Eosinophilic bronchial asthma

Eosinophils were first described by Paul Ehrlich almost 150 years ago as granulocytic leukocytes containing a bilobed nucleus (Bakakas 2019).

Harry Morrow Brown (Nelson 2020) discovered in the 1950s that systemic corticosteroids are less effective in patients without evidence of sputum eosinophilia-as is the case in type 2- low- asthma (Hinks 2021).

Metered-dose inhalers were first developed in the 1950s and came on the market beginning in 1956.

The first inhaled glucocorticoid called beclometasone came on the market in the 1970s. To this day, inhaled glucocorticoids are among the basic therapeutic principles of asthma therapy.

Leukotriene receptor antagonists (also called "antileukotrienes") have been on the market since 1998, biologics such as mepolizumab since 2016, reslizumab since 2017, and benralizumab since 2018 (Häussler 2020).

Eosinophilic asthma is a form of bronchial asthma in which there is an increase in eosinophils in the differential blood count, but this is not triggered by an allergic reaction (Girndt 2022).

Eosinophilic asthma is characterized by abnormal production of eosinophils, on which even high doses of inhaled corticosteroids often have little effect (Gonzalez 2019). Since the use of monoclonal antibodies in 2016, a new era began for patients with eosinophilic asthma (Klimek 2021).

The definition of eosinophilic asthma differs in different pivotal studies. For mepolizumab (a monoclonal antibody), it is defined as an "asthma with ≥ 150 eosinophils/µl blood and concomitant detection of 300 eosinophils/µl blood in the past year."

The manufacturers of reslizumab define it as a presence of "400 ≥ eosinophils / µl blood". There should also be evidence of > 300 eosinophils / µl blood at least 2 times outside of exacerbations in the last year (Buhl 2017).

Bronchial asthma is caused by type 2 inflammation. According to GINA (Global Initiative for Asthma), type- 2- inflammation is defined as:

• - FeNO ≥ 20 ppb
• and / or
• - Eosinophilia in the blood ≥ 150 µl
• and / or
• - clinical allergen-induced asthma (Lommatzsch 2021).

As therapeutic measures for asthma have recently expanded, a broader differentiation of the individual forms of asthma has become necessary. Currently, a distinction is made between:

1. type- 2- high- asthma

These include eosinophilic asthma and allergic asthma (Renner 2021). Type- 2- (T2) high- asthma is defined according to UKSAR (UK Severe Asthma Registry) as:

• - FeNO ≥ 25 ppb
• plus
• - Eosinophils in blood ≥ 150 / µl (Lommatzsch 2021).

2. type 2- low- asthma

These include, for example, asthma with increased neutrophilic inflammation and asthma in obesity (Renner 2021. Type- 2- low- asthma is defined according to UKSAR as:

• - FeNO < 25 ppb
• plus
• - Eosinophils in the blood < 150 / µl (Lommatzsch 2021).

Recently, differentiations of bronchial asthma into the following groups have proven more useful with regard to therapeutic measures:

- Phenotypes: Here we find certain clinical features, certain response to therapies and similar lung function measurements.

- Endotypes: Endotypes show a similar pathophysiological mechanism and thus can be more targeted for therapy (Nelson 2020).

The classic classification of bronchial asthma into:

• 1. allergic (also referred to as "extrinsic asthma").
• 2. non-allergic asthma (also referred to as "intrinsic asthma")

has been extended in recent years to include a third phenotype:

• 3. eosinophilic asthma (German Medical Association 2020).

Eosinophilic ast hma, together with allergic asthma, belongs to the group type- 2- (T2) high- asthma (Bundesärztekammer 2020). In type- 2- high- asthma, Th- 2- lymphocytes are found associated with certain cytokines such as IL- 4, IL- 5, IL- 13 (Renner 2021). The differentiation between allergic and eosinophilic asthma is of particular therapeutic importance, as eosinophilic asthma often results in an inadequate response to inhaled glucocorticoids and long-acting beta-2- agonists (LABAs) and monoclonal antibodies are indicated instead (Girndt 2022). For more details see below " Internal therapy".

Eosinophilic asthma occurs preferentially with rhinosinusitis and nasal polyps (Renner 2021).

More than 300 million people worldwide suffer from bronchial asthma. Of these, around 20% are asthmatics who are difficult to treat (which also includes eosinophilic asthma) and < 5% suffer from severe asthma (Renner 2021).

Eosinophilic asthma occurs preferentially in the 2nd half of life - in contrast to allergic asthma (German Medical Association 2020).

Severe eosinophilic asthma is found in approximately 50% of all patients with severe asthma (Bakakas 2019).

The pathophysiology of bronchial asthmais heterogeneous and far from being fully understood (Nelson 2020).

In eosinophilic asthma, in addition to an increase in eosinophils, abnormal production and release of T- cells such as T- helper type 2 lymphocytes (Th2) and innate lymphoid type 2 cells such as IL- 5 are found (Bakakas 2019 / Gonzalez 2019).

Eosinophil activation, differentiation, and survival are regulated by cytokine IL- 5 . IL- 5 sits on the surface of eosinophils and basophils and binds to the IL- 5 receptor (IL- 5R). IL- 5 plays a critical role in the pathogenesis of severe asthma. (Gonzalez 2019).

The clinical picture of eosinophilic asthma corresponds to that of bronchial asthma (see d.).

- Medical history (especially question about onset of symptoms and additional presence of rhinosinusitis)

- laboratory findings

- Determination of the FeNO level

- Allergy diagnostics (Renner 2021)

Typically, one finds

- ≥ 300 eosinophils / µl blood (Herold 2022).

- Eosinophils in sputum > 2 % (Bakakas 2019 / Renner 2021))

- Th2- cytokines IL- 4, IL 5 and IL 13 elevated (Stockert 2020).

Lung function

- FeNO- level (Fraction Expiratory Nitric Oxide) > 50 ppb (Bakakas 2019).

- Severe allergic asthma with eosinophilia (in which there is a causal relationship between the asthma symptoms and allergic sensitization (Hinks 2021).

- eosinophilic COPD

- eosinophilic pneumonia

- ABPA(allergic bronchopulmonary aspergillosis)

- EGPA(eosinophilic granulomatosis with polyangiitis = Churg- Strauss syndrome) (Hinks 2021)

Treatment of eosinophilic asthma is initially with an inhaled corticosteroid, a leukotriene receptor antagonist, short- or long-acting beta-2 mimetics, and monoclonal antibodies, which have been available since 2016 (Buhl 2017), according to the 5-step therapy guideline for adults (for more details, see also Bronchial asthma).

• Corticosteroids

Inhaled corticosteroids are used to treat asthma. For more details on dosage, etc., see Bronchial asthma.

However, severe eosinophilic asthma is characterized by corticosteroid resistance (Sada 2021).

• Bronchodilators

In question here are:

- Beta- 2 sympathomimetics (short-acting = SABA or long-acting = LABA).

SABA include e.g. salbutamol, fenoterol, LABA e.g. salmeterol, formoterol.

SABA and LABA:

- stimulate bronchial muscle relaxation via beta- 2 receptors

- suppress by release of mediator substances

- Increase mucociliary clearance in the bronchial system (Braun 2018).

For more details, see beta- 2 sympathomimetics.

• Leukotriene receptor antagonists

These are biologically active metabolites of arachidonic acid that have bronchodilator and anti-inflammatory effects, among others (Krogel 1997). For more details see Leukotriene receptor antagonists.

• Monoclonal antibodies

Monoclonal antibodies are a targeted therapy for severe eosinophilic asthma. The latter should have occurred by at least 2 times detection of > 300 eosinophils per µl blood in the past 2 years and outside of exacerbations (Bundesärztekammer 2020). It should be taken into account that systemic therapy with glucocorticoids has an influence on the number of eosinophil granulocytes (Buhl 2017).

If the above-mentioned treatment with an inhaled corticosteroid, leukotriene receptor antagonist, short- or long-acting beta- 2 mimetic has proven to be refractory to therapy - which is not uncommon in eosinophilic asthma (Girndt 2022) - there is an indication for the administration of monoclonal antibodies such as mepolizumab or reslizumab (Herold 2022) or benralizumab (Bundesärztekammer 2020).

These antibodies lead to a reduction in exacerbations and improvement in lung function (Bakakas 2019).

- Mepolizumab:

Trade name: Nucala

It is a humanized monoclonal IgG1- Kappa- antibody that reduces eosinophils in the blood (Aktoris 2022). It blocks interleukin- 4 and interleukin- 13 (Bakakas 2019), thereby inducing apoptosis of granulocytes (Aktoris 2022).

- Dosage recommendation: 100 mg s. c. 1 x monthly (Vogelmeier 2022).

- Reslizumab:

Trade name: Cinqaero (Schwabe 2018).

This is a monoclonal anti- IL- 5- IgG4- antibody that binds to the alpha subunit of the cytokine IL- 5 (Bakakas 2019). It leads to a reduction in eosinophils and inflammation (Aktoris 2022).

- Dosage recommendation: 3 mg / kg bw as i. v. infusion 1 x monthly (Buhl 2017).

- Benralizumab:

Trade name: Fasenra (Aktoris 2022).

This is a chimeric monoclonal IgG1- kappa antibody (Aktoris 2022). It targets the IL- 5Alpha- receptor and results in almost complete depletion of eosinophils in the blood (Bakakas 2019).

- Dosage recommendation: 30 mg s.c. at 4 weeks interval, after 3 times administration extend the injection interval to 8 weeks with the same dose (Vogelmeier 2022).

Therapy with monoclonal antibodies should be given for at least 4 months (Bundesärztekammer 2020).

Parallel to the treatment with monoclonal antibodies, the previous inhaled or oral asthma treatment should be maintained for at least 4 weeks (Buhl 2017). The dose of corticosteroids can usually always be reduced during therapy with monoclonal antibodies (Schulte Strathaus 2018).

Follow-up

Evaluation of monoclonal antibody therapy should be performed by physicians experienced with the treatment and reviewed at 4 months, 12 months, and 1x annually thereafter (Buhl 2017).

1. Aktoris K, Flockerzi V, Förstermann U, Hofmann F (2022) General and special pharmacology and toxicology. Elsevier Urban und Fischer Verlag Munich chapter 16.3.7.
2. Bakakas A, Loukides S, Bakako P. (2019) Severe eosinophilic asthma. J Clin Med. 8 (9) 1375 https://doi.org/10.3390/jcm8091375
3. Braun J, Müller- Wieland D (2018) Basic textbook of internal medicine. Elsevier Urban and Fischer Publishers Munich 415
4. Buhl R, Bals R, Berdel D, Criee C P, Gappa M, Gillissen A, Greulich T, Haidi P, Hamelmann E, Kardos P, Kenn K, Klimek L, Korn S, Lommatzsch M, Magnussen H, Nicolai T, Nowak D, Pfaar O, Rabe K F, Riedler J, Ritz T, Schultz K, Schuster A, Spindler T, Taube R C, Vogelmeier C, von Leupold A, Wantke F, Weise S, Wildhaber J, Worth H, Zacharasiewicz A (2017) S2k-guideline on diagnosis and therapy of patients with asthma. AWMF- registration number 020 - 009.
5. German Medical Association (BÄK), Association of Statutory Health Insurance Physicians (KBV), Association of the Scientific Medical Societies (AWMF) et al. (2020) Nationale VersorgungsLeitlinie: Asthma. AWMF- Register- No. nvl- 002
6. Girndt M, Michl P (2022) Internal medicine high 2. Elsevier Urban und Fischer Verlag Munich 699.
7. Gonzalez D, Benitez F M, Quirle S (2019) Benralizumab: A New Approach for the Treatment of Severe Eosinophilic Asthma. Journal of Investigational Allergology and Clinical Immunology 29 (2) 84 - 93.
8. Häussler B, Hoer A (2020) Arzneimittel- Atlas 2020. Medizinisch wissenschaftliche Verlagsgesellschaft (MWV) mbH Berlin 130 - 131.
9. Herold G et al (2022) Internal medicine. Herold Publishers 361, 369
10. Hinks T S C, Levine S J, Brussels G G (2021) Treatment options in type-2 low asthma. Eur Respir J. 57 (1) 2000528 doi: 10.1183/13993003.00528-2020.
11. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 1684 ???
12. Klimek L, Bergmann K C, Hagemann J, Bergmann C, Förster- Ruhrmann U, Becker S, (2021) Type 2- inflammation: place value of different biologics in practice. Dtsch Arztebl 118 (50) 5 - 7, 20 - 24.
13. Krogel C, König W, Jäger L (1997) Extended therapy of bronchial asthma: use of 5- lipooxygenase inhibitors and leukotriene receptor antagonists. Deutsch Arztebl 94 (26) A- 1802, B- 1523, C- 1421.
14. Lommatzsch M (2021) Severe asthma and type 2- inflammation. cme- medlearning. https://cme.medlearning.com/sanofi-aventis/severe_asthma_biologicatherapy/pdf/cme1.pdf.
15. Nelson R K, Bush A, Stokes J, Nair P, Akuthota P (2020) Eosinophilic asthma. The Journal of Allergy and Clinical Immunology: In Practise 8 (2) 465 - 473.
16. Renner A, Pohl W (2021) Update 2021 - bronchial asthma: antibody therapy and trial data. Update from: Universum Innere Medizin 9 / 2019, ÖGIM (Austrian Society of Internal Medicine) MedMedia Verlag Wien https://www.medmedia.at/im-fokus/typ2-inflammation/update-2021-asthma-bronchiale-antikoerpertherapie-und-studiendaten/
17. Sada M, Watanabe M, Inui T, Nakamoto K, Hirata A, Nakamura M, Honda K, Saraya T, Kurai D, Kimura H, Ishii H, Takizawa H (2021) Ruxolitinib inhibits poly(I:C) and type 2 cytokines-induced CCL5 production in bronchial epithelial cells: A potential therapeutic agent for severe eosinophilic asthma. Immune Inflamm Dis. 9 (2) 363 - 373
18. Schulte Strathaus R (2018) Severe eosinophilic asthma: antibodies as add-on therapy. Dtsch Arztebl. 115 (10) A - 440
19. Schwabe U, Paffrath D,Ludwig W D, Klauber J (2018) Drug prescription report 2018: current data, costs, trends and comments. Springer Verlag Germany 56
20. Stockert K (2020) Allergy prevention: modern strategies of allergy research in dialogue with TCM Springer Verlag Berlin 35 - 36, 222.
21. Vogelmeier C F (2022) Therapie- Handbuch Pneumologie: Das Wichtigste für Klinik und Praxis. Elsevier GmbH Munich 71