This is the second of three features in the limbic reporting on the ADVENT Advances in Type 2 Inflammatory Diseases medical education series by Sanofi Genzyme.

The first ADVENT tutorial reported here focused on the importance of identifying patients with type 2 inflammatory asthma, the second tutorial focuses on the clinical management of two patients with severe asthma.

“The high-quality ADVENT medical education series [run by Sanofi Genzyme] has provided an invaluable opportunity to discuss the management of severe uncontrolled asthma patients with our colleagues. I recommend respiratory colleagues check out the ADVENT Program”

Professor Connie Katelaris MBBS PhD FRACP.

Uncontrolled asthma

Some patients continue to have uncontrolled severe asthma, despite guideline-directed management and treatment.^1,2  In these patients, the aim of treatment is to reduce the burden of symptoms and minimise the risks of exacerbations, decline in lung function and medication-related side-effects.^2,3 A systematic stepwise approach is required to manage patients with difficult-to-treat asthma. This includes assessing the severe asthma phenotype and factors contributing to symptoms, quality of life and exacerbations and considering both non-biologic and biologic treatments to control symptoms.^2,4

Case study one: Investigate what is underlying the asthma

The first case presented was of a 44 year old female intensive care unit (ICU) nurse (box 1). She had childhood asthma that was initially mild, becoming more severe over the past two years. She noticed a gradual increase in shortness of breath (SOB) episodes and has presented to the emergency department (ED) four times in the past year.

Box 1. Patient characteristics: case one

Challenges in asthma management

Adherence can be a challenge, as it is common practice for patients with asthma to be prescribed an inhaler device without any adherence monitoring beyond the dose-counter of the device.⁵  A study of Australian asthma patients prescribed inhalers to control their asthma found more than half of patients with uncontrolled asthma were taking their preventer less than half the time prescribed.⁶ Accurately detecting poor adherence is impractical for clinicians⁷ and there remains a need for better ways of assessing adherence.

Comorbidities are numerous in difficult-to-treat asthma, and can affect patients throughout their airways.⁸ There are eight comorbidities that are prevalent in between a quarter to half of patients; allergic rhinitis, obesity, obstructive sleep apnoea, chronic rhinosinusitis, vocal cord dysfunction (VCD), anxiety or depression, dysfunctional breathing and gastroesophageal reflux.⁹ As specialists, diagnosis of these comorbidities can be a challenge, especially with the comorbidities of dysfunctional breathing and vocal cord dysfunction.¹⁰ In this context, screening questionnaires may be of particular benefit In detecting these comorbidities.

The use of systematic assessment for difficult-to-treat asthma has been found to improve patient outcomes and reduce the use of oral corticosteroids.¹¹  Key features of the systematic assessment include comorbidity screening questionnaires, electronic monitoring of the patient and access to and inclusion of a multidisciplinary team (MDT).¹²

 Case one: applying the systemic assessment

The patient reported occasional voice problems, which could be indicative of VCD. In order to investigate further, the patient history was revisited – a recommended practice – in order to identify any other symptoms suggestive of VCD. In this case, the classic triad of breathlessness, a feeling of ‘tightness’ in the throat and voice loss during breathlessness episodes was uncovered. Treatment with a short-acting beta agonist did not help.

The patient was referred to a VCD-MDT which included a physician, a specialist speech pathologist and an ENT surgeon. Her lung function was assessed and within normal parameters. A nasal laryngoscopy found vocal closure on inspiration, which was confirmed with a CT of her larynx. The treatment plan included laryngeal training with the speech pathologist, and though slow the patient responded.

VCD vs asthma at diagnosis

A large proportion (42%) of patients with the question of VCD vs asthma have both diagnoses.¹³ VCD can interact with other comorbidities, such as anxiety (which the patient in this case also has).¹⁴ In patients with difficult-to-treat asthma, VCD often coexists with dysfunctional breathing, despite relatively preserved lung function and minimal evidence of airway inflammation.¹⁵ For more information on managing VCD, refer to the Severe Asthma Centre of Excellence Toolkit, available here.

“Key points that are important… in difficult-to-treat asthma [include],… sub-optimal asthma diagnosis confirmation, sub-optimal detection of comorbidities, including VCD, and suboptimal inhaler adherence. [So] do assess objectively for variable airflow obstruction, comorbidities and adherence.”

Associate Professor Mark Hew MBBS (Melb) PhD (Lond) MSc (Oxon) FRACP.

Case two: Treatment approaches for uncontrolled severe asthma patients

The second case was of a 52 year old female accountant (box 2). She had been diagnosed as an  adult with severe asthma that has been worsening over the past eight years. She had been experiencing recurrent exacerbations, had been using 4–6 courses of oral corticosteroids a year with a cumulative dose of over 8 grams. Treatment with the anti-IL-5 monoclonal antibody mepolizumab was commenced, which resulted in improvement in breathlessness episodes and reduced exacerbations. Despite this, her nasal symptoms had not improved and her asthma remained uncontrolled.

Box 2: Patient characteristics: case two

Assess for type 2 inflammation

As outlined in the first ADVENT tutorial, the Global Initiative for Asthma (GINA) recommends assessing for and managing type 2 inflammation in patients with severe asthma. For more detail on this refer to the report of the first ADVENT tutorial, available here.

Minimising use of oral corticosteroids

GINA lists oral corticosteroids as a non-preferred controller for severe asthma with type 2 inflammation.¹⁶ This is due to the significant side effects and risks of side effects that accompanies their use, including:^16–18

• Osteoporosis and fractures
• Obesity
• Anxiety, depression, sleep disturbances
• Type II diabetes, adrenal suppression
• Dyslipidaemia, hypertension, thromboembolism
• Increased risk of infection
• Cataracts, glaucoma
• Gastrointestinal bleeds, ulcers

Further evidence of the need to reduce oral corticosteroid use comes from a study into Australian oral steroid use in asthma over a five year period. It found that a cumulative dose of oral steroids over 1g (or four short courses) across the entire study period was associated with increased co-dispensing of medications for diabetes and osteoporosis.⁶ So, despite the fact that oral steroids are effective and often necessary in the treatment of severe asthma, they are not without significant risks.

When to consider add-on biologic therapy

Treatment with biologic therapy depends on the type of asthma presented:¹⁶

• Anti-IgE is recommended for severe allergic asthma or chronic idiopathic urticaria.
• Anti-IL-5/5R is recommended for severe eosinophilic asthma.
• Anti-IL-4R (dual inhibition of IL-4 and IL-13 signalling) is recommended for severe eosinophilic/type 2 asthma, oral corticosteroid-dependent severe asthma as well as for moderate-to-severe atopic dermatitis. In addition, anti-IL-4R is available overseas, but not in Australia, to treat uncontrolled chronic rhinosinusitis with nasal polyposis.

Box 3 summarises the differences in eligibility criteria and predictors of good response for biologics available to treat patients with type 2 asthma.

 Box 3: Eligibility criteria and predictors of good response for various biologic therapies.

*Not registered In Australia for nasal polyposis

Adapted from the Global Initiative for Asthma (GINA). Difficult-to-treat & severe asthma in adolescent and adult patients: diagnosis and management. A GINA pocket guide for health professionals, V2.0 April 2019.

“[Key points to take away] in severe uncontrolled asthma, do assess for markers of type 2 inflammation (that is eosinophilia and exhaled nitric oxide) because they accompany chronic rhinosinusitis with nasal polyposis, they are able to predict frequent exacerbations, they predict response to oral corticosteroids (although with significant side effects), and predict response to biologic therapies, including anti-IgE, anti-IL5/R and anti-IL-4/13 receptor therapy”

Associate Professor Mark Hew MBBS (Melb) PhD (Lond) MSc (Oxon) FRACP.

Please click here for a copy of the currently approved Dupixent product information in Australia.

References:

1. Chung et al., Eur Respir J 2014; 43: 343–373.
2. GINA, Difficult to treat and severe asthma in adults and adolescents, 2019. Available at www.ginasthma.org. Accessed October 2020.
3. Israel and Reddel. N Engl J Med 2017;377:965-76.
4. Australian Asthma Handbook version 2.0 Published March 2020. Available at https://www.asthmahandbook.org.au/ Accessed October 2020.
5. Hew M & Reddel HK. JAMA. 2019; 321:1045-1046.
6. Hew M, et al. Med J Aust. 2020. MJA 213 (7) 5 October 2020. available at https://www.mja.com.au/system/files/issues/213_07/mja250758.pdf Accessed October 2020.
7. Lee J, Tay, et al. Eur Respir J. 2018;51:1701836.
8. Hew M, Heaney LG. Contribution of comorbidities, psychosocial factors, and adherence to the presentation of severe asthma. European Respiratory Society Monograph. Severe Asthma 2019. p. 30-48. Available at https://books.ersjournals.com/content/severe-asthma Accessed October 2020.
9. Radhakrishna N, et al. Respir Med. 2016;117:166-173.
10. Radhakrishna N, et al. Asthma. 2017;54 :294-299.
11. Denton E, et al. J Allergy Clin Immunol Pract. 2020;8:1616-1624.
12. Hew M, et al. J Allergy Clin Immunol Pract. 2020;8:2222-2233.
13. Lee JW, et al. Clin Exp Allergy. 2018;48:1622-1630.
14. Tay TR & Hew M. Allergy. 2018;73:1369-1382.
15. Lee J, et al. J Allergy Clin Immunol Pract. 2020;8:2256-2262.
16. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. Updated 2020. https://ginasthma.org/gina-reports/ Accessed October 2020.
17. Sullivan PW, et al. J Allergy Clin Immunol. 2018;141:110-116.
18. Bleecker ER, et al. Am J Respir CritCare Med. 2020; 201:276-293.
19. Corticosteroid stewardship statement https://www.aafa.org/media/2244/oral-corticosteroid-stewardship-statement-november-2018.pdf Accessed October 2020.

Sanofi-aventis Australia Pty ltd trading as Sanofi Genzyme, ABN 31 008 558 807. Talavera Corporate Centre, Building D, 12-24 Talavera Rd, Macquarie Park, NSW 2113. www.sanofi.com.au MAT-AU-2001619 First Issued October 2020.