Figures
- Figure 1–
Integration of factors, beginning with genetics, which may contribute to the ultimate phenotype of the severe asthma patient.
- Figure 2–
Potential immune-inflammatory and cellular interactions contributing to the pathogenesis of phenotypes of asthma. CXCL: CXC chemokine ligand; CCL24/26: CC chemokine ligand 24/26; DUOX: dual oxidase; EPO: eosinophil peroxidase; IFNγ: interferon-γ; IgE: immunoglobulin E; IL: interleukin; iNOS: inducible nitric oxide synthase; MUC5AC: mucin 5AC; NO: nitric oxide; OX40/L: CD134 ligand; PGD2: prostaglandin D2; Tc1: cytotoxic T-cell type 1; TGFβ: transforming growth factor-β; Th1: T-helper cell type 1; Th2: T-helper cell type 2; TSLP: thymic stromal lymphopoietin.
Tables
- Table 1– Recommendations
Context Recommendation Strength Quality of evidence Values and preferences Remarks Computed tomography of chest 1 In children and adults with severe asthma without specific indications for chest HRCT based on history, symptoms and/or results of prior investigations we suggest that a chest HRCT only be done when the presentation is atypical Conditional Very low This recommendation places a relatively high value on identification of alternative diagnosis and comorbidities and a relatively low value on avoiding potential complications and cost of chest HRCT An atypical presentation of severe asthma includes such factors as, for example, excessive mucus production, rapid decline in lung function, reduced carbon monoxide transfer factor coefficient and the absence of atopy in a child with difficult asthma Sputum eosinophil counts 2A In adults with severe asthma: we suggest treatment guided by clinical criteria and sputum eosinophil counts performed in centres experienced in using this technique rather than by clinical criteria alone Conditional Very low The recommendation to use sputum eosinophil counts to guide therapy in adults places a higher value on possible clinical benefits from adjusting the treatment in selected patients and on avoidance of inappropriate escalation of treatment and a lower value on increased use of resources Because, at the present time, measurement of sputum eosinophils has not yet been sufficiently standardised and is not widely available we suggest such an approach be used only in specialised centres experienced in this technique. Patients who are likely to benefit from this approach are those who can produce sputum, demonstrate persistent or at least intermittent eosinophilia and have severe asthma with frequent exacerbations Clinicians should recognise that different choices will be appropriate for different patients 2B In children with severe asthma: we suggest treatment guided by clinical criteria alone rather than by clinical criteria and sputum eosinophil counts Conditional Very low The recommendation not to use sputum eosinophil counts to guide therapy in children places higher value on avoiding an intervention that is not standardised and not widely available and lower value on the uncertain and possibly limited clinical benefit Exhaled nitric oxide 3 We suggest that clinicians do not use FeNO to guide therapy in adults or children with severe asthma Conditional Very low This recommendation places a higher value on avoiding additional resource expenditure and a lower value on uncertain benefit from monitoring FeNO Anti-IgE antibody
(omalizumab)4 In patients with severe allergic asthma we suggest a therapeutic trial of omalizumab both in adults and in children Conditional Low (adults)
Very low (children)This recommendation places higher value on the clinical benefits from omalizumab in some patients with severe allergic asthma and lower value on increased resource use Those adults and children aged ≥6 years with severe asthma who are considered for a trial of omalizumab, should have confirmed IgE-dependent allergic asthma uncontrolled despite optimal pharmacological and non-pharmacological management and appropriate allergen avoidance if their total serum IgE level is 30–700 IU·mL−1 (in three studies the range was wider: 30–1300 IU·mL−1) Treatment response should be globally assessed by the treating physician taking into consideration any improvement in asthma control, reduction in exacerbations and unscheduled healthcare utilisation, and improvement in quality of life If a patient does not respond within 4 months of initiating treatment, it is unlikely that further administration of omalizumab will be beneficial Methotrexate 5 We suggest that clinicians do not use methotrexate in adults or children with severe asthma Conditional Low This recommendation places a relatively higher value on avoiding adverse effects of methotrexate and a relatively lower value on possible benefits from reducing the dose of systemic corticosteroids Evidence from randomised trials is only available for adults Because of the probable adverse effects of methotrexate and need for monitoring therapy we suggest that any use of methotrexate is limited to specialised centres and only in patients who require daily OCS If a decision to use methotrexate is made chest radiography, complete blood count with differential and platelets, liver function tests, serum creatinine and DLCO are recommended prior to and after commencing therapy Macrolide antibiotics 6 We suggest that clinicians do not use macrolide antibiotics in adults and children with severe asthma for the treatment of asthma Conditional Very low This recommendation places a relatively higher value on prevention of development of resistance to macrolide antibiotics, and relatively lower value on uncertain clinical benefits This recommendation applies only to the treatment of asthma; it does not apply to the use of macrolide antibiotics for other indications, e.g. treatment of bronchitis, sinusitis or other bacterial infections as indicated Antifungal agents 7A We suggest antifungal agents in adults with severe asthma and recurrent exacerbations of ABPA Conditional Very low The recommendation to use antifungal agents in patients with severe asthma and ABPA places a higher value on possible reduction of the risk of exacerbations and improved symptoms, and a lower value on avoiding possible adverse effects, drug interactions and increased use of resources In children, the evidence is limited to isolated case reports Children should be treated with antifungals only after the most detailed evaluation in a specialist severe asthma referral centre As antifungal therapies are associated with significant and sometimes severe side-effects, including hepatotoxicity, clinicians should be familiar with these drugs and follow relevant precautions in monitoring for these side-effects, observing the limits to the duration of treatment recommended for each 7B We suggest that clinicians do not use antifungal agents for the treatment of asthma in adults and children with severe asthma without ABPA irrespective of sensitisation to fungi (i.e. positive skin prick test or fungus-specific IgE in serum) Conditional Very low The recommendation not to use antifungal agents in patients with severe asthma without confirmed ABPA (irrespective of sensitisation) places a higher value on avoiding possible adverse effects, interactions of antifungal agents with other medications and increased use of resources, and a lower value on uncertain possible benefits The recommendation not to use antifungal agents in patients with severe asthma without confirmed ABPA applies only to the treatment of asthma; it does not apply to the use of antifungal agents for other indications, e.g. treatment of invasive fungal infections Bronchial thermoplasty 8 We recommend that bronchial thermoplasty is performed in adults with severe asthma only in the context of an Institutional Review Board approved independent systematic registry or a clinical study (recommendation, quality evidence) Strong Very low This recommendation places a higher value on avoiding adverse effects, on an increased use of resources, and on a lack of understanding of which patients may benefit, and a lower value on the uncertain improvement in symptoms and quality of life This is a strong recommendation, because of the very low confidence in the currently available estimates of effects of bronchial thermoplasty in patients with severe asthma Both potential benefits and harms may be large and the long-term consequences of this new approach to asthma therapy utilising an invasive physical intervention are unknown Specifically designed studies are needed to define its effects on relevant objective primary outcomes, such as exacerbation rates, and on long-term effects on lung function Studies are also needed to better understand the phenotypes of responding patients, its effects in patients with severe obstructive asthma (FEV1 <60% of predicted value) or in whom systemic corticosteroids are used, and its long-term benefits and safety Further research is likely to have an important impact on this recommendation HRCT: high-resolution computed tomography; FeNO: exhaled nitric oxide fraction; OCS: oral corticosteroids; DLCO: transfer factor of the lung for carbon monoxide; ABPA: allergic bronchopulmonary aspergillosis; FEV1: forced expiratory volume in 1 s.
- Table 2– Interpretation of strong and conditional recommendations
Implications for Strong recommendation Conditional recommendation Patients Most individuals in this situation would want the recommended course of action, and only a small proportion would not The majority of individuals in this situation would want the suggested course of action, but many would not Clinicians Most individuals should receive the intervention Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences Recognise that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences Policy makers The recommendation can be adopted as policy in most situations Policy making will require substantial debate and involvement of various stakeholders - Table 3– Definition of severe asthma for patients aged ≥6 years
Asthma which requires treatment with guidelines suggested medications for GINA steps 4–5 asthma (high dose ICS# and LABA or leukotriene modifier/theophylline) for the previous year or systemic CS for ≥50% of the previous year to prevent it from becoming “uncontrolled” or which remains “uncontrolled“ despite this therapy Uncontrolled asthma defined as at least one of the following: 1) Poor symptom control: ACQ consistently ≥1.5, ACT <20 (or “not well controlled” by NAEPP/GINA guidelines) 2) Frequent severe exacerbations: two or more bursts of systemic CS (≥3 days each) in the previous year 3) Serious exacerbations: at least one hospitalisation, ICU stay or mechanical ventilation in the previous year 4) Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal) Controlled asthma that worsens on tapering of these high doses of ICS or systemic CS (or additional biologics) #: the definition of high dose inhaled corticosteroids (ICS) is age-specific (table 4). GINA: Global Initiative for Asthma; LABA: long-acting β2-agonists; CS: corticosteroids; ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; NAEPP National Asthma Education and Prevention Program.
- Table 4– Definition of high daily dose of various inhaled corticosteroids in relation to patient age
Inhaled corticosteroid Threshold daily dose in μg considered as high Age 6–12 years Age >12 years Beclomethasone dipropionate ≥800 (DPI or CFC MDI)
≥320 (HFA MDI)≥2000 (DPI or CFC MDI)
≥1000 (HFA MDI)Budesonide ≥800 (MDI or DPI) ≥1600 (MDI or DPI) Ciclesonide ≥160 (HFA MDI) ≥320 (HFA MDI) Fluticasone propionate ≥500 (HFA MDI or DPI) ≥1000 (HFA MDI or DPI) Mometasone furoate ≥500 (DPI) ≥800 (DPI) Triamcinolone acetonide ≥1200 ≥2000 Notes: 1) Designation of high doses is provided from manufacturers' recommendations where possible. 2) As chlorofluorocarbon (CFC) preparations are being taken from the market, medication inserts for hydrofluoroalkane (HFA) preparations should be carefully reviewed by the clinician for the equivalent correct dosage. DPI: dry powder inhaler; MDI: metered-dose inhaler.
- Table 5– Priority questions on phenotypes
1) The validation of the eosinophilic versus non-eosinophilic, and of the Th2 predominant versus non-Th2 asthma phenotype, are they persistent over time and do they predict distinct natural histories? 2) Are risk factors, comorbid factors and natural history also governed by specific immune-inflammatory phenotypes? 3) Are there genetic, epigenetic and inflammatory biomarkers of specific phenotypes or characteristics of severe asthma? 4) Is the innate immune response abnormal in severe asthma, and do these contribute to inflammation and remodelling of the airways? 5) What is the relationship between structural determinants, inflammation and airway function in severe asthma, and can imaging be used to noninvasively address these issues? 6) Is there an altered microbiome and virobiome in the airways of severe asthma? Th: T-helper cell.
- Table 6– Diseases which can masquerade as severe asthma
Children Dysfunctional breathing/vocal cord dysfunction Bronchiolitis Recurrent (micro)aspiration, reflux, swallowing dysfunction Prematurity and related lung disease Cystic fibrosis Congenital or acquired immune deficiency Primary ciliary dyskinesia Central airways obstruction/compression Foreign body Congenital malformations including vascular ring Tracheobronchomalacia Carcinoid or other tumour Mediastinal mass/enlarged lymph node Congenital heart disease Interstitial lung disease Connective tissue disease Adults Dysfunctional breathlessness/vocal cord dysfunction Chronic obstructive pulmonary disease Hyperventilation with panic attacks Bronchiolitis obliterans Congestive heart failure Adverse drug reaction (e.g. angiotensin-converting enzyme inhibitors) Bronchiectasis/cystic fibrosis Hypersensitivity pneumonitis Hypereosinophilic syndromes Pulmonary embolus Herpetic tracheobronchitis Endobronchial lesion/foreign body (e.g. amyloid, carcinoid, tracheal stricture) Allergic bronchopulmonary aspergillosis Acquired tracheobronchomalacia Churg–Strauss syndrome - Table 7– Comorbidities and contributory factors
1) Rhinosinusitis/(adults) nasal polyps 2) Psychological factors: personality trait, symptom perception, anxiety, depression 3) Vocal cord dysfunction 4) Obesity 5) Smoking/smoking related disease 6) Obstructive sleep apnoea 7) Hyperventilation syndrome 8) Hormonal influences: premenstrual, menarche, menopause, thyroid disorders 9) Gastro-oesophageal reflux disease (symptomatic) 10) Drugs: aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), β-adrenergic blockers, angiotensin-converting enzyme inhibitors - Table 8– Placebo-controlled studies of potential new treatments in severe asthma
First author [ref.] Severity Subjects n Design Treatment Outcomes Summary results Wenzel [99] Severe 309 R, db, pc, p Golimumab, anti TNF-α, 24 weeks FEV1, exacerbations AQLQ, PEFR FEV1 unchanged, no reduction in exacerbations, AQLQ, PEFR Adverse profile side-effects Pavord [56] Severe, with ≥2 exacerbations in past year 621 R, db, pc, p Mepolizumab (75, 250 or 750 mg infusions at 4 weeks), anti-IL-5, 52 weeks Rate of exacerbations All doses reduced exacerbations by 39–52% No effect on ACQ, AQLQ or FEV1 Haldar [157] Severe 61 R, db, pc, p Mepolizumab, anti-IL5, 50 weeks Exacerbations, symptoms, FEV1, AQLQ, AHR, sputum and blood eosinophils Reduced exacerbations Improved AQLQ Reduced eosinophils Nair [58] Severe 20 R, db, pc, p Mepolizumab, anti-IL5, 50 weeks Exacerbations, oral steroid reduction Reduced exacerbations, eosinophils and OCS dose Kips [159] Severe 26 R, db, pc, p SCH55700, anti-IL-5, 12 weeks Sputum and blood eosinophils, symptoms, FEV1 Reduced blood sputum eosinophils No other significant outcomes Castro [57] Poorly controlled on high-dose inhaled CS 53 R, db, pc, p Reslimuzab, anti-IL-5, 12 weeks ACQ, FEV1, Sputum eosinophils Improved ACQ score Reduction in sputum eosinophils Improved FEV1 Corren [160] Moderate-severe 294 R, db, pc, p AMG317, anti-IL-4Rα antibody, blocks IL-4 and IL-13, 12 weeks ACQ scores, exacerbations No effect on ACQ or exacerbations Corren [59] Moderate-severe 219 R, db, pc, p Lebrikizumab, anti-IL13 antibody, 24 weeks Change in pre-bronchodilator FEV1 Improved FEV1, compared with placebo, with greatest changes in high levels of periostin or FeNO group (post hoc analyses) No effect on ACQ-5 or diary measures Exacerbations were 60% lower in treated group with high Th2 Piper [60] Moderate-to-severe 194 R, db, pc, p Tralokinumab (150, 300, or 600 mg), IL-13 neutralising monoclonal antibody, 3 months Change from baseline in ACQ-6 at week 13 No change in ACQ-6 at 13 weeks FEV1 increase of 0.21 L versus 0.06 L with placebo (p=0.072) β2-agonist use decrease of -0.68 versus -0.10 with placebo (p=0.020) Better response in those with higher IL-13 levels in sputum Humbert [161] Severe, CS-dependent 44 R, db, pc, p Masitinib (3, 4.5 and 6 mg·kg−1·day−1), c-kit and PDGFR tyrosine kinase inhibitor, 16 weeks OCS dose ACQ, FEV1 No difference in OCS dose
ACQ improved, no difference in FEV1Busse [162] Moderate-to-severe R, db, pc, p Daclizumab, IL-2Rα chain antibody, 20 weeks Change in FEV1 (%)
Asthma exacerbationsImproved FEV1 Reduction in day-time asthma scores, use of SABA Prolonged time to severe exacerbations Reduction in blood eosinophils Nair [163] Severe asthma 34 R, db, pc, p SCH527123, CXCR2 receptor antagonist, 4 weeks Changes in sputum and neutrophil activation markers Reduction in blood and sputum neutrophil Reduction in mild exacerbations No reduction in ACQ score (p=0.053) R: Randomised; db: double-blind; pc: placebo-controlled; p: parallel; TNF-α: tumour necrosis factor-α; FEV1: forced expiratory volume in 1 s; AQLQ: Asthma Quality of Life Questionnaire; PEFR: peak expiratory flow rate; IL: interleukin; ACQ: Asthma Control Questionnaire; AHR: airway hyperresponsiveness; OCS: oral corticosteroids; CS: corticosteroids; FeNO: exhaled nitric oxide fraction; Th2: T-helper cell type 2; c-kit: stem cell factor receptor; PDGFR: platelet-derived growth factor receptor; IL-2Rα: IL-2 receptor-α; SABA: short-acting β-agonist.
- Table 9– Potential phenotype-targeted therapies in severe asthma#
Characteristic Associations Specifically targeted treatments Severe allergic asthma Blood and sputum eosinophils Anti-IgE (adults and children) High serum IgE Anti-IL-4/IL-13 High FeNO Anti-IL-4 receptor Eosinophilic asthma Blood and sputum eosinophils Anti-IL-5 Recurrent exacerbations Anti-IL-4/IL-13 High FeNO Anti-IL-4 receptor Neutrophilic asthma¶ Corticosteroid insensitivity Anti-IL-8 Bacterial infections CXCR2 antagonists Anti-LTB4 (adults and children) Macrolides (adults and children) Chronic airflow obstruction Airway wall remodelling as increased airway wall thickness Anti-IL-13
Bronchial thermoplastyRecurrent exacerbations Sputum eosinophils in sputum Anti-IL5 Reduced response to ICS and/or OCS Anti-IgE (adults and children) Corticosteroid insensitivity Increased neutrophils in sputum¶ p38 MAPK inhibitors Theophylline (adults and children) Macrolides (adults and children) FeNO: exhaled nitric oxide fraction; IL: interleukin; LTB4: leukotriene B4; ICS: inhaled corticosteroid; OCS: oral corticosteroid; MAPK: mitogen-activated protein kinase. #: Unless otherwise stated, these potential treatments apply to adults; ¶: neutrophilic asthma is rare in children.
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- New guidelines for severe asthma provide an updated definition of the disease and a new plan to tackle it - A new guideline has provided an updated definition of severe asthma along with new recommendations for treating the condition.
Vol 43 Issue 2
Table of Contents
International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma
