Identification of autoantigens and their potential post-translational modification in EGPA and severe eosinophilic asthma.

Background: The chronic airway inflammation in severe eosinophilic asthma (SEA) suggests potential autoimmune aetiology with unidentified autoantibodies analogous to myeloperoxidase (MPO) in ANCA-positive EGPA (eosinophilic granulomatosis with polyangiitis). Previous research has shown that oxidative post-translational modification (oxPTM) of proteins is an important mechanism by which autoantibody responses may escape immune tolerance. Autoantibodies to oxPTM autoantigens in SEA have not previously been studied. Methods: Patients with EGPA and SEA were recruited as well as healthy control participants. Autoantigen agnostic approach: Participant serum was incubated with slides of unstimulated and PMA-stimulated neutrophils and eosinophils, and autoantibodies to granulocytes were identified by immunofluorescence with anti-human IgG FITC antibody. Target autoantigen approach: Candidate proteins were identified from previous literature and FANTOM5 gene set analysis for eosinophil expressed proteins. Serum IgG autoantibodies to these proteins, in native and oxPTM form, were detected by indirect ELISA. Results: Immunofluorescence studies showed that serum from patients with known ANCA stained for IgG against neutrophils as expected. In addition, serum from 9 of 17 tested SEA patients stained for IgG to PMA-stimulated neutrophils undergoing NETosis. Immunofluorescent staining of eosinophil slides was evident with serum from all participants (healthy and with eosinophilic disease) with diffuse cytoplasmic staining except for one SEA individual in whom subtle nuclear staining was evident. FANTOM5 gene set analysis identified TREM1 (triggering receptor expressed on myeloid cells 1) and IL-1 receptor 2 (IL1R2) as eosinophil-specific targets to test for autoantibody responses in addition to MPO, eosinophil peroxidase (EPX), and Collagen-V identified from previous literature. Indirect ELISAs found high concentrations of serum autoantibodies to Collagen-V, MPO, and TREM1 in a higher proportion of SEA patients than healthy controls. High concentrations of serum autoantibodies to EPX were evident in serum from both healthy and SEA participants. The proportion of patients with positive autoantibody ELISAs was not increased when examining oxPTM compared to native proteins. Discussion: Although none of the target proteins studied showed high sensitivity for SEA, the high proportion of patients positive for at least one serum autoantibody shows the potential of more research on autoantibody serology to improve diagnostic testing for severe asthma. Clinical trial registration: ClinicalTrials.gov, identifier, NCT04671446.

Eosinopenia as a Prognostic Biomarker for Noninvasive Ventilation Use in COPD Exacerbations.

BACKGROUND: In recent years, blood eosinophils have been evaluated as a surrogate biomarker for eosinophilic airway inflammation and as a prognostic indicator of the outcomes of hospitalized COPD subjects. During an exacerbation of COPD, eosinopenia has been proposed as a prognostic marker of adverse outcomes. OBJECTIVES: The aim of the present post hoc analysis was to elucidate the effectiveness of blood eosinophils for predicting the need of NIV in subjects with COPD exacerbation. METHODS: Consecutive subjects admitted to a hospital for COPD exacerbation were included in the analysis. The eosinophil count from the first complete blood count was used to designate the eosinophil groups. The relationship between the clinical characteristics and blood eosinophil counts, as dichotomized using 150 cells/µL, was evaluated. Results Subjects with blood eosinophil number < 150 k/µL had a more severe disease on admission compared to subjects with ≥150 k/µL, regarding pH 7.400 (7.36, 7.44) vs. 7.42 (7.38, 7.45), p = 0.008, PO2/FiO2 levels 238.1 (189.8, 278.6) vs. 276.2 (238.2, 305.6), p < 0.001, CRP (mg/L) levels 7.3 (3.1, 19.9) vs. 3.5 (0.7, 7.8), p < 0.001 and required a longer hospital stay (days) 10.0 (8.0, 14.0) vs. 5.0 (3.0, 7.0) p < 0.001 respectively. The number of blood eosinophils correlated with the levels of CRP upon admission (p < 0.001, r = -0.334), with arterial pH upon admission (p < 0.030, r = 0.121), with PO2/FiO2 (p < 0.001, r = -0.248), and with duration of hospital stay (p < 0.001, r = -0.589). In the multinomial logistic regression analysis, blood eosinophil count < 150 k/µL was an independent predictor of the use of NIV during hospital stay. CONCLUSION: During COPD exacerbation, low blood eosinophil levels upon admission are related to more severe disease and can be used as a predictor of the need of NIV. Further prospective studies are needed to identify the use of blood eosinophil levels as a predictor of unfavorable outcomes.

Glycated Hemoglobin (HbA1c) as a Predictor of Outcomes during Acute Exacerbations of Chronic Obstructive Pulmonary Disease.

Systemic inflammation may be the common denominator between COPD and type 2 diabetes and may explain the correlation in both diseases' development and progress. The aim of this prospective observational study is to examine the prognostic value of glycated hemoglobin levels (HbA1c) and HbA1c-adjusted glycemic variables (glycemic gap, stress hyperglycemia ratio και modified stress hyperglycemia ratio) in an acute exacerbation of COPD (AECOPD) as well as in COPD disease's morbidity and mortality during the following year. We evaluated patients hospitalized only for COPD exacerbations. Levels of HbA1c and HbA1c-adjusted glycemic variables were recorded upon admission. The study outcomes included duration of hospital stay, need for mechanical ventilation and exacerbation outcome. All subjects were followed up for one year. A total of 156 patients were included in the study (74.4% men, age [mean ± SD] 72 ± 7 years). Patients (21.8%) had type 2 diabetes and 67.9% of patients were receiving ICS treatment. The median value of HbA1c was 5.9 (IQR: 5.4, 6.5). Necessity for mechanical ventilation was significantly higher for patients with lower values of HbA1c [median: 5.3 (IQR 5.02, 6.3) vs. 5.9 (IQR 5.5, 6.5), p = .038]. However, duration of hospitalization, death during hospitalization as well as the number of new exacerbation events, time to next exacerbation and mortality during the following year did not differ significantly. Moreover, none of the HbA1c-adjusted glycemic variables examined, demonstrated any statistical significance. In conclusion neither the preceding nor the present glycemic state exhibit a predictive value regarding short- or long-term outcomes of an AECOPD.

Device use errors among patients with asthma and COPD and the role of training: a real-life study.

Background and objectives: Administration of inhaled medication for asthma and COPD is often difficult and incorrect device use is associated with unfavorable outcomes. We aimed to evaluate device use errors in asthma and COPD patients and to associate incorrect use with the patient's characteristics and medical history.Methods: Demographics and medical history were recorded. The use of each prescribed device was evaluated according to predefined steps.Results: 607 patients (49.9% male, median age (IQR) 63 (51, 70) years performed 663 demonstrations (56 patients were using 2 different types of devices). 51.4% were treated for asthma and 48.6% for COPD. 79.6% of demonstrations were performed using DPIs. Errors were documented on 41.2% of demonstrations and were associated with the type of device, p < 0.001. Elderly patients were less frequently using their devices correctly compared to younger patients, 50.8% vs 62.2%, respectively, p = 0.007. Correct demonstrations were more among asthmatics compared to COPD patients 63.1% vs 54.5%, p = 0.024. Incorrect use was associated with more acute exacerbations in the preceding year [median(IQR), 1(0, 2) vs 1(0, 1)], for incorrect and correct use, respectively, p < 0.001. Upon demonstration, 15.5% of patients have never been trained (i.e., undergone actual demonstrations and observation while using their device) by anyone. Errors occurred more frequently among patients who reported not to be trained compared to those who were trained, 67.0% vs 14.6%, respectively, p < 0.001. The commonest error was associated with the inspiration maneuver and accounted for the 48.3% of errors in the DPIs and 53.0% of errors in the MDIs.Conclusion: Device use errors are common and associated with unfavorable outcomes. Trained patients were more likely to use the device correctly.

Blood eosinophils as predictor of outcomes in patients hospitalized for COPD exacerbations: a prospective observational study.

PURPOSE: In the present prospective multicentre observational study, we evaluated the potential role of blood eosinophils on the outcomes of patients hospitalized for COPD exacerbations. MATERIAL AND METHODS: Consecutive patients >40 years with a previous COPD diagnosis were recruited. Blood eosinophils were measured on admission prior to the initiation of treatment and were evaluated in three groups (<50, 50-149 and ≥150 cells/µL). Patients received standard care and were followed up for a year. RESULTS: A total of 388 patients were included (83.5% male, mean age 72 years). Patients with higher blood eosinophils had less dyspnoea (Borg scale), lower C-reactive protein (CRP) and higher PaO2/FiO2 (partial pressure for oxygen/fraction of inhaled oxygen), and were discharged earlier (median 11 vs. 9 vs. 5 days for patients with <50, 50-149 and ≥150 cells/µL, respectively). Patients with <50 cells/µL presented higher 30-day and 1-year mortality, whereas there were no differences in moderate/severe COPD exacerbations between the three groups. In a post hoc analysis, treatment with inhaled corticosteroids as per physicians' decision was associated with better exacerbation prevention during follow-up in patients with ≥150 cells/µL. CONCLUSIONS: Higher blood eosinophils were associated with better outcomes in hospitalized COPD patients, further supporting their use as a prognostic biomarker.

Ability of using different dry powder inhalers during COPD exacerbations.

BACKGROUND: Guidelines suggest that patients hospitalized for acute COPD exacerbations (AECOPD) are treated with short acting bronchodilators. Long acting bronchodilators, offer longer symptom relief but since they are usually administered via Dry Powder Inhalers (DPIs) it is considered that during AECOPD patients would not be able to achieve appropriate inspiratory flow (IF) to receive appropriate drug doses. The aim of the present study was to evaluate whether patients admitted to the hospital for AECOPD, are able to achieve the necessary IF using different DPIs. METHODS: IF was measured daily in patients admitted for AECOPD with a portable IF meter (In-Check Oral inhaler assessment kit), containing a series of adapters that simulate the resistance of 4 DPIs [Turbuhaler (T), Breezhaler/Aerolizer (B/F), Discus (A/A/D) and Handinhaler (HH)]. Dyspnea, spirometry and arterial blood gases were also recorded daily. RESULTS: 44 consecutive patients were included in the study. The majority of patients were able to achieve an IF over 30 L/min with all four device resistances. This minimum required IF was achieved in 90.9%, 100%, 95.5% and 81.8% of patients on admission and in 100%, 100%, 97.7%, and 95.5% of patients on discharge for T, B/F, A/A/D and HH respectively. No functional characteristic was able to predict the achievement of this minimum necessary IF. CONCLUSION: Most patients hospitalized for AECOPD, are able to receive treatment with long acting bronchodilators administered via DPIs. The possible beneficial effects of such an intervention should be tested in further studies.