Xia J, Gu S, Lei W, Zhang J, Wei H, Liu C, Zhang H, Lu R, Zhang L, Jiang M, Hu C, Cheng Z, Wei C, Chen Y, Lu F, Chen M, Bi H, Liu H, Yan C, Teng H, Yang Y, Liang C, Ge Y, Hou P, Liu J, Gao W, Zhang Y, Feng Y, Tao C, Huang X, Pan P, Luo H, Yun C, Zhan Q. High-flow nasal cannula versus conventional oxygen therapy in acute COPD exacerbation with mild hypercapnia: a multicenter randomized controlled trial. Crit Care. 2022 Apr 15;26(1):109. doi: 10.1186/s13054-022-03973-7. PMID: 35428349; PMCID: PMC9013098.
Background: High-flow nasal cannula (HFNC) can improve ventilatory function in patients with acute COPD exacerbation. However, its effect on clinical outcomes remains uncertain.
Methods: This randomized controlled trial was conducted from July 2017 to December 2020 in 16 tertiary hospitals in China. Patients with acute COPD exacerbation with mild hypercapnia (pH ≥ 7.35 and arterial partial pressure of carbon dioxide > 45 mmHg) were randomly assigned to either HFNC or conventional oxygen therapy. The primary outcome was the proportion of patients who met the criteria for intubation during hospitalization. Secondary outcomes included treatment failure (intolerance and need for non-invasive or invasive ventilation), length of hospital stay, hospital cost, mortality, and readmission at day 90.
Results: Among 337 randomized patients (median age, 70.0 years; 280 men [83.1%]; median pH 7.399; arterial partial pressure of carbon dioxide 51 mmHg), 330 completed the trial. 4/158 patients on HFNC and 1/172 patient on conventional oxygen therapy met the criteria for intubation (P = 0.198). Patients progressed to NPPV in both groups were comparable (15 [9.5%] in the HFNC group vs. 22 [12.8%] in the conventional oxygen therapy group; P = 0.343). Compared with conventional oxygen therapy, HFNC yielded a significantly longer median length of hospital stay (9.0 [interquartile range, 7.0-13.0] vs. 8.0 [interquartile range, 7.0-11.0] days) and a higher median hospital cost (approximately $2298 [interquartile range, $1613-$3782] vs. $2005 [interquartile range, $1439-$2968]). There were no significant differences in other secondary outcomes between groups.
Conclusions: In this multi-center randomized controlled study, HFNC compared to conventional oxygen therapy did not reduce need for intubation among acute COPD exacerbation patients with mild hypercapnia. The future studies should focus on patients with acute COPD exacerbation with respiratory acidosis (pH < 7.35). However, because the primary outcome rate was well below expected, the study was underpowered to show a meaningful difference between the two treatment groups
1: Sánchez-García V, Pérez-Alcaraz L, Belinchón-Romero I, Ramos-Rincón JM. Comorbidities in Patients with Autoimmune Bullous Disorders: Hospital-Based Registry Study. Life (Basel).
2022 Apr 18;12(4):595. doi: 10.3390/life12040595. PMID: 35455086.
The incidence of autoimmune bullous disorders has increased over the years, especially in elderly patients with multiple comorbidities, which has stimulated research into their association with other diseases. We performed a retrospective observational study used the Minimum Basic Data Set of hospital discharges to review records of patients admitted to Spanish public hospitals between 2016 and 2019 with a diagnosis of any autoimmune bullous disorder. The objectives were to describe the comorbidity profile and the clinical-epidemiological characteristics of patients with pemphigus and pemphigoid, and analyze the evolution of the incidence of these diseases. The study included 1950 patients with pemphigus and 5424 patients with pemphigoid. Incidence increased from 2016 to 2019. The main comorbidities were hypertension (40.19%) and diabetes mellitus (28.57%). Compared to patients with pemphigoid, those with pemphigus had a higher prevalence of neoplasms, osteoporosis, solid metastases and malignant lymphoma, while the prevalence of hypertension, kidney disease, diabetes, heart failure, dementia, chronic obstructive pulmonary disease and Parkinson’s disease was higher in the pemphigoid group (p < 0.05). Therefore, since autoimmune bullous disorders are associated with diverse comorbidities and their incidence has risen in recent years, the establishment of strategies to prevent the main comorbidities in these patients is justified.
2: Pépin JL, Degano B, Tamisier R, Viglino D. Remote Monitoring for Prediction and Management of Acute Exacerbations in Chronic Obstructive Pulmonary Disease (AECOPD). Life (Basel).
2022 Mar 29;12(4):499. doi: 10.3390/life12040499. PMID: 35454991.
The progression of chronic obstructive pulmonary disease (COPD) is characterized by episodes of acute exacerbation (AECOPD) of symptoms, decline in respiratory function, and reduction in quality-of-life increasing morbi-mortality and often requiring hospitalization. Exacerbations can be triggered by environmental exposures, changes in lifestyle, and/or physiological and psychological factors to greater or lesser extents depending on the individual’s COPD phenotype. The prediction and early detection of an exacerbation might allow patients and physicians to better manage the acute phase. We summarize the recent scientific data on remote telemonitoring (TM) for the prediction and management of acute exacerbations in COPD patients. We discuss the components of remote monitoring platforms, including the integration of environmental monitoring data; patient reported outcomes collected via interactive Smartphone apps, with data from wearable devices that monitor physical activity, heart rate, etc.; and data from medical devices such as connected non-invasive ventilators. We consider how telemonitoring and the deluge of data it potentially generates could be combined with electronic health records to provide personalized care and multi-disease management for COPD patients.
3: Eckhardt CM, Baccarelli AA, Wu H. Environmental Exposures and Extracellular Vesicles: Indicators of Systemic Effects and Human Disease. Curr Environ Health
Rep. 2022 Apr 21. doi: 10.1007/s40572-022-00357-5. Epub ahead of print. PMID: 35449498.
Purpose of review: Environmental pollutants contribute to the pathogenesis of numerous diseases including chronic cardiovascular, respiratory, and neurodegenerative diseases, among others. Emerging evidence suggests that extracellular vesicles (EVs) may mediate the association of environmental exposures with chronic diseases. The purpose of this review is to describe the impact of common environmental exposures on EVs and their role in linking environmental pollutants to the pathogenesis of chronic systemic diseases.
Recent findings: Common environmental pollutants including particulate matter, tobacco smoke, and chemical pollutants trigger the release of EVs from multiple systems in the body. Existing research has focused primarily on air pollutants, which alter EV production and release in the lungs and systemic circulation. Air pollutants also impact the selective loading of EV cargo including microRNA and proteins, which modify the cellular function in recipient cells. As a result, pollutant-induced EVs often contribute to a pro-inflammatory and pro-thrombotic milieu, which increases the risk of pollutant-related diseases including obstructive lung diseases, cardiovascular disease, neurodegenerative diseases, and lung cancer. Common environmental exposures are associated with multifaceted changes in EVs that lead to functional alterations in recipient cells and contribute to the pathogenesis of chronic systemic diseases. EVs may represent emerging targets for the prevention and treatment of diseases that stem from environmental exposures. However, novel research is required to expand our knowledge of the biological action of EV cargo, elucidate determinants of EV release, and fully understand the impact of environmental pollutants on human health
4: Ghosh AJ, Hobbs BD, Yun JH, Saferali A, Moll M, Xu Z, Chase RP, Morrow J, Ziniti J, Sciurba F, Barwick L, Limper AH, Flaherty K, Criner G, Brown KK, Wise R, Martinez FJ, McGoldrick D, Cho MH, DeMeo DL, Silverman EK, Castaldi PJ; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Hersh CP. Lung tissue shows divergent gene expression between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Respir Res. 2022 Apr 21;23(1):97. doi: 10.1186/s12931-022-02013-w. PMID: 35449067.
Background: Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are characterized by shared exposures and clinical features, but distinct genetic and pathologic features exist. These features have not been well-studied using large-scale gene expression datasets. We hypothesized that there are divergent gene, pathway, and cellular signatures between COPD and IPF.
Methods: We performed RNA-sequencing on lung tissues from individuals with IPF (n = 231) and COPD (n = 377) compared to control (n = 267), defined as individuals with normal spirometry. We grouped the overlapping differential expression gene sets based on direction of expression and examined the resultant sets for genes of interest, pathway enrichment, and cell composition. Using gene set variation analysis, we validated the overlap group gene sets in independent COPD and IPF data sets.
Results: We found 5010 genes differentially expressed between COPD and control, and 11,454 genes differentially expressed between IPF and control (1% false discovery rate). 3846 genes overlapped between IPF and COPD. Several pathways were enriched for genes upregulated in COPD and downregulated in IPF; however, no pathways were enriched for genes downregulated in COPD and upregulated in IPF. There were many myeloid cell genes with increased expression in COPD but decreased in IPF. We found that the genes upregulated in COPD but downregulated in IPF were associated with lower lung function in the independent validation cohorts.
Conclusions: We identified a divergent gene expression signature between COPD and IPF, with increased expression in COPD and decreased in IPF. This signature is associated with worse lung function in both COPD and IPF.
5: Barrett NA, Hart N, Daly KJR, Marotti M, Kostakou E, Carlin C, Lua S, Singh S, Bentley A, Douiri A, Camporota L. A randomised controlled trial of non-invasive ventilation compared with extracorporeal carbon dioxide removal for acute hypercapnic exacerbations of chronic obstructive pulmonary disease. Ann Intensive Care. 2022 Apr 21;12(1):36. doi: 10.1186/s13613-022-01006-8. PMID: 35445986; PMCID: PMC9021560.
Background: Patients presenting with acute hypercapnic respiratory failure due to exacerbations of chronic obstructive pulmonary disease (AECOPD) are typically managed with non-invasive ventilation (NIV). The impact of low-flow extracorporeal carbon dioxide removal (ECCO2R) on outcome in these patients has not been explored in randomised trials.
Methods: Open-label randomised trial comparing NIV (NIV arm) with ECCO2R (ECCO2R arm) in patients with AECOPD at high risk of NIV failure (pH < 7.30 after ≥ 1 h of NIV). The primary endpoint was time to cessation of NIV. Secondary outcomes included device tolerance and complications, changes in arterial blood gases, hospital survival.
Results: Eighteen patients (median age 67.5, IQR (61.5-71) years; median GOLD stage 3 were enrolled (nine in each arm). Time to NIV discontinuation was shorter with ECCO2R (7:00 (6:18-8:30) vs 24:30 (18:15-49:45) h, p = 0.004). Arterial pH was higher with ECCO2R at 4 h post-randomisation (7.35 (7.31-7.37) vs 7.25 (7.21-7.26), p < 0.001). Partial pressure of arterial CO2 (PaCO2) was significantly lower with ECCO2R at 4 h (6.8 (6.2-7.15) vs 8.3 (7.74-9.3) kPa; p = 0.024). Dyspnoea and comfort both rapidly improved with commencement of ECCO2R. There were no severe or life-threatening complications in the study population. There were no episodes of major bleeding or red blood cell transfusion in either group. ICU and hospital length of stay were longer with ECCO2R, and there was no difference in 90-day mortality or functional outcomes at follow-up.
Interpretation: There is evidence of benefit associated with ECCO2R with time to improvement in respiratory acidosis, in respiratory physiology and an immediate improvement in patient comfort and dyspnoea with commencement of ECCO2R. In addition, there was minimal clinically significant adverse events associated with ECCO2R use in patients with AECOPD at risk of failing or not tolerating NIV. However, the ICU and hospital lengths of stay were longer in the ECCO2R for similar outcomes. Trial registration The trial is prospectively registered on ClinicalTrials.gov: NCT02086084. Registered on 13th March 2014, https://clinicaltrials.gov/ct2/show/NCT02086084?cond=ecco2r&draw=2&rank=8.
6: Mk A, Gn N. Cardiac Troponin I in Acute Exacerbation of Chronic Obstructive Pulmonary Disease. J Assoc Physicians India. 2022 Apr;70(4):11-12. PMID: 35443477.
COPD is one of the leading causes of death worldwide and is very commonly associated with cardiovascular disorders and comorbidities. This study was carried out to assess the prognostic significance of cardiac troponin I when measured during an acute exacerbation of COPD.
Material: This is a cross-sectional study conducted for a period of 18 months among a total of 50 study subjects who presented with an acute exacerbation of COPD to the Medicine/Emergency Medicine/Pulmonary Medicine inpatient department after consideration of the inclusion and exclusion criteria. All the study subjects were tested for cardiac troponin I at admission and 24hrs later. Levels above 0.05 were considered positive. A detailed history, examination and relevant investigations were performed. All the categorical variables were expressed in proportions and continuous variables were expressed in means and standard deviation or medians and interquantile ranges. Chi square test was done to analyze the categorical variables. A p value of <0.05 was considered statistically significant.
Observation: Among the 50 patients, 20 were females and 30 were males. cTnI was positive in 40% of patients. Patients with cTnI positive were included in group 1 and those with a negative cTnI were considered to be in group 2. Prevalence of comorbidities, the need for ICU admission and ventilatory support and in hospital mortality was higher in group 1 when compared to group 2.
Conclusion: Cardiac Troponin I is a strong and independent predictor of in hospital mortality in patients admitted with acute exacerbation of COPD. Patients with elevated Troponin I had longer duration of COPD and a higher incidence of IHD. Cardiac Troponin I elevation was associated with a greater need for ICU admission and ventilatory support.
7: Zhou J, Li X, Wang X, Yu N, Wang W. Accuracy of portable spirometers in the diagnosis of chronic obstructive pulmonary disease A meta-analysis. NPJ Prim Care Respir Med. 2022 Apr 19;32(1):15. doi: 10.1038/s41533-022-00275-x. PMID: 35440665.
Portable spirometers has been approved for diagnosing chronic obstructive pulmonary disease (COPD). However, their diagnostic accuracy has not been reviewed. Therefore, the purpose of this study was to systematically evaluate the diagnostic value of portable spirometers in detecting COPD. A comprehensive literature search for relevant studies was conducted in PubMed, Embase, CNKI, Wan Fang, and Web of Science databases. Pooled sensitivity, specificity, summary receiver operating characteristic (SROC), area under the curve (AUC), and other related indices were calculated using the bivariate mixed-effect model. Subgroup analysis was performed to explore the source of heterogeneity. Thirty one studies were included in the meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic ratio (DOR), SROC, and AUC of the SROC of portable spirometers were 0.85 (0.81-0.88), 0.85 (0.81-0.88), 5.6 (4.4-7.3), 0.18 (0.15-0.22), 31 (21-46) and 0.91 (0.89-0.94), respectively. Among the three commonly used types of portable spirometers, the accuracy of PIKO-6 was higher (0.95) than that of COPD-6 (0.91) and PEF (0.82). Subgroup analysis indicated that the accuracy of a multi-indices portable spirometer was higher than that of a single-index one (P < 0.05). In addition, portable spirometry performed by professional technicians in tertiary hospitals was more accurate than for those conducted by trained technicians in primary care facilities and communities (P < 0.05). Moreover, the accuracy of studies conducted in developing country was superior to developed country (P < 0.05). Portable spirometers have high accuracy in the diagnosis of COPD. Multi-index COPD-6 and PIKO-6 displayed higher accuracy than others. Standardized training of instrument operators should be considered to achieve reliable results.
8: Çolak Y, Nordestgaard BG, Lange P, Vestbo J, Afzal S. Prognosis of Patients with COPD Not Eligible for Major Clinical Trials. Am J Respir Crit Care Med. 2022 Apr 19. doi: 10.1164/rccm.202110-2441OC. Epub ahead of print. PMID:35438616.
Rationale: Randomised controlled trials only include a subset of patients with chronic obstructive pulmonary disease(COPD) fulfilling strict inclusion criteria. Thus, most patients with COPD in a real-world setting do not have the necessary evidence to support treatment effectiveness.
Objective: To test the hypotheses that most individuals with COPD in the general population are not represented in major clinical trials despite clinically significant disease with exacerbations and early death.
Methods: In 105,630 adults from a Danish contemporary population-based cohort, we defined COPD as age≥40 years, chronic respiratory symptoms, history of smoking exposure, and airflow limitation with forced expiratory volume in 1 second(FEV1)/forced vital capacity(FVC)<0.70. Outcomes included acute exacerbations and all-cause mortality. Symptomatic smokers without COPD were used as a reference group.
Measurements and main results: Of all, 7,516(7%) and 16,079(15%) were symptomatic smokers with and without COPD. Only 44% of those with COPD were eligible for major clinical trials when applying FEV1<80% predicted, smoking history≥10 pack-years, and no comorbid asthma as common inclusion criteria. During median 8.9 years follow-up, we observed 2,130 acute exacerbations and 3,973 deaths in symptomatic smokers. Compared to symptomatic smokers without COPD, multivariable adjusted hazard ratios(HRs) for exacerbations were 7.45(95% confidence interval:5.41-10.3) and 29.0(21.1-39.8) in those with COPD respectively excluded and eligible for clinical trials. Corresponding HRs for all-cause mortality were 1.21(1.11-1.31) and 1.67(1.54-1.81), respectively.
Conclusion: More than half of individuals with COPD in the general population are excluded from major clinical trials; however, these individuals have clinically significant disease with exacerbations and early death compared to symptomatic smokers without COPD.
9: Huang JT, Cant E, Keir HR, Barton AK, Kuzmanova E, Shuttleworth M, Pollock J, Finch S, Polverino E, Bottier M, Dicker AJ, Shoemark A, Chalmers JD. Endotyping COPD, Bronchiectasis and the ‘COPD-bronchiectasis Association’. Am J Respir Crit Care Med. 2022 Apr 18. doi: 10.1164/rccm.202108-1943OC. Epub ahead of print. PMID: 35436182.
Rationale Bronchiectasis and chronic obstructive pulmonary disease (COPD) are two disease entities with overlapped clinical features and co-diagnosis frequently occurs (termed as the ‘COPD-bronchiectasis association’). Objectives To investigate the sputum microbiome and proteome in patients with bronchiectasis, COPD, and the ‘COPD-bronchiectasis association’ with the aim of identifying endotypes that may inform treatment. Methods Sputum microbiome and protein profiling were carried out using 16S rRNA amplicon sequencing and a label-free proteomics workflow, respectively, in a cohort comprising patients with COPD (n=43), bronchiectasis (n=30) and the ‘COPD-bronchiectasis association’ (n=48). Results were validated in an independent cohort of 91 patients (n=28-31 each group) using targeted measurements of inflammatory markers, mucins and bacterial culture. Measurements and main results Principal component analysis of sputum microbiome and protein profiles showed a partial separation between the COPD and the ‘COPD-bronchiectasis association’ group. Further analyses revealed that patients with the ‘COPD-bronchiectasis association’ had a higher abundance of proteobacteria, higher expression of mucin-5AC and proteins from the “neutrophil degranulation” pathway compared to those with COPD. In contrast, COPD patients had an elevated expression of mucin-5B and several peptidase inhibitors, higher abundance of common commensal taxa, and a greater microbiome diversity. The profiles of ‘COPD-bronchiectasis association’ and bronchiectasis groups were largely overlapping. Five endotypes were proposed with differential inflammatory, mucin and microbiological features. The key features related to the ‘COPD-bronchiectasis association’ were validated in an independent cohort. Conclusion Neutrophilic inflammation, differential mucin expression and Gram-negative infection are dominant traits in patients with the ‘COPD-bronchiectasis association’.
10: Hirano T, Matsunaga K. Measurement of Blood Eosinophils in Asthma and Chronic Obstructive Pulmonary Disease. Intern Med. 2022 Apr 16. doi: 10.2169/internalmedicine.9339-22. Epub ahead of print. PMID: 35431305.
Eosinophils are important effector cells in airway inflammation, as pleiotropy and heterogeneity can be linked to various pathophysiologies in asthma and chronic obstructive pulmonary disease (COPD). Sputum eosinophils can reflect the heterogeneity of airway inflammation, and owing to their traits, blood eosinophils can be a surrogate and potential biomarker for managing both conditions. Blood eosinophils are activated via the stimulation of type 2 cytokines, such as interleukin (IL)-5, IL-4/13, granulocyte-macrophage colony-stimulating factor, IL-33, and thymic stromal lymphopoietin. There is sufficient evidence to support the relationship between the blood eosinophil count and clinical outcomes, including pulmonary function decline, exacerbations, all-cause mortality, and treatment response to inhaled corticosteroids and biologics. Thus, there is growing interest in the use of blood eosinophils for the management of these diseases. Compiling recent evidence, we herein review the significance of measuring blood eosinophils in asthma and COPD.
11: Mannino D, Bogart M, Wu B, Germain G, Laliberté F, MacKnight SD, Jung Y, Stiegler M, Duh MS. Adherence and persistence to once-daily single-inhaler versus multiple-inhaler triple therapy among patients with chronic obstructive pulmonary disease in the USA: A real-world study. Respir Med. 2022 Mar 18;197:106807. doi: 10.1016/j.rmed.2022.106807. Epub ahead of print. PMID: 35429764.
Background: Triple therapy comprising an inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2 agonist (ICS/LAMA/LABA) is recommended for chronic obstructive pulmonary disease (COPD) patients at risk of exacerbation. Multiple-inhaler triple therapy (MITT) is associated with poor adherence and persistence; however, these outcomes have not been evaluated for single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI).
Methods: This retrospective analysis of the IQVIA PharMetrics Plus claims database identified patients with COPD initiating triple therapy between 18 September 2017 and 30 June 2019. The first date of single-inhaler FF/UMEC/VI dispensing, or first day of overlapping ICS, LAMA, and LABA medications for MITT users, defined the index date. Patients were ≥40 years, had ≥12 months of continuous insurance coverage pre-index (baseline) and ≥6 months’ coverage post-index; those with MITT during baseline were excluded. Inverse probability weighting was used to balance baseline characteristics. Adherence was assessed using proportion of days covered (PDC) and was evaluated using linear and log-binomial models. Persistence (non-persistence identified as >30-day gap between fills) was evaluated using Cox models.
Results: 9942 patients (FF/UMEC/VI: 2782; MITT: 7160) were included. Adherence was significantly higher for FF/UMEC/VI versus MITT users (mean PDC, 0.66 vs. 0.48; p < 0.001), and FF/UMEC/VI users were twice as likely to be adherent (PDC ≥0.8) than MITT users (46.5% vs. 22.3%; risk ratio [95% CI]: 2.08 [1.85-2.30]; p < 0.001). After 12 months, significantly more FF/UMEC/VI users persisted on therapy than MITT users (35.7% vs. 13.9%; hazard ratio [95% CI]: 1.91 [1.81-2.01]; p < 0.001).
Conclusions: COPD patients initiating single-inhaler FF/UMEC/VI had significantly improved adherence and persistence compared with MITT.
Contoli M, Santus P, Menzella F, Rocchi C, Radovanovic D, Baraldi F, Martelli C, Casanova S, Barbetta C, Micheletto C, Scichilone N, Beghè B, Carpagnano E, Papi A. Effects of anti-IL5 biological treatments on blood IgE levels in severe asthmatic patients: A real-life multicentre study (BIONIGE). Clin Transl Allergy. 2022 Apr 7;12(4):e12143. doi: 10.1002/clt2.12143. PMID: 35423001; PMCID: PMC8988861.
Background: Mepolizumab and benralizumab are clinically effective biological treatments for severe eosinophilic asthmatic patients by hampering eosinophilic inflammation. The effects of these compound on the immunoglobulin (Ig)E T2 component are virtually unknown.
Objectives: To evaluate the change in total IgE levels at 4 ± 2 months after initiation of the mepolizumab (primary outcome) or benralizumab. When available, the changes of blood inflammatory cell counts, lung function and asthma control test (ACT) were also assessed and correlated with changes in total IgE levels.
Methods: Observational, retrospective, multicentre, cohort study. Severe eosinophilic atopic asthmatic patients treated with mepolizumab or benralizumab were included in the analysis.
Results: Three-month treatment (on average) with mepolizumab (n = 104) or benralizumab (n = 82) resulted in significantly higher reduction of blood eosinophil and basophil levels in patients treated with benralizumab compared to mepolizumab. Mepolizumab did not significantly modified the levels of blood total IgE during the study period, whereas benralizumab significantly reduced (-35%, p < 0.001) total blood IgE levels. In patients treated with benralizumab the reduction of blood total Ig-E levels correlated with the reduction of blood basophils (but not eosinophils) and weakly with the improvement of asthma control.
Conclusion: Benralizumab but not mepolizumab, treatment led to a significant reduction of circulating IgE level. The study provides different and specific mechanisms of action for anti-IL5-pathway treatments.
1: Buchheit KM, Sohail A, Hacker J, Maurer R, Gakpo D, Bensko JC, Taliaferro F, Ordovas-Montanes J, Laidlaw TM. Rapid and sustained effect of dupilumab on clinical and mechanistic outcomes in aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2022 Apr 20:S0091-6749(22)00542-5. doi: 10.1016/j.jaci.2022.04.007. Epub ahead of print. PMID: 35460728.
Background: Dupilumab, a monoclonal antibody targeting IL-4Rα, improves upper and lower airway symptoms in patients with aspirin-exacerbated respiratory disease (AERD), but the mechanisms leading to clinical improvement are not fully elucidated.
Objective: To identify the mechanistic basis of clinical improvement in AERD patients treated with dupilumab.
Methods: Twenty-two patients with AERD were treated with dupilumab for 3 months for severe asthma and/or chronic rhinosinusitis with nasal polyps. Clinical outcomes were assessed at baseline and at one and three months after initiation of dupilumab. Nasal fluid, urine, blood, and inferior turbinate scrapings were collected at the three time points for mediator levels, cellular assays, and RNA-sequencing.
Results: Participants had rapid improvement in clinical measures including sense of smell, sinonasal symptoms, and lung function after 1 month of dupilumab, which were sustained after 3 months of dupilumab. Baseline severity of smell loss correlated with lower nasal prostaglandin E2 levels. Dupilumab increased nasal prostaglandin E2 and decreased levels of nasal albumin, nasal and urinary leukotriene E4, and serum and nasal IgE. Transcripts related to epithelial dysfunction and leukocyte activation and migration were downregulated in inferior turbinate tissue after treatment with dupilumab. There were no dupilumab-induced changes in nasal eosinophilia.
Conclusion: Inhibition of IL-4Rα in AERD led to rapid improvement in respiratory symptoms and smell, with a concomitant improvement in epithelial barrier function, a decrease in inflammatory eicosanoid levels, and an increase in the anti-inflammatory eicosanoid prostaglandin E2. The therapeutic effects of dupilumab are likely due to decreased IL-4Rα signaling on respiratory tissue granulocytes, epithelial cells, and B cells.
2: Ravi A, Chowdhury S, Dijkhuis A, Dierdorp BS, Dekker T, Kruize R, Sabogal Piñeros YS, Majoor CJ, Sterk PJ, Lutter R. Imprinting of bronchial epithelial cells upon <i>in vivo</i> rhinovirus infection in people with asthma. ERJ Open Res. 2022 Apr 19;8(2):00522-2021. doi: 10.1183/23120541.00522-2021. PMID: 35449758; PMCID: PMC9016171.
Background: Defective translocation of the translational repressor TIAR (T-cell internal antigen receptor) in bronchial epithelial cells (BECs) from asthma patients underlies epithelial hyperresponsiveness, reflected by an exaggerated production of a select panel of inflammatory cytokines such as CXCL-8, interleukin (IL)-6, granulocyte colony-stimulating factor, CXCL-10, upon exposure to tumour necrosis factor (TNF) and IL-17A. With this study we aimed to clarify whether epithelial hyperresponsiveness is a consistent finding, is changed upon in vivo exposure to rhinovirus (RV)-A16 and applies to the bronchoconstrictor endothelin-1.
Methods: BECs were obtained from asthma patients (n=18) and healthy individuals (n=11), 1 day before and 6 days post-RV-A16 exposure. BECs were cultured and stimulated with TNF and IL-17A and inflammatory mediators were analysed. The bronchoalveolar lavage fluid (BALF) was obtained in parallel with BECs to correlate differential cell counts and inflammatory mediators with epithelial hyperresponsiveness.
Results: Epithelial hyperresponsiveness was confirmed in sequential samples and even increased in BECs from asthma patients after RV-A16 exposure, but not in BECs from healthy individuals. Endothelin-1 tended to increase in BECs from asthma patients collected after RV-A16 exposure, but not in BECs from healthy individuals. In vitro CXCL-8 and endothelin-1 production correlated. In vivo relevance for in vitro CXCL-8 and endothelin-1 production was shown by correlations with forced expiratory volume in 1 s % predicted and CXCL-8 BALF levels.
Conclusion: Epithelial hyperresponsiveness is an intrinsic defect in BECs from asthma patients, which increases upon viral exposure, but not in BECs from healthy individuals. This epithelial hyperresponsiveness also applies to the bronchoconstrictor endothelin-1, which could be involved in airway obstruction.
3: Sicras-Mainar A, Gómez Rodríguez B, Traseira-Lugilde S, Fernández-Sánchez T, Velasco Garrido JL. Treatment persistence and exacerbations in patients with asthma initiating treatment with inhaled corticosteroids and beta-adrenergic agonists: retrospective cohort study. BMJ Open. 2022 Apr 20;12(4):e053964. doi: 10.1136/bmjopen-2021-053964. PMID: 35443946.
Objective: To determine treatment persistence and exacerbations in patients initiating inhaler treatment with fixed-dose combinations of inhaled corticosteroids/long-acting beta-2-adrenergic agonists (ICS/LABA) for the treatment of asthma.
Design: Retrospective observational study conducted by review of electronic medical records (database: Fundación RediSS).
Setting: Retrospective cohort study. The follow-up period was 1 year.
Participants: The study included patients aged ≥18 years who started treatment with ICS/LABA and met the inclusion/exclusion criteria.
Main outcomes and measures: The study groups were fluticasone propionate/salmeterol (FP/SAL), beclomethasone/formoterol (BDP/FORM), budesonide/formoterol (BUD/FORM), fluticasone furoate/vilanterol (FF/VI) and fluticasone propionate/formoterol (FP/FORM). The main measurements were persistence, medication possession ratio (MPR) and exacerbations. Statistical significance was established as p<0.05.
Results: In total, 3203 patients were recruited for the study. By groups, 31.1% FP/SAL, 28.6% BDP/FORM, 25.0% BUD/FORM, 8.2% FF/VI and 7.0% FP/FORM. The mean age was 52.2 years, 60.8% were female and 44.9% had persistent-moderate asthma. Treatment persistence was 61.7% (95% CI 60.0% to 63.4%) and by study group it was FP/SAL: 60.7%, BDP/FORM: 61.2%, BUD/FORM: 60.3%, FF/VI: 66.7% and FP/FORM: 67.6% (p=0.046). MPR by study group was FP/SAL: 74.3%, BDP/FORM: 73.8%, BUD/FORM: 74.6%, FF/VI: 79.4% and FP/FORM: 80.6% (p=0.028). The mortality rate was 2.9%. By treatment group, exacerbations were FP/SAL: 21.9% (95% CI 19.3% to 24.5%), BDP/FORM: 22.2% (95% CI 19.5% to 24.9%), BUD/FORM: 22.8% (95% CI 19.9% to 25.7%), FF/VI: 17.9% (95% CI 14.9% to 20.7%) and FP/FORM: 16.0% (95% CI 12.2% to 19.3%), p=0.036.
Conclusions: Patients undergoing treatment with FP/FORM and FF/VI versus FP/SAL, BDP/FORM and BUD/FORM were associated with greater treatment adherence (persistence, MPR) and lower rates of exacerbations. However, further studies will be needed to strengthen the consistency of the results.
4: van der Burg N, Stenberg H, Ekstedt S, Diamant Z, Bornesund D, Ankerst J, Georén SK, Cardell LO, Bjermer L, Erjefält J, Tufvesson E. Neutrophil phenotypes in bronchial airways differentiate single from dual responding allergic asthmatics. Clin Exp Allergy. 2022 Apr 19. doi: 10.1111/cea.14149. Epub ahead of print. PMID: 35437872.
Introduction: Allergic asthmatics with both an early (EAR) and a late allergic reaction (LAR) following allergen exposure are termed ‘dual responders’ (DR), while ‘single responders’ (SR) only have an EAR. Mechanisms that differentiate DR from SR are largely unknown, particularly regarding the role and phenotypes of neutrophils. Therefore, we aimed to study neutrophilsin DR and SR asthmatics.
Methods: Thirty-four allergic asthmatics underwent an inhaled allergen challenge, samples were collected before and up to 24 h post-challenge. Cell differentials were counted from bronchial lavage, alveolar lavage and blood; and tissue neutrophils were quantified in immune-stained bronchial biopsies. Lavage neutrophil nuclei lobe segmentation was used to classify active (1-4 lobes) from suppressive neutrophils (≥5 lobes). Levels of transmigration markers: soluble (s)CD62L and interleukin-1Ra, and activity markers: neutrophil elastase (NE), DNA-histone complex and dsDNA were measured in lavage fluid and plasma.
Results: Compared to SR at baseline, DR had more neutrophils in their bronchial airways at baseline, both in the lavage (p=0.0031) and biopsies (p=0.026) and elevated bronchial neutrophils correlated with less anti-transmigratory IL-1Ra levels (r=-0.64). DR airways had less suppressive neutrophils and more 3-lobed (active) neutrophils (p=0.029) that correlated with more bronchial lavage histone (p=0.020) and more plasma NE (p=0.0016). Post-challenge, DR released neutrophil extracellular trap factors in the blood earlier and had less pro-transmigratory sCD62L during the late phase (p=0.0076) than SR.
Conclusion: DR have a more active airway neutrophil phenotype at baseline and a distinct neutrophil response to allergen challenge that may contribute to the development of an LAR. Therefore, neutrophil activity should be considered during targeted diagnosis and bio-therapeutic development for DR.
5: Chung HL. Diagnosis and management of asthma in infants and preschoolers.
Clin Exp Pediatr. 2022 Apr 19. doi: 10.3345/cep.2021.01746. Epub ahead of print.
Asthma is one of the most common chronic disease affecting children, and it often starts in infancy and preschool years. In previous birth cohorts, frequent wheezing in early life was associated with the development of asthma in later childhood and reduced lung function persisting into adulthood. Preschool wheezing is considered an umbrella term for distinctive diseases with different clinical features (phenotypes), each of which may be related to different underlying pathophysiologic mechanisms (endotypes). The classification of phenotypes of early wheezing is needed to identify children at high risk for developing asthma later who might benefit from early intervention. However, diagnosis of asthma in infants and preschoolers is particularly difficult because objective lung function tests cannot be performed and definitive biomarkers are lacking. Moreover, management of early asthma is challenging because of its different phenotypic presentations. Many prediction models and asthma guidelines have been developed that provide useful information for physicians to assess young children with recurrent wheezing and present helpful approaches to manage them appropriately. Many recent studies have investigated the application of personalized medicine for early asthma by identifying specific phenotypes and biomarkers. Further researches, including genetic and molecular studies, are needed to establish a clear definition of asthma and develop more targeted therapeutic approaches in this age group
6: Extremera Ortega AM, Moreno Lozano L, González Jiménez OM, Borja Segade J, Joyanes Romo JB, Muñoz Rodríguez JR, Feo-Brito F, Galindo Bonilla PA. Findings in Chest High-Resolution Computed Tomography in Severe Asthma. J Investig Allergol Clin Immunol. 2022 Apr 19;32(2):146-147. doi: 10.18176/jiaci.0725. Epub 2021 Jul 2. PMID: 34213422.
7: Bobolea I, Bañas D, Melero C, de Andrés AI, Joksaite S, Sánchez-Herrero G.
Exacerbation Rate Reduction With Mepolizumab Stratified by Maintenance Oral Corticosteroids Use and Eosinophil Levels: A Post Hoc Analysis of the DREAM and MENSA Studies. J Investig Allergol Clin Immunol. 2022 Apr 19;32(2):148-150. doi: 10.18176/jiaci.0714. Epub 2021 Jun 4. PMID: 34085935
Background: Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds.
Methods: We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab (
Dream: 75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per μL, ≥300 cells per μL, ≥400 cells per μL, and ≥500 cells per μL) and baseline blood eosinophil ranges (<150 cells per μL, ≥150 cells per μL to <300 cells per μL, ≥300 cells per μL to <500 cells per μL, and ≥500 cells per μL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis.
Findings: Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL, predicted efficacy of mepolizumab was reduced.
Interpretation: Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab.
1: Soyyiğit S, Aydın Ö, Seçil D, Doğan C, Gökmen D, Sin BA, Mısırlıgil Z, Mungan
VD. Pre-seasonal immunotherapy is effective in both monosensitized and polysensitized patients with allergic rhinitis. Eur Ann Allergy Clin Immunol.
2022 Apr 22. doi: 10.23822/EurAnnACI.1764-1489.252. Epub ahead of print. PMID: 35448936.
Background. The effectiveness of pre-seasonal allergoid immunotherapy in polysensitized patients are not well-known. The aim of the present study was to compare the clinical efficacy and immunological changes of pre-seasonal allergoid immunotherapy in mono- and polysensitized patients with grass pollen allergy. Methods. Fourty six patients with seasonal allergic rhinitis undergoing pre-seasonal grass pollen immunotherapy and 28 cases followed by conventional drug treatment were included. These groups were divided into monosensitized and polysensitized ones. All patients were followed between March-September with symptom-medication scores, and visual analogue scale (VAS). The quality of life was assessed using the Mini-RQLQ questionnaire. Phleum pratense (Phl p) specific IgE and IgG4 (UNI-CAP 100, Phadia) measurements were performed before and after 7 weeks of immunotherapy. Results. In the immunotherapy group, 15th weekly symptom-medication scores and VAS scores between May and August were found to be significantly lower than those in the control group (p less than 0.05). Phl p specific IgE and IgG4 levels were significantly higher after immunotherapy compared to those before immunotherapy (p = 0.001). Furthermore, P