Real-World Effectiveness of Anti-IL-5/5R Therapy in Severe Atopic Eosinophilic Asthma with Fungal Sensitization.

BACKGROUND: Severe asthma with fungal sensitization (SAFS) is a complex clinical phenotype associated with poorly controlled type 2 inflammation and significant morbidity from both the disease itself and a high steroid burden. OBJECTIVE: To assess the effectiveness of biologic therapies targeting eosinophilic inflammation in SAFS. METHODS: We assessed the effectiveness of treatment with mepolizumab or benralizumab in patients with SAFS, and compared outcomes with patients with severe atopic asthma without fungal sensitization and patients with severe nonatopic asthma. Baseline clinical characteristics and clinical outcomes at 48 weeks were evaluated. A subgroup analysis was performed of patients who met the criteria for allergic bronchopulmonary aspergillosis (ABPA) rather than SAFS. RESULTS: A total of 193 patients treated with mepolizumab (n = 63) or benralizumab (n = 130) were included. Patients with SAFS had higher baseline IgE level compared with patients with severe atopic asthma without fungal sensitization and severe nonatopic asthma (733 ± 837 IU/mL vs 338 ± 494 and 142 ± 171, respectively; both P < .001). There were no other significant baseline differences in clinical characteristics between groups. At 48 weeks, there were significant improvements in 6-item asthma control questionnaire score and exacerbation frequency, and reduction in maintenance oral corticosteroid dose across all groups (all P < .05). No significant between-group differences in outcomes were observed at 48 weeks. Patients with ABPA (n = 9) had a significant reduction in exacerbation frequency (P = .013) with treatment. CONCLUSIONS: Treatment with eosinophil-targeting biologics led to improvements in exacerbation frequency, oral corticosteroid requirements, and patient-reported outcomes in patients with SAFS, with a reduction in exacerbations in the subgroup of patients with ABPA. These data highlight the potential clinical utility of targeting eosinophilic inflammation in SAFS and ABPA.

A pragmatic guide to choosing biologic therapies in severe asthma.

There are now several monoclonal antibody (mAb) therapies ("biologics") available to treat severe asthma. Omalizumab is an anti-IgE mAb and is licensed in severe allergic asthma. Current evidence suggests it may decrease exacerbations by augmenting deficient antiviral immune responses in asthma. Like all other biologics, clinical efficacy is greatest in those with elevated T2 biomarkers. Three biologics target the interleukin (IL)-5-eosinophil pathway, including mepolizumab and reslizumab that target IL-5 itself, and benralizumab that targets the IL-5 receptor (IL-5R-α). These drugs all reduce the exacerbation rate in those with raised blood eosinophil counts. Mepolizumab and benralizumab have also demonstrated steroid-sparing efficacy. Reslizumab is the only biologic that is given intravenously rather than by the subcutaneous route. Dupilumab targets the IL-4 receptor and like mepolizumab and benralizumab is effective at reducing exacerbation rate as well as oral corticosteroid requirements. It is also effective for the treatment of nasal polyposis and atopic dermatitis. Tezepelumab is an anti-TSLP (thymic stromal lymphopoietin) mAb that has recently completed phase 3 trials demonstrating significant reductions in exacerbation rate even at lower T2 biomarker thresholds. Many patients with severe asthma qualify for more than one biologic. To date, there are no head-to-head trials to aid physicians in this choice. However, post-hoc analyses have identified certain clinical characteristics that are associated with superior responses to some therapies. The presence of allergic and/or eosinophilic comorbidities, such as atopic dermatitis, nasal polyposis or eosinophilic granulomatosis with polyangiitis, that may additionally benefit by the choice of biologic should also be taken into consideration, as should patient preferences which may include dosing frequency. To date, all biologics have been shown to have excellent safety profiles.

Real-World Effectiveness of Benralizumab in Severe Eosinophilic Asthma.

BACKGROUND: Benralizumab is an IL5-receptor monoclonal antibody licensed for the treatment of severe eosinophilic asthma (SEA). It has demonstrated efficacy in clinical trials in reducing asthma exacerbation rates and maintenance oral corticosteroids (mOCSs). RESEARCH QUESTION: What is the real-world effectiveness of benralizumab and what baseline characteristics are associated with response to therapy? STUDY DESIGN AND METHODS: We assessed outcomes in all SEA patients who began benralizumab treatment at our specialist center. At each dosing visit, exacerbation history, mOCS dose, spirometry, and Asthma Control Questionnaire (ACQ6) and Mini-Asthma Quality of Life Questionnaire (mAQLQ) scores were recorded. Response to treatment was defined as a reduction of ≥ 50% in annualized exacerbation rate (AER) or in mOCS dose after 48 weeks of treatment. Super response was defined as zero exacerbations and no mOCSs for asthma. RESULTS: One hundred thirty patients were included in the analysis. At 48 weeks, a 72.8% reduction in AER was noted, from 4.92 ± 3.35 per year in the year preceding biologic treatment to 1.34 ± 1.71 per year (P < .001), including 57 patients (43.8%) who were exacerbation-free with benralizumab. In those receiving mOCSs (n = 74 [56.9%]), the median daily prednisolone dose fell from 10 mg (interquartile range, 5-20 mg) to 0 mg (interquartile range, 0-5 mg; P < .001), and 38 of 74 patients (51.4%) were able to discontinue mOCS therapy. Clinically and statistically significant improvements were found in ACQ6 scores, mAQLQ scores, and FEV1. Overall, 51 patients (39%) met the super responder definition and 112 patients (86%) met the responder definition. The optimal regression model of super responders vs other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease. Eighteen patients (13.8%) were nonresponders to benralizumab. Evidence of chronic airway infection was observed in 6 of 18 patients, and an increase in the blood eosinophil count consistent with the development of anti-drug antibodies was observed in 5 of 18 patients. INTERPRETATION: In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures. A lack of response was seen in a minority of patients and should be a focus for future investigation.

Steroid-sparing effects of benralizumab in patients with eosinophilic granulomatosis with polyangiitis.

Benralizumab reduces oral corticosteroid requirements in patients with EGPA and leads to improved patient-reported outcome measures https://bit.ly/2GI0vhf.

Real-World Effectiveness and the Characteristics of a "Super-Responder" to Mepolizumab in Severe Eosinophilic Asthma.

BACKGROUND: Mepolizumab was the first licensed anti-IL5 monoclonal antibody for severe eosinophilic asthma (SEA). To date there are few data to confirm its efficacy in the real-world setting or assessment of baseline characteristics associated with response. RESEARCH QUESTION: How do patients with severe eosinophilic asthma respond to mepolizumab in the real world setting and which characteristics are associated with a super-response to this therapy? STUDY DESIGN AND METHODS: We conducted a retrospective review of all patients who received at least 16 weeks of treatment with mepolizumab (100 mg subcutaneously) for SEA at our regional asthma center in the United Kingdom. Clinical data were collected at each 4-week visit. At 16, 24, and 52 weeks, patients were classified as "responders" or "nonresponders." A response was defined as ≥50% reduction in exacerbations; for patients whose condition requires maintenance oral corticosteroids (mOCS), a response was defined as ≥50% reduction in prednisolone dose. Super responders were defined as exacerbation-free and off mOCS at one year. RESULTS: Ninety-nine patients were included in the analysis. Asthma exacerbations decreased from a baseline of 4.04 ± 2.57 to 1.86 ± 2.17 per year at one year (54% reduction; P < .001). Sixty-eight patients were receiving mOCS at the time of commencing mepolizumab. By one year, the daily median dose fell from 10 mg (interquartile range, 10 to 15) to 0 mg (interquartile range, 0 to 10; P < .001). Fifty-seven percent of them were able to discontinue mOCS; 72.7% (95% CI, 63.0 to 80.7) of the patients were classified as responders, and 28.3% (95% CI, 20.2 to 38.0) of the patients were classified as super responders. Baseline characteristics associated with responder and super responder status included the presence of nasal polyposis (P = .012), lower baseline Asthma Control Questionnaire 6 (P = .006), a lower BMI (P = .014), and, in those patients receiving mOCS, a significantly lower prednisolone dose at baseline (P = .005). At 16 weeks, the one-year responder status was correctly identified in 80.8% patients; by 24 weeks, this status rose to 92.9%. INTERPRETATION: In a real-world SEA cohort, treatment with mepolizumab reduced exacerbation frequency and mOCS requirements. Nasal polyposis, a lower BMI, and a lower maintenance prednisolone requirement at baseline were associated with better outcomes. Twelve-month response was identifiable in >90% of patients by week 24.

Adherence to corticosteroids and clinical outcomes in mepolizumab therapy for severe asthma.

INTRODUCTION: Inhaled corticosteroids (ICS) achieve disease control in the majority of asthmatic patients, although adherence to prescribed ICS is often poor. Patients with severe eosinophilic asthma may require treatment with oral corticosteroids (OCS) and/or biologic agents such as mepolizumab. It is unknown if ICS adherence changes on, or alters clinical response to, biologic therapy. METHODS: We examined ICS adherence and clinical outcomes in OCS-dependent severe eosinophilic asthma patients who completed 1 year of mepolizumab therapy. The ICS medicines possession ratio (MPR) was calculated (the number of doses of ICS issued on prescription/expected number) for the year before and the year after biologic initiation. Good adherence was defined as MPR >0.75, intermediate 0.74-0.51 and poor <0.5. We examined outcomes after 12 months of biologic therapy, including OCS reduction and annualised exacerbation rate (AER), stratified by adherence to ICS on mepolizumab. RESULTS: Out of 109 patients commencing mepolizumab, 91 who had completed 12 months of treatment were included in the final analysis. While receiving mepolizumab, 68% had good ICS adherence, with 16 (18%) having poor ICS adherence. ICS use within the cohort remained similar before (MPR 0.81±0.32) and during mepolizumab treatment (0.82±0.32; p=0.78). Patients with good adherence had greater reductions in OCS dose (median (interquartile range) OCS reduction 100 (74-100)% versus 60 (27-100)%; p=0.031) and exacerbations (AER change -2.1±3.1 versus 0.3±2.5; p=0.011) than those with poor adherence. Good ICS adherence predicted the likelihood of stopping maintenance OCS (adjusted OR 3.19, 95% CI 1.02-9.94; p=0.045). CONCLUSION: ICS nonadherence is common in severe eosinophilic asthma patients receiving mepolizumab, and is associated with a lesser reduction in OCS requirements and AER.

Oral corticosteroid-sparing effects of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis.

Blockade of interleukin-5 with reslizumab appears to have significant oral corticosteroid sparing effects in patients with eosinophilic granulomatosis with polyangiitis and severe eosinophilic asthma http://bit.ly/2D2yYSK.

Over- and under-diagnosis in asthma.

Asthma is extremely common with a prevalence of approximately 10% in Europe. It presents with symptoms which have a broad differential diagnosis and examination can be entirely normal. There is no agreed gold standard to diagnose asthma, and the objective tests that can aid diagnosis are often poorly available to primary care physicians. There is evidence that asthma is widely misdiagnosed. Overdiagnosis leads to unnecessary treatment and a delay in making an alternative diagnosis. Underdiagnosis risks daily symptoms, (potentially serious) exacerbations and long-term airway remodelling. An agreed standardised approach to diagnosis, with inclusion of objective measurements prior to treatment, is required to reduce misdiagnosis of asthma. KEY POINTS: Asthma presents with common respiratory symptoms and physical examination is often normal; in addition, the most widely available tests (peak flow and spirometry) can be normal unless the patient is exacerbating.Treating asthma prior to carrying out objective tests decreases their sensitivity and can make confirmation of the diagnosis difficult.There is no single gold standard test to diagnose asthma, and there are significant differences between the suggested algorithms in commonly used guidelines.Both under- and over-diagnosis are widespread and lead to significant risks to patients.

Sleep and asthma.

PURPOSE OF REVIEW: There is a longstanding recognition of the detrimental effect of poorly controlled asthma on sleep, but recent years have seen a growing interest in how asthma and sleep may interact. This review examines the current evidence of relationships between asthma, sleep and sleep disorders. RECENT FINDINGS: Poor quality sleep and sleep disturbance is highly prevalent in asthmatic patients, and particularly in those with severe asthma. Impaired sleep quality correlates with worse asthma control and quality of life. Sleep disturbance in asthma may be related to due circadian variation in airway inflammation, but may also be related to specific sleep disorders. Obstructive sleep apnoea (OSA) appears to be significantly more common in asthmatic patients than nonasthmatic patients, and treatment of OSA with continuous positive airway pressure (CPAP) may lead to improved asthma-specific quality of life. Nocturnal CPAP may also be of benefit to asthmatic patients without OSA, potentially because of stretching of airway smooth muscle. Insomnia is also highly prevalent in severe asthma patients, and is associated with a history of poor asthma control and increased healthcare utilization. SUMMARY: Asthma, sleep and sleep disorders appear to have complex, but significant relationships. Prospective observational and controlled interventional studies are needed to quantify how addressing sleep difficulties may benefit asthma patients.

Treatment of Interstitial Lung Disease Associated Cough: CHEST Guideline and Expert Panel Report.

BACKGROUND: Chronic cough in interstitial lung disease (ILD) causes significant impairment in quality of life. Effective treatment approaches are needed for cough associated with ILD. METHODS: This systematic review asked: Is there evidence of clinically relevant treatment effects for therapies for cough in ILD? Studies of adults aged > 18 years with a chronic cough ≥ 8 weeks' duration were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using CHEST guideline methodology. RESULTS: Eight randomized controlled trials and two case series (≥ 10 patients) were included that reported data on patients with idiopathic pulmonary fibrosis, sarcoidosis, and scleroderma-related ILD who received a variety of interventions. Study quality was high in all eight randomized controlled trials. Inhaled corticosteroids were not supported for cough associated with sarcoidosis. Cyclophosphamide and mycophenolate were not supported for solely treating cough associated with scleroderma-associated ILD. A recommendation for thalidomide to treat cough associated with idiopathic pulmonary fibrosis did not pass the panel vote. In view of the paucity of antitussive treatment options for refractory cough in ILD, the guideline panel suggested that the CHEST unexplained chronic cough guideline be followed by considering options such as the neuromodulator gabapentin and speech pathology management. Opiates were also suggested for patients with cough refractory to alternative therapies. CONCLUSIONS: The evidence supporting the management of chronic cough in ILD is limited. This guideline presents suggestions for managing and treating cough on the best available evidence, but future research is clearly needed.

Adult and paediatric cough guidelines: Ready for an overhaul?

Cough is one of the most common reasons that patients seek medical attention. Cough guidelines from numerous countries and societies are available to assist the clinician to investigate and manage patients with cough. We review some of the recent progress in the field of cough that may lead to revision of these guidelines. In adults with chronic cough, new causes such as obstructive sleep apnoea have been identified. A new terminology, cough hypersensitivity syndrome (CHS), has been proposed for patients with chronic cough, which emphasises cough reflex hypersensitivity as a key feature. New therapeutic options are now available, particularly for patients with refractory or idiopathic chronic cough, which include gabapentin, speech pathology management and morphine. There has been great progress in the assessment of cough with the development of validated quality of life questionnaires and cough frequency monitoring tools. In children, common aetiologies differ from adults and those managed according to guidelines have better outcomes compared to usual care. New diagnostic entities such as protracted bacterial bronchitis have been described. Paediatric-specific cough assessment tools such as the Parent/Child Quality of Life Questionnaire will help improve the assessment of patients. Further research is necessary to improve the evidence base for future clinical guideline recommendations. Guidelines in future should also aim to reach a wider audience that includes primary care physicians, non-specialists and patients.