Asthma remission one, none and one-hundred thousand: the relevance of the patient's view.

OBJECTIVE: Achieving remission in severe asthma holds paramount importance in elevating patient quality of life and reducing both individual and societal burdens associated with this chronic condition. This study centers on identifying pivotal patient-relevant endpoints through standardized, reproducible methods, while also developing a patient-centric definition of remission, essential for effective disease management. METHODS: A discrete choice experiment (DCE) was conducted to assess patients' perceptions on the four primary criteria for defining severe asthma remission, as outlined by the SANI survey. Additionally, it investigated the correlation between these perceptions and improvements in the doctor-patient therapeutic alliance during treatment decision-making. RESULTS: 249 patients (70% aged between 31-60, 59% women and 82% without other pathologies requiring corticosteroids) prioritize the use of oral corticosteroids (OCS, 48%) and the Asthma Control Test (ACT, 27%) in defining their condition, ranking these above lung function and exacerbations. This preference for OCS stems from its direct role in treatment, tangible tracking, immediate symptom relief, and being a concrete measure of disease severity compared to the less predictable and quantifiable exacerbations. CONCLUSIONS: This study explores severe asthma remission from patients' perspectives using clinician-evaluated parameters. The DCE revealed that most patients highly value OCS and the ACT, prefer moderate improvement, and avoid cortisone cycles. No definitive preference was found for lung function status. Integrating patient-reported information with professional insights is crucial for effective management and future research. Personalized treatment plans focusing on patient preferences, adherence, and alternative therapies aim to achieve remission and enhance quality of life.

Future Perspectives of Revaluating Mild COPD.

In 2020, COPD was the third leading cause of death worldwide. Lung function is central for the diagnosis of this disease, and COPD severity is still partially classified based on airflow obstruction, which can range from "mild" (GOLD 1 group, FEV1 ≥80% predicted) to "very severe" (GOLD 4, FEV1 <30% predicted). However, the term "mild COPD" needs to be carefully analyzed. Several studies have shown that even in the presence of a mild obstruction, patients can have significant symptoms, physiological deterioration, evidence of emphysema, and suffer from recurrent exacerbations. Small airways pathology significantly correlates with the presence of symptoms, and it has been demonstrated that the onset of bronchiolitis occurs earlier than that of emphysema. These damages have long been known to not be detectable with conventional tests, and exclusive reliance on spirometry is not enough to adequately study and stage a patient with "mild COPD." Therefore, early identification of COPD is of utmost importance in the light of modifying the natural course of the disease. However, patients with early lung damage are yet to be included and studied in interventional clinical trials.

Prevalence of SARS-CoV-2, Verona, Italy, April-May 2020.

We used random sampling to estimate the prevalence of severe acute respiratory syndrome coronavirus 2 infection in Verona, Italy. Of 1,515 participants, 2.6% tested positive by serologic assay and 0.7% by reverse transcription PCR. We used latent class analysis to estimate a 3.0% probability of infection and 2.0% death rate.

Assessment of COVID-19 progression on day 5 from symptoms onset.

BACKGROUND: A major limitation of current predictive prognostic models in patients with COVID-19 is the heterogeneity of population in terms of disease stage and duration. This study aims at identifying a panel of clinical and laboratory parameters that at day-5 of symptoms onset could predict disease progression in hospitalized patients with COVID-19. METHODS: Prospective cohort study on hospitalized adult patients with COVID-19. Patient-level epidemiological, clinical, and laboratory data were collected at fixed time-points: day 5, 10, and 15 from symptoms onset. COVID-19 progression was defined as in-hospital death and/or transfer to ICU and/or respiratory failure (PaO2/FiO2 ratio < 200) within day-11 of symptoms onset. Multivariate regression was performed to identify predictors of COVID-19 progression. A model assessed at day-5 of symptoms onset including male sex, age > 65 years, dyspnoea, cardiovascular disease, and at least three abnormal laboratory parameters among CRP (> 80 U/L), ALT (> 40 U/L), NLR (> 4.5), LDH (> 250 U/L), and CK (> 80 U/L) was proposed. Discrimination power was assessed by computing area under the receiver operating characteristic (AUC) values. RESULTS: A total of 235 patients with COVID-19 were prospectively included in a 3-month period. The majority of patients were male (148, 63%) and the mean age was 71 (SD 15.9). One hundred and ninety patients (81%) suffered from at least one underlying illness, most frequently cardiovascular disease (47%), neurological/psychiatric disorders (35%), and diabetes (21%). Among them 88 (37%) experienced COVID-19 progression. The proposed model showed an AUC of 0.73 (95% CI 0.66-0.81) for predicting disease progression by day-11. CONCLUSION: An easy-to-use panel of laboratory/clinical parameters computed at day-5 of symptoms onset predicts, with fair discrimination ability, COVID-19 progression. Assessment of these features at day-5 of symptoms onset could facilitate clinicians' decision making. The model can also play a role as a tool to increase homogeneity of population in clinical trials on COVID-19 treatment in hospitalized patients.

CT radiomic models to distinguish COVID-19 pneumonia from other interstitial pneumonias.

PURPOSE: To classify COVID-19, COVID-19-like and non-COVID-19 interstitial pneumonia using lung CT radiomic features. MATERIAL AND METHODS: CT data of 115 patients with respiratory symptoms suspected for COVID-19 disease were retrospectively analyzed. Based on the results of nasopharyngeal swab, patients were divided into two main groups, COVID-19 positive (C +) and COVID-19 negative (C-), respectively. C- patients, however, presented with interstitial lung involvement. A subgroup of C-, COVID-19-like (CL), were considered as highly suggestive of COVID pneumonia at CT. Radiomic features were extracted from the whole lungs. A dual machine learning (ML) model approach was used. The first one excluded CL patients from the training set, eventually included on the test set. The second model included the CL patients also in the training set. RESULTS: The first model classified C + and C- pneumonias with AUC of 0.83. CL median response (0.80) was more similar to C + (0.92) compared to C- (0.17). Radiomic footprints of CL were similar to the C + ones (possibly false negative swab test). The second model, however, merging C + with CL patients in the training set, showed a slight decrease in classification performance (AUC = 0.81). CONCLUSION: Whole lung ML models based on radiomics can classify C + and C- interstitial pneumonia. This may help in the correct management of patients with clinical and radiological stigmata of COVID-19, however presenting with a negative swab test. CL pneumonia was similar to C + pneumonia, albeit with slightly different radiomic footprints.

Pneumonic versus Nonpneumonic Exacerbations of Chronic Obstructive Pulmonary Disease.

Patients with chronic obstructive pulmonary disease (COPD) often suffer acute exacerbations (AECOPD) and community-acquired pneumonia (CAP), named nonpneumonic and pneumonic exacerbations of COPD, respectively. Abnormal host defense mechanisms may play a role in the specificity of the systemic inflammatory response. Given the association of this aspect to some biomarkers at admission (e.g., C-reactive protein), it can be used to help to discriminate AECOPD and CAP, especially in cases with doubtful infiltrates and advanced lung impairment. Fever, sputum purulence, chills, and pleuritic pain are typical clinical features of CAP in a patient with COPD, whereas isolated dyspnea at admission has been reported to predict AECOPD. Although CAP may have a worse outcome in terms of mortality (in hospital and short term), length of hospitalization, and early readmission rates, this has only been confirmed in a few prospective studies. There is a lack of methodologically sound research confirming the impact of severe AECOPD and COPD + CAP. Here, we review studies reporting head-to-head comparisons between AECOPD and CAP + COPD in hospitalized patients. We focus on the epidemiology, risk factors, systemic inflammatory response, clinical and microbiological characteristics, outcomes, and treatment approaches. Finally, we briefly discuss some proposals on how we should orient research in the future.

Impact of ICS/LABA and LABA/LAMA FDCs on functional and clinical outcomes in COPD: A network meta-analysis.

BACKGROUND: Inhaled corticosteroid (ICS)/long-acting ß2 agonist (LABA) fixed-dose combinations (FDCs) and LABA/long-acting muscarinic antagonist (LAMA) FDCs are extensively used to treat chronic obstructive pulmonary disease (COPD). The aim of the present network meta-analysis was to assess the comparative efficacy of all the currently available dual therapies in patients with moderate-to-severe COPD. METHODS: A network meta-analysis (≥3 nodes, Bayesian method) was performed by searching for randomized clinical trials (RCTs) that compared the impact of different LABA/LAMA FDCs vs. ICS/LABA FDCs on both primary and secondary endpoints. The primary endpoints were: the change from baseline in trough forced expiratory volume in 1 s (FEV1) and the risk of exacerbation of COPD (AECOPD). The secondary endpoints were: peak FEV1, St' George's Respiratory Questionnaire (SGRQ), Transition Dyspnea Index (TDI), and rescue medication use. RESULTS: Data of 17,734 COPD patients were extracted from 16 RCTs. The length of treatment ranged from 6 weeks to 52 weeks. All LABA/LAMA FDCs, except aclidinium/formoterol, produced a statistically significant improvement compared to ICS/LABAs in trough FEV1. The surface under the cumulative ranking curve (SUCRA) analysis indicated that umeclidinium/vilanterol, glycopyrronium/indacaterol and glycopyrrolate/formoterol fumarate were the most effective FDCs in improving trough FEV1. Across the FDCs analyzed for the risk of AECOPD, glycopyrronium/indacaterol significantly reduced the exacerbation risk compared to fluticasone propionate/salmeterol and resulted the most effective combination in the SUCRA analysis. Similar trend were also observed for the peak FEV1. No significant differences were detected across the investigated FDCs regarding SGRQ, TDI, and use of rescue medication. CONCLUSIONS: The results of this meta-analysis show that LABA/LAMA combinations are consistently more effective than ICS/LABA FDCs for most of the evaluated outcomes. However, differences have also been observed between FDCs belonging to the same class. Across the investigated LABA/LAMA FDCs, glycopyrronium/indacaterol revealed a consistent and robust efficacy profile.

Clinical and Functional Characteristics of COPD Patients Across GOLD Classifications: Results of a Multicenter Observational Study.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease. The severity grading systems proposed by the Global initiative for Chronic Obstructive Lung Disease (GOLD) have changed over time. The aim of the study was to evaluate if the different GOLD classifications can capture the complexity of the disease by investigating the distribution of lung function and clinical parameters across the GOLD classification systems. This was an observational, retrospective, multicentre study. COPD patients were stratified according to the GOLD severity grading proposed in the 2007, and to the ABCD assessment tool present in the 2011, and 2017 versions of the initiative. Data from body plethysmography, DLCO, comorbidities, exacerbation history, pharmacological therapy and eosinophil counts were collected. A total of 1360 patients (73.4% males) were included in the analysis. Overall, 37% of the patients were severe-very severe according to GOLD 2007. Compared with GOLD 2011, applying the GOLD 2017 criteria, the proportion of the at risk categories (C and D) was reduced by ∼23%. Impairment in inspiratory capacity, DLCO and the prevalence of emphysema paralleled the GOLD 2007 classification only. The proportion of patients with ≥ 200 eosinophils/µL was higher in GOLD 2007 stages 3-4 compared with stages 1-2 (P = 0.008). Eosinophil levels were similar across risk classes in GOLD 2011 and 2017. Overall, 41.8% and 52.4% of the patients in the low risk groups according to GOLD 2011 and 2017 were exposed to inhaled corticosteroids. The GOLD 2011 and 2017 classifications, despite exploring symptoms and exacerbations, might miss other relevant patients' clinical characteristics such as lung function and phenotypes, which have a significant impact on outcomes and disease severity.

Omalizumab management beyond clinical trials: the added value of a network model.

BACKGROUND: Omalizumab is effective and safe in severe allergic asthma. Few data are available about its impact on lung function and on asthma comorbidities, long-term follow-up of treated patients, adherence, non-responders profile, and optimal treatment duration. OBJECTIVE: We aimed at evaluating omalizumab-related clinical outcomes and unmet needs in a real-life setting. METHODS: We created a collaborative network (NEONet - North East Omalizumab Network) involving 9 Allergy and Respiratory referral centres for severe asthma placed in the North-East of Italy. Patients' data were entered into a common study database shared by all the participating physicians. A preliminary retrospective analysis was performed. RESULTS: Patients come from a common well-defined geographical and environmental district providing a homogeneous population sample. A moderate but statistically significant improvement of the FEV1, and an increasing proportion of exacerbations-free patients were observed since the treatment start. These findings were independent of the baseline severity of bronchial obstruction. A positive impact of omalizumab on rhinitis in patients with both asthma and rhinitis was detected. Moreover the efficacy of omalizumab on asthma seemed not to be affected by the baseline severity of rhinitis. CONCLUSION: Our retrospective analysis represents a preliminary report from the NEONet activity. It confirmed omalizumab efficacy and provided some new insights about its impact on lung function and on comorbid rhinitis. The network approach, under a prospective view, allows creating a large uniform database, by means of a standardized shared tool for data collecting, and joining a multidisciplinary expertise.

Development and validation of a prediction score to assess the risk of incurring in COPD-related exacerbations: a population-based study in primary care.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fourth most important cause of death in high-income countries. Inappropriate use of COPD inhaled therapy, including the low adherence (only 10 %-40 % of patients reporting an adequate compliance) may shrink or even nullify the proven benefits of these medications. As such, an accurate prediction algorithm to assess at national level the risk of COPD exacerbation might be relevant for general practictioners (GPs) to improve patient's therapy. METHODS: We formed a cohort of patients aged 45 years or older being diagnosed with COPD in the period between January 2013 to December 2021. Each patient was followed until occurrence of COPD exacerbation up to the end of 2021. Sixteen determinants were adopted to assemble the CopdEX(CEX)-Health Search(HS)core, which was therefore developed and validated through the related two sub-cohorts. RESULTS: We idenfied 63763 patients aged 45 years or older being diagnosed with COPD (mean age: 67.8 (SD:11.7); 57.7 % males).When the risk of COPD exacerbation was estimated via CEX-HScore, its predicted value was equal to 14.22 % over a 6-month event horizon. Discrimination accuracy and explained variation were equal to 66 % (95 % CI: 65-67 %) and 10 % (95 % CI: 9-11 %), respectively. The calibration slope did not significantly differ from the unit (p = 0.514). CONCLUSIONS: The CEX-HScore was featured by fair accuracy for prediction of COPD-related exacerbations over a 6-month follow-up. Such a tool might therefore support GPs to enhance COPD patients' care, and improve their outcomes by facilitating personalized approaches through a score-based decision support system.

Safety of dupilumab in T2 airways conditions: focus on eosinophilia across trials and real-life evidence.

INTRODUCTION: Dupilumab, a monoclonal antibody targeting the IL-4 receptor alpha subunit, effectively blocks both IL-4 and IL-13 mediated pathways. Its introduction has represented a significant advancement in the treatment of severe asthma and other Type 2 (T2) conditions, including nasal polyps, atopic dermatitis, and eosinophilic esophagitis. To date, Dupilumab has demonstrated optimal efficacy and safety profile. AREAS COVERED: The safety profile of dupilumab has been extensively studied, especially for its effects on blood eosinophil count. Transient eosinophil increase during treatment is typically insignificant from a clinical point of view and related to its mechanism of action. Rare cases of hyper-eosinophilia associated with clinical conditions like eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES) have been reported. Those cases are often related to the drug's steroid-sparing effect or the natural trajectory of the underlying disease rather than a direct cause-effect relationship with dupilumab. EXPERT OPINION: The management of hyper-eosinophilia during dupilumab treatment requires comprehensive diagnostic work-up and strict follow-up monitoring for early detection of systemic disease progression in order to avoid unnecessary discontinuation of an effective treatment. This approach highlights the importance of a personalized treatment.

Exacerbation Burden in COPD and Occurrence of Mortality in a Cohort of Italian Patients: Results of the Gulp Study.

Objective: To describe the burden of moderate to severe exacerbations and all-cause mortality; the secondary objectives were to analyze treatment patterns and changes over follow-up. Design: Observational, multicenter, retrospective, cohort study with a three year follow-up period. Setting: Ten Italian academic secondary- and tertiary-care centers. Participants: Patients with a confirmed diagnosis of COPD referring to the outpatient clinics of the participating centers were retrospectively recruited. Primary and Secondary Outcome Measures: Annualized frequency of moderate and severe exacerbations stratified by exacerbation history prior to study enrollment. Patients were classified according to airflow obstruction, GOLD risk categories, and divided in 4 groups: A = no exacerbations; B = 1 moderate exacerbation; C = 1 severe exacerbation; D = ≥2 moderate and/or severe exacerbations. Overall all-cause mortality stratified by age, COPD category, and COPD therapy. A logistic regression model assessed the association of clinical characteristics with mortality. Results: 1111 patients were included (73% males), of which 41.5% had a history of exacerbations. As expected, the proportion of patients experiencing ≥1 exacerbation during follow-up increased according to pre-defined study risk categories (B: 79%, C: 84%, D: 97.4%). Overall, by the end of follow-up, 45.5% of patients without a history of exacerbation experienced an exacerbation (31% of which severe), and 13% died. Deceased patients were significantly older, more obstructed and hyperinflated, and more frequently active smokers compared with survivors. Severe exacerbations were more frequent in patients that died (23.5%, vs 10.2%; p-value: 0.002). Chronic heart failure and ischemic heart disease were the only comorbidities associated with a higher odds ratio (OR) for death (OR: 2.2, p-value: 0.001; and OR: 1.9, p-value: 0.007). Treatment patterns were similar in patients that died and survivors. Conclusion: Patients with a low exacerbation risk are exposed to a significant future risk of moderate/severe exacerbations. Real life data confirm the strong association between mortality and cardiovascular comorbidities in COPD.

Dupilumab Efficacy on Asthma Functional, Inflammatory, and Patient-Reported Outcomes across Different Disease Phenotypes and Severity: A Real-Life Perspective.

Dupilumab is currently approved for the treatment of Type 2 severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). Few studies have specifically reported on dupilumab efficacy on asthma outcomes as a primary objective in a real-life setting, in patients with and without CRSwNP. Our study aimed to explore the efficacy of dupilumab on functional, inflammatory, and patient-reported outcomes in asthma patients across different disease phenotypes and severity, including mild-to-moderate asthma coexisting with CRSwNP. Data from 3, 6, and 12 months follow-up were analyzed. Asthma (FEV1%, Tiffeneau%, ACT, FeNO, oral steroid use, exacerbation rate, and blood eosinophilia) and polyposis (SNOT22, VAS, NPS) outcomes showed a rapid (3 months) and sustained (6 and 12 months) significant change from baseline, despite most of the patients achieving oral steroid withdrawal. According to the sensitivity analysis, the improvement was not conditioned by either the presence of polyposis or severity of asthma at baseline. Of note, even in the case of milder asthma forms, a significant further improvement was recorded during dupilumab treatment course. Our report provides short-, medium-, and long-term follow-up data on asthma outcomes across different diseases phenotypes and severity, contributing to the real-world evidence related to dupilumab efficacy on upper and lower airways T2 inflammation.

Unlocking the Long-Term Effectiveness of Benralizumab in Severe Eosinophilic Asthma: A Three-Year Real-Life Study.

Background: Benralizumab has been shown to restore good control of severe eosinophilic asthma (SEA). Robust data on benralizumab effectiveness over periods longer than 2 years are scarce. Methods: This retrospective multicentric study was conducted on 108 Italian SEA patients treated with benralizumab for up to 36 months. Partial and complete clinical remission (CR) were assessed. Data were analyzed with descriptive statistics or using linear, logistic, and negative binomial mixed-effect regression models. Results: At 36 months, benralizumab reduced the exacerbation rate by 89% and increased the forced expiratory volume in 1 second (FEV1) (+440 mL at 36 months, p < 0.0001). Benralizumab improved asthma control as well as sinonasal symptoms in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). Up to 93.33% of patients either reduced or discontinued OCS; benralizumab also decreased ICS use and other asthma medications. Overall, 84.31% of patients achieved partial or complete CR. Conclusions: Benralizumab improved asthma and sinonasal outcomes up to 36 months. These findings support the potential of benralizumab to induce CR, emphasizing its role as a disease-modifying anti-asthmatic drug for the management of SEA. Further research is warranted to expand these findings by minimizing data loss and assessing benralizumab's long-term safety.

Low-dose anti-IL 5 treatment in idiopathic hypereosinophilic syndrome: towards a precision medicine approach for remission maintenance.

Mepolizumab at the dose of 300 mg/4 weeks has been recently approved as an add-on therapy for patients with uncontrolled hypereosinophilic syndrome (HES) without any identifiable non-hematologic secondary cause. According to the available real-life evidence mepolizumab 300 mg and 100 mg, licensed for severe eosinophilic asthma, are comparable in terms of drug efficacy. However, the clinical rationale for selecting one dose or the other has not been explored. We investigated the efficacy and safety of mepolizumab 100 mg in idiopathic HES (I-HES) patients as a steroid sparing strategy for disease remission maintenance by assessing clinical conditions, blood eosinophil count (BEC) and adverse events at baseline and at 3-6-12 months follow-up. Overall, 11 patients were enrolled (females 4-36%) with a median age of 62 years (IQR 55.0-72.0). At 3-month visit both prednisone daily dose and BEC significantly decreased from baseline, whilst a substantial improvement of Brief fatigue inventory score (BFI) was not recorded before the 6 months assessment. More than 70% of patients completely stopped prednisone at 12-months follow-up, without any flare in terms of BEC and BFI. No adverse event was registered. Although larger studies are needed, our report firstly describes that in a well-defined population, diagnosed with I-HES and in disease remission, low dose mepolizumab is a safe and effective steroid-sparing option for remission maintenance. It suggests that a personalized treatment dose might be explored according to the disease classification and activity at the time of biologic treatment start.

Sex differences in excessive oral corticosteroid exposure in poor adherent adult asthmatics overusing short-acting ß-2 agonists.

BACKGROUND: We know that excessive short-acting ß2-agonists (SABA) use in asthma may be associated to high exacerbation risks. We studied whether such excessive SABA consumption is connected with different higher oral corticosteroid (OC) prescriptions in the two sexes. METHODS: In our prescribing database, we searched subjects aged 18-40 years that were prescribed at least one SABA package/year and/or at least two ICS or two ICS/LABA boxes/year to identify asthmatics. Their OC prescriptions/year were also examined. Subjects were divided into 4 groups according to SABA packages/year prescribed (0, 1-2,3-6 and ≥7), considering sexes separately. RESULTS: Individuals recruited were 9,102. Subjects with at least one OC prescription were higher in each group and were females (P<0.001). The OC packages/year number was also more elevated in women especially those with >7 SABA prescriptions/year (0.96 in males vs. 2.64 in females, P<0.001). 94.7%/93.6% males/females, who never used SABA, took at least one ICS/LABA (mean 5.84/5.48 packages/year), while the subject percentage adhering to ICS/LABA dropped to 28-47% (mean 0.94-3.82 packages/year) in those who used SABA (P<0.001). Higher SABA prescriptions were associated with an increasing OC dispensation (ß=0.057, P<0.0001). We observed also a greater risk of using >3 OC packages/year in subjects with 3-6 (OR: 2.98 [95% CI: 2.19-4.06], P<0.001) and ≥7 (OR: 3.49 [95% CI: 2.39-5.10], P<0.001) SABA prescriptions compared to those that never used SABA. Besides, we found that using ICS (OR:0.51 [95% CI: 0.35-0.75], P<0.001) or ICS/LABA (OR:0.07 [95% CI: 0.05-0.09], P<0.001) may significantly reduce SABA prescriptions. CONCLUSIONS: Poor adherence to maintenance treatment appears to associated with excessive SABA prescriptions that may lead to a higher OC consumption particularly noticeable in women.