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Use of an anti–IL-5 agent in a patient with uncontrolled severe eosinophilic asthma

Dr. Lam-Hin Shek
Specialist in Respiratory Medicine
Hong Kong
23 Dec 2020

History, presentation and initial treatment

A 43-year-old female with a history of allergic rhinitis and severe asthma first presented in October 2019 when she was hospitalized for a severe asthma exacerbation that required treatment with systemic steroids. She is a nonsmoker and works as a waitress. Other than a diagnosis of anxiety requiring treatment with medication, she had no other comorbidities.

Prior to presentation, the patient had been managed with low-dose inhaled corticosteroid (ICS) and salbutamol for her chronic symptoms. Investigations carried out at presentation revealed forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio of 0.89/1.73 with bronchodilator response, blood eosinophilic count (BEC) of 660 cells/µL, a CD-sens immunoglobulin E (IgE) level of 413 IU/mL, and an Asthma Control Test (ACT) score of about 5. As her symptoms were not controlled despite the above treatment, the ICS dose was stepped up and a long-acting muscarinic antagonist (LAMA), tiotropium bromide inhalation spray, was added to the ongoing treatment.

Although the patient felt better with the increased ICS dose and inhaled tiotropium treatment, her symptoms were still not well controlled, with ACT score range of 5–10. She still complained of persistent cough and shortness of breath, which worsened during menstruation every month. In addition, her sleep quality was poor due to bothersome nocturnal symptoms, which woke her 2–3 times every night. The patient still suffered from anxiety despite treatment with medication. Her asthma treatment had to be stepped up further to include a long-term oral corticosteroid (OCS), prednisolone 5–10 mg, on top of maximal ICS and inhaled tiotropium.

Despite the intensified treatment, the patient’s asthma symptoms remained poorly controlled, and she still required additional prednisolone about twice a month to control exacerbations. 

Treatment with an anti–IL-5 agent and response

A subcutaneous (SC) 4-weekly injection of mepolizumab 100 mg was added to the patient’s treatment regimen in March 2020. As she was considered a high-risk asthma patient, admission was arranged for inpatient administration of the first dose of mepolizumab, so that she could be closely monitored for possible adverse reactions to treatment, such as sudden asthma attacks or allergic reactions to other ingredients of the medication. As recommended before commencing treatment with biologics, the patient was screened for active infections including Aspergillus.

The patient responded well to add-on mepolizumab treatment, with a remarkable decrease in BEC to approximately 50 cells/µL after 3 months. The use of additional OCS for symptom control was reduced to only once a month during the first 2 months of mepolizumab treatment, and there were no instances of exacerbations requiring hospitalization.

The patient experienced significant improvements in symptom control by the fourth month of treatment with mepolizumab, with a much lower frequency of night waking due to nocturnal symptoms. In the subsequent month, the prednisolone 5 mg daily dose was tapered off.

The patient has tolerated mepolizumab treatment well without any adverse effects. She is able to enjoy better sleep quality with her anti-anxiety medication and is feeling better and happier overall. Due to the coronavirus disease 2019 (COVID-19) pandemic, routine lung function tests could not be carried out to monitor the patient’s lung function response to mepolizumab treatment until recently. Last seen in October 2020, her ACT score was 17 and FEV1/FVC was 1.77/2.05.  

Discussion

The 2020 update of the Global Initiative for Asthma’s (GINA) Global Strategy for Asthma Management and Prevention recommends biologics targeting type 2 inflammation as add-on therapy for severe asthma in the final step (Step 5) of asthma management, in patients with exacerbations or poor symptom control despite maximal or optimal ICS/long-acting beta agonist (LABA) therapy or add-on tiotropium, who need maintenance therapy with OCS or have eosinophilic or allergic biomarkers, with or without type 2 comorbidities such as nasal polyposis.1

Our patient was a case who could have benefitted from GINA-recommended specialized treatment earlier had she been referred to specialist care promptly for further assessment to rule out conditions mimicking asthma and for identification of asthma subtype. Investigations, particularly baseline BEC, carried out when the patient was not having an acute exacerbation and not on long-term or high-dose OCS confirmed severe eosinophilic asthma (SEA). Testing for parasitic infections was also performed to rule out such infections as the cause of elevated BEC. CT scans, tests for autoimmune markers and skin-prick tests further confirmed the diagnosis.

Mepolizumab is a humanized interleukin-5 (IL-5) monoclonal antibody that directly inhibits IL-5, a key cytokine generated in type 2 inflammation. This reduces eosinophils in the circulation and tissue sites, thus inhibiting eosinophilic inflammation and effectively reducing exacerbations as well as the need for OCS treatment in SEA.2,3

Our case illustrates the efficacy of mepolizumab in SEA. Mepolizumab was selected for the patient due to its consistent efficacy regardless of baseline BEC, demonstrated in a matching-adjusted indirect comparison of mepolizumab and benralizumab (an IL-5 receptor inhibitor recommended by GINA).1,4 In the indirect treatment comparison, both treatments at their approved doses significantly reduced the rate of clinically significant exacerbations and improved asthma control vs placebo in patients with SEA in all baseline BEC subgroups. Mepolizumab, however, was associated with significantly greater improvements in clinically significant exacerbations compared with benralizumab in patients with similar BECs (rate ratio [RR] for BEC >400 cells/µL: 0.55; 95 percent confidence interval [CI], 0.35 to 0.87) (RR for BEC >300 cells/µL: 0.61; 95 percent CI, 0.37 to 0.99) (RR for BEC >150 cells/µL: 0.66; 95 percent CI, 0.49 to 0.89) (all p<0.05), as well as better asthma control (p<0.05 in all subgroups).4 (Figure 1)

HK-GLA-372md_01

The use of mepolizumab in our patient is further supported by the SIRIUS (Steroid Reduction with Mepolizumab Study) trial, which showed that in patients with SEA requiring daily OCS therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect vs placebo (overall odds ratio [OR] for reduction in OCS dose, 2.39; 95 percent CI, 1.25 to 4.56; p=0.008) (median reduction from baseline in daily OCS dose at week 24, 50 percent vs no reduction; p=0.007). Despite the OCS reduction, patients in the mepolizumab group had a 32 percent relative reduction in annualized rate of exacerbations (p=0.04) at week 24, as well as significantly improved control of asthma symptoms (p=0.004), vs those in the placebo group.3 (Figure 2)

HK-GLA-372_02

The MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) study also found that in patients treated with high-dose ICS with or without maintenance OCS for asthma control, treatment with mepolizumab reduced exacerbations by approximately half, improved quality of life, and resulted in better asthma control. In patients who received SC mepolizumab 100 mg, the rate of exacerbations was reduced by 53 percent vs placebo (95 percent CI, 36 to 65; p<0.001), and exacerbations necessitating an emergency department visit or hospitalization were reduced by 61 percent (95 percent CI, 17 to 82; p=0.02).2 A secondary analysis of MENSA revealed larger reductions in exacerbation rates with mepolizumab vs placebo in patients with higher baseline BEC (RR for BEC ≥150 cells/µL: 0.61; 95 percent CI, 0.45 to 0.82) (RR for BEC ≥300 cells/µL: 0.49; 95 percent CI, 0.38 to 0.63) (RR for BEC ≥400 cells/µL: 0.45; 95 percent CI, 0.34 to 0.58) (RR for BEC ≥500 cells/µL: 0.42; 95 percent CI, 0.31 to 0.55).5

The long-term safety and durability of mepolizumab response have been demonstrated in the COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects) study, which included 347 patients monitored over an average of 3.5 years (maximum, 4.5 years; total exposure, 1,201 patient-years). Results showed that after long-term use in patients with SEA, mepolizumab maintained clinical efficacy and continued to demonstrate a favourable safety profile, with no evidence of inducing neutralizing antibodies. Common adverse effects occurring in more than 10 percent of the patients during the study were respiratory tract infection, headache and sinusitis.6

Our patient tolerated mepolizumab well without experiencing side effects. Other than immunosuppressive side effects such as parasitic infections associated with biologic treatments that physicians should look out for, there are no major contraindications to the use of mepolizumab in patients with SEA. As there is insufficient safety data on the use of mepolizumab in pregnancy, in female patients, pregnancy should be ruled out before commencing treatment, and mepolizumab should be avoided in those planning to conceive. Furthermore, mepolizumab should be discontinued in those who become pregnant after treatment commencement. It is also advisable to space out mepolizumab injections and avoid administration during an acute exacerbation episode. 

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Pearl Toh, 19 Dec 2020
With the release of the latest interim efficacy results for ChAdOx1 nCoV-19, the adenovirus-vectored vaccine against COVID-19 is inching a step closer towards regulatory approval — and eventually, widespread use that will hopefully put an end to the relentless carnage by the pandemic.
Audrey Abella, 04 Jan 2021
In a fully remote, preliminary study evaluating adult outpatients with mild COVID-19, the likelihood of clinical deterioration* over 15 days was lower among those treated with fluvoxamine – an SSRI** and a strong σ-1 receptor (S1R) agonist – compared with those receiving placebo.
Pearl Toh, 10 Jan 2021
People infected with SARS-CoV-2 appear to be highly infectious within the first week following symptom onset, with the highest viral load and live virus detected during this period, according to a systematic review and meta-analysis of three human coronaviruses.