EOSINOPHIL

Severe asthma

Severe asthma with eosinophilic phenotype is a distinct phenotype of severe asthma. This phenotype is characterized by airway inflammation, increased blood/sputum eosinophil (EOS) concentrations, poor asthma control, and increased rate of exacerbations.1

Half of severe asthma patients have persistent airway tissue eosinophils resulting in poor prognosis and frequent exacerbations.2

Airway inflammation in severe asthma3

INFLAMMATORY PATHWAY

IgE=immunoglobulin E; IL=interleukin; ILC2=group 2 innate lymphoid cells; NKT=natural killer T; Th2=T helper 2; TSLP=thymic stromal lymphopoietin.

Eosinophils release a range of cytokines and chemokines that contribute to the pathophysiology of asthma, including4-8,17-19:

IL-4

  • Macrophage polarization

IL-5

  • Responsible for maturation, activation, and survival of eosinophils

IL-13

  • Macrophage polarization
  • Basophil activation
  • Contributes to mucus production
  • Contributes to airway hyperresponsiveness

Transforming growth factor beta (TGF-β)

  • Promotes airway remodeling

Leukotrienes

  • Contribute to airway hyper-responsiveness

Major basic protein (MBP)

  • Stimulates mast cells and basophils
  • Causes tissue damage by stimulating tissue-residing epithelial cells to express profibrotic mediators
  • Stimulates IL-8 secretion from neutrophils, which can lead to neutrophilia

Eosinophil peroxidase (EPO)

  • Stimulates mast cells
  • Causes tissue damage by simulating tissue-residing epithelial cells to express profibrotic mediators
  • Induces platelet aggregation

Eosinophilic Cationic Protein (ECP)

  • Cell cytotoxicity
  • Host defense
  • Cancer surveillance

Eosinophil-Derived Neurotoxin (EDN)

  • Antiviral activity
  • Chemotactic for dendritic cells (DCs)

Chemokine RANTES (Regulated upon Activation, Normal T Cell Expressed and Secreted)

  • Eosinophil migration
EOSINOPHIL

Eosinophils in Severe asthma increase the risk of exacerbations

The chronic inflammation caused by eosinophils may result in harmful and potentially irreversible structural airway changes known as remodeling, which leads to bronchial wall thickening and reduced air flow. This inflammation could also cause damage resulting in airway smooth muscle hyperplasia and/or hypertrophy, loss of lung function, and hyperresponsiveness.9

Remodeling can also increase the frequency and worsen the severity of exacerbations.1

Elevated EOS are associated with asthma exacerbations10,11

Patients with asthma and blood eosinophils ≥300 cells/μL and fractional exhaled nitric oxide (FeNO) ≥50 ppb were nearly 4x more likely to have a severe exacerbation than those with lower blood eosinophils (<300 cells/μL) and low FeNO (<25 ppb).10 Intermediate and high blood eosinophils were associated with asthma-related visits to the emergency department.11

EOS counts in severe asthma diagnosis and treatment decisions

BLOOD EOSINOPHIL

Determine if blood eosinophil concentrations are elevated

Due to the multifunctional nature of eosinophils, it’s important to understand whether eosinophilic inflammation is present as part of the clinical evaluation process.12

In patients with severe asthma, an eosinophil count from a complete blood count with differential can help identify patients with an eosinophilic phenotype.12 Blood eosinophil concentrations can be used as a guide to initiate individualized treatment of severe asthma. If patients with severe asthma still have uncontrolled symptoms, consider if eosinophilic inflammation could be the cause.13

OCS use could put your patients at risk of developing adverse effects

Patients with asthma who are intermittently exposed to multiple prescriptions of systemic steroids have a higher risk of experiencing adverse effects including13,16,17:

CVD

Cardiovascular/cerebrovascular disease

DEPRESSION

Depression/anxiety

HYPERTENSION

Hypertension

OSTEOPOROSIS

Osteoporosis/fracture

SLEEP

Sleep disturbance

OBESITY

Weight gain/obesity

CATARACTS

Cataracts

GI ULCERS

Gastrointestinal ulcers/bleeds

INFECTION

Infection

KIDNEYS

Renal impairment

DIABETES

Type 2 diabetes

Blood eosinophils as a biomarker in severe asthma

Targeting eosinophil concentrations and inflammation could be critical to managing severe asthma. Eosinophil concentrations can help identify the severe eosinophilic/Type 2 inflammation phenotype in patients on high-dose ICS or daily OCS, using the following criteria13:

  • Blood eosinophil concentrations of ≥150 cells/µL, and/or
  • FeNO ≥20 ppb, and/or
  • Sputum eosinophils ≥2%
EOS > 150

EOSINOPHILS/𝝻L

In addition, blood eosinophil concentrations of ≥150 or ≥300 cells/µL or FeNO ≥25 ppb are also often used by payers to determine biologic therapy eligibility and higher blood eosinophils or FeNO are potentially predictive of good responsiveness to different biologic therapies.13

Eosinophil concentrations can vary considerably in patients; it is advised to measure at least three times before assuming the patient is not an eosinophilic phenotype, as 27-65% of patients can demonstrated increased blood concentrations in subsequent testing to which they presented with lower values previously.13,20

It is important to note that ~65% of patients on medium- to high-dose ICS-long-acting beta2-agonist shift their eosinophil concentrations over a period of 12 months, and therefore, additional assessments in patients with low blood eosinophils have been recommended. Additionally, OCS can suppress eosinophil concentrations, therefore, assessments should be made either before OCS start or at the lowest possible OCS dose.13

Knowing your severe asthma patients’ eosinophil count can help you give them a more targeted treatment13

References

  1. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma [published correction appears in Eur Respir J. 2014;43(4):1216. Dosage error in article text] [published corrections appear in Eur Respir J. 2014;43(4):1216 and Eur Respir J. 2018;52(1):1352020.]. Eur Respir J. 2014;43(2):343-373.
  2. Buhl R, Humbert M, Bjermer L, et al. Severe eosinophilic asthma: a roadmap to consensus. Eur Respir J. 2017;49(5):1700634.
  3. Brusselle G, Bracke K. Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11 Suppl 5:S322-S328.
  4. Varricchi G, Senna G, Loffredo S, Bagnasco D, Ferrando M, Canonica GW. Reslizumab and eosinophilic asthma: one step closer to precision medicine? Front Immunol. 2017;8:242.
  5. Ramirez GA, Yacoub MR, Ripa M, et al. Eosinophils from physiology to disease: a comprehensive review. Biomed Res Int. 2018;2018:9095275.
  6. Kouro T, Takatsu K. IL-5- and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol. 2009;21(12):1303-1309.
  7. McBrien CN, Menzies-Gow A. The biology of eosinophils and their role in asthma. Front Med (Lausanne). 2017;4:93.
  8. Wen T, Rothenberg ME. The regulatory function of eosinophils. Microbiol Spectr. 2016;4(5):10.1128/microbiolspec.MCHD-0020-2015.
  9. Trivedi SG, Lloyd CM. Eosinophils in the pathogenesis of allergic airways disease. Cell Mol Life Sci. 2007;64(10):1269-1289.
  10. Price DB, Bosnic-Anticevich S, Pavord ID, et al. Association of elevated fractional exhaled nitric oxide concentration and blood eosinophil count with severe asthma exacerbations. Clin Transl Allergy. 2019;9:41.
  11. Malinovschi A, Fonseca JA, Jacinto T, Alving K, Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol. 2013;132(4):821-827.e1-5.
  12. De Groot JC, ten Brinke A, Bel EH. Management of the patient with eosinophilic asthma: a new era begins [published correction appears in ERJ Open Res. 2016;2(3):00024-2015-ERR.]. ERJ Open Res. 2015;1(1):00024-2015.
  13. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2022
  14. Baldini C, Talarico R, Della Rossa A, Bombardieri S. Clinical manifestations and treatment of Churg-Strauss syndrome. Rheum Dis Clin North Am. 2010;36(3):527-543.
  15. Sullivan PW, Ghushchyan VH, Globe G, Schatz M. Oral corticosteroid exposure and adverse effects in asthmatic patients. J Allergy Clin Immunol. 2018;141(1):110-116.e7.
  16. Price DB, Trudo F, Voorham J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study. J Asthma Allergy. 2018;11:193-204.
  17. Topic. Biochemia Medica 2011;21(2):111-21
  18. Yang. Blood 2003;102:3396-3403
  19. Davoine Front Imm 2014;5(570):1
  20. Corren J Allergy Clin Immunol Pract 2021;9:1224-31

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