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Severe asthma

Learn more about severe asthma, including signs and symptoms, and current treatment options

Explore information on severe asthma

What is severe asthma?

In patients aged ≥6 years, severe asthma is asthma that requires treatment with high-dose inhaled corticosteroids (ICS) plus a second controller (and/or systemic corticosteroids), to prevent it from becoming ‘uncontrolled’, or asthma that remains ‘uncontrolled’ despite this therapy.1

Compared with milder disease, severe asthma is associated with a heavy burden of disease due to daily symptoms such as cough and dyspnoea, and frequent exacerbations, often requiring hospitalisation.2

An estimated 200,000 people in the UK have severe asthma.3

The infographic below illustrates the prevalence of general, difficult and severe asthma in the UK population.

UK asthma prevalence based on 2017 data:3

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What are the signs and symptoms of severe asthma?

Asthma symptoms such as wheezing, chest tightness, shortness of breath and cough typically vary in frequency and intensity.4 In patients with severe asthma, these symptoms remain uncontrolled despite adherence with optimised high-dose ICS long-acting b2-agonist (LABA) and treatment of contributory factors, or worsen when high-dose treatment is decreased.4 Below are potential signs that indicate a patient may have severe asthma.

Poor symptom control1,3

The patient experiences asthma symptoms that are hard to control, even with prescribed treatments. Defined as Asthma Control Questionnaire (ACQ) consistently >1.5, Asthma Control Test (ACT) <20 (or ‘not well controlled’ by National Asthma Education and Prevention Program [NAEPP] or Global Initiative for Asthma [GINA] guidelines over the 3 months of evaluation).

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Frequent severe exacerbations1,3

The patient has had two or more asthma exacerbations requiring bursts of systemic corticosteroids (≥3 days each) in the previous year.

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Serious exacerbations1

The patient has had at least one hospitalisation, intensive care unit stay or mechanical ventilation in the previous year.

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Airflow limitation1

The patient has limited airflow, i.e. forced expiratory volume in 1 second (FEV1) <80% predicted (in the presence of reduced FEV1/forced vital capacity [FVC] defined as less than the lower limit of normal) following a withhold of both short- and long-acting bronchodilators.

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Asthma worsens1

The patient’s controlled asthma worsens on tapering of corticosteroids.

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What is the difference between severe, difficult-to-treat and uncontrolled asthma?

Proportion of adults with difficult-to-treat or severe asthma4

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Why is it important to distinguish between severe and uncontrolled asthma?

Distinguishing between severe and uncontrolled asthma is important because uncontrolled asthma is the more common reason for persistent symptoms and exacerbations, and can be improved upon investigation.4 The most common reasons for uncontrolled asthma, which should be excluded before making a diagnosis of severe asthma, are:4

  • Poor inhaler technique
  • Poor medication adherence
  • Incorrect diagnosis of asthma, with symptoms due to alternative conditions such as inducible laryngeal obstruction, cardiac failure or lack of fitness
  • Multimorbidity such as rhinosinusitis, gastroesophageal reflux disease (GERD), obesity and obstructive sleep apnoea
  • Ongoing exposure to sensitising or irritant agents in the home or work environment

What role do eosinophils play in severe asthma?

Most patients with severe asthma have type 2 inflammation,4 often associated with elevated levels of eosinophils.5,6 The reported proportion of severe asthma patients with eosinophilic inflammation varies, and there is a lack of consensus in defining the subtype.7,8 However, eosinophilic asthma has been reported as the most common asthmatic phenotype, accounting for over 50% of cases of severe asthma.8

While eosinophils are thought to play a role in maintaining health by helping to regulate the immune system and defend the body from attack,9,10 in severe asthma, they are a contributor to airway inflammation, hyperresponsiveness and remodelling.9,11,12 Studies have shown elevated numbers of eosinophils are associated with an increased risk of exacerbations in asthma patients.9,11,12

Eosinophil recruitment, activation, growth, differentiation and survival is regulated by the cytokine interleukin (IL)-5.9,13 Thus, targeting IL-5 (or IL-5 receptors) can be a plausible approach to the treatment of patients with severe eosinophilc asthma.13 In clinical trials where patients with severe asthma were treated with mepolizumab (Nucala), a humanised monoclonal antibody that targets IL-5 with high affinity, reduction in blood eosinophils, and consistent reductions in exacerbation rate were observed.*†14–16

For more information on how Nucala targets IL-5, visit the Nucala Homepage.

*COLUMBA was an open-label extension study in patients with severe eosinophilic asthma (SEA) previously enrolled in DREAM (Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma, NCT01000506). Patients received 100 mg of subcutaneous (SC) Nucala every 4 weeks plus standard of care until a protocol-defined stopping criterion was met. 347 patients were enrolled for an average of 3.5 years (maximum, 4.5 years; total exposure, 1201 patient-years). Blood eosinophil counts were suppressed by 78% from a geometric mean of 240 cells/uL (SD logs, 1.016 cells/uL) at baseline to 50 cells/uL (SD logs, 0.951 cells/uL) at week 4 and remained suppressed throughout the study period.14

REALITI-A is a 2-year, international, prospective, single-arm, observational cohort study of patients aged 18 years and over with severe asthma prescribed Nucala 100 mg SC once every 4 weeks at physician’s discretion (N=822).16 Primary endpoint was rate of clinically significant exacerbations was reduced from 4.28 at 12 months prior to mepolizumab exposure (n=821) to 1.23 in the 12 months post-exposure (n=820); RR 0.29 (95% CI:0.26, 0.32); p<0.001.16

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Severe asthma patient referrals

Patients of any age with persistent symptoms or exacerbations despite correct inhaler technique and good adherence with ICS-LABA/formoterol treatment, and in whom other controller options have been considered, should be referred to a specialist with expertise in investigation and management of severe asthma.4

Consider referral to a specialist or severe asthma clinic at any stage, but particularly if a patient exhibits any of the following:4

  • There is difficulty confirming the diagnosis of asthma
  • They have frequent urgent healthcare utilisation
  • They require frequent or maintenance OCS
  • Occupational asthma is suspected
  • Food allergy or anaphylaxis, as this increases risk of death
  • Symptoms are suggestive of infective or cardiac cause
  • Symptoms are suggestive of complications such as bronchiectasis
  • Patient has multimorbidity

OCS use in severe asthma

OCS are used in addition to ICS to maintain some degree of asthma control in approximately 8–64% of patients with severe asthma.1,18,19 However, systemic corticosteroid use is associated with an increased risk of adverse events and mortality.20–25

The GINA 2022 guideline recommends OCS use should be reduced where possible to minimise risk of serious side effects and recommend low-dose OCS as a ‘last resort’ for only some patients with severe asthma.4

Despite these recommendations, according to the UK Severe Asthma Registry (UKSAR), the world's largest national severe asthma registry, approximately one in two patients in the UK are on maintenance OCS (n=2,225; average ACQ-6 score of 2.9).26 These patients averaged four short OCS bursts per year and continued to have high exacerbation rates, with poorly controlled asthma.26

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Adverse events in OCS use for severe asthma

  • The risk of adverse events associated with OCS use

    Even low doses of OCS have been associated with significantly higher risk of adverse events in patients with asthma, compared to those not exposed.24

    In a UK-based historical matched cohort study (N=24,117 matched pairs of patients), increased risk of adverse events was evident at cumulative exposures to systemic corticosteroids, including OCS, as low as 0.5 g to <1 g (versus >0 to <0.5).24

    Risk of developing adverse events such as hypertension and osteoporosis was significantly higher with increasing cumulative doses.24

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  • Adverse events associated with long-term OCS use

    Long-term OCS use is associated with a greater risk of acute and chronic corticosteroid-related complications such as osteoporosis, type-2 diabetes and obesity compared with no OCS use.27

    Adverse events associated with long-term OCS and systemic corticosteroids use can be seen in the infographic below.27–30

    Adverse events associated with long-term OCS and SCS use27–30

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  • Adverse events associated with repeated short-course OCS use

    It is not just long-term OCS use that is associated with an increased risk of adverse events; repeated short-term OCS use is associated with increased risk of infections, gastrointestinal, ocular, cardiovascular, metabolic, and bone-related complications in asthma patients.31

    A nested case-control study using data from the Clinical Practice Research Datalink (165,900–269,368 asthma patients were included) showed current users of oral prednisolone had increased risk for all adverse outcome measures except glaucoma, compared with non-users.31

    Current use of oral prednisolone and the risk of 11 study outcomes among asthma patients, by cumulative dose ever prescribed31

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Patient perspectives on OCS

From a UK-wide, cross-sectional, questionnaire-based survey of symptom experiences, treatment concerns and adherence, including people with asthma and asthma-treating clinicians. Completed questionnaires were returned by 1,524 people with asthma taking ICS, 233 taking OCS and 244 clinicians (67% of clinicians were primary care nurses).32

Biologic treatments for severe asthma management

Biologic treatments provide an add-on treatment option for people with severe asthma who continue to experience asthma attacks, despite taking usual treatments (such as inhaled steroids).33

Biologic treatments target the disrupted pathways causing airway inflammation, which may help to manage symptoms, reduce relapses and reduce reliance on OCS.34

There are currently six biologic treatments approved for use as add-on therapies in the UK and available on the NHS to treat severe asthma.33

What treatments do GSK offer for patients with severe asthma?

Explore Nucala for the treatment of severe eosinophilic asthma

Abbreviations

ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; BMI, body mass index; CI, confidence interval; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GERD, gastroesophageal reflux disease; GINA, Global Initiative for Asthma; ICS, high-dose inhaled corticosteroids; IgE, immunoglobulin E; IL, interleukin; LABA, long-acting b2-agonists; NAEPP, National Asthma Education and Prevention Program; OCS, oral corticosteroids; OR, overall response; RR, relative risk; SC, subcutaneous; SD, standard deviation; T2DM, type 2 diabetic mellitus; UKSAR, UK Severe Asthma Registry.

References

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  3. Asthma UK. Slipping through the net report. Available at: https://www.asthma.org.uk/supportus/campaigns/publications/difficult-and-severe-asthma-report/. Accessed January 2023.
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  26. Jackson DJ, et al. Thorax. 2021;76(3):220–227.
  27. Bleecker ER, et al. Am J Respir Crit Care Med. 2020;201:276–293.
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  29. Sarnes E, et al. Clin Ther. 2011;33:1413–1432.
  30. Walsh LJ, et al. Thorax. 2001;56:279–284.
  31. Bloechliger M, et al. Respir Res. 2018;19:75.
  32. Cooper V, et al. NPJ Prim Care Respir Med. 2015;25:15026.
  33. NHS England. Asthma Biologics – Rapid Uptake Product. Available at https://www.england.nhs.uk/aac/what-we-do/innovation-for-healthcare-inequalities-programme/rapiduptake-products/asthma-biologics/. Accessed January 2023.
  34. NHS Oxford Academic Health Science Network. Asthma biologics overview. Available at https://www.oxfordahsn.org/our-work/asthma-biologics-toolkit/asthma-biologics-overview/. Accessed January 2023.
  35. Chupp GL, et al. Lancet Respir Med. 2017;5:390–400.
  36. Ortega HG, et al. N Engl J Med. 2014;371:1198–1207.
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  38. Lugogo N, et al. Clin Ther. 2016;38:2058–2070.
  39. Caruso C, et al. International, prospective study of mepolizumab in severe asthma: REALITI-A at 2yrs. Abstract presented at European Respiratory Society (ERS); 4–6 September 2022; Barcelona, Spain.
  40. GlaxoSmithKline. Nucala (mepolizumab) EU Summary of Product Characteristics (SmPC). April 2022.

Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/ or search for MHRA Yellowcard in the Google Play or Apple App store. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.

Nucala is indicated as an add-on treatment for severe refractory eosinophilic asthma in adults, adolescents and children aged 6 years and older. The recommended dose of Nucala is 100 mg subcutaneously (SC) once every 4 weeks in adults and adolescents 12 years and older. The licenced dose of Nucala in children aged 6–11 years is 40 mg SC once every 4 weeks regardless of weight.40

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February 2023 | PM-GB-MPL-WCNT-200003 (V4.0)