Effectiveness of omalizumab in an asthmatic patient with severe airway and blood eosinophilia

Omalizumab is a monoclonal antibody raised against class E immunoglobulin (IgE), approved for the treatment of chronic severe (in the EU) or moderate-to-severe (in the USA) IgE-mediated asthma. Omalizumab is effective in reducing asthma exacerbations, hospitalizations and emergency visits due to exacerbations as well as in improving patients’ quality of life (QoL) [1–3].
Here we report on a 41-year-old man suffering from severe allergic asthma with systemic and airway eosinophilia, despite using high-dose systemic corticosteroids. The disease began at the age of 36 with cough, dyspnea and poor exercise tolerance. The therapy included high-dose inhaled corticosteroids (ICS) in combination with long-acting 2-agonists (LABA), antileukotriene antagonists and rescue short acting 2-agonists (SABA). From the beginning, the disease has been severe and uncontrolled. Since 2011, dyspnea had been so severe that the patient permanently received 16 mg of methylprednisolone per day. Reduction of this dose ended up with a loss of asthma control. Moreover, the patient underwent functional endoscopic sinus surgery, due to turbinate hypertrophy.
In 2012, the patient was referred to our Department for a thorough diagnostic assessment. A 2-week washout from oral corticosteroids (OCS) was performed. On admission, the patient complained of significant breathlessness, wheezing, persistent productive cough and substantial limitation of exercise capacity. Physical examination revealed soft vesicular sound with a prolonged expiratory phase, numerous wheezes and rhonchi. Spirometry showed severe airflow limitation (FEV1 = 1.47 l (36% of a normal value (N)), FVC = 4.15 l (88% N), FEV1%FVC = 35.42%); reversibility test with bronchodilator was negative. Skin prick tests were positive for house dust mites and Alternaria sp. A class 2 specific IgE level was determined for Alternaria sp. by ELISA.
The blood eosinophil count was significantly increased (EO = 1.7 × 103/µl – 15.9% of white blood cells). Bronchoscopy revealed thick secretions covering bronchi and a very high airway eosinophilia (EO = 56.2%), as measured in bronchoalveolar lavage. Additional tests excluded parasites and protozoans infection as well as hypereosinophilic syndrome.
The final diagnosis at discharge was persistent severe asthma associated with chronic rhinosinusitis.
The patient was deemed to qualify for omalizumab treatment but due to reimbursement problems he could start this therapy only in April 2013, when the program of treatment of severe IgE-dependent asthma with omalizumab began (funded by the National Health Fund – NFZ). Until that time, despite persistent OCS therapy (16 mg methylprednisolone/day), blood eosinophil count remained high (EO = 0.58 × 103/µl – 6.5%).
The calculated dose of omalizumab, based on patient’s IgE level (306 kU/l) and weight (88 kg), was 600 mg every 4 weeks. After 16 weeks of therapy, asthma control significantly improved (Asthma Control Questionnaire – ACQ) decreased from 3.7 to 2.5 points. The daily dose of OCS could be reduced (from 16 to 4 mg methylprednisolone/day) without asthma exacerbations. Lung function and patient’s QoL improved (FEV1 from 44% to 60% N; Asthma Quality-of-Life Questionnaire (AQLQ) from 3.2 to 4.3 points). Moreover, the peripheral blood eosinophil count normalized (EO = 0.08 × 103/µl – 1.1%), despite a significant decrease in OCS dose. The effectiveness in the Global Effectiveness Treatment Evaluation (GETE) scale was assessed as good.
Omalizumab acts by blocking free circulating IgE and inhibiting their binding to IgE high-affinity receptors. Additionally, omalizumab down-regulates IgE receptor expression on effector cells. This way, omalizumab inhibits mast cell and basophil degranulation and the consequent release of inflammatory mediators. However, its role within the context of allergic inflammation is perhaps much more complex [2].
Airway eosinophilic inflammation is a characteristic feature of asthma and can be associated with a mild peripheral blood eosinophilia [4]. The number of sputum eosinophils closely correlates with asthma severity [5] as well as with a risk and severity of exacerbations. Furthermore, assessment of anti-inflammatory treatment in asthma, based on the eosinophil count in sputum, is more efficient than assessment based on symptoms and lung function [6, 7]. Eosinophils are extremely sensitive to corticosteroids but there is a subpopulation of asthmatics who are resistant to OCS, even at a high dose. Endobronchial biopsies and bronchoalveolar lavage performed in patients with steroid-resistant asthma show a high eosinophil number despite therapy with OCS [8].
In our patient both severe airway eosinophilia and systemic eosinophilia appeared to be related to severe asthma. Sixteen weeks of omalizumab treatment not only improved asthma control and prevented exacerbation but also allowed a four-fold reduction in OCS daily dose and normalized blood eosinophils.
New data are showing the effectiveness of omalizumab in asthmatic patients with blood eosinophilia, as observed also by us in another patient with severe asthma and chronic urticaria [9]. A similar effect was observed in 5 patients with asthma and severe peripheral blood eosinophilia. After 16 weeks of OMA, the eosinophil count decreased to nearly normal levels, simultaneously with a reduction in OCS daily dose and the number of monthly exacerbations [10].
In Massanari’s pooled analysis of five clinical studies on the effectiveness of omalizumab in patients with moderate-to-severe persistent allergic asthma, post-treatment eosinophil count in peripheral blood compared to baseline was reduced in the omalizumab group only. Investigators found that a decrease in peripheral blood eosinophils was parallel to the improvement in various clinical outcomes (severe exacerbations, FEV1, GETE) [11]. In another study, a significant (56%) reduction in severe asthma exacerbations by omalizumab, as compared to placebo, was achieved only in the high eosinophil group (≥ 260 EO/µl) [12].
Yet another study assessed the effect of omalizumab on airway eosinophilia in 45 patients with mild-to-moderate asthma and sputum eosinophilia (EO ≥ 2%). After 16 weeks of treatment, the number of eosinophils in induced sputum and in bronchial tissues (obtained by bronchial biopsies) were significantly reduced (although airway hyperresponsiveness to methacholine did not improve) [13].
The effect of omalizumab on eosinophils, besides neutralization of IgE, seems to be another important mechanism of its action in asthma. Patients with severe refractory asthma and airway and systemic eosinophilia seem to be good candidates for treatment with this drug. Eosinophils, on the other hand, could be a potential biomarker for prediction of the omalizumab treatment outcome.

Conflict of interest

Izabela Kupryś-Lipińska and Piotr Kuna declare honoraria from Novartis for lectures. Marta Kołacińska-Flont, Jerzy Marczak, Paweł Górski and Zofia Kurmanowska declare no conflict of interest.

References

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