20 March 2022

COPD

Tang et al. Mucus Plugs Persist in Asthma and Changes in Mucus Plugs Associate with Changes in Airflow Over Time. AJRCCM 2022, March. On line + Editorial
Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function.
Methods: In a longitudinal analysis of baseline and year 3 CT lung scans in SARP-3 participants, radiologists generated mucus plug scores to assess mucus plug persistence over time. Changes in mucus plug score were analyzed in relation to changes in lung function and CT air trapping measures.
Measurements and Main Results: In 164 participants, the mean (range) mucus plug score was similar at baseline and year 3 (3.4 [0-20] vs 3.8 [0-20]). Participants and bronchopulmonary segments with a baseline plug were more likely to have plugs at year 3 than those without baseline plugs (RR 2.8, 95% CI 2.0-4.1, p<0.001 and RR 5.0, 95% CI 4.5-5.6, p<0.001, respectively). The change in mucus plug score from baseline to year 3 was significantly negatively correlated with change in FEV1% predicted (rp = – 0.35, p<0.001) and with changes in CT air trapping measures (all p values < 0.05).
Conclusions: Mucus plugs identify a persistent asthma phenotype and susceptibility to mucus plugs occurs at the subject and the bronchopulmonary segment level. The association between change in mucus plug score and change in airflow over time supports a causal role for mucus plugs in mechanisms of airflow obstruction in asthma.

Gelbman BD, Reed CR. An Integrated, Multimodal, Digital Health Solution for Chronic Obstructive Pulmonary Disease: Prospective Observational Pilot Study. JMIR Form Res. 2022 Mar 17;6(3):e34758. doi: 10.2196/34758. PMID: 35142291.

Dransfield M, Rowe S, Vogelmeier CF, Wedzicha J, Criner GJ, Han MK, Martinez FJ, Calverley P. Cystic Fibrosis Transmembrane Conductance Regulator: Roles in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2022 Mar 15;205(6):631-640. doi: 10.1164/rccm.202109-2064TR. PMID: 34982651.

Mannino D, Bogart M, Germain G, Huang SP, Ismaila AS, Laliberté F, Jung Y, MacKnight SD, Stiegler MA, Duh MS. Benefit of Prompt versus Delayed Use of Single-Inhaler FluticasoneFuroate/Umeclidinium /Vilanterol (FF/UMEC/VI) Following a COPD Exacerbation. Int J Chron Obstruct Pulmon Dis. 2022 Mar 5;17:491-504. doi: 10.2147/COPD.S337668. PMID: 35281476; PMCID: PMC8906822.

Lei J, Yang T, Liang C, Huang K, Wu S, Wang C. Comparison of Clinical Characteristics and Short-Term Prognoses Within Hospitalized Chronic Obstructive Pulmonary Disease Patients Comorbid With Asthma, Bronchiectasis, and Their Overlaps: Findings From the ACURE Registry. Front Med (Lausanne). 2022 Feb 25;9:817048. doi: 10.3389/fmed.2022.817048. PMID: 35280888; PMCID: PMC8914031.

ASTHMA

Niewodowski D, Langton D. Learning curve for bronchial thermoplasty. Respirology. 2022 Mar 16. doi: 10.1111/resp.14248. Epub ahead of print. PMID: 35293074.

Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, Jison M, Brooks CL, Papeleu P, Katial R. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. Adv Ther. 2022 Mar 14. doi: 10.1007/s12325-022-02098-1. Epub ahead of print. PMID: 35287231.
ABSTRACT
Introduction: Consensus definitions for clinical remission and super-response were recently established for severe asthma. Benralizumab is an interleukin-5 (IL-5) receptor α-directed monoclonal antibody for severe, uncontrolled asthma; efficacy and safety were demonstrated in previous pivotal phase 3 trials (SIROCCO, CALIMA, ZONDA). This analysis applied a composite remission definition to characterize individual responses to benralizumab after 6 and 12 months.
Methods: In previous phase 3 studies, eligible patients were those with severe, uncontrolled asthma receiving medium- or high-dosage inhaled corticosteroids plus long-acting β2-agonists. This post hoc analysis included patients randomized to the approved benralizumab dose and not receiving oral corticosteroids (OCS) at baseline (SIROCCO/CALIMA) or OCS ≤ 12.5 mg per day (ZONDA). Individual remission components were zero exacerbations; zero OCS use; Asthma Control Questionnaire-6 (ACQ-6) score < 1.5 or ≤ 0.75; and pre-bronchodilator forced expiratory volume in 1 s (FEV1) increase ≥ 100 mL; clinical remission incorporated zero exacerbations, zero OCS use, ACQ-6 score ≤ 0.75, and pre-bronchodilator FEV1 increase ≥ 100 mL after 6 or 12 months.
Results: Overall, 609 patients (N = 301 and N = 308) and 586 patients (N = 293 and N = 293) receiving benralizumab in SIROCCO and CALIMA were included at 6 and 12 months, respectively; 40 ZONDA patients were included after 6 months. In SIROCCO/CALIMA, similar to 6-month findings, approx. 83% and approx. 49% receiving benralizumab, and 77% and 37% on placebo achieved ≥ 2 and ≥ 3 remission components after 12 months; 14.5% (85/586) on benralizumab and 7.7% (48/620) on placebo achieved clinical remission at 12 months. Among ZONDA patients, 75% and approx. 48% on benralizumab and 35% and 20% on placebo achieved ≥ 2 and ≥ 3 remission components at 6 months, respectively; 22.5% (9/40) on benralizumab and 7.5% on placebo achieved clinical remission.
Conclusions: This analysis demonstrates clinical remission is achievable by targeting the underlying drivers of inflammation. Precision medicines can help shift treatment paradigms toward treat-to-target, with clinical remission as the ultimate therapeutic goal in severe asthma.

RHINITIS-ALLERGY-ALLERGIC ASTHMA

Kum E, Guyatt GH, Munoz C, Beaudin S, Li SA, Abdulqawi R, Badri H, Boulet LP, Chen R, Dicpinigaitis P, Dupont L, Field SK, French CL, Gibson PG, Irwin RS, Marsden P, McGarvey L, Smith JA, Song WJ, O’Byrne PM, Satia I. Assessing cough symptom severity in refractory or unexplained chronic cough: findings from patient focus groups and an international expert panel. ERJ Open Res. 2022 Mar 14;8(1):00667-2021. doi: 10.1183/23120541.00667-2021. PMID: 35295233; PMCID: PMC8918938.

Badri H, Gibbard C, Denton D, Satia I, Al-Sheklly B, Dockry RJ, Holt K, McGuiness K, Treadway S, Whorwell P, Houghton L, Lee A, Escott KJ, Lee T, Wilkinson G, Holt A, Canning BJ, Smith JA. A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough. ERJ Open Res. 2022 Mar 14;8(1):00546-2021. doi: 10.1183/23120541.00546-2021. PMID: 35295236; PMCID: PMC8918934.

Van Hulst G, Jorssen J, Jacobs N, Henket M, Louis R, Schleich F, Bureau F, Desmet CJ. Anti-IL5 mepolizumab minimally influences residual blood eosinophils in severe asthma. Eur Respir J. 2022 Mar 17;59(3):2100935. doi: 10.1183/13993003.00935-2021. PMID: 34475229.
ABSTRACT
Neutralising antibodies against the cytokine interleukin (IL)5 have become widely used for the control of severe eosinophilic asthma. Remarkably, patients receiving neutralising anti-IL5 biological therapies retain a very stable population of residual blood eosinophils. Whether these residual eosinophils are endowed with particular biological activity has not yet been studied, but is of importance in predicting potential long-term effects of IL5 neutralisation in patients. To tackle the effect of IL5 depletion on residual eosinophils, we used a comparative RNA-sequencing approach and compared the gene expression programme of eosinophils arising in IL5-depleted or IL5-replete human or murine hosts, at steady-state in vivo and following in vitro stimulation with the eosinophil-activating alarmin IL33. We compared blood eosinophils from patients with severe allergic eosinophilic asthma treated with anti-IL5 mepolizumab therapy to those of healthy controls and matched asthma patients receiving anti-IgE omalizumab therapy. We made similar comparisons on bone marrow eosinophils from mice genetically deficient or not for IL5. We report that restriction of IL5 availability did not elicit any detectable transcriptional response in steady-state residual eosinophils in mepolizumab-treated patients or IL5-deficient mice, and influenced only a handful of genes in their response to IL33. Together, these results support the notion that treatment with IL5 neutralising antibodies spares a pool of circulating residual eosinophils largely resembling those of healthy individuals.

Sharma V, Ricketts HC, Steffensen F, Goodfellow A, Cowan DC. Obesity affects type 2 biomarker levels in asthma. J Asthma. 2022 Mar 17:1-8. doi: 10.1080/02770903.2022.2051548. Epub ahead of print. PMID: 35260034.
ABSTRACT
Objective: Type 2 (T2) inflammation offers a therapeutic target for biologics. Previous trials suggest obesity influences T2-biomarker levels in asthma, though have not accounted for key variables, e.g. inhaled (ICS)/oral corticosteroid (OCS) use. We hypothesized that body mass index (BMI) would affect T2-biomarker levels, after adjusting for covariates.
Methods: A retrospective analysis of data from two recent local trials of 153 participants with asthma (102 difficult-to-treat, 51 mild). Measurements included BMI, fractional exhaled nitric oxide (FeNO) and eosinophils. Correlation and regression analysis were performed for each biomarker to describe their relationship with BMI. Data was analyzed overall, and by asthma severity, T2-status and BMI tertile.
Results: Increasing BMI was associated with reduction in FeNO when stratified by BMI tertile (25 ppb lowest tertile, 18 ppb highest tertile; p = 0.014). Spearmans rank showed a negative correlation between BMI and FeNO in difficult-to-treat asthma (ρ= -0.309, p = 0.002). Linear regression adjusting for sex, age, smoking, atopy, allergic/perennial rhinitis, ICS and OCS confirmed BMI as a predictor of FeNO overall (β= -2.848, p = 0.019). Eosinophils were reduced in the highest BMI tertile versus lowest in difficult-to-treat asthma (0.2×109/L, 0.3×109/L respectively; p = 0.02).
Conclusions: Increasing BMI is associated with lower FeNO in asthma when adjusted for relevant covariates, including steroid use. There also appears to be an effect on eosinophil levels. Obesity, therefore, affects T2 biomarker levels with implications for disease endotyping and determination of eligibility for biologic therapy. Whether this is due to masking of underlying T2-high status or development of a truly T2-low endotype requires further research.

Posted in Libra Journal Club.