Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=zecr20 European Clinical Respiratory Journal ISSN: (Print) 2001-8525 (Online) Journal homepage: http://www.tandfonline.com/loi/zecr20 Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults Celeste Porsbjerg, Charlotte Ulrik, Tina Skjold, Vibeke Backer, Birger Laerum, Sverre Lehman, Crister Janson, Thomas Sandstrøm, Leif Bjermer, Barbro Dahlen, Bo Lundbäck, Dora Ludviksdottir, Unnur Björnsdóttir, Alan Altraja, Lauri Lehtimäki, Paula Kauppi, Jussi Karjalainen & Hannu Kankaanranta To cite this article: Celeste Porsbjerg, Charlotte Ulrik, Tina Skjold, Vibeke Backer, Birger Laerum, Sverre Lehman, Crister Janson, Thomas Sandstrøm, Leif Bjermer, Barbro Dahlen, Bo Lundbäck, Dora Ludviksdottir, Unnur Björnsdóttir, Alan Altraja, Lauri Lehtimäki, Paula Kauppi, Jussi Karjalainen & Hannu Kankaanranta (2018) Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults, European Clinical Respiratory Journal, 5:1, 1440868, DOI: 10.1080/20018525.2018.1440868 To link to this article: https://doi.org/10.1080/20018525.2018.1440868 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 06 Mar 2018. Submit your article to this journal Article views: 104 View related articles View Crossmark data REVIEW ARTICLE Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults Celeste Porsbjerg a,b , Charlotte Ulrik a,c , Tina Skjold d , Vibeke Backer a,b , Birger Laerum e , Sverre Lehman f,g , Crister Janson h , Thomas Sandstrøm i , Leif Bjermer j , Barbro Dahlen k , Bo Lundbäck l , Dora Ludviksdottir m , Unnur Björnsdóttir m,n , Alan Altraja o , Lauri Lehtimäki p,q , Paula Kauppi r , Jussi Karjalainen s and Hannu Kankaanranta p,s a Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; b Respiratory Research unit, Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark; c Department of Respiratory Medicine, Hvidovre Hospital, Hvidovre, Denmark; d Dept of Respiratory Medicine, Aarhus University Hospital, Aarhus C, Denmark; e LHL-klinikkene Bergen, Nesttun, Norway; f Department of Clinical Science, University of Bergen, Bergen, Norway; g Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway; h Department of Medical Sciences: Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden; i Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, Umeå, Sweden; j Department of Respiratory Medicine & Allergology, Skåne University Hospital, Lund, Sweden; k Division of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden; l Institute of Medicine/Krefting Research Centre University of Gothenburg, Gothenburg, Sweden; m Dept. of Allergy, Respiratory Medicine and Sleep Landspitali University Hospital Reykjavik Iceland, University of Iceland, Reykjavik, Iceland; n Faculty of Medicine, University of Iceland, Reykjavik, Iceland; o Department of Pulmonary Medicine, University of Tartu and Department of Pulmponary Medicine, Tartu University Hospital, Tartu, Estonia; p Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; q Allergy Centre, Tampere University Hospital, Tampere, Finland; r Department of Allergy, Respiratory Diseases and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; s Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland ABSTRACT Although a minority of asthma patients suffer from severe asthma, they represent a major clinical challenge in terms of poor symptom control despite high-dose treatment, risk of exacerbations, and side effects. Novel biological treatments may benefit patients with severe asthma, but are expensive, and are only effective in appropriately targeted patients. In some patients, symptoms are driven by other factors than asthma, and all patients with suspected severe asthma (‘difficult asthma’) should undergo systematic assessment, in order to differentiate between true severe asthma, and ‘difficult-to-treat’patients, in whom poor control is related to factors such as poor adherence or co-morbidities. The Nordic Consensus Statement on severe asthma was developed by the Nordic Severe Asthma Network, consisting of members from Norway, Sweden, Finland, Denmark, Iceland and Estonia, including representatives from the respective national respiratory scientific societies with the aim to provide an overview and recommendations regarding the diagnosis, systematic assessment and management of severe asthma. Furthermore, the Consensus Statement proposes recommendations for the organization of severe asthma management in primary, secondary, and tertiary care. ARTICLE HISTORY Received 2 October 2017 Accepted 7 February 2018 KEYWORDS Asthma; severe; prevalence; diagnosis; co-morbidities; management; guideline Introduction Although the majority of asthma patients have mild to moderate disease, a proportion of asthma patients have difficulty in achieving control on standard treatment or require very high doses of treatment to maintain asthma control, and risk of side effects [1,2]: In the patients with severe asthma, control is not obtained despite correction of comorbidities and correct use of high doses of asthma medications. Patients with severe asthma represent a major unmet need, as they experience frequent exacerbations, are hospitalized more often, and utilize the majority of health care expenses in asthma [3]. There are a number of potential causes of poor symptom control in asthma [4], and systematic assessment is important when differentiating between patients with severe asthma, and patients with other causes of poor asthma control, such as lack of adherence or co-morbidities, termed ‘difficult-to-treat’asthma. A number of novel treatments for severe asthma are under development, some of which have been approved for clinical use: treatment with anti-IgE and anti-IL5 monoclonal antibodies are effective in reducing the risk of asthma exacerbations [5,6]. However, as the biological treatments target very specific pathways in the immune system, they are only effective in CONTACT Celeste Porsbjerg [email protected] EUROPEAN CLINICAL RESPIRATORY JOURNAL, 2018 VOL. 5, 1440868 https://doi.org/10.1080/20018525.2018.1440868 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. specific phenotypes of severe asthma [7]. Accordingly, phenotyping of severe asthma patients has become increasingly important, in order to target novel treatments tailored to the appropriate patient. Systematic assessment and phenotyping of patients with possible severe asthma requires a highly specialized setting, to ensure an appropriate and effective diagnostic work-up [8]. The Nordic Countries share similar healthcare systems, as well as a similar demography: Based on the reported prevalence rates of severe asthma [9,10], approximately 33,000 patients among the 22 million inhabitants of the Nordic countries can be estimated to suffer from severe asthma. The Nordic Severe Asthma Network (NSAN) was established under NORA, the Nordic Respiratory Societies in 2016, and consists of severe asthma specialists from Iceland, Norway, Sweden, Denmark, Finland, and Estonia. The aim of the NSAN is to increase awareness of severe asthma in the Nordic Countries, as well as improving the standard of care by providing guidelines on the management of severe asthma. The present Nordic consensus statement on severe asthma aims to provide pragmatic, clinically useful guidance on how to approach the patients with possible severe asthma; how to perform systematic assessment, how to identify potential candidates for biological treatments, and how to organize a severe asthma clinic. The definition of severe asthma The ERS/ATS guidelines on severe asthma published in 2014 define severe asthma as ‘asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller or systemic CS, which remains “uncontrolled”despite this therapy, or to prevent it from becoming “uncontrolled”’ [1]. Hence, this definition includes patients, who are well controlled on high-dose therapy, but lose symptom control when down-titrated [1]. The definitions of high dose ICS are summarized in Table 1.‘Second controllers’include long-acting beta-2 agonist, leukotriene antagonists, long-acting anti-cholinergics or methylxantines. However, before a diagnosis of severe asthma can be made, patients need to undergo a systematic assessment: The ERS/ATS guidelines state that in patients with ‘difficult asthma’,(highdoseICStreatment + a second controller), the diagnosis of asthma should be confirmed, and comorbidities addressed, before a diagnosis of severe asthma can be made (Figure 1). Patients in whom poor asthma control is related to other factors, such as poor adherence or comorbidities, are termed ‘difficult-to-treat asthma’ 1 (Figure 1). Table 1. Definitions of high dose inhaled steroids (ICS)*. Name Daily dose (μg)* Budesonide ≥1600 Fluticasone dipropionate ≥1000 Mometasone furoate ≥800 Beclomethason dipropionate ≥2000 (DPI or CFC MDI) Ciclesonide ≥320 Fluticasone furoate ≥184 Triamcinolone acetonide ≥2000 * According to the ERS/ATS guidelines on severe asthma [1]. Table 2. Co-morbidities in severe asthma: diagnosis and management. Co-morbidity Prevalence Test Management Rhinosinusitis/Nasal polyps 50% [61] SNOT-22 questionaire CT of sinuses Nasendoscopy (ENT assessment) Nasal lavage Nasal steroid spray/drops Surgery Allergic Rhinoconjuctivitis (*Positive skin prick test to aeroallergens) 70% [61]* History + skin prick test/specific IgE Nasal steroids Antihistamines Montelukast COPD 20% [171] History incl smoking DLCO/HRCT (emphysema) Add LAMA Add Roflumilast Rehabilitation Dysfunctional Breathing 19–52 [59,172]% History/Nijmegen questionaire Physioterapy –breathing retraining VCD 32–50% [59,74]- Laryngoscopy Speech therapist Anxiety/Depression 4–17% [9,17] HADS questionnaire Psychiatric assessment Psychiatrist Medical treatment Psychotherapy OSAS 31% [80] Screening with STOP-BANG Polysomnography/respiratory polygraphy Weight loss CPAP Obesity 37% [18] BMI Dietician Gastro-esophageal Reflux 17–74% [18,22,61,173] 3 months of empiric PPI 24-hours pH monitoring PPI Lifestyle interventions Bronchiectasis 25–40% [91,92] HRCT Physiotherapy, inhalation of hyperosmolar agents, low-dose macrolides ABPA 1–2% [96] Total IgE, IgE and IgG to aspergillus fumigatus, B-eosinophils, HRCT Prednisolone. Anti-fungal treatment. OSAS: Obstructive Sleep Apnea Syndrome. VCD: Vocal Chord Dysfunction. ABPA: Allergic Bronchopulmonary Aspergillosis. 2C. PORSBJERG ET AL. Systematic assessment of severe asthma [Systematic assessment of patients with severe asthma has been proven effective in reducing the number of exacerbations, as well as overall health care utilization 2,11]. The process may be conceptualized as three overall steps (Figure 2): 1) confirming the diagnosis, assessing the level of asthma control, and describing the phenotype, 2) assessing potential treatment barriers, for example inhalation technique and adherence, and 3) assessing potential exposures, such as allergens or occupational exposure, and co-morbidities that may contribute to symptoms. Step 1. Asthma diagnosis, asthma control, and phenotype a. Diagnosis of asthma Adiagnosis of asthma should be based on a combination of clinical symptoms and the objective demonstration of variable airflow limitation [1,12]. The presence of at least two of the following increases the likelihood of asthma: wheeze, shortness of breath, chest tightness or cough, which vary in intensity and over time, and may be triggered by factors, such as viral infections, allergens, and non-specific irritants (strong smells, smoke). Isolated symptoms or atypical symptoms decrease the likelihood of asthma [13]. Variable airflow limitation is defined as either reversibility to beta-2-agonist or steroids, peak flow variation, or airway hyperresponsiveness to triggers such as exercise, methacholine, histamine, or mannitol. The choice of test will depend on the local availability and preference of the clinician: Bronchial challenge tests (BCTs) with methacholine, histamine, mannitol, exercise, and eucapnic voluntary hyperpnea (EVH) have a higher sensitivity than the reversibility test(s) and PEF variation, and may therefore be the preferred initial test [14]. Importantly, it is often necessary to perform more than one diagnostic test in order to confirm the diagnosis objectively, and it may be more effective to include a standard test panel in the diagnostic work-up of severe asthma, for exampl a combination of reversibility testing, PEF diary, and a BCT [14]. In patients with an FEV 1 < 70%, which prohibits performing a bronchial challenge test, reversibility testing with either beta 2 -agonists or prednisolone and PEF monitoring are the only possible tests. Importantly, patients with severe asthma may have fixed airflow obstruction, which is not reversible. This does not preclude a diagnosis of asthma. The objective confirmation of an asthma diagnosis is of particular importance in patients with difficult asthma, to avoid overtreatment and side effects. A recent study patients managed for severe asthma across five asthma clinics in Denmark, only approximately Difficult asthma (High dose ICS + 2. controllers or OCS > 50% during the last 12 months) Difficult-to-treat asthma Severe asthma Systematic assessment* *Includin g a minimum o f three months o f s p ecialist mana g ement Poor control related to: • Poor adherence/ inhalation technique • Exposure to allergens/irritants • Co-morbidities Poor control despite • Good adherence/inhalation technique • Management of exposures and co-morbiditites Figure 1. Severe asthma: definition and systematic assessement. EUROPEAN CLINICAL RESPIRATORY JOURNAL 3 50% had their diagnosis confirmed by an objective test, despite having been managed by an asthma specialist for a minimum of 2 years [15]. It is important to note that it is not always possible to verify the diagnosis objectively, but in patients without variable airflow obstruction, down-titration of the dose of ICS followed by retesting should be considered. b. Differential diagnoses A number of conditions may mimic asthma (Box 1) [1]. These differential diagnoses should be kept in mind when assessing difficult asthma, and the diagnostic work-up performed accordingly. On the other hand, co-morbidities are important contributors to asthma symptoms. Their prevalence and management are described in the sections below. c. Asthma control The level of asthma control should be routinely assessed, using definitions proposed by the ERS/ATS guidelines on severe asthma: Regarding the level of asthma control, the ERS/ATS guidelines define uncontrolled severe asthma as the presence of at least one of the following four criteria: (1) Poor symptom control, i.e. Asthma Control Questionnaire (ACQ) consistently > 1.5 or Asthma Control Test (ACT) < 20 (or not well controlled as defined by The Global Initiative for Asthma (GINA) over 3 months of evaluation). (2) Frequent severe exacerbations, defined as needing two or more bursts of systemic corticosteroids (>3 days each) during the previous year. Box 1. Differential diagnoses in severe asthma*. ●COPD ●Bronchiectasis ●Sarcoidosis ●Bronchiolitis obliterans ●Cystic Fibrosis ●Hypersensitivity pneumonitis ●Hypereosinophilic lung diseases ●Tracheobronchomalacia ●Pulmonary embolism ●Coronary Heart Failure ●Endobronchial tumor/foreign body *Differential diagnostic conditions which commonly co-exist with asthma are listed under co-morbidities in Table 2. •Confirmed diagnosis of asthma? •Poor asthma control? •Asthma phenotype? Diagnosis and phenotype? •Optimal adherence ? •Correct use of inhalers? •Asthma education necessary? Treatment barriers? •Exposures? •Co-morbidities? Triggers? Figure 2. Systematic assessment of possible severe asthma. 4C. PORSBJERG ET AL. (3) Serious exacerbations, defined as at least one hospitalization, intensive care unit stay, or mechanical ventilation in the previous year. (4) Airflow limitation, defined as a forced expiratory volume in 1 s (FEV 1 ) < 80% predicted (in the presence of reduced FEV 1 /forced vital capacity (FVC) while withholding both shortand long-acting bronchidilators. d. The phenotype of asthma Phenotyping severe asthma is important for predicting treatment response. Phenotypes may be based on the presence and level of inflammation, which may be termed inflammatory phenotypes [16], or based on a combination of clinical characteristics, physiological, and inflammatory markers, which may be termed clinical phenotypes [17–22]. Inflammatory phenotypes are ideally assessed by induced sputum and divided into four groups: eosinophilic asthma (>3% of the total sputum cells), neutrophilic asthma (>61%), mixed granulocytic asthma (both eosinophilia and neutrophilia), and pauci-granulocytic asthma (both eosinophil and neutrophil counts in normal ranges) [23]. Blood eosinophils and exhaled nitric oxide (FeNO) may be used as markers of eosinophilic airway inflammation [24,25]: There is at present no consensus on the most appropriate cut-off for blood eosinophils, but a higher cut-off improves the predictive value of sputum eosinophils: A cut-off of 0.30 x 10 9 cells/L yields a positive predictive value (PPV) of 66%, which increases to 89% at a cut-off of 0.45 x 10 9 cells/L [26]. However, the increase in PPV is accompanied by a decrease in sensitivity from 60% to 49% [26]. Similarly for FeNO, a value > 50 ppb indicates a high likelihood of eosinophilic airway inflammation, whereas a FeNO < 25 ppb indicates a low likelihood of eosinophilia [25]. Many patients have intermediate FeNO values (25–50ppb), in these cases the FeNO is less informative. Of note, neutrophilic airway inflammation can only be assessed by induced sputum, as the level of blood neutrophils does not accurately predict airway neutrophils [24]. At present, there is no clear consensus on the definition of clinical phenotypes of asthma [1]. However, the ERS/ATS guidelines state that the following phenotypes of severe asthma are generally recognized: ‘an early-onset allergic phenotype, a later onset obese (primarily female) phenotype and a later onset eosinophilic phenotype’[1]. A systematic assessment should include information on the following phenotypic characteristics: a) age at onset (early/late); b) IgE-mediated allergy; c) eosinophilia/elevated FeNO; d) fixed airflow obstruction; and e) obesity. From a pragmatic, clinical perspective, phenotypic traits can be used in the daily clinical care to targetspecific treatments: eosinophilia combined with exacerbations predicts effect of anti-IL5 [27] and patients with fixed airflow obstruction and exacerbations may benefit from tiotropium [28]. Furthermore, perennial allergic sensitization, airflow obstruction (FEV1 < 80%) and exacerbations predict effect of anti-IgE [5]. Step 2. Treatment barriers (adherence, inhalation technique, understanding of asthma) Treatment barriers are factors that impede the adequate delivery of asthma medications to the airways: They are frequent causes of poor asthma control, and should be addressed routinely in patients with severe asthma. Unfortunately, adherence and inhalation technique are not routinely checked, and there appears to be significant room for improvement: In a recent real life study of patients managed for severe asthma, adherence was only recorded in 30% of patients, and inhalation technique in 19% [15]. a. Adherence with controller medication Poor adherence in asthma is well-documented [29,30], even in difficult asthma: A study of adults referred to a clinic for difficult asthma revealed that 35% of the patients filled their ICS prescriptions less than 50% of the time [31]. Poor adherence with controller medication is associated with poor disease control, and it is estimated that 24% of exacerbations and 60% of asthma-related hospital admissions may be attributed to poor adherence [29,32]. The high proportion of non-adherent patients poses a major challenge for asthma specialists in identifying patients suffering from severe asthma, that is asthma not responding to high-dose medication. This may lead to non-adherent patients inadvertently being prescribed expensive biological medications [19]. Adherence with asthma controller medications should therefore always be checked, preferably by objective assessment, for example filling of prescriptions in electronic registers. b. Inhalation technique Assessment of the individual patient’s inhaler technique is important [33], and should be checked at each visit [23].Errors in the use of inhalers are common [34,35] and have previously been reported in up to EUROPEAN CLINICAL RESPIRATORY JOURNAL 5 80% of patients [33]. A further challenge in severe asthma is that patients may be treated with two or more different inhaler types, which may increase the risk of errors. Also, the increasing number of inhalation devices contributes to difficulties for health care providers to have sufficient knowledge in the correct method of use. A comprehensive, inhaler specific checklist can be downloaded at https://www.nationalasthma.org.au/liv ing-with-asthma/resources/health-professionals/charts/ inhaler-technique-checklists. c. Patient education A shared-care approach to asthma management improves outcomes [36,37], and requires development of a partnership between the asthmatic and the health care providers. Perhaps more than in other diseases patients require good partnerships for adequate treatment, they must learn to recognize potential triggers and symptoms of exacerbations, when to adjust medications and contact health care personnel [13,38]. Step 3: Identifying potential triggers: exposures and co-morbidities a. Exposures Identifying potential triggers causing potential asthma symptoms and exacerbations is essential, and this section describes exposures that should be identified as part of the systematic assessment, including allergens, smoking, occupational exposures and medications that may aggravate symptoms. Indoor allergens Common indoor allergens that may trigger asthma include pets—cats and dogs—house dust mite, moulds, cockroaches, and rodents [39–41], and an important part of the patients history includes asking about possible exposures to indoor allergens such as pets, carpeting, and damp housing. Outdoor allergens Outdoor allergens such as pollen and mould spores can trigger asthma exacerbations and increase asthma severity in sensitized individuals. Exposure to fungi, especially Alternaria and Cladosporium, have been associated with an increase in asthma exacerbations and asthma severity [42,43]. Pollen such as grass and birch allergens induce primarily nasal and conjunctival symptoms, but may also exacerbate asthma symptoms [44]. Tobacco smoke Unfortunately, a large proportion of asthma patients have a significant smoking history or are exposed to passive smoking. Several lines of evidence demonstrate that active and passive smoking leads to greater severity of asthma and act as a triggers to exacerbate asthma [45,46]. It appears that the diminished antioxidant capacity along with the oxidant excess associated with tobacco smoke leads to bronchial hyperresponsiveness and worsening airways obstruction [47,48] Due to the accelerated loss of lung function, there is an increased risk of development of COPD in asthmatics who smoke (see ‘Co-morbidities’)[49]. However, it is also important to recognize that smoking per se does not preclude a diagnosis of asthma, and fixed airflow obstruction in severe asthma is not synonymous with COPD. Importantly, asthma patients who develop COPD appear to have a better prognosis than COPD patients without pre-existing asthma [50,51]. Occupational exposure Exposure to multiple occupational allergens have been associated with work-related asthma. These include flour and grain dust (bakers, farmers), isocyanates (painters, automotive industry workers, adhesive workers), formaldehyde (health care workers, hairdressers, cosmetic workers) wood dusts (carpenters) platinum salts (dentists, chemists, photographers, electricians), latex (health care workers, food handlers), and animal allergens (veterinarians, animal breeders and workers, laboratory workers) [52]. In patients with these occupations, as well as patients who report worsening of their symptoms at work, a referral to a specialist in occupational medicine should be considered. Drugs Aspirin and other NSAIDs may trigger severe airway obstruction in up to 10–15% of adults with asthma [53–55]; typically patients with severe and adult onset eosinophilic asthma and comorbid nasal polyposis, a condition termed Samter´s triad, aspirin-exacerbated respiratory disease (AERD) or Non-steroidal antiinflammatory drugs-exacerbated respiratory disease (N-ERD) [56]. The intolerance is not an IgE mediated allergy and there is no in vitro test for diagnosis. β-receptor antagonists may trigger asthma and nonselective systemic β-receptor antagonists should be avoided in asthmatics. However, even the β 1 -selective antagonists are not completely risk-free; 20% of patients experience symptoms and airflow obstruction after exposure, even to local β-receptor antagonists such as eye drops [57,58]. 6C. PORSBJERG ET AL. b. Co-morbidities associated with severe asthma Co-morbidities are a common feature of severe asthma, which may contribute to poor symptom control [59]. Conversely, co-morbidities may be caused by severe asthma; steroid treatment is associated with an increased risk of iatrogenic co-morbidities including obesity, osteoporosis, diabetes, depression, and gastrointestinal reflux [1,60,61](Table 2). The prevalence, diagnosis, and management of the most common co-morbidities in severe asthma are summarized in Table 1, and described in further detail below: Chronic rhinosinusitis (CRS) Clinical studies have demonstrated that 50–90% of subjects with severe asthma have signs of chronic rhinosinusitis [62,63]. Patients with CRS may have coexisting nasal polyps (CRSwNP), which is commonly a feature of severe late-onset, eosinophilic asthma, and may furthermore be associated with Aspirin/NSAID sensitivity [56]. Patients with difficult asthma and CRS report more lung symptoms, in particular more cough and sputum, and have more exacerbations [62]. The presence of CRS is assessed on the basis of clinical symptoms such as nasal discharge, in combination with facial pain/pressure or loss of smell, present for a period of at least 12 weeks [64]. The SNOT-22 questionnaire may be used for assessing symptoms [64], and CT of the sinuses and rhinoscopy may be used to assess the presence of sinus inflammation and polyposis [64]. Allergic rhinitis Allergic rhinitis is common in asthma in general, and seems to play a more important role in early onset severe asthma, whereas in late-onset, severe asthma, allergy generally seems to have less clinical impact [59]. COPD Fixed airflow obstruction is a common feature of severe asthma, and it may be impossible to differentiate severe asthma from COPD, in patients with a significant smoking history [65]. Additionally, a significant proportion of severe asthma starts in adulthood, and adult onset asthma in general is associated with low lung function: As many as 46% of adults with asthma onset after the age of 65 years have an FEV1 < 80% prior to being diagnosed with asthma [66]. Hence, asthma may precede COPD, or vice versa, and the clinical impact of this order of development is as yet unclear. There is no gold standard for differentiating severe asthma from COPD. The GINA guidelines on asthmaCOPD overlap syndrome suggest that the likelihood of having either asthma or COPD is based on a thorough assessment of smoking exposure, symptoms (e.g. variable versus persistent symptoms, family history and response to treatment) [67]. Additionally, assessing components of emphysema, for example with DLCO or HRCT may be helpful [50,68]. Dysfunctional breathing Dysfunctional breathing (DB) may accompany asthma or be an asthma mimicker. Defined as ‘chronic changes in breathing pattern that result in dyspnoea and other symptoms, in the absence or in excess of the magnitude of physiological respiratory or cardiac disease’[69], DB is observed in up to 52% of subjects with difficult asthma. DB seems to be most common in the obese and non-eosinophilic phenotypes of severe asthma [70,71]. Patients typically report very excessive dyspnea at relatively low levels of physical activity, that is dyspnea that is disproportionate with the objective level of asthma severity. Furthermore, extra-pulmonary complaints such as dizziness, fatigue or tingling of the fingers/around the mouth are common. There is no gold standard for diagnosing DB, but patients may be screened using the Nijmegen questionnaire, where a score > 23 indicates an increased likelihood of DB [72]. Vocal cord dysfunction Vocal cord dysfunction (VCD) is an important mimicker of asthma: The vocal cords are inappropriately adducted leading to a sense of dyspnea and shortness of breath with associated stridor rather than wheezing [73]. VCD can present as a single disease but in up to 50 % of patients concomitant VCD and asthma are seen and may complicate diagnosis and treatment in ‘treatment-resistant’asthma [74]. The diagnosis of VCD may be challenging, as laryngoscopy may be normal when the subject is not experiencing symptoms. No validated protocols for diagnosing VCD exist, however provocation with stimuli such as perfume may be attempted. A typical symptom of VCD is hoarseness during attacks. Patients may be screened for VCD with the Pittsburgh questionnaire [75], and referral to a speech pathologist should be considered. VCD may also be provoked by exercise. Continuous laryngoscopic exercise testing (CLE) may be performed to visualize the larynx during exercise. CLE testing has demonstrated that a large proportion of patients with symptoms suggestive of VCD may demonstrate supraglottic closure of the aryepiglottic folds [76]. The term Inducible Laryngeal Obstruction (ILO) has been EUROPEAN CLINICAL RESPIRATORY JOURNAL 7 proposed, to cover both glottic and supraglottic obstruction, induced by stimuli such as exercise (EILO) or external stimulants [76]. The relative prevalence of glottic (VCD) versus supraglottic obstruction in severe asthma is unknown. CLE may be a useful test for ILO in severe asthma, however protocols for validity and safety for this type of testing have yet to be established. Anxiety and depression Anxiety and depression are prevalent conditions among patients with severe asthma, and may contribute to symptoms, but also be the result of having a severe and chronic disease [77]. Patients may be screened with questionnaires such as the Hospital depression and Anxiety Scale (HADS) [78,79], although there are as of yet no validated questionnaires for asthma specifically. If anxiety or depression are suspected, the patient should be referred for psychiatric assessment at a center with experience in psychiatric disorders in chronic disease. Obstructive sleep apnea syndrome Obstructive Sleep Apnea Syndrome (OSAS) is common in severe asthma, and is associated with poor symptom control and frequent exacerbations [80]. A potential vicious cycle may result as OSAS may induce asthma symptoms, and asthma increase the risk of OSAS [70]. Screening of patients for OSAS can be performed with validated questionnaires such as the, STOP-BANG or the Berlin Questionaire [81,82]. If OSAS is suspected, patients should be referred for polysomnography [83]. Obesity Overall, obesity is associated with worse asthma outcomes, especially an increased risk of exacerbations and asthma-related hospitalizations [68,84]. This data may be confounded by other obesity related co-morbidities which also affect asthma exacerbations such as gastroesophageal reflux and sleep apnea [85]. Furthermore, obese asthmatics may have a lower threshold for symptoms: A study comparing asthmatics with higher levels of BMI (>31) compared with lean asthmatics, found that the obese group had a 50% increased risk of asthma exacerbations and a 94% increase in use of rescue inhalers [86,87]. Gastroesophageal reflux disease (GERD) GERD is associated with poor symptom control, as well as more frequent exacerbations in severe asthma [59,88]. Although the causal link is unclear, co-existence of gastroesophageal reflux is very common in patients with asthma [89]. As the diagnosis of GERD may be difficult, with limited sensitivity of both gastric pH monitoring and endoscopy, a trial treatment with PPI may be used as the initial diagnostic step in symptomatic patients [90]. Of note, high use of beta 2 -agonist has been shown to relax the sphincter between the oesophagus and the ventricle, which increases the tendency to reflux, potentially inducing a vicious cycle of high SABA use, reflux and increasing asthma symptoms leading to high SABA use. Bronchiectasis The prevalence of bronchiectasis in patients with severe asthma is relatively high; with 25–40% of patients having radiological signs of bronchiectasis [91,92], compared to 3% in a population of generally milder asthma [93]. Asthma patients with co-existing bronchiectasis appear to be at higher risk of asthma exacerbations and hospitalizations [93,94].Bronchiectasispersemaycauseobstructive airflow limitation [92], and is thus a also a differential diagnosis of asthma [95]. Furthermore, bronchiectasis increases the susceptibility to infections [95]. Bronchiectasis is associated with allergic bronchopulmonary aspergillosis (ABPA) in severe asthma [96], see below. Allergic bronchopulmonary aspergillosis (ABPA) ABPA is a hypersensitivity reaction to aspergillus fumigatus [96]: Although a relatively rare condition, ABPA may have significant impact on asthma control. Typically patients experience symptoms of chronic mucus hypersecretion and have an associated accelerated loss of lung function [96]. The most recently diagnostic criteria for ABPA, proposed by ISHAM (The international Society for Human and Animal Mycology), in 2013 [97], are summarized below: Predisposing conditions ●Bronchial asthma, cystic fibrosis Obligatory criteria (both should be present) ●Type I Aspergillus skin test positive (immediate cutaneous hypersensitivity to Aspergillus antigen) or elevated IgE levels against Aspergillus fumigatus. ●Elevated total IgE levels (> 1000 IU/mL) (If the patient meets all other criteria, an IgE value < 1000 IU/mL may be acceptable). Other criteria (at least two of three) ●Presence of precipitating or IgG antibodies against A. fumigatus in serum. 8C. PORSBJERG ET AL. prevalence and burden of severe asthma in different countries and regions, where in many cases the data are scarce or absent [170]. Moreover, little is know about the impact of local and socio-cultural factors on the diagnosis and treatment of severe asthma and how this may impact the possibilities to utilize add-on and novel personalized therapies to improve the outcomes in each area [170]. Barriers associated with cost of medication and approval/reimbursement of expensive therapies are an additional challenge and add to this complexity. [170]. Further cost-effectiveness analyses are necessary. The biological (e.g. anti-IL-5 and anti-IgE antibodies) and other specialized (e.g. bronchial thermoplasty) treatments are expensive. The costs are another factor limiting the number of patients being offered these therapies. National differences in these expensive treatments may differ due to different funding strategies between countries. This undermines the need for international guidelines facilitating the selection of subjects most likely to respond the these novel treatments . On a national level, local severe asthma centers in collaboration with the authorities should provide a list of appropriate criteria for selection of patients to receive novel biological treatments in the respective countries. The decision to initiate these treatments should then be made at the severe asthma centers after a multidisciplinary systematic assessment process, and the efficacy of the treatment should be monitored systematically, to ensure that the treatment is effective and was targeted to the appropriate patients. Finally, national registers of patients treated with expensive biologicals will be important in ensuring evidence on the ‘real-life’use and efficacy of these drugs. In conclusion, severe asthma is a difficult clinical challenge, which requires highly specialized care. The development of novel biological treatments, which are expensive, and only effective in selected groups of patients, has further necessitated a high level of expertise among specialists. 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Inhalation technique checked and correct?: _______________________________ 7. Adherence assessed and acceptable?: ____________________________________ 8. Exposures (Work history, possible exposure to allergens (home, hobbies and work) and other exposures): ___________________________________________________________ 9. Information on concomitant diseases: _____________________________________ 10. Include: Most recent evaluations of respiratory health and asthma (including chest X-ray, spirometry, peak flow follow-ups and challenge tests as well as laboratory values such blood eosinophils, neutrophils and total immunoglobulin E levels). *if proper diagnostic evaluations have not been done, relevant diagnostic work-up should be performed by the treating generalist or respiratory specialist before referring the patient to specialized severe asthma clinic (von Bulow, et al. 2017). EUROPEAN CLINICAL RESPIRATORY JOURNAL 15 studies of severe eosinophilic asthma. J Allergy Clin Immunol. 2016. 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