THE NORDIC SEVERE ASTHMA NETWORK: POCKET GUIDE FOR SYSTEMATIC ASSESSMENT AND MANAGEMENT OF POSSIBLE SEVERE ASTHMA IN ADULTS – 2020

Aim

The purpose of this pocket guide is to provide a condensed, practical and pragmatic clinical overview on the assessment and management of possible severe asthma in adults.

The content of this pocket guide is based on the recommendations from the Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults 2018¹ , where a more detailed description is found.

This Pocket guide is developed by the Nordic Severe Asthma Network (NSAN) established under the Nordic Respiratory Academy (NORA) with severe asthma specialists from Norway, Sweden, Denmark, Iceland, Finland and Estonia as members

Introductory summary

Asthma is increasingly recognised as a complex, heterogeneous disease consisting of a variety of clinical, pathophysiological and inflammatory characteristics with an inconsistent and variable response to treatment^2–4 . Most patients can achieve well-controlled asthma on low to medium dose of inhaled corticosteroids (ICS). However, a small group of patients remains a major challenge as they persistently require intensive asthma therapy, including high doses of inhaled steroids as well as “second controllers”^5–7 . Poor asthma control may, however, be due to several factors. Hence, patients, who are prescribed high-dose asthma treatment, should undergo a thorough systematic assessment in a specialist care setting to confirm the diagnosis of asthma and identify and address potential aggravating comorbidities and environmental triggers, poor adherence to controller medication before being classified as having severe asthma^5–8 . The prevalence of severe asthma is estimated to be up to 8 percent of all asthma patients^9–12. However, this relatively small proportion of patients with asthma presents the largest burden of disease due to frequent exacerbations, poor quality of life and increased health care costs^13,14. Additionally, different targeted, biological therapies are becoming increasingly available for subsets of patients with severe asthma. However, these treatments target very specific pathways in the immune systems and are thus only effective in selected subgroups of severe asthma. Therefore, highlighting the need for a detailed phenotyping of patients with severe asthma.

Definition of severe asthma

The ERS/ATS guidelines^5,7 define severe asthma as asthma that remains uncontrolled or where acceptable control is only achieved when receiving high-dose ICS (Table 1) and a second controller (≥ 12 months) or systemic corticosteroids (≥6 months/previous year). The second controllers include long-acting beta-agonists (LABA), leukotriene antagonists (LTRA), long-acting muscarinic antagonists (LAMA) or methylxanthines. The definition excludes patients in whom the poor asthma
control is related to external factors, such as poor adherence or unmanaged comorbidities (difficult-to-treat asthma) (Figure 1). To differentiate these two patient populations, other causes including comorbidities affecting asthma control
should be addressed and managed, including reassessment in specialist care after 3-6 months, before a diagnosis of severe asthma is assigned.

Figure 1: Differentiation of difficult-to-treat versus severe asthma

Systematic assessment

Several factors including comorbidities and diseases of the upper and lower airways may influence asthma control and mimic severe asthma ^5,8. Consequently, a careful stepwise systematic assessment is important to support the diagnosis of
severe asthma^5,8,15. There is evidence that after a careful systematic evaluation and management of patients with difficult asthma in a severe asthma centre, less than half can be classified as having severe asthma after 12 months of follow-up¹⁶.
The main objective of systematic assessment is to differentiate between severe asthma and difficult-to-treat asthma, the latter being cases in which poor asthma control is mainly caused by external factors (such as poor adherence, untreated
comorbidities and unaddressed triggers).

Overall, systematic evaluation is recommended to include three steps (Figure 2):

1. Confirm the asthma diagnosis, assess asthma control, assess the phenotype

2. Identify and address potential treatment barriers (adherence, poor inhaler technique)

3. Evaluate and manage comorbidities and environmental exposures

Step 1: Diagnosis and phenotype

A. Confirmed asthma diagnosis?

A diagnosis of asthma requires a detailed history including the presence of asthma symptoms combined with objective confirmation of variable airflow limitation (Box 1). Be aware that an inconsistent response to treatment can be due to an
alternative/overlapping diagnosis, especially if non-typical asthma symptoms are dominating or variable airflow limitation is lacking (Table 3). Exclusion of alternative diagnoses:

• Several conditions may mimic severe asthma.
• An alternative or overlapping diagnosis to asthma should always be kept in mind in patients with:

   – Inconsistent response to treatment

   -Atypical asthma symptoms

   -Inability to verify the asthma diagnosis objectively

• Diagnostic work-up according to the clinical suspicion, see Table 3.
• Some conditions co-exist in patients with difficult/severe asthma and are important contributors to asthma symptoms, these are listed in Table 6

Figure 2: Systematic assessment of patients with possible severe asthma (difficult asthma)

B. Level of asthma control

Uncontrolled severe asthma according to the ERS/ATS guidelines⁵ :

Inadequate symptom control?

   o ACQ ≥1.5

   o ACT <20

or

   o Uncontrolled according to GINA guidelines6 : frequent symptoms or reliever use, activity limited by wheeze, chest tightness and cough interfere with daily activities, awakenings due to asthma.

≥ 2 OCS requiring exacerbations in the last 12 months≥1 serious exacerbation: hospitalisation, ICU stay or mechanical ventilationAirflow limitation (pre-bronchodilator FEV1 <80 % and FEV1/FVC

C. Clinical phenotype

Overall, there is no clear consensus on the definition of clinical phenotypes for asthma. However, in severe asthma these phenotypes are generally evaluated in clinical practice as follows⁵:

Early-onset allergic phenotypeLate-onset obese phenotypeLate-onset eosinophilic phenotypeFrom a pragmatic clinical point of view the following features should be systematically described.

Early/late onset asthma? (Onset of asthma symptoms in childhood or in adulthood)

Evidence of Type 2 (T2) inflammation:

• Evidence of eosinophilic airway inflammation (current and/or historical):
  • Blood eosinophil count ≥0.3 x109 cells/L^19,20
  • Sputum eosinophil count ≥3% (only available in some specialised asthma centres)²¹
  • FeNO >25 ppb*²²

In patients with no evidence of eosinophilic airway inflammation, consider repeating blood eosinophilic count and FeNO several times, and if possible perform induced sputum or consider bronchoscopy with cell counts in BAL before assuming
non-T2 asthma.

*FeNO >50 ppb indicates high likelihood of eosinophilic airway inflammation. Whereas, FeNO <25 indicates low likelihood of eosinophilia²².

• IgE mediated allergy?
  • Positive skin prick test, elevated specific IgE (>0.35 kU/L) for aeroallergens with relevant symptoms? ²³
• Fixed airflow obstruction (FEV1<80% and FEV1/FVC <0.7)?Obesity (BMI >30kg/m2 )
• Smoking history?

Step 2: Treatment barriers

Identification of factors that impede the delivery of asthma medication to the airways, including nonadherence to treatment and incorrect inhaler technique, is crucial. A diagnosis of severe asthma presupposes that medication is taken as

prescribed, but non-adherence is unfortunately common, even in patients on highdose treatment5,8. If adherence is not systematically evaluated in patients with poor symptom control despite high dose treatment, non-adherent patients are
likely to be misclassified as having severe asthma. This potentially leads to an inappropriate intensification of treatment including commencement of OCS (with the risk of systemic side-effects²⁴) or expensive biological therapies^25–27.

A. Adherence:

• Poor adherence to ICS in patients with difficult asthma is common (40-65 %)^28–30 and is related to poor asthma outcomes including higher use of SABA, poor quality of life, lower FEV1, exacerbations and asthma related hospital admissions^29,31.
  Consequently, we recommend that adherence be routinely assessed
• There is no clear consensus on the cut-off describing non-adherence. However, if using electronic registries for prescription fillings, patients are often considered adherent if ≥80% of ICS prescriptions are filled^9,28,30,32
• See Table 4 for more details

B. Inhaler technique:

• Poor inhaler technique in patients with difficult asthma is common (20-60 %)^9,28,30 and leads to poor asthma control and increased risk of exacerbations³³. It is a particular challenge that these patients often have multiple inhalers each
  requiring different techniques to ensure correct administration. Consequently, we recommend inhaler technique to be thoroughly taught and checked at each new prescription, and systematically evaluated during each visit to the outpatient
  clinic. At every visit to the outpatient clinic, patients should demonstrate inhaler technique. Thus, ensuring that critical errors are systematically identified and corrected.
• More details are listed in Table 4

C. Self-management skills:

• Patients need a minimum set of skills to manage their disease adequately and optimise asthma control. Asthma patients need a basic understanding of their disease. This includes knowledge of triggers and comorbidities. They need to understand how their different medications work and their respective side effects. Additionally they need to be able to recognize the advent of exacerbations and how to handle them³⁴. Asthma education and guidance have shown to improve quality
  of life and reduce hospital admissions.

• Written action plans: guidance on maintenance therapy, recognition and management of exacerbations.

• Self-management education by specialised asthma nurses The identification and management strategies of treatment barriers are shown in Table 4.

Step 3 Exposures and comorbidities

Identification of comorbidities and exposures are central to the systematic evaluation of patients with possible severe asthma.

A. Exposures and modifiable risk factors

Asthma symptoms can be aggravated by several external triggers or irritants including allergens, smoking, pollution and certain drugs^6,37. Assessment requires a detailed history including smoking history, exposure to different allergens,
drugs and occupational exposure and is listed in Table 5.

B. Evaluation and management of comorbidities in severe asthma

Comorbidities in patients with difficult or severe asthma are common^{12,16,28,38,39}. Some comorbidities can mimic asthma symptoms and others are associated with poor asthma outcomes^38,40. Consequently, by identifying and managing comorbidities,
potential overtreatment of asthma may be avoided and a correct diagnosis of severe asthma ensured^{39, 41}. The most common and important comorbidities and their respective symptoms, diagnostic tests and management are listed in Table 6.
A detailed description of comorbidities in severe asthma is available in the original “Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults” ¹ .

Management of severe asthma

Overall, the management of severe asthma can be divided into three domains as shown in Figure 3: Nonpharmacological management, pharmacological treatments and management of comorbidities.

Figure 3: Treatment strategies for severe asthma:

The principles of asthma treatment presented in this guide are mostly based on the 2019 GINA guidelines⁶ with some modifications (Figure 4). We propose a stepwise approach according to the inflammatory phenotype when managing severe asthma (Figure 5).

Figure 4: Treatment steps according to GINA 2019/6

Figure 5: Stepwise therapeutic approach in patients with severe uncontrolled asthma

Optimising step 5 treatment

Patients with severe asthma are per definition treated with high-dose ICS and a second controller. Before considering biological treatments, regular asthma therapy should be optimized. Potential contributing factors must be addressed and
managed, such as external triggers, comorbidities and treatment barriers.

• Consider optimising inhalers: from metered-dose inhalers (pMDI) to dry powder inhalers (DPI) or vice versa according to patients/treating specialists preference, consider spacers if using pMDI
• Consider additional controllers as add-on treatments:
  • LAMA: especially in patients with exacerbations ^64,65
  • LTRA: consider in patients with AERD or allergic rhinitis⁶
  • Theophylline

• Consider reliever treatments: as needed ICS-formoterol is preferred in patients with exacerbations⁶⁶
• In patients, who are not well-controlled on high dose ICS-LABA, consider referral to a severe asthma specialist/centre^1,5

Still poor asthma control despite optimised asthma treatment and management?

Further treatment opportunities according to the inflammatory phenotype (Figure 5):

Evidence of T2 inflammation:

• Reconsider adherence!
• Consider increasing ICS6 – be aware of side effects!
• Consider low-dose macrolides:
  • Conflicting results, however there is some evidence that treatment with azithromycin 250-500 mg three times a week reduces exacerbations in patients with eosinophilic as well as noneosinophilic airway inflammation^67,68
  • Be aware of: prolonged QTc, hearing loss/tinnitus and potential bacterial resistance⁶⁷
• Consider low dose OCS:
  • Low evidence, therefore the lowest dose for as short time as possible.
  • Be aware of side-effects: diabetes, hypertension, peptic ulcers, osteoporosis^24,69,70

• Consider ABPA: Specific IgE/IgG against Aspergillus fumigatus, total IgE, blood eosinophils, bronchiectasis (HRCT)⁷¹
• Consider biological therapies (according to eosinophilic or allergic predominance):
  • Allergic asthma:
    • Anti-IgE:
    • Perennial atopy combined with allergen induced symptoms+ exacerbations + total IgE within dose range* ^72–74
    • Reduces exacerbations, improves symptom control and lung function^72,75,76
    • Predictors of treatment response: see Figure 6
  • Eosinophilic asthma:
    • Anti-IL5/anti-IL5R:
      • Exacerbations + blood eosinophil count ≥ 0.3 x 109 /L (lower if patients on long-term OCS)*^6,19
      • Reduces exacerbations^19,77,78
    • Less effect on symptoms and lung function^78–80.
    • OCS sparing effect^81,82
    • Effect on chronic rhinosinusitis with nasal polyps⁸³
    • Predictors of treatment response: see Figure 6
  • Anti-IL4/13:
    • Exacerbations + blood eosinophil count ≥ 0.15 x 109 / FeNO≥25 ppb (lower if patients are on long-term OCS)* ^6,84
    • Reduces exacerbations, increases lung function and symptom control ⁸⁴

        • OCS sparing effect 85

    • Effect on chronic rhinosinusitis with nasal polyps 86 and atopic dermatitis 87

    • Predictors of treatment response: See Figure 6

*Check local eligibility criteria for the different biological treatments, as these may vary from those listed.

At present, no direct comparisons between any of the biological therapies exist.

T2 low inflammation

• Reconsider important comorbidities/alternative diagnosis: e.g. VCD, DB, COPD, bronchiectasis, obesity etc. (Table 3, Table 6): consider HRCT, lung volumes, DLCO, induced sputum if not done
• Add LAMA if not yet in use (especially if FEV1 <80% and exacerbations)
• Consider low-dose macrolides:

   o Conflicting results, however there is some evidence that treatment with azithromycin 250-500 mg three times a week reduces exacerbations in patients with non-eosinophilic as well as eosinophilic airway inflammation67,68

   o Be aware of: prolonged QTc, hearing loss/tinnitus and potential bacterial resistance (sputum cultures should be obtained if bronchiectasis is present)67

• Consider bronchial thermoplasty

   o Reduces long-term exacerbations, but is associated with increased risk of exacerbations in relation to the procedure 88

   o Contraindications: bronchiectasis, FEV1<50%

   o Lack of long-term follow up data 5

Figure 6: Predictors of treatment response to anti-IgE, anti-IL5/IL5R and anti IL4/13:

Minimum assessment before commencing a biological drug

Patients with difficult asthma should undergo a detailed systematic assessment according to the three evaluation steps described earlier in this document (Figure 2)

1. Diagnosis & phenotype

2. Identification of treatment barriers

3. Identification and management of exposures and comorbidities

Before commencing a biological drug, we advocate that at minimum the following to be evaluated and managed including reviewing response to management after approximately 3-6 months to ensure a true diagnosis of severe refractory asthma,
as illustrated in Figure 7.

Figure 7: Recommended minimum assessment before commencing T2-targeted biological therapies for severe asthma.

Referral to a severe asthma centre:

Consider referral if:

• Difficult and persistent uncontrolled asthma (low lung function, poor symptom control or frequent exacerbations) on GINA step 5 treatments (high dose ICS + second controller) despite good adherence, correct inhaler therapy and attempts
  to optimise therapy with different inhalers and addon therapies
• Treatment with maintenance OCS

Content in referral letter to a severe asthma centre is illustrated in Box 2

Abbreviations:

ABPA: Allergic bronchopulmonary aspergillosis

ACE: Angiotensin-converting enzyme

ACT: Asthma Control Test

ACQ: Asthma Control Questionnaire

AHR: Airway hyperresponsiveness

ASA: acetylsalicylic acid

ATS: American Thoracic Society

COPD: Chronic obstructive pulmonary disease

CPAP: Continuous Positive Airway Pressure

CT: Computed tomography

DB: Dysfunctional breathing

DLCO: Diffusing capacity for carbon monoxide

DPI: Dry powder inhaler

ERS: European Respiratory Society

FEV1: Forced expiratory volume in 1 second

FVC: Forced vital capacity

FeNO: Fractional exhaled nitric oxide

GERD: Gastroesophageal reflux disease

GINA: Global Initiative for Asthma

GSRS: Gastrointestinal Symptom Rating Scale

HADS: Hospital Anxiety and Depression Scale

HRCT: High resolution computed tomography

ICS: Inhaled corticosteroids

IL: Interleukins

ILO: Inducible laryngeal obstruction

LABA: Long-acting beta-agonist

LAMA: Long-acting muscarinic antagonist

LTRA: Leukotriene antagonist

MDI: Metered-dose Inhaler

NSAID: Nonsteroidal anti-inflammatory drug

NSAN: Nordic Severe Asthma Network

NORA: Nordic Respiratory Academy

OCS: Oral corticosteroids

OSAS: Obstructive sleep apnea syndrome

PEF: Peak expiratory flow

SABA: Short-acting beta-agonist

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