cytokines. The unexpected negative correlation between DEHP and these biomarkers of inflammatory response contrasts with previous studies that hypothesized DEHP stimulates the inflammatory process [ 30 ]. However, a study using rat alveolar macrophages suggested that MEHP can induce both pro-inflammatory and anti-inflammatory responses [ 31 ]. Additionally, research on human lung epithelial cells indicated a non-linear, inverted U-shaped relationship between the effects of phthalates, including MEHP, on cytokines such as IL-6 and IL-8 [ 32 ]. Moreover, a mouse study found a significant negative correlation between ingesting DMP (Dimethyl phthalate, a plasticizer) and blood levels of IL-4, IL-6, and IFN-γ. The authors demonstrated that DMP confirms this finding through immune toxicity induced by oxidative damage and mechanisms such as cell apoptosis [ 33 ], aligning with recent epidemiological research results [ 34 ]. Although there is currently no conclusive explanation for the observed correlation between DEHP and cytokines in our study, and phthalates may share similar metabolic and toxicological mechanisms, the higher DEHP exposure in our study population compared to other studies cannot be ruled out. The potential impact of high exposure on immune toxicity requires further validation through subsequent relevant basic and epidemiological research.

Positive correlations were identified between urinary DEHP metabolite concentrations and HEL in various subgroups, with the control group displaying a significant positive correlation with 4-HNE. Despite the absence of a correlation between DEHP exposure and HEL in different asthma phenotypes, a connection was observed between DEHP exposure and elevated HEL levels in asthma patients without comorbidities such as T2DM, hypertension, or the combination of T2DM and hypertension. These findings indicate that HEL may serve as an early marker for lipid peroxidation and a more sensitive indicator of environmental exposures, including DEHP, in both asthma patients and healthy control groups. Elevated oxidative stress triggers enzymatic processes that enhance sphingolipid (SL) metabolism, generating bioactive lipid metabolites and crucial signaling mediators. Notably, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) play pivotal roles in regulating angiogenesis and inflammation. S1P, for instance, governs various inflammatory processes through its interaction with S1P receptors (S1PRs), influencing mast cell responses, airway smooth muscle contraction, and airway hyperreactivity. In the context of asthma comorbidities, the total of MEHP and MEHHP pose a co-exposure risk. The subsequent response, characterized by increased HEL and decreased S1P levels, serves as a common factor with varying degrees of risk, suggesting potential differences in regulatory mechanisms.

Novelties and limitations

In summary, our discussion on the clinical significance of DEHP exposure in different asthma phenotypes and comorbidities involved a thorough consideration of various factors. We conducted a detailed analysis of asthma phenotypes, covering symptom severity, disease duration, and treatment response. Simultaneously, we assessed comorbidities like T2DM and hypertension to compare DEHP exposure risk with asthma alone, offering insights into its clinical significance for patients with multiple chronic conditions. We also investigated the impact of DEHP exposure on asthma control, using tools like the ACT to evaluate its effects on quality of life and treatment outcomes. When exploring genetic and immune differences among asthma phenotypes, we focused on individual characteristics influencing DEHP response, aiding in determining sensitivity and potential variations in different immune backgrounds. Considering the influence of dietary habits on DEHP exposure, particularly in foods and beverages with plastic packaging, our analysis of patients with different asthma phenotypes provided deeper insights into potential effects on DEHP concentrations. These comprehensive studies have provided a more holistic understanding of the clinical impact of DEHP exposure on various asthma phenotypes and comorbid patients, leading to more insightful research results and clinical recommendations. This study had several limitations. Firstly, being a case-control study, it was unable to establish direct causal relationships between DEHP exposures and physiological indicators. Secondly, the limited availability of information on asthma comorbidities among the study participants restricted the exploration of potential risk factors associated with DEHP exposure and its impact on asthma comorbidities. Additionally, the lack of detailed questionnaire data related to dietary habits was another limitation. Considering more potential confounders (education and household income), the sample size within certain clusters is quite small (Table 3 and 4 ), which may be mentioned among the study limitations.

DEHP, a widely used plasticizer in plastic products, may influence asthma heterogeneity and associated comorbidities. To address this, we examined DEHP exposure variations across asthma phenotypes and comorbidities using primary and secondary DEHP metabolites. Integrating physiological biomarkers, we highlighted DEHP’s impact on asthma and comorbidities, signaling a unique research direction. Results revealed higher risk of DEHP’s secondary metabolite, MEHHP, in various subgroups, surpassing the sum of primary and secondary metabolites. Asthma patients, especially in Cluster E, using plastic packaging extensively, showed elevated DEHP risk. Asthma patients without comorbidities had higher DEHP ORs, and severe/very severe asthma exhibited higher DEHP ORs than mild/moderate cases. Notably, allergic rhinitis was linked to higher DEHP ORs. However, asthma patients without allergic rhinitis still had higher DEHP ORs, underscoring a complex relationship. We observed a consistent negative correlation between DEHP metabolites and selected cytokines across physiological indicators. It is essential to acknowledge potential influences, such as blood collection and environmental factors. This suggests an innovative research avenue, requiring further epidemiological and animal studies to explore the potential physiological effects of this phenomenon with more robust evidence.

Data availability

Not applicable.

Abbreviations

Di-(2-ethylhexyl) phthalate

Nε-(hexanoyl)-lysine

4-hydroxynonenal

Asthma control test

Mono(2-ethylhexyl) phthalate

Mono(2-ethyl-5-hydroxyhexyl) phthalate

Liquid chromatography-tandem mass spectrometry

Sphingosine-1-phosphate

Ceramide-1-phosphate

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This work was supported, in part, by grants from National Health Research Institutes, Taiwan (EOPP10-014, EOSP07-014 and NHRI-102A1-PDCO-03010201) and Ministry of Health and Welfare, Taiwan (EODOH01), National Science Council (NSC 102-2314-B-037-052), Ministry of Science and Technology (MOST 103-2320-B-110-001), and Academia Sinica (BM-102021170), Taiwan. These funding agencies had no role in study design, the collection and analysis of data, the decision to publish or the preparation of the manuscript.

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Yuan-Ting Hsu, Chien-Jen Wang, Huei-Ju Liu, Hua-Ling Chen & Shau-Ku Huang

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Yuan-Ting Hsu: Methodology, Software, Validation, Formal Analysis, Data Curation, Writing - Original Draft, Writing - Review & Editing, and Visualization. Chao-Chien Wu, Chin-Chou Wang, Chau-Chyun Sheu, Yi-Hsin Yang, Ming-Yen Cheng, Ruay-Sheng Lai, Sum-Yee Leung, Chi-Cheng Lin, Yu-Feng Wei, Yung-Fa Lai, Meng-Hsuan Cheng, Huang-Chi Chen, Chih-Jen Yang, Chien-Jen Wang, Huei-Ju Liu, and Hua-Ling Chen: Investigation, Resources, Data Curation, and Project administration. Chih-Hsing Hung, Chon-Lin Lee, and Ming-Shyan Huang: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing - Review & Editing, Supervision, Project administration, and funding acquisition. Shau-Ku Huang: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing - Original Draft, Writing - review & editing, Supervision, Project administration, and funding acquisition. All of the authors’ approval of final document.

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Hsu, YT., Wu, CC., Wang, CC. et al. Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters. Respir Res 25 , 139 (2024). https://doi.org/10.1186/s12931-024-02764-8

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Anxiety, depression, and asthma: New perspectives and approaches for psychoneuroimmunology research

The field of psychoneuroimmunology has advanced the understanding of the relationship between immunology and mental health. More work can be done to advance the field by investigating the connection between internalizing disorders and persistent airway inflammation from asthma and air pollution exposure. Asthma is a prominent airway condition that affects about 10% of developing youth and 7.7% of adults in the United States. People who develop with asthma are at three times increased risk to develop internalizing disorders, namely anxiety and depression, compared to people who do not have asthma while developing. Interestingly, sex differences also exist in asthma prevalence and internalizing disorder development that differ based on age. Exposure to air pollution also is associated with increased asthma and internalizing disorder diagnoses. New perspectives of how chronic inflammation affects the brain could provide more understanding into internalizing disorder development. This review on how asthma and air pollution cause chronic airway inflammation details recent preclinical and clinical research that begins to highlight potential mechanisms that drive comorbidity with internalizing disorder symptoms. These findings provide a foundation for future studies to identify therapies that can simultaneously treat asthma and internalizing disorders, thus potentially decreasing mental health diagnoses in asthma patients.

1. Introduction

Internalizing conditions are characterized by inward-focused symptoms, including sadness, fear, and social withdrawal, and understanding of mechanisms underlying internalizing disorders, namely anxiety and mood disorders, has increased dramatically in recent years ( Wilner et al., 2016 ). Overall in the United States, mental health conditions affect 20.6% of the adult population, and anxiety disorders and major depression affect 19.1% and 7.1% of adults, respectively ( NIH Mental Health Information: Statistics, 2021 ). Lifetime risk was reported as 31% for developing any anxiety disorder and 21.4% for any mood disorder by age 75 years, and this was greater in females compared to males ( Altemus, 2006 ; Costello et al., 2003 ; Jalnapurkar et al., 2018 ; Katon et al., 2007 ; Kessler et al., 2007 ; Strine et al., 2008 ). Brain regions (e.g. amygdala, hippocampus, prefrontal cortex) and neurotransmitters/proteins (e.g. serotonin, brain derived neurotrophic factor (BDNF), gamma-Amniobutyric acid, glutamate) implicated in these types of disorders are becoming better understood, and their activation pathways are harnessed for treatment of mental health conditions ( McEwen et al., 2012 ; Rieder et al., 2017 ; Spear, 2000 ). An important predictor of depression, anxiety, and other mental health conditions is respiratory function/problems (i.e. asthma, exposure to air pollution), and mental health research may well be served by understanding mechanisms specific to these precursors. (see Fig. 1 )

Fig. 1

Jasmine Caulfield. Jasmine's neuroimmunology research journey began at the University of Delaware in 2013 as an undergraduate research assistant in Dr. Jaclyn Schwarz's laboratory. She earned her bachelor's degree in May 2015 with a double major in Neuroscience and Cognitive Science. She completed her Neuroscience undergraduate thesis with Dr. Schwarz's guidance using a rodent model to investigate neuroimmune function, microglia, and the impact of a neonatal immune challenge on juvenile cognition and anxiety-related behavior. Jasmine began her doctoral training with Dr. Sonia Cavigelli in August 2015 ​at Pennsylvania State University. Her research under Dr. Cavigelli utilized a mouse model for adolescent asthma to investigate long-term anxiety- and depression-related ramifications in adulthood using metrics including behavior, HPA function, and cytokine gene expression. During her time at Penn State, Jasmine earned numerous dissertation awards, including the Alumni Association Dissertation Award, a prestigious university-wide dissertation award only granted to a select few graduate students to recognize outstanding achievements in scholarship and other professional accomplishments. Jasmine earned her PhD in Neuroscience in June 2020, and in August 2020 she began a postdoctoral associate position at Yale University in the department of Medical Oncology with Dr. Harriet Kluger to develop novel therapies for treatment of kidney cancer, melanoma, and brain metastases. Jasmine has a strong passion for mentorship in neuroscience and served as a peer mentor to help new neuroscience graduate students transition to the program each year while at Penn State. Additionally, she trained over 30 undergraduate research assistants (including 5 thesis students) in the Cavigelli lab in all aspects of research, from reading and dissecting scientific literature, to collecting, analyzing, interpreting, and presenting data in a poster format for scientific conferences. Jasmine looks forward to continued opportunities for research progress and mentorship in neuroimmunology research in the years to come.

Psychoneuroimmunology research broadly focuses on understanding the interaction of mental health and immunology. Specifically related to mental health, elevated cytokine levels have been associated with anxiety and depression disorders. For example, elevated interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and C reactive protein are more frequently observed in patients with anxiety compared to controls ( Costello et al., 2019 ). Elevated circulating IFN-γ and interleukin (IL)-6 were observed in major depression disorder (MDD) compared to control subjects ( Gabbay et al., 2009 ; Mitchell and Goldstein, 2014 ). Increased peripheral cytokine levels activate brain cells, including microglia and astrocytes, to promote cytokine production in the brain, leading to manifestation of mood disorder symptoms ( Brites and Fernandes, 2015 ; Capuron and Miller, 2011 ). Gene and protein IL-1β, TNF-α, and IL-6 levels were elevated in prefrontal cortex samples from people with DSM-IV-diagnosed depression-related conditions who committed suicide compared to non-depressed patient samples ( Pandey et al., 2012 ). Enlarged, hyperactive microglia in this and other emotion-related brain regions are associated with increased depression- and anxiety-like behavior in rodents, and sex differences exist in glial and mental disorder development ( Schwarz and Bilbo, 2012 ; Stein et al., 2017 ). There is still much work needed to optimize treatments for patients with mental health conditions, however recent mechanistic studies highlight an important role of the immune system in the brain and mental health.

Psychoneuroimmunology research focuses on immune-brain interactions and how immune function relates to mental health. Significant work details how short-term/transient immune and stress challenges that briefly activate the immune system also alter behavior ( Arad et al., 2017 ; Cavigelli et al., 2018 ; Gibb et al., 2011 ; Gibney et al., 2013 ; Henry et al., 2008 ; Wohleb et al., 2012 ). A broader scope in this work will help understand how immune activation affects mental health, particularly in the case of chronic immune activation. This will require a better integration of studies in the psychoneuroimmunology literature that use different kinds of long-term immune system activation and outcome measures that are highly specific to mental health symptoms. The purpose of this review is to highlight how chronic challenges to the immune system, specifically those associated with asthma and air pollution, cause lasting inflammation that can have specific mental health implications. Preclinical models and clinical research are only beginning to identify important connections between immune system and brain areas/pathways associated with mental health conditions. This work serves as the foundation to improve treatment for patients affected by chronic immune and comorbid mental health conditions.

2. Asthma and air pollution: lung immunology and mental health relationship

Asthma affects ∼10% of youth in the United States and ∼36% of youth worldwide, making it the most common chronic health challenge that children and adolescents experience ( Akinbami et al., 2012 , 2016 ; Mattiuzzi and Lippi, 2020 ). Asthma can persist throughout life, and overall asthma prevalence as of 2018 in the United States was 8.9% ( Zhou and Liu, 2020 ). Sex differences exist in asthma that differ by age, where asthma is more prevalent and experienced as worse disease in boys under 10 years of age but in girls at/after puberty and in adulthood ( Flores et al., 2019 ; McCallister and Mastronarde, 2008 ; Skobeloff et al., 1992 ). Lung inflammation is a hallmark characteristic of asthma. Dendritic cells in the airway stimulated by antigens promote a T H 2 immune response featuring critical cytokines, including IL-4, IL-5, and IL-13, that promote recruitment of eosinophils, proliferation of mast cells, mucus buildup, and B cell class switching to immunoglobulin E ( Burrows et al., 1989 ; Busse and Lemanske, 2001 ; Fujita et al., 2012 ; Gour and Wills-Karp, 2015 ; Holgate, 2008 ; Kips, 2001 ). Asthma has a distinct immunology that can lead to many outward symptoms, including bronchoconstriction, wheezing, and mucus production ( Gordon, 2008 ). Such chronic immune activation and inflammatory symptoms experienced early in development can lead to perpetuating later-life health consequences.

Air pollution serves as a significant stressor for healthy living, can affect respiratory health, and is associated with elevations in cytokines and immune molecules. Individuals with greater exposure to air pollution demonstrated higher breath levels of TNF-α, leukotriene B 4 , and nitrous oxide derivatives compared to those with lower exposure ( Dauchet et al., 2018 ; Vossoughi et al., 2014 ). Air pollution exposure during early life was also associated with higher circulating IL-6 and IL-10 ( Dauchet et al., 2018 ). Urban environments are detrimental for human health due to high exposure to air pollution among other health stressors, and as such, urbanization is a significant risk factor for asthma onset (e.g. odds ratio: 1.2, 95% CI: 1.04 to 1.5, p ​= ​0.01) and worse asthma disease ( Aligne et al., 2000 ; Beasley et al., 2015 ; Kurt et al., 2016 ; Theoharides et al., 2012 ; To et al., 2012 ). Interestingly, people living in urban environments are at greater odds to develop anxiety (21%) and mood disorders (39%) compared to people in rural environments ( Peen et al., 2010 ). Thus, it is important to consider how external environmental factors like air pollution affect a person's asthma, immunology, and mental health.

One important downstream co-morbidity observed after having childhood asthma is later-life anxiety and/or depression, with onset as early as adolescence. A recent meta-analysis indicated anxiety disorders were prevalent in almost 23% of adolescents with asthma, as compared to 7–8% prevalence in the general youth population ( Dudeney et al., 2017 ; Ghandour et al., 2019 ). Adolescents with asthma also had higher incidence and likelihood to develop major depression compared to controls ( Chen et al., 2014 ). Other survey studies have indicated between 16.3 and 35% of participants met criteria for anxiety or depressive disorder diagnoses, and these conditions were more common in people with worse asthma symptoms ( Katon et al., 2007 ; Richardson et al., 2006 ; Vila et al., 2000 ). Similar findings are indicated in rodent models of asthma, where mice or rats exposed to allergens later exhibited increased anxiety-like and depression-like behaviors ( Caulfield et al., 2017 , 2018 ; Lewkowich et al., 2020 ; Tonelli et al., 2009 ). While research clearly shows a link between having asthma in early life and subsequent development of internalizing disorder symptoms, work has just begun to uncover potential driving mechanisms. A focus on this connection between asthma-related immunology and mental health would help fill this gap in the literature and help broaden the scope and depth of psychoneuroimmunology research.

3. Preclinical models of asthma

Recent preclinical studies have begun to investigate broad mechanisms underlying the connection between asthma and anxiety. In one model, inflammation and bronchoconstriction were independently induced with chronic house dust mite (HDM) and methacholine (MCH) exposure, respectively, during development ( Caulfield et al., 2017 , 2018 , 2021b ). HDM exposure stimulated increased expression of genes associated with an acute inflammatory response (e.g. increases in IL-5, IL-1β mRNA). Increased airway inflammation, mucus, and T H 2 cytokine gene expression were also observed in adulthood three months after the end of HDM exposure, indicating a long-term inflammatory effect. Mice exposed to HDM demonstrated depressive-like behaviors three months after exposures ceased, demonstrating a lasting effect on mental health paired with the persistent airway inflammation ( Caulfield et al., 2017 , 2018 , 2021b ). After chronic exposure to MCH throughout development, mice demonstrated increased anxiety-like behaviors and increased corticosteroid production in adulthood, along with decreased brainstem serotonin transporter expression, increased hippocampal corticotropin releasing hormone (CRH) receptor 1 (Crhr1), and elevated hippocampal serotonin receptor 1a expression ( Caulfield et al., 2017 ). Further, marginal increases in hippocampal microglial activation were observed in early adulthood following chronic MCH exposure ( Caulfield et al., 2021b ). Together, these results reveal that central nervous system changes, specifically related to serotonin- and CRH-signaling pathways, are implicated in the relationship between different asthma and internalizing disorder symptoms.

In another rodent study on broad immune effects related to post-traumatic stress disorder and panic disorder, adult male mice exposed to HDM did not show anxiety-like or depression-like behavior (elevated zero maze and forced swim test, respectively). However, exposure to HDM did produce increased freezing behavior in a contextual fear paradigm, global brain increases in IL-17 ​A-secreting cells, and elevated neuronal activation in emotion-associated brain regions (prefrontal cortex and basolateral amygdala) ( Lewkowich et al., 2020 ). Another rodent study indicated that re-exposure to ovalbumin (OVA) caused increased anxiety-like behaviors in mice as well as increased activity in and greater activation of microglia and astrocytes in the amygdala and medial prefrontal cortex ( Dehdar et al., 2019 ). Together, these findings indicate that peripheral immune challenges to stimulate allergic asthma symptoms also alter prefrontal cortex, hippocampus, and amygdala activity and immune cell activity in the brain. These are all potential pathways that may influence symptoms associated with anxiety and depression and set the stage for further investigation into underlying mechanisms.

Other preclinical research has been conducted to identify behavioral and brain changes associated with asthma therapy. Inhaled corticosteroids, a common class of medications for asthma, are used to control lung inflammation by reducing immune cells in the airway and preventing cytokine production and other factors that enhance inflammation ( Barnes, 2010 , 2017 ; Crim et al., 2001 ; Hossny et al., 2016 ). The two most common corticosteroids used are fluticasone propionate (FLU) and budesonide. In one study, mice were chronically exposed to HDM and FLU during development – a period that is analogous to when asthma is most prevalent in humans. FLU exposure led to reduced weight gain during development, elevated basal glucocorticoid concentrations in circulation, and reduced anxiety-like behavior in adulthood. Additionally, HPA function-associated gene expression in the hippocampus (CRH, Crhr1, and CRH receptor 2), circulating corticosterone, and anxiety-like behavior were associated with one another ( Caulfield et al., 2021a ). Another study, which utilized OVA and budesonide in adolescent female mice, demonstrated that OVA exposure increased anxiety-like behavior, decreased dendritic length and number of spines on hippocampal pyramidal cells, and increased hippocampal BDNF expression. Budesonide reversed some anxiety-like behaviors and the number of dendritic spines, but it did not affect dendrite length in hippocampal neurons or BDNF expression ( Zhuang et al., 2018 ). Overall, animal studies suggest that corticosteroid treatment during development may alleviate anxiety-related behavioral symptoms associated with allergic asthma but not associated hippocampal function. In humans, worse anxiety and depression symptoms have been reported in clinical asthma patients who are corticosteroid dependent, and asthma patients with depression suffer from worse asthma symptoms and increased emergency room visits ( Ahmedani et al., 2013 ; Amelink et al., 2014 ). A better understanding of how inhaled corticosteroids affect mental health pathways in asthma could inform novel clinical therapies for patients that exhibit asthma and develop comorbid internalizing disorders.

4. Preclinical models of air pollution

Some rodent studies have investigated airway inflammation in the context of air pollution and its relation to anxiety and depression-like behaviors, and the results are informative and represent real-world human experiences. One study investigated the effects of exposure to traffic-related particulate matter in utero and during early development in male rat pups. Rats exposed to pollution particulates had decreased circulating IL-18 and vascular endothelial growth factor, increased anxiety-like behavior, and less developed neurons in the anterior cingulate and hippocampus ( Nephew et al., 2020 ). Another study chronically exposed male mice to particulate matter for nine months beginning in adolescence, which resulted in increased depressive-like behaviors in the forced swim test and increased anxiety-like behavior on the open field test. Mice exposed to this particulate matter also demonstrated increased pro-inflammatory cytokine expression (TNF-α, IL-1β) and decreased neuronal spine density in the hippocampus ( Fonken et al., 2011 ). Thus, these results provide further evidence toward the importance of understanding long-term effects of chronic immune activation on mental health measures. Research on young male and female mice aimed to determine how maternal stress and prenatal exposure to diesel exhaust pollution would affect mental health-related outcomes in the offspring. Male and female offspring differentially regulated IL-10 expression in the brain in utero (embryonic day 18), and only males exposed to pollution exhibited increased IL-1β in the brain in adulthood. Stress and pollution exposure together resulted in a synergistic increase in Tlr4 gene expression in the brain at postnatal day 30 and increased anxiety-like behavior in adulthood ( Bolton et al., 2013 ). Thus, exposure to air pollution as an immune stressor can affect the brain and mental health-related outcomes, suggesting possible mechanisms to further explore to better understand how such immune challenges are driving behavior.

5. Clinical asthma and mental health connections

Clinical research on asthma patients has established a significant comorbidity with mental health conditions, especially in younger populations ( Dudeney et al., 2017 ; Peters and Fritz, 2011 ). In recent years, studies have investigated brain areas that may play a mechanistic role in asthma and internalizing disorder comorbidity in humans using magnetic resonance imaging (MRI). For example, patients with asthma demonstrated abnormal structural connectivity in the bilateral frontal gyri, right-side temporal and parietal cortices, and limbic regions compared to healthy controls, suggesting altered emotion-related brain area function in patients with asthma ( Gao et al., 2019 ). Activity in emotion-processing brain circuits (e.g. anterior insula) has also been associated with increased inflammation in asthma ( Rosenkranz et al., 2012 ). In one study, patients with asthma were assessed to have high or low chronic life stress. Following the Trier Social Stress Test, those with low stress had increased glucose metabolism in the anterior insula and decreased glucose metabolism in the mid-cingulate cortex and higher levels of airway inflammation as measured by fraction of exhaled nitric oxide (FeNO) compared to high-stress patients. Additionally, worse asthma control was associated with worse internalizing disorder symptoms (anxiety and depression). Expression of IL-17 pathway cytokines in sputum may serve as markers for the relationship between psychological stress and asthma-related inflammation ( Rosenkranz et al., 2016 ). In patients with asthma, smaller volume of pallidum was associated with increased anxiety in response to a stressor, whereas in controls the anxiety responses were associated with hippocampus and amygdala volume, suggesting that different regions are involved in anxiety pathology in asthma ( Ritz et al., 2020 ). Further, among participants with asthma, those with depression demonstrated decreased homogeneity in the pallidum compared to that of participants without depression, and this was associated with worse and unusual asthma symptoms ( Xiong et al., 2016 ). Together, these findings implicate critical limbic and emotion-related brain areas in the pathology of asthma that may serve as links to internalizing disorders. These studies suggest that these brain regions should be an area of focus for further research on asthma and mental health comorbidity. In addition, these areas could be targeted for improved treatment to prevent internalizing disorder development in people with asthma.

6. Conclusions and future directions

To better understand how different aspects of immunology are associated with mental health outcomes, utilizing preclinical models is vital and can allow for a more controlled setting to understand disease processes and highlight translational relevance to real-world conditions. These studies can inform clinical research by pointing to specific brain regions and pathways that may be the most important biological mechanisms underlying asthma-mental health comorbidity. Knowledge of underlying mechanisms will help optimize development of targeted therapies. Preclinical and clinical evidence suggests that asthma is associated with development of internalizing disorder symptoms, and broad pathways have been described that should be further investigated to elucidate specific mechanisms driving these connections. The future of psychoneuroimmunology can benefit from embracing these lines of study, highlighting relationships and uncovering mechanisms connecting mental health and chronic immune activation. Preclinical models are translationally relevant to the clinical world. Treatments can be designed that target specific immunological challenges and dysregulation. Further, once neural pathways are identified, specific treatments can be developed that may alleviate both asthma and internalizing disorder symptoms, potentially allowing for decreased rates of internalizing disorders and symptom development in these asthma patients. Finally, we must recognize that many health conditions do not present the same way in both males and females, and with this understanding, we can approach future research where both sexes are accounted for and that studies are designed with the power to examine sex differences in all analyses for the best clinical success.

Conflict of interest statement

The author has no conflicts of interest to declare. The author does not have any conflicts of interest to declare.

The current work did not receive any funding.

Acknowledgements

The author would like to thank ZO, DD, and SAC for proofreading the article.

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    All primary research studies including asthma, psychological or physical health factors, and quality of life were included. ... Overall, patients with asthma demonstrated impaired QoL, which was ...

  4. Biological therapy for severe asthma

    This biologic drug is licensed as an add-on treatment for uncontrolled severe eosinophilic asthma in patients ≥18 years with ≥300 blood eosinophils/μl [ 56, 57 ]. A 30 mg dose of benralizumab is injected subcutaneously every 28 days for the first 3 administrations and afterwards every 56 days.

  5. Update in Adult Asthma 2020

    Longitudinal studies of adult asthma and airway obstruction have shed light on the importance of considering occupational and environmental exposures in a patient's evaluation. Trends in work-related asthma (WRA) were evaluated using data from the Michigan surveillance program from 1988 to 2018 . Although there was a decreased overall ...

  6. Improving primary care management of asthma: do we know what ...

    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 ...

  7. Severe and Difficult-to-Treat Asthma in Adults

    Patients with severe asthma make up only 3% 1 to 10% 2 of the population of adults with asthma, ... substantial research is needed to identify the patients most (or least) likely to have a ...

  8. Asthma

    Asthma is one of the most common chronic non-communicable diseases worldwide and is characterised by variable airflow obstruction, causing dyspnoea and wheezing. Highly effective therapies are available; asthma morbidity and mortality have vastly improved in the past 15 years, and most patients can attain good asthma control. However, undertreatment is still common, and improving patient and ...

  9. Asthma patients' and physicians' perspectives on the burden and

    The Asthma Patients' and Physicians' Perspectives on the Burden and Management of Asthma (APPaRENT) study was a multinational, cross-sectional online survey of patients and physicians in four countries: Australia, Canada, China, and the Philippines. ... Sample sizes were based on previous research [10] and selected to be sufficient for within ...

  10. Treatment strategies for asthma: reshaping the concept of asthma

    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, ... and research conducted by the BEST study group ...

  11. Asthma 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. ... (ACRC) Network, which implements patient-centered clinical trials, and has helped to change the nature ...

  12. Mechanisms and Management of Asthma Exacerbations

    National Heart, Lung, and Blood Institute's Severe Asthma Research Program-3 Investigators. Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations. Am J Respir Crit Care Med 2017;195: 302 - 313.

  13. Full article: An update on asthma diagnosis

    Despite these contradictions amongst asthma diagnostic guidelines, it is evident that future recommendations are trending toward diagnosing asthma using objective tests. Future research is warranted to define the optimal diagnostic and treatable traits approach, especially for patients with severe asthma, as they may benefit from the advent of ...

  14. Evaluation of adherence to guideline-directed therapy and risk factors

    Between July 1, 2021 and July 1, 2022, there were 1,107 patients who met inclusion criteria for this study. In evaluating the primary outcome, of those 1,107 patients, 284 patients (26%) did not have documentation of guideline-directed therapy for mild asthma during the study period, while 823 (74%) were on guideline-directed therapy (Diff:48.7%; 95% CI:45.1 to 52.3%, p < 0.001).

  15. Assessment and management of adults with asthma during the ...

    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. Box 1.

  16. Diagnostics

    Asthma is a diverse disease that affects over 300 million individuals globally. The prevalence of asthma has increased by 50% every decade since the 1960s, making it a serious global health issue. In addition to its associated high mortality, asthma generates large economic losses due to the degradation of patients' quality of life and the impairment of their physical fitness.

  17. Researchers find new way to curb asthma attacks

    Once triggered by an allergen, ILC2s drive the inflammatory cascade that cause airways to swell and tighten, making it tough for asthma patients to draw breath. In mouse research, researchers ...

  18. Wellness on Wheels to complete study on app for asthma patients

    At CHOC Research Day 2023, Linda presented a research poster on the study, "Feasibility of Remote Patient Monitoring to Improve Childhood Asthma." Asthma is the most common chronic condition in kids under 18 years old, affecting about 4 million (about 9%) kids in the U.S., Linda explained, but it's also one of the most disparate health ...

  19. 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.

  20. Increased di-(2-ethylhexyl) phthalate exposure poses a differential

    To continue from our previous research [10, 11], this study employed the phenotypic clusters established in previous study to explore the variations in DEHP exposure among different phenotypes of asthma patients. Cluster A was a group of older non-atopic and non-smoker females with late onset asthma, while Cluster B included primarily older ...

  21. Improving primary care management of asthma: do we know what really

    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 ...

  22. The impact of COVID-19 on patients with asthma

    These results warrant further research in patients with asthma and other clinical populations. Strengths and limitations. The strengths of the present study include immediacy, large sample size and access to real-world evidence. In addition, our results must be interpreted in light of the following limitations. First, the main limitation of ...

  23. Medication Non-adherence and predictor factors among adult Asthmatic

    Abstract. Objective: A pronounced burden is evident in individuals with asthma, with approximately half of them not adhering to their prescribed medication. Therefore this study aimed to assess the pooled prevalence of anti-asthma medications non-adherence in Ethiopia. Data sources: A comprehensive search was conducted across multiple electronic databases including PubMed, Africa Index Medicus ...

  24. Anxiety, depression, and asthma: New perspectives and approaches for

    Clinical research on asthma patients has established a significant comorbidity with mental health conditions, especially in younger populations (Dudeney et al., 2017; Peters and Fritz, 2011). In recent years, studies have investigated brain areas that may play a mechanistic role in asthma and internalizing disorder comorbidity in humans using ...