Worsening Of Asthma Research Articles

Real-life impact of COVID-19 pandemic lockdown on the management of pediatric and adult asthma: A survey by the EAACI Asthma Section.

BackgroundThe restrictions imposed by the COVID‐19 pandemic impact heavily the management of chronic diseases like asthma. This study aimed to evaluate the management of adults and children with asthma during COVID‐19‐related lockdown.MethodsA survey was launched by the European Academy of Allergy and Clinical Immunology (EAACI) via e‐mail, website, and social media to EAACI members and members of peer societies.ResultsThe survey was completed by 339 healthcare professionals from 52 countries. 79% of follow‐up consultations were replaced by phone calls, whereas 49% of newly referred patients attended the clinic. 62%, 76%, 66%, 76%, and 87% of responders did not conduct spirometry, impulse oscillometry, bronchodilator test, FeNO, or methacholine provocation, respectively, for asthma diagnosis in adults. The numbers were similar for children. 73% of responders based the initial asthma diagnosis and the prescription of inhaled therapy on clinical parameters only. Lung function tests were used in 29% of cases to monitor asthma worsening, and only 56% of participants were recommended to their patients ambulatory peak expiratory flow (PEF) measurements. Using a 1 (not at all) to 5 (very much) scale, the responders considered that the quality of healthcare provided and the patients’ asthma status had deteriorated during the lockdown with 3.2 points and 2.8 points, respectively.ConclusionCollectively, these results suggest that all necessary resources should be allocated to ensure the performance of lung function tests for initial diagnosis, whereas digital remote monitoring should be reinforced for the follow‐up of children and adults with asthma.

Procena uticaja čađi u vazduhu na pogoršanje alergijskog rinitisa i astme u regionu Užica u Srbiji

Many epidemiological studies have shown a positive association between black carbon (BC) concentrations and exacerbation of allergic rhinitis and asthma. The aim of this study was to examine, for the first time in Serbia, the connection between visits to emergency services due to worsening of allergic rhinitis and allergic asthma and the concentration of BC in the air. Materials and methods: A time-stratified case crossover design was applied for emergency room visits due to allergic rhinitis and worsening asthma that occurred in the Užice region between 2012-2014. Data on visits were routinely collected at the Uzice Health Center. Results: A statistically significant association was observed between the worsening of allergic rhinitis and BC concentration two days before the visit to the emergency department (UO = 359, UO = 3.20 and UO = 3.24, depending on whether the analysis is not adjusted or adjusted for appropriate weather conditions). There was also a statistically significant association between worsening of allergic asthma and BC concentration two days before the emergency service visit (UO = 3.15, GP = 0.98-10.14) and three days before the emergency service visit (UO = 2.98; UO = 3.23 ; UO = 2.98). Conclusion: Exposure to soot, especially during the heating season, increases the risk of emergency services due to worsening of allergic rhinitis and asthma.

Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial

ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18-75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39-0·65; p<0·0001) over the 24-week treatment period and provided clinically meaningful and statistically significant improvement from baseline to week 24 in SGRQ total score versus placebo (least squares mean change from baseline -8·11 (95% CI -11·41 to -4·82; p<0·0001), with similar differences at earlier timepoints. Benralizumab improved FEV1, PEF, ACQ-6, CGI-C, PGI-C, PSIA, and SNOT-22 at week 24 versus placebo, with differences observed early (within weeks 1 to 4). Adverse events were reported for 271 (63%) of 427 patients on benralizumab versus 143 (62%) of 229 patients on placebo. The most commonly reported adverse events for the 427 patients receiving benralizumab (frequency >5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. AstraZeneca.

Association Between Fungal Spore Exposure in Inner-City Schools and Asthma Morbidity

SN Baxi, WJ Sheehan, JE Sordillo. Ann Allergy Asthma Immunol . 2019;122(6):610–615.e1 To evaluate the association of school-based fungal spore exposures on asthma symptom days in children with asthma. Children 4–13 years of age with persistent asthma attending an elementary school in the Northeast US from 2008–2013, where environmental sampling was obtained. Children had to have physician diagnosed asthma with symptoms in the prior 12 months, daily controller medication usage, or unscheduled medical visits for asthma in the past year. Children were recruited from participating schools …

Association Between Bedroom Particulate Matter Filtration and Changes in Airway Pathophysiology in Children With Asthma

X Cui, Z Li, Y Teng. JAMA Pediatr . 2020;174(6):533–542 To examine whether reducing fine particles of 2.5 µm or smaller in diameter (PM2.5), a risk factor for asthma exacerbation, improves small airway physiology among children with asthma. Forty-three children with mild to moderate asthma (5–13 years old) were recruited from an outpatient clinic affiliated with Shanghai General Hospital. Data were collected from a randomized, double-blind, cross-over study, and participants had 2 intervention sessions between February 14–April 24, 2017. During the true filtration session, a portable air purifier, that …

Role of biomarkers and effect of FIP-fve in acute and chronic animal asthma models.

Asthma is a consequence of complex gene-environment interactions. Exploring the heterogeneity of asthma in different stages is contributing to our understanding of its pathogenesis and the development of new therapeutic strategies, especially in severe cases. This study aimed to further understand the relationship between manifestations of acute and chronic asthma and various endotypes, and explore the severity of lung inflammation, cell types, cytokine/chemokine differences, and the effects of FIP-fve. Acute and chronic OVA-sensitization mouse asthma models, based on our previously published method, were used and FIP-fve was used to evaluate the effect on these two models. BALF cytokines/chemokines were detected according to the manufacturer's protocol. Seventeen cytokine/chemokine secretions were higher in the chronic stage than in the acute stage. Whether in acute stage or chronic stage, the FIP-fve treatment groups had reduced airway hyperresponsiveness, infiltration of airway inflammatory cells, secretion of cytokines, chemokines by Th2 cells, and TNF-α, IL-8, IL-17, CXCL-1, CXCL-10, CCL-17, and CCL-22, and it was also found that the Treg cell cytokine IL-10 had increased significantly. PCA (Principal Component Analysis) was also used to compare statistics and laboratory data to find the important biomarkers in different stages and after treatment with FIP-fve. There are many different immune responses in the different stages of the asthma process. Drug treatment at the appropriate times might help reduce the worsening of asthma.

Variability in airway inflammation, symptoms, lung function and reliever use in asthma: anti-inflammatory reliever hypothesis and STIFLE study design.

Asthma is a chronic inflammatory airway disease. Increase in airway inflammation is hypothesised to contribute to worsening of asthma symptoms and deterioration in lung function, resulting in the use of reliever medication. Short-acting β2-agonists only treat the symptoms, whereas an anti-inflammatory reliever is believed to treat both symptoms and the underlying inflammation, thereby arresting the progression to an exacerbation. As-needed budesonide/formoterol as an anti-inflammatory reliever reduces the risk of severe exacerbations. However, supporting mechanistic evidence has not yet been described, specifically the temporal dynamics of parameters including airway inflammation, over time and during asthma worsening.The STIFLE study aims to characterise daily variability in airway inflammation, symptoms, lung function and reliever use in people with asthma. This phase IV, open-label, parallel-group, multicentre, exploratory study will enrol 60–80 adult patients with asthma receiving low- or medium-dose inhaled corticosteroids/long-acting β2-agonists (EudraCT identifier number 2018-003467-64). Participants will be randomised 1:1 to either as-needed budesonide/formoterol dry-powder inhaler or salbutamol reliever for 24 weeks, in addition to their maintenance therapy. Daily data will be captured for fractional exhaled nitric oxide, spirometry, asthma symptoms and medication use using devices connected to a smartphone via the STIFLE application. STIFLE will thereby enable not only characterisation of the variability of airway inflammation and clinical outcomes in relation to asthma worsening, but also elucidate the effect of as-needed budesonide/formoterol on airway inflammation against a background of daily maintenance therapy.

Efficacy and safety of inhalation budesonide in the treatment of pediatric asthma in the emergency department: a systematic review and meta-analysis

This study was aimed to evaluate the beneficial role of inhalation budesonide(BUD) in improving the pulmonary functions, and reducing the hospital admission rate, worsening of asthma and commonly encountered adverse events in pediatric asthma. The electronic search was performed using PubMed, Scopus, CENTRAL (Cochrane Central Register of Controlled Trials) and Google scholar databases to identify the randomized control trials(RCTs). 21 RCTs involving 12,787 subjects were included. The meta-analysis revealed that the BUD has reduced the hospitalization rate (Mantel-Haenszel (M-H), random effects odd ratio (RE-OR) of 0.34, p = 0.003, I2 = 75%), and worsening of asthma (M-H, RE-OR 0.38, p = 0.001, I2 = 73%); significantly improved the pulmonary functions such as FEV1 (Inverse variance (IV): 1.05, p < 0.0001, I2 = 94%), PEFR (IV: 1.40, p < 0.0001, I2 = 87%), morning PEF (IV: 1.04, p < 0.0001, I2 = 91%), and evening PEF (IV: 1.29, p < 0.0001, I2 = 92%) compared to control. Further, the incidences of adverse events like Pharyngitis (M-H, RE-OR 0.88, at 95% CI, p = 0.69, I2 = 0%), Sinusitis (M-H, RE-OR 0.78, p = 0.79, I2 = 0%), Respiratory infections (M-H, RE-OR 0.96, p = 0.46, I2 = 0%), Otitis media (M-H, RE-OR 0.82, p = 0.32, I2 = 12%) and Fever (M-H, RE-OR 0.78, p = 0.64, I2 = 0%) were almost same between BUD and control. The outcomes of the meta-analysis suggest that high-dose inhalation BUD could benefit the pediatric patients in minimizing the worsening of asthma and hospitalization rate, along with improving the pulmonary functions, with negligible adverse drug reactions.

A cross sectional observational study of severity of allergic rhinitis and its impact on asthma

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Allergic rhinitis (AR) and asthma are chronic diseases that often coexist and whose prevalence is increasing day by day. Uncontrolled allergic rhinitis may be associated with worsening of asthma and hence optimal treatment of AR may improve the coexisting asthma. The objective of the study was to study the severity of allergic rhinitis and its impact on asthma.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; A cross sectional study was conducted on 60 patients, at our Institute from November 2017 to June 2019 who were clinically diagnosed to have AR and asthma. Patients were evaluated by proper history taking, in detailed clinical examination and diagnostic nasal endoscopy and spirometry. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; In our study out of 60 patients, majority fell in 20 to 40 age group. According to allergic rhinitis and its impact on asthma (ARIA) classification 10 (17%) had mild intermittent AR, 12 (20%) had mild persistent AR, 5 (8%) had moderate/severe intermittent AR and 33 (55%) had moderate or severe persistent AR. In case of moderate/severe persistent AR: 4 had intermittent, 9 had mild persistent, 10 had moderate persistent and 10 severe persistent asthma. Spearman’s rank correlation was done between severity of AR and severity of asthma, spearman’s rho: 0.365, p&amp;lt;0.004 was significant.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; We noted that as the severity of allergic rhinitis increased, severity of asthma also increased, which was a linear correlation.&lt;/p&gt;

Health effects of concurrent ambient and tobacco smoke-derived particle exposures at low concentrations in children with asthma.

Exposure to particulate matter less than 2.5 microns from either ambient pollution (AMB-PM2.5) or secondhand smoke (SHS-PM2.5) have been associated with asthma worsening, but there is little information on effects and relative potency with concurrent exposures. We studied health effects of concurrent exposures to AMB-PM2.5 and SHS-PM2.5 over a 6-year period in schoolchildren with asthma. Regression calibration with instrumental variables (RCIV) was utilized to estimate effects of personal exposure to low-level SHS and AMB-PM2.5 on daily albuterol usage and urinary leukotriene E4 (uLTE4; a biomarker of asthma-related inflammation) using urine cotinine and concentrations from fixed and personal pollution monitors. Each IQR increase in SHS-PM2.5 exposure was associated with a 6.7% increase (95% CI: 1.0-12.8%) in uLTE4 on the same day and 9.4% increase (95% CI: -2.6 to 22.7%) in albuterol use the next day, when children were co-exposed to mean levels of AMB-PM2.5. The dose-response relationship between health outcomes and one pollutant was higher at lower levels of the other pollutant. For example, at lower levels of predicted SHS-PM2.5 exposure, increases in health outcomes per IQR increase in AMB-PM2.5 ranged between 2 and 5%, but were negligible at higher SHS-PM2.5 levels. Comparing at equivalent co-exposure levels, SHS-PM2.5 was 1.6 times more potent than AMB-PM2.5 for uLTE4 (95% CI: 1.1-2.3); estimates for albuterol usage were similar but less significant. Effects at mean co-exposure levels were closer [SHS to AMB-PM2.5 potency ratio = 1.2 (95% CI: 0.9-1.5) for uLTE4 and 1.2 (95% CI: 0.7-1.9) for albuterol usage]. In summary, concurrent exposure to relatively low levels of SHS and AMB-PM2.5 were associated with health outcomes in asthmatic schoolchildren. Dose responses varied with changes in the relative amounts of each pollutant; SHS-PM2.5 was observed to be more potent than AMB-PM2.5 when co-exposure levels were equivalent.

Physician-Patient Communication Regarding the Potential Role of Workplace Exposures in Asthma Onset and Severity: Progress Towards Healthy People 2020

Physician-patient communication is an essential element of care. In 2010, an estimated 13.5% of employed adults with current asthma communicated with a health professional about the role of work in the causation or exacerbation of their asthma. We aimed to assess progress toward the Healthy People 2020 goal seeking to increase the proportion of persons with current asthma who discussed with their health care provider whether their asthma was work related. Data from 25,417 non-institutionalized U.S. adult respondents of the 2018 National Health Interview Survey were analyzed. Adults employed at any time in the 12 months prior to the interview with a health-professional diagnosis of current asthma who have been told by a health professional that their asthma was probably work-related or ever discussed asthma work-relatedness were identified. Weighted proportions were calculated. An estimated 8.1% (95% CI, 6.4%–9.9%) of employed adults with current asthma (11.8 million) have been told that their asthma is work-related. Among those not so informed, 4.2% (95% CI, 2.8%–5.5%) ever discussed asthma work-relatedness. Considering responses from both questions, the proportion of employed adults with current asthma who communicated with a health professional about asthma work-relatedness was 12.0% (95% CI, 9.9%–14.1%). Proportion of employed adults with asthma who reported communicating with their health professionals about their asthma and work did not change substantially over time. Clinical decision support provided through electronic health records could enhance discussions of work-relatedness with adult patients with recent onset or worsening of asthma.

Effect of the DP2 antagonist, GB001, on asthma worsening in patients with mild-moderate asthma

Effect of the DP2 antagonist, GB001, on asthma worsening in patients with mild-moderate asthma

Problems of management of non-corona respiratory diseases in the era of COVID-19

This pandemic, COVID-19 caused by the novel coronavirus SARS-CoV-2, has not only devastated the public health, but also posed an immense impact on the societal, economical, and geopolitical conditions. The severe stress on essential health services has also adversely affected the prevalence, recognition, and management of non-COVID diseases. In particular, the management of respiratory diseases has suffered the most because of the clinical similarities between COVID-19 and non-COVID flu, respiratory allergies, pneumonias, and respiratory failure. Because of these similarities, some of the patients tend to avoid seeking treatment lest they be diagnosed as COVID-19 infection. Diagnostic tests such as spirometry and invasive investigations (bronchoscopies and thoracoscopies) are avoided by physicians for the fear of spread of the infection. Patients with acute worsening of asthma and chronic obstructive pulmonary disease requiring nebulization therapy are thus not even entertained by medical facilities. Many patients themselves are often afraid of inhalation therapy. In this article, we have summarized the problems faced by the patients suffering from respiratory disorders and their physicians as well as some of the important issues related to their therapy during this pandemic.

Safety of live attenuated influenza vaccine (LAIV) in children with moderate to severe asthma

BackgroundLive attenuated influenza vaccine (LAIV) is recommended for annual influenza vaccination in children from age 2 years. However, some guidelines recommend against its use in children with asthma or recurrent wheeze due to concerns over its potential to induce wheezing.ObjectiveWe sought to assess the safety of LAIV in children with moderate to severe asthma, and in preschool children with recurrent wheeze.MethodsProspective, multicenter, open-label, phase IV intervention study in 14 specialist UK clinics. LAIV was administered under medical supervision, with follow-up of asthma symptoms 72 hours and 4 weeks late, using validated questionnaires.ResultsA total of 478 young people (median, 9.3; range, 2-18 years) with physician-diagnosed asthma or recurrent wheeze were recruited, including 208 (44%) prescribed high-dose inhaled corticosteroids and 122 (31%) with severe asthma. There was no significant change in asthma symptoms in the 4 weeks after administration (median change, 0; P = .26, McNemar test), with no impact of level of baseline asthma control/symptoms in predicting either a worsening of asthma or exacerbation after LAIV using a regression model. A total of 47 subjects (14.7%; 95% CI, 11%-19.1%) reported a severe asthma exacerbation in the 4 weeks after immunization, requiring a short course of systemic corticosteroids; in 4 cases, this occurred within 72 hours of vaccination. No association with asthma severity, baseline lung function, or asthma control was identified.ConclusionsLAIV appears to be well tolerated in the vast majority of children with asthma or recurrent wheeze, including those whose asthma is categorized as severe or poorly controlled.

Nocturnal bilevel positive airway pressure for the treatment of asthma

Nocturnal worsening of asthma may be due to reduced lung volumes and fewer sigh breaths, which have been shown to increase airway resistance and bronchoreactivity. We hypothesized that mimicking deep inspiration using nocturnal mechanical support would improve symptoms in patients with asthma.Subjects with asthma underwent usual care and bilevel positive airway pressure (PAP) therapy for 4 weeks, separated by 4 weeks, and methacholine challenge (PC20) and subjective assessments.13 patients with asthma alone and 8 with asthma + OSA completed the protocol. Change in bronchoreactivity (ratio of Post/Pre PC20) was not significantly different during usual care and bilevel PAP [0.86 (IQR 0.19, 1.82) vs 0.94 (IQR 0.56, 2.5), p = 0.88], nor was the change in Asthma Control Test different: 0.1 ± 2.2 vs. –0.2 ± 2.9, p = 0.79, respectively.Bilevel PAP therapy for four weeks did not improve subjective or objective measures of asthma severity in patients with asthma or those with asthma and OSA, although there was heterogeneity in response.

Tiotropium in children and adolescents with asthma

BackgroundAsthma is a major cause of morbidity in children, despite the availability of various treatments. In adults, tiotropium—a long-acting muscarinic antagonist—as add-on therapy to an inhaled corticosteroid with or without a long-acting β2-agonist provides clinical benefit with a safety profile similar to placebo. ObjectiveTo review published evidence on the efficacy and safety of tiotropium as add-on a long-acting muscarinic antagonist therapy in children and adolescents with asthma that is uncontrolled despite use of an inhaled corticosteroid with or without additional controller medication(s). MethodsWe searched PubMed from inception until June 12, 2018, for randomized controlled trials of children and adolescents aged 1 to 17 years treated with tiotropium and reporting a primary outcome of any pulmonary function test and a secondary outcome of adverse events. ResultsOverall, 7 randomized controlled trials of 1902 preschool children (aged 1-5 years; n = 102), school-age children (aged 6-11 years; n = 905), and adolescents (aged 12-17 years; n = 895) with moderate to severe asthma were included in the analysis. Once-daily tiotropium (5, 2.5, or 1.25 μg) improved lung function parameters, including peak and trough forced expiratory volume in 1 second, vs placebo. Commonly reported adverse events across treatment groups included asthma worsening or exacerbations, decreased peak expiratory flow rate, nasopharyngitis, viral respiratory tract infection, and respiratory tract infection. ConclusionOnce-daily tiotropium as add-on therapy is efficacious and safe in adolescents and children with moderate to severe asthma. These results support the expanded indication by regulatory authorities for add-on tiotropium in patients 6 years or older.

Development and initial validation of the Asthma Severity Scoring System (ASSESS)

Tools for quantification of asthma severity are limited. We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. ASSESS scores ranged from 0 to 20 (8.78± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both. LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454. Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo. In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options. Sanofi and Regeneron Pharmaceuticals.

Oral Corticosteroid Use for the Treatment of Chronic Eosinophilic Disease: A Patient's and His Physician's Experience.

This article, coauthored by a patient with eosinophilic granulomatosis with polyangiitis (EGPA) initially presenting as severe eosinophilic asthma and his physician-specialist, discusses the use and management of oral corticosteroid (OCS) treatment. It also considers the importance of early diagnosis of a rare disease and patient education. The patient describes his journey from progressive worsening of asthma and eventual diagnosis of EGPA to long-term OCS treatment and then participation in a clinical trial for this rare disease, involving the introduction of targeted biologic therapy with OCS tapering. The physician describes the importance of patient referral to obtain a correct diagnosis and optimal maintenance treatment, the balance between risk of adverse events associated with long-term OCS use and benefits of disease control, and various aspects of patient participation in clinical trials. Finally, the patient describes the role of continual patient education in the management of disease and OCS treatment. These considerations can apply to all chronic inflammatory diseases requiring maintenance OCS treatment.Funding: AstraZeneca.

Burden of Asthma and Role of 2.5µg Tiotropium Respimat® as an Add-On Therapy: A Systematic Review of Phase 2/3 Trials.

IntroductionTiotropium, a long-acting muscarinic antagonist, is approved for maintenance treatment of asthma in patients at least 6 years of age in the USA. We systematically reviewed published evidence on the efficacy and safety of 2.5 µg tiotropium Respimat® add-on therapy to inhaled corticosteroid (ICS) with or without additional controller medication(s) in children, adolescents, and adults with asthma.MethodsWe searched PubMed from inception until October 3, 2018, for phase 2 and 3 randomized controlled trials (RCTs) evaluating the effects of 2.5 µg tiotropium Respimat® on lung function parameters in patients with asthma. We extracted adjusted mean differences for lung function data and adverse events (AEs) from relevant articles.ResultsOverall, 11 RCTs (three phase 2 and eight phase 3 studies) including 3244 patients (2.5 µg tiotropium Respimat®, n = 1642; placebo, n = 1602) met the predefined inclusion criteria. Once-daily 2.5 µg tiotropium Respimat® improved lung function parameters, including peak and trough forced expiratory volume in 1 s and peak and trough forced vital capacity, versus placebo. Overall, the safety profile of 2.5 µg tiotropium Respimat® was comparable to that of placebo, with the most commonly reported AEs being asthma worsening, reduction in peak expiratory rate, nasopharyngitis, and respiratory tract infections.ConclusionOn the basis of the results of phase 2 and 3 studies, 2.5 µg tiotropium Respimat® as add-on to ICS therapy was safe and associated with consistent improvements in lung function in patients with asthma of varying severities across different age groups.FundingDevelopment of the manuscript was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI).Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01062-w) contains supplementary material, which is available to authorized users.