Fractional nitric oxide measurement in exhaled air (FeNO): perspectives in the management of respiratory diseases.

Exhaled nitric oxide (NO) production, upregulated by inflammatory cytokines and mediators in central and peripheral airways, can be easily and non-invasively detected in exhaled air in asthma and other respiratory conditions as a promising tool for disease monitoring. The American Thoracic Society and European Respiratory Society released recommendations that standardize the measurement of the fractional exhaled NO (FeNO). In asthma, increased FeNO reflects eosinophilic-mediated inflammatory pathways and, as a biomarker of T2 inflammation can be used to identify asthma T2 phenotype. In this setting its measurement has shown to be an important tool especially in the diagnostic process, in the assessment and evaluation of poor adherence or predicting positive response to inhaled corticosteroids treatment, in phenotyping severe asthma patients and as a biomarker to predict the response to biologic treatments. The discovery of the role of NO in the pathogenesis of different diseases affecting the airways and the possibility to estimate the predominant site of increased NO production has provided new insight on its regulatory role in the airways, making it suitable for a potential extended use in clinical practice for different pulmonary diseases, even though its role remains less clear than in asthma. Monitoring FeNO in pulmonary obstructive lung diseases including chronic bronchitis and emphysema, interstitial lung diseases, obstructive sleep apnea and other pulmonary diseases is still under debate but has opened up a window to the role NO may play in the management of these diseases. The use of FeNO is reliable, cost effective and recommendable in both adults and children, and should be implemented in the management of patients with asthma and other respiratory conditions.

COVID-19-Associated Pulmonary Mucormycosis.

COVID-19-associated mucormycosis (CAM) emerged as an epidemic in certain parts of the world amidst the global COVID-19 pandemic. While rhino-orbital mucormycosis was well reported during the pandemic, in the absence of routine diagnostic facilities including lower airway sampling, pulmonary mucormycosis was probably under-recognized. In this review, we have focused on the epidemiology and management of COVID-19-associated pulmonary mucormycosis (CAPM). CAPM is a deadly disease and mortality can be as high as 80% in the absence of early clinical suspicion and treatment. While histopathological examination of tissue for angio-invasion and cultures have remained gold standard for diagnosis, there is an increasing interest in molecular and serological methods to facilitate diagnosis in critically ill patients and often, immune-suppressed hosts who cannot readily undergo invasive sampling. Combined medical and surgical treatment offers more promise than standalone medical therapy. Maintaining adequate glycemic control and prudent use of steroids which can be a double-edged sword in COVID-19 patients are the key preventative measures. We would like to emphasize the urgent need for the development and validation of reliable biomarkers and molecular diagnostics to facilitate early diagnosis.

Dupilumab and tezepelumab in severe refractory asthma: new opportunities.

Bronchial asthma is a chronic inflammatory condition with increasing prevalence worldwide that may present as heterogeneous phenotypes defined by the T2-mediated pattern of airway inflammation T2-high and T2-low asthma. Severe refractory asthma includes a subset of asthmatic patients who fail to control their disease despite maximal therapy and represent a group of patients needing marked resource utilization and hence may be eligible to add-on biological therapies. Among the new biologics, we focused our attention on two monoclonal antibodies: dupilumab, exerting a dual blockade of cytokine (interleukin (IL)-4 and IL-13) signaling; and tezepelumab, acting at a higher level preventing the binding of thymic stromal lymphopoietin (TSLP) to its receptor, thus blocking TSLP, IL-25, and IL-33 signaling, hence modulating airway T2 immune responses. With their different mechanisms of action, these two biologics represent important options to provide an enhanced personalized treatment regimen. Several clinical trials have been conducted testing the efficacy and safety of dupilumab in severe refractory asthmatic patients showing improvements in lung function, asthma control, and reducing exacerbations. Similar results were reported with tezepelumab that, differently from dupilumab, acts irrespectively on eosinophilic or non-eosinophilic phenotype. In this review, we provide an overview of the most important highlights regarding dupilumab and tezepelumab characteristics and mechanism of action with a critical review of the principal results of clinical (Phase II and III) studies concluded and those still in progress.

Health impact of e-cigarettes and heated tobacco products in chronic obstructive pulmonary disease: current and emerging evidence.

INTRODUCTION: Quitting is the only proven method to attenuate the progression of chronic obstructive pulmonary disease (COPD). However, most COPD smokers do not seem to respond to smoking cessation interventions and may benefit by lessening the negative health effects of long-term cigarette smoke exposure by switching to non-combustible nicotine delivery alternatives, such as heated tobacco products (HTPs) and e-cigarettes (ECs). AREAS COVERED: Compared with conventional cigarettes, HTPs and ECs offer substantial reduction in exposure to toxic chemicals and have the potential to reduce harm from cigarette smoke when used as tobacco cigarette substitutes. In this review, we examine the available clinical studies and population surveys on the respiratory health effects of ECs and HTPs in COPD patients. EXPERT OPINION: The current research on the impact of ECs and HTPs on COPD patients' health is limited, and more high-quality studies are needed to draw definitive conclusions. However, this review provides a comprehensive overview of the available literature for health professionals looking to advise COPD patients on the use of these products. While ECs and HTPs may offer some benefits in reducing harm from cigarette smoke, their long-term effects on COPD patients' health are still unclear.

Implications of incidental findings from lung screening for primary care: data from a UK pilot.

Regional lung cancer screening (LCS) is underway in England, involving a "lung health check" (LHC) and low-dose CT scan for those at high risk of cancer. Incidental findings from LHCs or CTs are usually referred to primary care. We describe the proportion of participants referred from the West London LCS pilot to primary care, the indications for referral, the number of general practitioner (GP) attendances and consequent changes to patient management, and provide an estimated cost-burden analysis for primary care. A small proportion (163/1542, 10.6%) of LHC attendees were referred to primary care, primarily for suspected undiagnosed chronic obstructive pulmonary disease (55/163, 33.7%) or for QRISK® (63/163, 38.7%) assessment. Ninety one of 159 (57.2%) participants consenting to follow-up attended GP appointments; costs incurred by primary care were estimated at £5.69/LHC participant. Patient management changes occurred in only 36/159 (22.6%) referred participants. LHCs result in a small increase to primary care workload provided a strict referral protocol is adhered to. Changes to patient management arising from incidental findings referrals are infrequent.

Autoptic identification of disseminated mucormycosis in a young male presenting with cerebrovascular event, multi-organ dysfunction and COVID-19 infection.

Among the secondary fungal infections in Coronavirus-19 (COVID-19) infection, Aspergillosis has been reported more often than Mucormycosis. Disseminated mucormycosis is almost always a disease of severely immunosuppressed hosts. We report a young obese Asian male who was admitted with an acute anterior cerebral artery (ACA) territory infarct and severe COVID-19 pneumonitis to the intensive care unit (ICU). He had a complicated stay with recurrent episodes of vasoplegic shock and multi-organ dysfunction. At autopsy, he was confirmed to have disseminated mucormycosis. We believe this to be the first documented case of disseminated mucormycosis in an immunocompetent host with COVID-19 infection. The lack of sensitive non-invasive modalities and biomarkers to diagnose mucormycosis, along with the extremely high mortality in untreated cases, present a unique challenge to clinicians dealing with critically ill patients with COVID-19.

Health outcomes in COPD smokers using heated tobacco products: a 3-year follow-up.

Given that many patients with chronic obstructive pulmonary disease (COPD) smoke despite their symptoms, it is important to understand the long-term health impact of cigarette substitution with heated tobacco products (HTPs). We monitored health parameters for 3 years in COPD patients who substantially attenuated or ceased cigarette consumption after switching to HTPs. Changes in daily cigarette smoking, annualized disease exacerbations, lung function indices, patient-reported outcomes (CAT scores) and 6-minute walk distance (6MWD) from baseline were measured in COPD patients using HTPs at 12, 24 and 36 months. These were compared to a group of age- and sex-matched COPD patients who continued smoking. Complete data sets were available for 38 patients (19 in each group). Subjects using HTPs had a substantial decrease in annualized COPD exacerbations within the group mean (± SD) from 2.1 (± 0.9) at baseline to 1.4 (± 0.8), 1.2 (± 0.8) and 1.3 (± 0.8) at 12-, 24- and 36-month follow-up (p < 0.05 for all visits). In addition, substantial and clinically significant improvements in CAT scores and 6MWD were identified at all three time points in the HTP cohort. No significant changes were observed in COPD patients who continued smoking. This study is the first to describe the long-term health effects of HTP use in COPD patients. Consistent improvements in respiratory symptoms, exercise tolerance, quality of life, and rate of disease exacerbations were observed in patients with COPD who abstained from smoking or substantially reduced their cigarette consumption by switching to HTP use.

COPD smokers who switched to e-cigarettes: health outcomes at 5-year follow up.

BACKGROUND AND AIMS: The long-term health effects of the use of electronic cigarettes (ECs) in patients with chronic obstructive pulmonary disease (COPD) are largely unexplored. We present findings from a 5-year prospective assessment of respiratory parameters in a cohort of COPD patients who substantially reduced conventional smoking or achieved abstinence by switching to ECs. METHODS: Patients were evaluated prospectively for their measurements of respiratory exacerbations, spirometric indices, quality of life using the COPD assessment tool (CAT), 6-min walk distance (6MWD), as well as conventional cigarette consumption. Baseline measurements prior to switching to EC use were compared with follow-up visits at 12-, 24-, 48- and 60-months. Age- and sex-matched COPD patients reporting to be regular smokers (not using ECs) were the reference group for the analysis. RESULTS: Complete data were available from 39 patients. Those in the EC user group achieved a marked decline in cigarette smoking or abstinence. COPD EC users had a significant diminution in COPD exacerbations; with the mean (±SD) exacerbation rate falling from 2.3 (±0.9) at baseline to 1.1 (±1.0) at 5 years (p < 0.001), whereas no significant changes were observed in the control group.Significant and constant improvements in lung function, CAT scores and 6MWD were reported in the EC user group over the 5-year observation period compared with the reference group (p < 0.05). CONCLUSION: The present study suggests that EC use may ameliorate objective and subjective COPD outcomes, and that the benefits gained appear to persist long term. EC use for abstinence and smoking reduction may ameliorate some of the harm resulting from tobacco smoking in COPD patients.

Baseline Results of the West London lung cancer screening pilot study - Impact of mobile scanners and dual risk model utilisation.

OBJECTIVES: The West London lung screening pilot aimed to identify early-stage lung cancer by targeting low-dose CT (LDCT) to high risk participants. Successful implementation of screening requires maximising participant uptake and identifying those at highest risk. As well as reporting pre-specified baseline screening metrics, additional objectives were to 1) compare participant uptake between a mobile and hospital-based CT scanner and 2) evaluate the impact on cancer detection using two lung cancer risk models. METHODS: From primary care records, ever-smokers aged 60-75 were invited to a lung health check at a hospital or mobile site. Participants with PLCOM2012 6-yr risk ≥1.51 % and/or LLPv2 5-yr risk ≥2.0 % were offered a LDCT. Lung cancer detection rate, stage, and recall rates are reported. Participant uptake was compared at both sites (chi-squared test). LDCT eligibility and cancer detection rate were compared between those recruited under each risk model. RESULTS: Of 8366 potential participants invited, 1047/5135 (20.4 %) invitees responded to an invitation to the hospital site, and 702/3231 (21.7 %) to the mobile site (p = 0.14). The median distance travelled to the hospital site was less than to the mobile site (3.3 km vs 6.4 km, p < 0.01). Of 1159 participants eligible for a scan, 451/1159 (38.9 %) had a LLPv2 ≥2.0 % only, 71/1159 (6.1 %) had a PLCOM2012 ≥1.5 % only; 637/1159 (55.0 %) met both risk thresholds. Recall rate was 15.9 %. Lung cancer was detected in 29/1145 (2.5 %) participants scanned (stage 1, 58.6 %); 5/29 participants with lung cancer did not meet a PLCOM2012 threshold of ≥1.51 %; all had a LLPv2 ≥2.0 %. CONCLUSION: Targeted screening is effective in detecting early-stage lung cancer. Similar levels of participant uptake at a mobile and fixed site scanner were demonstrated, indicating that uptake was driven by factors in addition to scanner location. The LLPv2 model was more permissive; recruitment with PLCOM2012 alone would have missed several cancers.

Symptoms and exacerbations in asthma: an apparent paradox?

BACKGROUND: There is a dearth of data on prospectively recorded symptoms in patients with uncontrolled asthma. Asthma symptoms and exacerbation rate are commonly thought to be associated. The aim of this study was to analyse asthma symptoms of cough, wheeze, chest tightness and breathlessness in an uncontrolled asthma cohort. We also examined the effect of maintenance and reliever therapy (MART) on these symptoms and its effect on exacerbation rate. METHODS: Adults with uncontrolled asthma electronically recorded their asthma symptom severity scores twice-daily over a period of 48 weeks following randomisation to beclometasone/formoterol twice daily plus pro re nata (prn) salbutamol or MART. Subjects with symptom scores of ⩾2 (ranging from 0 to 3 for each symptom) were considered more symptomatic, whereas those below a score of 2 were considered less severe. The influence treatment on exacerbation frequency and symptom profiles were then correlated. RESULTS: Of the 1701 subjects in the analyses, 1403 were symptomatic with ⩾100 symptom episodes for one symptom. The remaining 298 subjects were classified as pauci-symptomatic. There was poor association between the frequency and symptom severity score for each symptom. Surprisingly, wheeze was the least reported symptom. Females were more likely to be polysymptomatic. MART compared with prn salbutamol markedly attenuated severe asthma exacerbations. This effect was most notable in subjects with fewer symptoms. CONCLUSIONS: In uncontrolled asthma, there is a poor correlation between reported symptoms and exacerbation frequency. This post hoc analysis suggests that MART should not be reserved for symptomatic subjects but achieves the greatest benefit in pauci-symptomatic patients with asthma. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00861926.

An evaluation of mepolizumab for the treatment of severe asthma.

Introduction: Asthma is considered one of the most common chronic conditions globally, characterized by variable airflow obstruction and symptoms. Severe asthma is diagnosed when asthma control requires high-intensity therapy or continues to remain uncontrolled despite treatment. Eosinophilic inflammation is known to be perpetuated by the activity of IL-5 in a proportion of severe asthma subjects, and targeting IL-5 may offer a therapeutic option. Areas covered: In this review, we discuss the role and pathogenesis of IL-5 and eosinophils in asthma and rationale of antagonizing IL-5 in severe eosinophilic asthma. Mepolizumab is the first of three anti-IL-5 biologics licensed in 2015 for use in this subgroup of patients. We discuss clinical and real-life studies leading up to its approval and post-marketing outcomes in terms of efficacy and safety to-date, as well as its pros and cons. Expert opinion: IL-5 antagonism has paved the way for an additional personalized therapeutic opportunity for use in severe asthma with eosinophilic inflammation, though there is limited evidence on the long-term implications of suppressing/depleting eosinophils and the duration for which they should be administered.

Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience.

Asthma is a chronic inflammatory condition involving the airways with varying pathophysiological mechanisms, clinical symptoms and outcomes, generally controlled by conventional therapies including inhaled corticosteroids and long-acting ß2 agonists. However, these therapies are unable to successfully control symptoms in about 5-10% of severe asthma patients. Atopic asthma, characterized by high immunoglobulin (Ig)E or eosinophilia, represents about 50% of asthmatic patients. Interleukin (IL)-5 is the main cytokine responsible of activation of eosinophils, hence therapeutic strategies have been investigated and developed for clinical use. Biologics targeting IL-5 and its receptor (first mepolizumab and subsequently, reslizumab and benralizumab), have been recently approved and used as add-on therapy for severe eosinophilic asthma resulting in a reduction in the circulating eosinophil count, improvement in lung function and exacerbation reduction in asthma patients. Despite these biologics having been approved for stratified severe asthma patients that remain uncontrolled with high doses of conventional therapy, a number of patients may be eligible for more than one biologic. Presently, the lack of head-to-head studies comparing the biological agents among themselves and with conventional therapy make the choice of optimal therapy for each patient a challenge for clinicians. Moreover, discontinuation of these treatments, implications for efficacy or adverse events, in particular in long-term treatment, and needs for useful biomarkers are still matters of debate. In this review we evaluate to date, the evidence on mepolizumab that seems to demonstrate it is a well-tolerated and efficacious regimen for use in severe eosinophilic asthma, though more studies are still required.

Health effects in COPD smokers who switch to electronic cigarettes: a retrospective-prospective 3-year follow-up.

Background: Health effects of electronic cigarette (EC) use in patients with chronic obstructive pulmonary disease (COPD) are largely unexplored. Aim: We present findings from a long-term prospective assessment of respiratory parameters in a cohort of COPD patients who ceased or substantially reduced conventional cigarette use with ECs. Methods: We prospectively re-evaluated COPD exacerbations, spirometric indices, subjective assessments (using the COPD Assessment Tool [CAT] scores), physical activity (measured by the 6-minute walk distance [6MWD]), and conventional cigarette use in EC users with COPD who were retrospectively assessed previously. Baseline measurements prior to switching to EC use were compared to follow-up visits at 12, 24, and 36 months. Age- and sex-matched regularly smoking COPD patients who were not using ECs were included as reference (control) group. Results: Complete data were available from 44 patients. Compared to baseline in the EC-user group, there was a marked decline in the use of conventional cigarettes. Although there was no change in lung function, significant improvements in COPD exacerbation rates, CAT scores, and 6MWD were observed consistently in the EC user group over the 3-year period (p<0.01). Similar findings were noted in COPD EC users who also smoked conventional cigarettes ("dual users"). Conclusion: The present study suggests that EC use may ameliorate objective and subjective COPD outcomes and that the benefits gained may persist long-term. EC use may reverse some of the harm resulting from tobacco smoking in COPD patients.

The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.

Treatment of Allergic Rhinitis as a Strategy for Preventing Asthma.

PURPOSE OF REVIEW: To evaluate the impact of allergic rhinitis (AR) on the development of asthma and to update readers on recent literature suggesting that early treatment of allergic subjects with immunotherapy may prevent asthma onset. RECENT FINDINGS: AR is frequently associated with asthma, leading to the concept that these two conditions are different aspects of the same disease. There is increasing evidence that AR precedes the onset of asthmatic symptoms and current treatment strategies are beneficial in symptom control with no impact prevention. There is limited knowledge about the risk factors responsible for the progression of AR to asthma, though recent data supports the notion that it is possible to prevent asthma onset by allergen immunotherapy. Despite significant advances in specific immunotherapy (SIT) therapy strengthening its efficacy in AR and possible prevention of progression to asthma, the adoption of this therapeutic strategy is still restricted in comparison to therapies directed towards treatment of AR symptoms. Unlike corticosteroids and other symptomatic therapies, the benefit of SIT treatment in allergic individuals has been shown to prevent the development of allergic conditions. Hence, large well-conducted randomized clinical trials with long-term efficacy of SIT are required to confirm or refute the concept that SIT may abrogate the progression of AR to asthma in patients.

Biologic agents for severe asthma patients: clinical perspectives and implications.

Asthma is a chronic inflammatory multifactorial disorder of the airways characterized by the involvement of immune cells and mediators in its onset and maintenance. Traditional therapeutic strategies have been unsatisfactory in controlling the underlying pathology, especially in the more severe states. Hence in the last couple of decades, new biological approaches targeting molecular mediators have been developed. In this narrative review we examine biological agents currently available for the management of severe asthma, focusing our attention on their clinical application, pros and cons, and in particular on gaps regarding the use of these agents. The most well-known and used biologic agent in clinical practice is omalizumab, though there is emerging evidence for mepolizumab too. The future of these biological therapies is to broaden our knowledge of their practical use and ascertain predictive biomarkers, or define an algorithm, useful in the optimal application of these 'biological weapons'.