Last updated: Febuary 2020

POCKET GUIDE TO SYSTEMATIC ASSESSMENT AND MANAGEMENT OF POSSIBLE SEVERE ASTHMA IN ADULTS –2020

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

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Authors: 

: Anna von Bülow1, Asger Sverrild1, Charlotte Ulrik2,3, Tina Skjold4, Vibeke Backer5, Ole Hilberg6, Birger Laerum7, Sverre Lehman8,9, Bernt Bøgvald9, Christer Janson10, Thomas Sandström11, Leif Bjermer12, Apostolos Bossios13, Barbro Dahlen13, Valentyna Yasinska13, Helena Backman14, Bo Lundbäck15, Dora Ludviksdottir16, Unnur Björnsdottir16,17, Alan Altraja18, Maritta Kilpeläinen19,20, Arja Viinanen19,20, Lauri Lehtimäki21,22, Paula Kauppi23, Jussi Karjalainen24, Hannu Kankaanranta21,24 and Celeste Porsbjerg1,2

1Respiratory research unit, Department of Respiratory Medicine, Bispebjerg Hospital, Copenhagen, Denmark; 2 Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 3Department of Respiratory Medicine, Hvidovre Hospital, Denmark; 4Department of Respiratory Medicine, Aarhus University Hospital, Aarhus, Denmark; 5Centre of Physical Activity Research, Rigshospitalet, Copenhagen, Denmark; 6Department of Respiratory Medicine, Vejle Hospital, Vejle, Denmark; 7LHL-klinikkene Bergen, Nesttun, Norway; 8Department of Clinical Science, University of Bergen, Bergen, Norway; 9Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway; 10Department of Medical Sciences: Respiratory, Allergy & Sleep Research, Uppsala University, Uppsala, Sweden; 11Department of Public Health and Clinical Medicine, Department of Public Health and Clinical Medicine,  Medicine unit, Umeå University, Umeå, Sweden; 12Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden; 13Department of Respiratory Medicine and Allergy, Karolinska University Hospital, and Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden; 14Section of Sustainable Health, The OLIN Unit, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; 15Krefting Research Centre, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; 16Department of Allergy, Respiratory Medicine and Sleep Landspitali University Hospital Reykjavik Iceland, University of Iceland, Reykjavik, Iceland; 17Faculty of Medicine, University of Iceland, Reykjavik, Iceland; 18Department of Pulmonary Medicine, University of Tartu and Lung Clinic, Tartu University Hospital, Tartu, Estonia; 19Division of Medicine, Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland. 20Department of Pulmonary Diseases and Clinical Allergology, University of Turku, Turku, Finland; 21Faculty of Medicine and Health Technology, Tampere University, Tampere Finland; 22Allergy Centre, Tampere University Hospital, Tampere, Finland; 23Department of Allergy, Respiratory Diseases and Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 24Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland

1.0 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.

2.0 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 asthma5–8.

The prevalence of severe asthma is estimated to be up to 8 percent of all asthma patients9–12. 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 costs13,14.  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.

3.0 Definition of severe asthma

The ERS/ATS guidelines5,7 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

figureone

Table 1. Definitions of high dose inhaled steroids (ICS)*

Table 1. Definitions of high-dose inhaled steroids1,5

 

Daily dose (μg)

Budesonide

≥1600

Fluticasone dipropionate

≥1000

Mometasone furoate

≥800

Ciclesonide

≥320

Beclomethason dipropionate

≥1000 (HFA MDI) ; ≥2000 (DPI)

Fluticasone furoate

≥200

Triamcinolone acetone

≥2000

HFA: hydroflouroalkane; MDI: metered dose inhaler; DPI: dry powder inhalers

 

4.0 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 asthma5,8,15. 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

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

figure2

4.1 Step 1: Diagnosis and phenotype

4.1.1 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).

Box 1 Confirmation of asthma diagnosis:

1: History of typical asthma symptoms:

  • Wheezing, shortness of breath, chest tightness and/or cough which vary both in intensity and over time
  • Often symptoms are triggered by viral infections, allergens and non-specific irritants (smoke, perfumes, cold air, exercise etc.)

And

2: Objective confirmation of variable airflow limitation (current or historical):

  • The preferred diagnostic test depends on local availability and clinicians’ preference. Bronchial challenge tests have higher sensitivity than reversibility tests and PEF monitoring – and may therefore be preferred initially in patients with preserved lung function (mannitol: pre-bronchodilator FEV1 ≥70%89; methacholine: pre-bronchodilator FEV1 ≥60%17).

PEF is a cost-effective complementary measurement that may add additional information, with regard to both confirming and rejecting variable airflow limitation.

  • The diagnostic criteria for confirmed variable airflow limitation are described in Table 2
  • It is often necessary to perform more than one diagnostic test to verify the asthma diagnosis objectively28
  • In patients with symptoms and preserved lung function (FEV1 ≥70%) but with no signs of reversibility or airway hyperresponsiveness: consider down-titration of controller treatment (ICS) followed by retesting (after 2-8 weeks)8
  • Some patients with severe asthma develop fixed airflow obstruction over time due to airway remodelling­­­, but this does not preclude a diagnosis of asthma90. Evidence of a past history of reversibility or airway hyperresponsiveness may be helpful in these situations

 

Table 2: Diagnostic criteria for confirmed variable airflow limitation:

Reversibility to SABA/ICS/OCS

 

Increase in FEV1 of >12% and >200 mL*6

Peak flow monitoring

Daily PEF for 2-3 weeks: diurnal PEF variability** >10%6

Bronchial challenge test

Methacholine (only if pre-bronchodilator FEV1 ≥60 %)

FEV1 ≥20% decrease with a cumulative dose of methacholine ≤8 μmol***17

Mannitol (only if pre-bronchodilator FEV1 ≥70 %)

FEV1 ≥15 % decrease from baseline with a provocation dose of mannitol ≤ 635 mg
or ≥10 % decrease in FEV1 between two consecutive doses18

*Measured 10-15 minutes after administration of SABA (200-400 mcg salbutamol or equivalent or after 4 weeks with anti-inflammatory treatment.

**Diurnal variability of PEF: ([Day’s highest – day’s lowest]/mean of day’s highest and lowest) x 100, then the average of each day’s value is calculated over 1–2 weeks.

***The cumulative dose may vary according to different dosimetric methods.

 

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

Table 3: Alternative diagnoses to severe asthma

Table 3: Alternative/overlapping diagnoses to severe asthma

 

Assessment

COPD*/emphysema

Diffusing capacity, HRCT

Bronchiectasis*

HRCT

Sarcoidosis

HRCT, biopsy

Cystic Fibrosis

Sweat test, genetic testing

Hypersensitivity pneumonitis

HRCT, precipitins

Hyper-eosinophilic lung diseases

(EGPA)

Blood eosinophils, HRCT, biopsy of affected organs,

anti-neutrophilic cytoplasmic antibodies

Recurrent pulmonary embolism

D-dimer, CT thorax angiography, ventilation/perfusion scintigraphy

Congestive heart failure

Transthoracic echocardiography, BNP

Endobronchial tumour/foreign body

Bronchoscopy

ILO*

Laryngeal video recording under attack or provocation

Tracheobronchomalacia/EDAC

Dynamic CT thorax, bronchoscopy

Dysfunctional breathing*

Nijmegen questionnaire, BPAT, physiotherapist assessment

*May be an alternative diagnosis to severe asthma but is commonly a co-existing diagnosis

COPD: chronic obstructive pulmonary disease; HRCT: high resolution computer tomography;
EDAC: excessive dynamic airway collapse; EGPA: eosinophilic granulomatosis with polyangiitis; ILO:
Inducible laryngeal obstruction

 

 

4.1.2 Level of asthma control

 

Uncontrolled severe asthma according to the ERS/ATS guidelines5:

  • Inadequate symptom control?
    • ACQ ≥1.5
    • ACT <20

or

  • 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 ventilation
  • Airflow limitation (pre-bronchodilator FEV1 <80 % and FEV1/FVC<lower limit of normal).

 

4.1.3 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 phenotype
  • Late-onset obese phenotype
  • Late-onset eosinophilic phenotype        

From 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/L19,20
      • 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?

4.2 Step 2: Identification of treatment barriers

Identification of factors that impede the delivery of asthma medication to the airways, including non-adherence 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 high-dose 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 therapies25–27.

4.2.1 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 admissions29,31. 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 filled9,28,30,32
  • See Table 4 for more details

4.2.2 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

4.2.3 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 them.34. 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

Table 4: Identification and management of treatment barriers

 Identification/evaluation

Management/intervention

Adherence

Fillings of prescription for asthma medication in electronic registries (if available).

·         Strength: objective assessment

·         Limitation: Do not necessarily reveal short-term changes in adherence

 

Self-reported adherence: e.g. “How many times the previous week have you taken
your inhalers as prescribed” – zero days, one day, two days, three days…”35

·         Strength: easy to use, inexpensive

·         Limitation: Tendency of over-estimation 36

Check dates on inhalers

1. Identify causes of non-adherence:

Intentional:

·         Side-effects or fear of side effects to treatment

·         Perception that treatment is unnecessary

Non-intentional:

·         Due to forgetfulness

·         Misunderstanding of instructions

·         Cost of medication

2. Intervention

Intentional non-adherence:

·         Requires an empathic discussion with the patients regarding pros and cons or their  treatment

Non-intentional non-adherence:

·         Consider simplifying the treatment to a more feasible regime such as once daily dosing

·         Recommend systematic intake of asthma medication: e.g. before brushing teeth  or reminders to use of inhalers.

·         Consider the costs of medications before prescribing.

Inhaler technique

Ask the patient to show you how they use their inhalers at each clinic visit

 

Use inhaler-specific-checklists (Direct link)

Choose the optimal device for the individual patient. If different options are available try to include the patients in the decision making 6

Consider spacers for pMDI inhalers

Avoid different types of inhalers whenever possible

When prescribing a new inhaler, physically demonstrate the use of the inhaler with a placebo inhaler and ask the patient to demonstrate the inhaler use afterwards 6

Frequently reassess inhaler technique, as errors often reappear 6

4.3 Step 3 Exposures and comorbidities

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

4.3.1 Exposures and modifiable risk factors

Asthma symptoms can be aggravated by several external triggers or irritants including allergens, smoking, pollution and certain drugs6,37. Assessment requires a detailed history including smoking history, exposure to different allergens, drugs and occupational exposure and is listed in Table 5.

Table 5: Potential asthma triggers including evaluation and management

Table 5: Potential asthma triggers including evaluation and management

 

 

Evaluation/Test

 

Management

Indoor allergens: Pets (cats, dogs), house dust mites, moulds, cockroaches, rodents

·         SPT, specific IgE for aeroallergens (incl. Aspergillus fumigatus)

Evaluate the correlation to symptoms. If sensitised to pets, consider avoidance of pets. Remediation of dampness.

Antihistamines, nasal steroids, LTRA

Outdoor allergens: pollen, mould

·         SPT, specific IgE for aeroallergens (incl. Aspergillus fumigatus)

Antihistamines, nasal steroids, LTRA

 

Tobacco smoke (active – passive)

 

Smoking cessation

Drugs: ASA, NSAID, Beta-blockers, ACE-inhibitors

·         Samter’s triad: severe eosinophilic asthma, nasal polyposis and NSAID-exacerbated respiratory disease?

·         ACE-inhibitors: cough

Avoid ACE-inhibitors and non-selective systemic beta-blockers

Occupational exposure

 

Symptoms aggravate with exposure at workplace*

Specific exposures

·         Flour, grain: bakers/farmers

·         Isocyanates: painters, automotive industry workers, foam plastic production, insulation, polyurethane foam use

·         Formaldehyde: health care workers, hairdressers, cosmetic workers

·         Wood dusts: carpenters

·         Platinum salts: dentists, chemist, photographers, electricians

·         Animal allergens: farmers, veterinarians, animal breeders

Consider referral to specialists in occupational medicine

*NB:  Severe asthma may develop many years after an exposure

ACE: angiotensin converting enzyme; ASA: acetylsalicylic acid; NSAID: non-steroidal anti-inflammatory drug; LTRA: leukotriene antagonist; SPT: skin prick test

4.3.2 Evaluation and management of comorbidities in severe asthma

Comorbidities in patients with difficult or severe asthma are common12,16,28,38,39. 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 ensured39,41. 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.

Table 6: Common comorbidities in severe asthma

Table 6: Common comorbidities in severe asthma 

Comorbidity (prevalence)

Symptoms

Test

Management

Chronic rhinosinuitis /nasal polyps (CRSwNP) (50%)42

Nasal obstruction, rhinorrhoea, facial congestion,headache, anosmial 43

SNOT-22 questionnaire

Nasal endoscopy

(CT of sinuses)

Nasal lavage,

Nasal steroids,

Surgery

Allergic rhinoconjuctivitis (70%42*)

(*Positive skin prick test to aeroallergens)

Rhinorrhoea, sneezing, nasal obstruction, nasal, eye itching 23

History + skin prick test/ specific IgE

Nasal steroids

Antihistamines

LTRA

COPD (20%)44

Wheezing, dyspnoea

History incl. smoking

DLCO/HRCT (emphysema)

Add LAMA

Add roflumilast

Rehabilitation

Dysfunctional Breathing (30%)28,40

Heterogeneous symptoms: Hyperventilation, breathlessness, deep sighing,
apical breath pattern often combined with extra pulmonary symptoms: dizziness, fatigue, tingling around fingers/mouth45

History/

Nijmegen questionnaire 46

BPAT47

Physiotherapy – breathing retraining 45,48

ILO (32-50%)40,49,50

Shortness of breath, dyspnoea, stridor rather than wheezing during attacks, hoarseness during attacks41

Screening with Pittsburgh VCD-index51

Continuous laryngoscopy under attacks

Speech therapist

Anxiety/depression (4-17%)10,52

Anxiety, depression symptoms

HADS questionnaire Psychiatric assessment

Psychiatrist

Medical treatment

Psychotherapy

OSAS (31%)53

Snoring, day time sleepiness, obesity, Night-time awakenings with breathing difficulty without asthmatic signs 54

Screening with STOP-BANG/Berlin questionnaire 55, Screening for daytime sleepiness with Epworth Sleepiness scale56

Polysomnography/ respiratory polygraphy

Weight loss

CPAP41

Obesity (37-63%)3,12

BMI >30 kg/m2

BMI

Dietician, weight loss57

Gastro-esophageal reflux (17-74%)3,16,42,58

Heartburn, acid regurgitation, cough, laryngeal symptoms

3 months of empiric PPI

24-hours pH monitoring

PPI 59

Lifestyle interventions

Fundoplication

Bronchiectasis (25-40%)60,61

Cough, recurrent pulmonary infections

HRCT, sputum cultures,

Physiotherapy, long term mucoactive treatment, low-dose macrolides41,62

ABPA (1-2%)63

Poor asthma control, often chronic mucus hyper secretion41

Total IgE, IgE and IgG to Aspergillus fumigatus, blood eosinophilia, HRCT (bronchiectasis)

Prednisolone. Anti-fungal treatment. Omalizumab  may be considered in some cases.

ABPA: allergic bronchopulmonary aspergillosis; BMI: body mass index; CPAP: continuous Positive Airway Pressure; ILO: Inducible laryngeal obstruction; HRCT: high resolution computed tomography;
LAMA:  long-acting muscarinic antagonist;  LTRA:  leukotriene antagonist; OSAS: obstructive sleep apnea syndrome; PPI: proton pump inhibitors

 

5.0 Management of severe asthma

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

Figure 3: Treatment strategies for severe asthma:

figure4

5.1 Stepwise therapeutic approach to treat severe asthma

The principles of asthma treatment presented in this guide are mostly based on the 2019 GINA guidelines6 with some modifications (Figure 4).

Figure 4: Treatment steps according to GINA guidelines

figure4

We propose a stepwise approach according to the inflammatory phenotype when managing severe asthma (Figure 5).

5.1.1 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 rhinitis 6
    • 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/centre1,5

5.1.2 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 non-eosinophilic airway inflammation67,68
    • Be aware of: prolonged QTc, hearing loss/tinnitus and potential bacterial resistance 67
  • 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, osteoporosis24,69,70
  • 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 polyps 83
        • 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:
    • 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
    • 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
    • Reduces long-term exacerbations, but is associated with increased risk of exacerbations in relation to the procedure 88
    • Contraindications: bronchiectasis, FEV1<50%
    • Lack of long-term follow up data 5

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

figure5

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

figure6

5.2 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.

Figure7

5.3 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 add-on therapies
  • Treatment with maintenance OCS

           

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

Box 2. The referral letter to the severe asthma centre should include as much as available of the following information to facilitate the systematic assessment in the specialised severe asthma centre/team

1. Difficult asthma (high dose ICS + second controller)? (Y/N)

2. Asthma control:

               Key symptoms:

               Exacerbations last 12 months (n):

3. Asthma diagnosis confirmed (Y/N), if yes, which test and when?

4. Current medications

5. Results of any treatment trials (LAMA, LTRA, oral steroids etc)

6. Inhalation technique checked and correct?

7. Adherence checked and acceptable? (Including how adherence is assessed –prescriptions fillings, self-reported)

8. Exposures (work history, possible exposure to allergens (home, hobbies, at work) and other exposures)?

9. Information on concomitant diseases (allergic rhinitis, chronic rhinosinusitis, obesity, OSAS, GERD, bronchiectasis, COPD etc.)

10. Test results: include most recent evaluations of respiratory and asthma (including X-ray, spirometry, peak flow follow-ups, bronchial challenge tests, FeNO, blood eosinophil counts, total IgE)

*If proper diagnostic evaluation have not been done, relevant diagnostic work-up should be performed be the treating generalist or respiratory specialist before referring the patient to a severe asthma centre.

6.0 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

7.0 References

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