Characteristics of severe asthma patients on biologics: a real-life European registry study.

Background: The use of anti-interleukin-5 (IL5) for severe asthma is based on criteria from randomised controlled trials (RCTs), but in real-life patients might not fulfil the eligibility criteria but may benefit from biologics. We aimed to characterise patients starting anti-IL5(R) in Europe and evaluate the discrepancies between initiation of anti-IL5(R) in real life and in RCTs. Materials and methods: We performed a cross-sectional analysis with data from the severe asthma patients at the start of anti-IL5(R) in the Severe Heterogeneous Asthma Research collaboration Patient-centred (SHARP Central) registry. We compared the baseline characteristics of the patients starting anti-IL5(R) from 11 European countries within SHARP with the baseline characteristics of the severe asthma patients from 10 RCTs (four for mepolizumab, three for benralizumab and three for reslizumab). Patients were evaluated following eligibility criteria from the RCTs of anti-IL5 therapies. Results: Patients starting anti-IL5(R) in Europe (n=1231) differed in terms of smoking history, clinical characteristics and medication use. The characteristics of severe asthma patients in the SHARP registry differed from the characteristics of patients in RCTs. Only 327 (26.56%) patients fulfilled eligibility criteria of all the RCTs; 24 patients were eligible for mepolizumab, 100 for benralizumab and 52 reslizumab. The main characteristics of ineligibility were: ≥10 pack-years, respiratory diseases other than asthma, Asthma Control Questionnaire score ≤1.5 and low-dose inhaled corticosteroids. Conclusion: A large proportion of patients in the SHARP registry would not have been eligible for anti-IL5(R) treatment in RCTs, demonstrating the importance of real-life cohorts in describing the efficacy of biologics in a broader population of patients with severe asthma.

Precision Medicine in Asthma Therapy.

Asthma is a complex, heterogeneous disease that necessitates a proper patient evaluation to decide the correct treatment and optimize disease control. The recent introduction of new target therapies for the most severe form of the disease has heralded a new era of treatment options, intending to treat and control specific molecular pathways in asthma pathophysiology. Precision medicine, using omics sciences, investigates biological and molecular mechanisms to find novel biomarkers that can be used to guide treatment selection and predict response. The identification of reliable biomarkers indicative of the pathological mechanisms in asthma is essential to unravel new potential treatment targets. In this chapter, we provide a general description of the currently available -omics techniques, focusing on their implications in asthma therapy.

Comparison between Suspected and Confirmed COVID-19 Respiratory Patients: What Is beyond the PCR Test.

COVID-19 modified the healthcare system. Nasal-pharyngeal swab (NPS), with real-time reverse transcriptase-polymerase (PCR), is the gold standard for the diagnosis; however, there are difficulties related to the procedure that may postpone it. The study aims to evaluate whether other elements than the PCR-NPS are reliable and confirm the diagnosis of COVID-19. This is a cross-sectional study on data from the Lung Unit of Pavia (confirmed) and at the Emergency Unit of Palermo (suspected). COVID-19 was confirmed by positive NPS, suspected tested negative. We compared clinical, laboratory and radiological variables and performed Logistic regression to estimate which variables increased the risk of COVID-19. The derived ROC-AUCcurve, assessed the accuracy of the model to distinguish between COVID-19 suspected and confirmed. We selected 50 confirmed and 103 suspected cases. High Reactive C-Protein (OR: 1.02; CI95%: 0.11-1.02), suggestive CT-images (OR: 11.43; CI95%: 3.01-43.3), dyspnea (OR: 10.48; CI95%: 2.08-52.7) and respiratory failure (OR: 5.84; CI95%: 1.73-19.75) increased the risk of COVID-19, whereas pleural effusion decreased the risk (OR: 0.15; CI95%: 0.04-0.63). ROC confirmed the discriminative role of these variables between suspected and confirmed COVID-19 (AUC 0.91). Clinical, laboratory and imaging features predict the diagnosis of COVID-19, independently from the NPS result.

Management of severe asthma during the first lockdown phase of SARS-CoV-2 pandemic: Tips for facing the second wave.

SARS-CoV-2 pandemic has contributed to implement telemedicine, allowing clinicians to follow the patient remotely, therefore minimizing the risk of any exposure to positive COVID-19 patients. We summarize the approaches adopted to treat and monitor severe asthmatic patients during the lockdown phase of the pandemic. Our experience supports the strategy that every effort should be made to minimize patient contact with the health-care system, planning a pathway that allows patients to receive appropriate medical care and continue the biological therapies, thus preventing the loss of disease control and acute severe exacerbations.

Does the frequency of switching inhalers represent a predictive factor of exacerbation in asthma?

OBJECTIVE: Management of asthma includes monitoring of inhaler technique and level of adherence to treatment. Both factors could be influenced by high frequency of switching inhaler devices. We explored whether switching inhalers is an independent predictive factor of exacerbations. METHODS: Data were collected from 2015 to 2017 from the outpatient clinic of asthma at the University of Palermo, Italy. This observational study consisted of two phases: Phase 1 included subjects of at least three visits in the previous year who reported the frequency of inhalers switched; Phase 2 included subjects of at least two visits during the second year, and the rate of switches and exacerbations was recorded. We included adult (24-84 years old) mild/moderate asthmatics under regular inhaled treatment; uncontrolled asthma was defined as poor symptom control, exacerbations (≥2/year) requiring oral corticosteroids (OCS), or serious exacerbations (≥1/year) requiring hospitalization. RESULTS: A total of 109 records were retrieved for the analysis. A significant correlation between the rate of switches in Phase 1 and exacerbations in Phase 2 was found (p = 0.001). Age and the rates of exacerbations in Phase 1 were also independently associated with a higher number of exacerbations in Phase 2 (p < 0.0001). The multivariate regression model showed that the numbers of switches, as well as exacerbations in Phase 1, were independently correlated to the number of exacerbations in Phase 2 (p = 0.003). CONCLUSIONS: The frequency of switching inhalers independently affects the risk of exacerbations in asthma. These results imply that changing inhaler requires careful management in clinical practice.

Severe asthma and COVID-19: lessons from the first wave.

OBJECTIVE: Severe asthma is considered a risk factor for SARS-Coronavirus 2 (SARS-CoV-2) infection but scientific evidences are lacking. METHODS: we performed a literature search and review based on PubMed database national, international recommendations as well as papers on severe asthmatic patients and their management during SARS-CoV-2 pandemic. RESULTS: the majority of international recommendations, expert panels and editorials provide indications about management of severe asthmatic patients. No published studies evaluated the effects of biologic agents on severe asthmatic patients during SARS-CoV-2 pandemic. CONCLUSIONS: the relationship between SARS-CoV-2 and asthma is variable worldwide and severe asthmatic patients were seldom reported in published cohorts. International recommendations suggest maintaining asthma under control to limit exacerbations occurrence, by using all available treatment. The minimum steroid dosage effective to control symptoms should be maintained to avoid exacerbations; biologic agents administration should be regularly scheduled encouraging patient support programmes.

Exhaled Metabolite Patterns to Identify Recent Asthma Exacerbations.

Asthma is a chronic respiratory disease that can lead to exacerbations, defined as acute episodes of worsening respiratory symptoms and lung function. Predicting the occurrence of these exacerbations is an important goal in asthma management. The measurement of exhaled breath by electronic nose (eNose) may allow for the monitoring of clinically unstable asthma and exacerbations. However, data on its ability to perform this is lacking. We aimed to evaluate whether eNose could identify patients that recently had asthma exacerbations. We performed a cross-sectional study, measuring exhaled breath using the SpiroNose in adults with a physician-reported diagnosis of asthma. Patients were randomly divided into a training (n = 252) and validation (n = 109) set. For the analysis of eNose signals, principal component (PC) and linear discriminant analysis (LDA) were performed. LDA, based on PC1-4, reliably discriminated between patients who had a recent exacerbation from those who had not (training receiver operating characteristic (ROC)-area under the curve (AUC) = 0.76,95% CI 0.69-0.82), (validation AUC = 0.76, 95% CI 0.64-0.87). Our study showed that, exhaled breath analysis using eNose could accurately identify asthma patients who recently had an exacerbation, and could indicate that asthma exacerbations have a specific exhaled breath pattern detectable by eNose.

The potential role of SP-D as an early biomarker of severity of asthma.

Surfactant decreases the surface tension of peripheral airways and modulates the immunological responses of the lung. The alterations of surfactant due to the airway inflammation suggest a role in the pathogenesis of asthma. We aim to test the hypothesis that serum levels of SP-A (Surfactant Protein A) and SP-D (Surfactant Protein-D) are altered in patients with mild asthma compared to healthy controls and those alterations are related to functional abnormalities of peripheral airways, which are an early marker of progression of asthma. In this pilot study, we recruited 20 mild asthmatics and 10 healthy controls. We measured serum SP-A and SP-D and all subjects underwent clinical, lung functional and biological assessments. Serum SP-D was significantly higher in asthmatics compared to healthy controls (mean (SD) values: 7.9(4.65) vs 3.31(1.71) ng ml-1,p-value: 0.008). In the asthmatic group, serum SP-D was significantly correlated to CalvNO (alveolar NO concentration) (R-squared: 0.26;p-value: 0.014). These preliminary findings suggest that serum SP-D could be used as a lung-specific biomarker of small airways damage thus predicting the progression to the most severe forms of asthma.

The impact of SARS-COV2 pandemic on the management oF IPF patients: Our narrative experience.

BACKGROUND: The SARS-CoV-2 pandemic has changed the health-care systems around the world in a remarkable way. We describe the strategies adopted to cope with the limitations imposed by the pandemic to the access to health care by patients diagnosed with idiopathic Pulmonary Fibrosis (IPF). MATERIAL AND METHODS: We conducted a retrospective observational analysis including IPF patients under antifibrotic drugs (nintedanib and pirfenidone) that accessed to the Outpatient clinic of the University of Palermo, Italy. Patients received a phone number and an email address in case of any urgency and a virtual meeting was settled up monthly. RESULTS: 40 patients (M/F: 30/10) were followed up, 33 under nintedanib treatment, 7 under pirfenidone. Among patients under nintedanib, 1 patient reported high fever (T max 39 °C) and purulent sputum with no sign of infections, 1 had hemoptysis that was spontaneously resolved. 2 patients accessed to the emergency department for the worsening of dyspnea; 5 patients had diarrhea that resolved with symptomatic drugs in few days. 3 patients had an increase of alkaline phosphatase levels, leading to the withdrawal of the antifibrotic drug for 15 days, and subsequent normalization of the plasmatic levels. Among patients under pirfenidone, one subject had an increase of ferritin serum levels with no symptoms. The remaining subjects were in stable clinical conditions. None of the patients reported hospitalization or exacerbations, and did not experience antifibrotic withdrawal. CONCLUSIONS: We were able to demonstrate that by implementing alternative ways to monitor the disease, patients did not incur in increased rates of acute exacerbations or higher frequency of side effects and antifibrotic treatment withdrawal.

Treating severe asthma: Targeting the IL-5 pathway.

Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)-4, IL-5 and IL-13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL-5R and IL-5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late-onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non-response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL-5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non-response.

The Influence of Smoking Status on Exhaled Breath Profiles in Asthma and COPD Patients.

Breath analysis using eNose technology can be used to discriminate between asthma and COPD patients, but it remains unclear whether results are influenced by smoking status. We aim to study whether eNose can discriminate between ever- vs. never-smokers and smoking <24 vs. >24 h before the exhaled breath, and if smoking can be considered a confounder that influences eNose results. We performed a cross-sectional analysis in adults with asthma or chronic obstructive pulmonary disease (COPD), and healthy controls. Ever-smokers were defined as patients with current or past smoking habits. eNose measurements were performed by using the SpiroNose. The principal component (PC) described the eNose signals, and linear discriminant analysis determined if PCs classified ever-smokers vs. never-smokers and smoking <24 vs. >24 h. The area under the receiver-operator characteristic curve (AUC) assessed the accuracy of the models. We selected 593 ever-smokers (167 smoked <24 h before measurement) and 303 never-smokers and measured the exhaled breath profiles of discriminated ever- and never-smokers (AUC: 0.74; 95% CI: 0.66-0.81), and no cigarette consumption <24h (AUC 0.54, 95% CI: 0.43-0.65). In healthy controls, the eNose did not discriminate between ever or never-smokers (AUC 0.54; 95% CI: 0.49-0.60) and recent cigarette consumption (AUC 0.60; 95% CI: 0.50-0.69). The eNose could distinguish between ever and never-smokers in asthma and COPD patients, but not recent smokers. Recent smoking is not a confounding factor of eNose breath profiles.

Management of suspected COVID-19 patients in a low prevalence region.

The spread of the SARS-CoV-2 infection among population has imposed a re-organization of healthcare services, aiming at stratifying patients and dedicating specific areas where patients with suspected COVID-related respiratory disease could receive the necessary health care assistance while waiting for the confirmation of the diagnosis of COVID-19 disease. In this scenario, the pathway defined as a "grey zone" is strongly advocated. We describe the application of rules and pathways in a regional context with low diffusion of the infection among the general population in the attempt to provide the best care to respiratory patients with suspected COVID-19. To date, this process has avoided the worst-case scenario of intra-hospital epidemic outbreak.

Fever and dyspnoea in a tracheostomised patient.

Pneumonia of unknown origin in tracheostomised patient https://bit.ly/3hZHBA0.

Urinary Incontinence in Chronic Obstructive Pulmonary Disease: A Common Co-morbidity or a Typical Adverse Effect?

Urinary incontinence (UI) is defined as a loss of bladder control and is characterized by the complaint of any involuntary leakage of urine. Evidence suggests that the prevalence of UI is higher in subjects with chronic obstructive pulmonary disease (COPD) than in age-matched controls in both sexes. UI is classified as stress, urge, and mixed, and has a considerable impact on quality of life. However, the prevalence of UI in individuals with COPD is mostly unexplored in clinical research and often underestimated in clinical practice. Interestingly, although the involuntary leakage of a small amount of urine during coughing (e.g., stress UI) is among the most plausible causes of UI in patients with COPD, its importance has been questioned by some researchers. Moreover, UI as a respiratory drug-related adverse effect is largely overlooked; only a few randomized controlled trials have reported the presence of urinary symptoms, mainly as urinary retention due to anticholinergic agents. In this narrative review, we explored whether, and to what extent, UI occurs in COPD individuals, and what the proposed actions to improve this condition are. We found that the association between UI and COPD is largely unexplored, mostly because UI tends to be attributed to older age. We infer that the prevalence of UI in individuals with chronic respiratory symptoms is often underestimated in clinical practice. The misinterpretation of urinary symptoms as related to the respiratory condition can delay diagnostic and therapeutic approaches. The use of simple self-administered questionnaires to assess the presence of UI is encouraged.

Are biological drugs effective and safe in older severe asthmatics?

INTRODUCTION: The treatment of asthma in older ages follows the recommendations of international guidelines for the management of asthma in younger ages, although older age has always represented an exclusion criterion for eligibility to pharmacological trials. This poses a clinical challenge when deciding whether elderly severe asthmatics are candidates for biological drugs. AREAS COVERED: The current article has a narrative structure to review the current literature on efficacy and safety of novel pharmacological drugs against immunoglobulins and interleukins that mediate and orchestrate the main inflammatory pathways in severe asthma, in order to explore whether older subjects (i.e. > 65 years of age) are included. EXPERT OPINION: Asthma in older ages is not a rare entity, and loss of symptom control is common in most advanced ages. Current evidence from randomized clinical trials (RCTs) on the safety of biological drugs in elderly asthmatics is scarce and does not allow drawing definitive conclusions. An urgent call for studies specifically designed for elderly populations is needed, with the purpose to assess the efficacy and safety of target biological therapies in advanced ages. We envision the design of large multi-center clinical trials to decide whether and when geriatric population could benefit from biological therapies.

Age does not affect the efficacy of anti-IL-5/IL-5R in severe asthmatics.

BACKGROUND: Healthcare decisions made on the basis of insufficient evidence may potentially have ineffective or even harmful consequences. The proportion of older ages (over 65 years) in randomized controlled trials (RCTs) for severe asthma is not enough to establish whether anti-IL-5/IL-5R therapies are equally effective in the elderly as in younger subjects. METHODS: In order to assess the relationship between age and the efficacy of anti-IL-5 monoclonal antibodies (mABs) with respect to the risk of exacerbations and changes in FEV1, a meta-regression analysis via random-effect method was carried out by plotting the effect estimates (outcome variables) resulting from the pairwise meta-analysis with the age of asthmatic subjects (explanatory variable). A comprehensive literature search was performed for pivotal RCTs on the effects of anti-IL-5/IL-5R in severe asthma, with the following keywords: "asthma and mepolizumab", "asthma and reslizumab" and "asthma and benralizumab". The study was restricted to "clinical trials", "age over 65" and "humans". Data were checked for age, exacerbation rates, changes from baseline in FEV1, and blood eosinophil (Eos) count. Secondary outcomes included inhaled and oral medication use, clinical scores and quality of life. RESULTS: A total of 10 studies were analysed. Age did not modulate the efficacy of anti-IL-5/IL-5R treatment against the risk of exacerbation neither in the overall population (coefficient -0.007, P = 0.89), nor in patients with high blood Eos count (coefficient 0.075, P = 0.30). The blood Eos level drove the efficacy of anti-IL-5/IL-5R mABs against the risk of exacerbation regardless of age (coefficient -0.27, P < 0.001). Age did not significantly affect the efficacy of anti-IL-5/IL-5R mABs with respect to the change in FEV1 (coefficient -7.15, P = 0.190); however, in high Eos subjects this improvement tended to be less evident in the more advanced age ranges (coefficient -15.18, P = 0.087). In addition, anti-IL-5/IL-5R mABs reduced ACQ score (P < 0.001 vs. placebo), SGRQ score (P < 0.001 vs. placebo), Total Asthma Symptom Score (P < 0.05 vs. placebo), and the use of oral glucocorticoids (P < 0.001 vs. placebo). CONCLUSIONS: Age does not negatively affect the efficacy of anti-IL-5/IL-5R mABs. These findings support the use of anti-IL-5/IL-5R mABs in asthmatics of different age ranges.

Sleep Disturbances in COPD are Associated with Heterogeneity of Airway Obstruction.

Individuals with Chronic Obstructive Pulmonary Disease (COPD) experience sleep disturbances due to the impact of respiratory symptoms on sleep quality. We explored whether sleep disturbances in COPD are linked to heterogeneity of airway constriction. The impact of breathing problems on sleep quality was measured in consecutive COPD outpatients with the COPD and Asthma Sleep Impact Scale (CASIS) questionnaire. Impulse oscillometry technique (IOS) was employed to assess heterogeneity of airway constriction. Subjects with a previous or concomitant diagnosis of asthma or obstructive sleep apnea (OSA) were excluded. Fifty COPD subjects (M/F 40/10; age: 71 ± 8 yrs, Body Mass Index (BMI): 26.2 ± 4.7 kg/m2, Forced Expiratory Volume in the first second (FEV1): 65 ± 25% predicted; mean ± SD) were enrolled. The mean CASIS score was 36 ± 3.3, and the R5-R20 value was 0.2 ± 0.15 kPa s L-1. The CASIS score was significantly higher in subjects with increased R5-R20 (>0.07 kPa s L-1) (39 ± 24; p = 0.02) compared to normal R5-R20 (21 ± 17). When subjects were categorized on the basis of lung function in severely versus non severely obstructed (FEV1 ≤ or >50% predicted) or air trappers versus non air trappers (Residual Volume, RV ≥ or <120% predicted) the CASIS score remained unchanged (for FEV1: 37 ± 23 versus 33 ± 25, respectively, p = 0.61; for RV: 30 ± 20 versus 40 ± 23, p = 0.16). Sleep disturbances due to COPD symptoms are associated with heterogeneity of airway constriction, possibly reflecting peripheral airway dysfunction.