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.

Asthma phenotypes: do cough and wheeze predict exacerbations in persistent asthma?

Little is known of the long-term symptom profile in uncontrolled asthma and whether symptoms can predict distinct phenotypes. The primary objective of these analyses was to assess diurnal profile of cough and wheeze in an uncontrolled asthma population. Secondary outcomes were to examine how these symptom profiles influence response to treatment.Twice-daily electronically recorded data from 1701 patients were examined in relation to the population demographics. Reliever treatment with salbutamol was then compared with extra-fine beclometasone/formoterol maintenance and reliever therapy (MART). Exacerbation frequency was then correlated with the symptom profile.Symptoms were commoner in older patients with an increased body mass index. In most patients, reported cough and wheeze were closely correlated (r=0.73). Two phenotypes of cough- and wheeze-predominant patients were identified; the former were overweight, older females and the latter older males. Diurnal symptoms of cough and wheeze were similarly attenuated by both therapies. MART reduced exacerbation frequency by a third compared with salbutamol, and this effect was greatest in patients with fewest reported symptoms.While cough and wheeze are highly correlated in uncontrolled asthma, some patients predominantly have cough whereas others wheeze. Symptoms and exacerbation frequency appear poorly associated, suggesting an alternative pathophysiology. MART may be the preferred option in those with fewest symptoms.

Inhaled Corticosteroid use and the Risk of Pneumonia and COPD Exacerbations in the UPLIFT Study.

RATIONALE: Unlike many other COPD studies, the 4-year UPLIFT trial permitted inhaled corticosteroid (ICS) use during run-in and treatment phases. This provided the opportunity to prospectively observe the continuing effects of ICS on respiratory events in closely observed COPD population. OBJECTIVES: We aimed to determine rate and number of episodes of pneumonia and exacerbations of COPD in patients entering the study on no ICS, fluticasone proprionate (FP), and other ICS. METHODS: The UPLIFT dataset was examined retrospectively, and patients were divided into three groups based on their medications at entry: no ICS, FP and other ICS. Poisson regression was used to compare the frequency of respiratory adverse events. MEASUREMENTS AND MAIN RESULTS: At entry, the groups were well matched apart from a higher FEV1% predicted (38 vs. 41%; ICS vs. no ICS, respectively) and prevalence of current smoking (26 vs. 36%; ICS vs. no ICS, respectively). Incidence rates of pneumonia were significantly higher in patients taking ICS compared to no ICS (0.068 vs. 0.056 respectively; p = 0.012). When the FP group was compared to the other ICS, the event rate was even higher (0.077 vs. 0.058, respectively; p < 0.001). COPD exacerbations were more frequent in patients taking ICS, with significantly greater rate in the FP group compared to that seen with other ICS (0.93 vs. 0.84 respectively; p = 0.013). CONCLUSIONS: ICS use was associated an increase in respiratory adverse event rates, but whether this was due to more severe illness at entry is unknown. In subgroup analysis, the excess of morbidity in the ICS group appeared to be mainly associated with those receiving FP at randomisation.

Changes in breathomics from a 1-year randomized smoking cessation trial of electronic cigarettes.

BACKGROUND: Electronic cigarette (EC) use is an emerging behaviour that has been shown to help smokers to reduce cigarette consumption. The aim of this study was to illustrate long-term changes in exhaled breath measurements and respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to ECs. MATERIALS AND METHODS: Prospective evaluation of cigarette consumption, fractional nitric oxide concentration in exhaled breath (FeNO), exhaled carbon monoxide (eCO) and symptom scores was performed in a 1-year randomized, controlled trial of 'healthy' smokers receiving 2·4% nicotine, 1·8% nicotine or no nicotine ECs. FeNO and eCO data are presented on the basis of participants' pooled continuous smoking phenotype classification (failures, reducers and quitters). RESULTS: A significant effect of quitting classification was found on FeNo and eCO at all time points (P < 0·0001). Among quitters, FeNO (medians and interquartile range) rose from 5·5 (4·5-6·9) ppb to 17·7 (13·3-18·9) ppb by week 52. Baseline eCO (medians and interquartile range) decreased from 17 (12-20) ppm to 3 (1-4) ppm by week 52. No significant changes in FeNO and eCO levels were observed in failures and reducers. Improvements in FeNO and eCO levels were correlated with attenuations in symptom scores. CONCLUSIONS: Smokers invited to switch to electronic cigarettes who completely abstained from smoking showed steady progressive improvements in their exhaled breath measurements and symptom scores. FeNo and eCO normalization is highly supportive of improved respiratory health outcomes and adds to the notion that quitting from tobacco smoking can reverse harm in the lung.

Evidence for harm reduction in COPD smokers who switch to electronic cigarettes.

BACKGROUND: Electronic cigarettes (ECs) are battery-operated devices designed to vaporise nicotine, which may help smokers quitting or reducing their tobacco consumption. There is a lack of data on the health effects of EC use among smokers with COPD and whether regular use results in improvement in subjective and objective COPD outcomes. We investigated long-term changes in objective and subjective respiratory outcomes in smokers with a diagnosis of COPD who quit or reduced substantially their tobacco consumption by supplementing with or converting only to ECs use. METHODS: We conducted a retrospective chart review of patients with COPD to identify those reporting regular daily use of ECs on at least two follow-up visits at 12- (F/up1) and 24-months (F/up2). Regularly smoking COPD patients were included as a reference group. RESULTS: A marked reduction in cigarette consumption was observed in ECs users. A significant reduction in COPD exacerbations was reported in the COPD EC user group, their mean (±SD) decreasing from 2.3 (±1) at baseline to 1.8 (±1; p = 0.002) and 1.4 (±0.9; p < 0.001) at F/up1 and F/up2 respectively. A significant reduction in COPD exacerbations was also observed in ECs users who also smoked conventional cigarettes (i.e. 'dual users'). COPD symptoms and ability to perform physical activities improved statistically in the EC group at both visits, with no change in the control group. CONCLUSIONS: These findings suggest that ECs use may aid smokers with COPD reduce their cigarette consumption or remain abstinent, which results in marked improvements in annual exacerbation rate as well as subjective and objective COPD outcomes.

Airway responsiveness to adenosine after a single dose of fluticasone propionate discriminates asthma from COPD.

BACKGROUND: Regular treatment with inhaled corticosteroids (ICS) is known to reduce airway hyperresponsiveness (AHR) to adenosine 5'-monophosphate (AMP) in asthma even after a single dose of fluticasone propionate (FP). AIM: To determine whether this rapid protective effect of a single dose of FP is also present in COPD. METHODS: 23 mild asthmatic and 24 COPD subjects with documented AHR to both AMP and methacholine took part in a randomized, double-blind, placebo-controlled, crossover study to measure AHR to inhaled AMP and methacholine 2 h after either 1000 µg FP or matched placebo. RESULTS: In subjects with asthma, 1000 µg FP in a single dose significantly attenuated the constrictor response to AMP, geometric mean (range) PC20AMP values increasing from a 19.2 (1.3-116.3) to 81.5 (9.6-1600.0) (p < 0.001; post-placebo vs post-FP) mg/ml. Change in the airways response to inhaled AMP after FP was well within test variability in patients with COPD, with PC20AMP values 59.6 (11.3-183.9) and 76.3 (21.0-445.3) (p = 0.022; post-placebo vs post-FP) mg/ml. Additionally, FP failed to significantly attenuate the bronchial response to methacholine in both asthma and COPD subjects. A change in doubling dilution, between placebo and following a single dose of FP, in AMP had a better sensitivity and specificity of 95.8% and 65.2%, compared to methacholine of 79.2% and 43.5% respectively in delineating between COPD and asthma. CONCLUSION: A single dose of 1000 µg FP rapidly improves AHR to AMP in asthmatics but not in COPD subjects. This may provide a convenient way by which provocation challenge with inhaled AMP may help in discriminating asthma from COPD.

Inhaled corticosteroids in chronic obstructive pulmonary disease: a pro-con perspective.

Current guidelines limit regular use of inhaled corticosteroids (ICS) to a specific subgroup of patients with chronic obstructive pulmonary disease (COPD) in whom the forced expiratory volume in 1 s is <60% of predicted and who have frequent exacerbations. In these patients, there is evidence that ICS reduce the frequency of exacerbations and improve lung function and quality of life. However, a review of the literature suggests that the evidence available may be interpreted to favour or contradict these observations. It becomes apparent that COPD is a heterogeneous condition. Clinicians therefore need to be aware of the heterogeneity as well as having an understanding of how ICS may be used in the context of the specific subgroups of patients with COPD. This review argues for and against the use of ICS in COPD by providing an in-depth analysis of the currently available evidence.

Preventing progression of allergic rhinitis to asthma.

The prevalence of allergic rhinitis (AR) is on the increase and this condition is frequently associated with asthma, thus leading to the concept that these two conditions are different aspects of the same disease. There is now accumulating evidence that AR often precedes the onset of asthmatic symptoms. This notion has important implications, not only for the diagnosis and management of these common allergic conditions but also for the potential progression of disease. Very little is known about the risk factors responsible for the progression of AR to asthma; current treatment options can control symptoms but do not prevent or cure the disease. However, there are recent data supporting the notion that it is possible to prevent new asthma cases by modifying the immune response and clinical outcome with allergen immunotherapy. This review article evaluates the impact of AR on the development of asthma, examines putative predictors for the progression of AR to asthma, and reviews recent, promising literature suggesting that early treatment of allergic individuals with immunotherapy may aid in asthma prevention.

Success rates with nicotine personal vaporizers: a prospective 6-month pilot study of smokers not intending to quit.

BACKGROUND: Electronic cigarettes (e-Cigs) are an attractive long-term alternative nicotine source to conventional cigarettes. Although they may assist smokers to remain abstinent during their quit attempt, studies using first generation e-Cigs report low success rates. Second generation devices (personal vaporisers - PVs) may result in much higher quit rates, but their efficacy and safety in smoking cessation and/or reduction in clinical trials is unreported. METHOD: We conducted a prospective proof-of-concept study monitoring modifications in smoking behaviour of 50 smokers (unwilling to quit) switched onto PVs. Participants attended five study visits: baseline, week-4, week-8, week-12 and week-24. Number of cigarettes/day (cigs/day) and exhaled carbon monoxide (eCO) levels were noted at each visit. Smoking reduction/abstinence rates, product usage, adverse events and subjective opinions of these products were also reviewed. RESULTS: Sustained 50% and 80% reduction in cigs/day at week-24 was reported in 15/50 (30%) and 7/50 (14%) participants with a reduction from 25cigs/day to 6cigs/day (p < 0.001) and 3cigs/day (p < 0.001), respectively. Smoking abstinence (self-reported abstinence from cigarette smoking verified by an eCO ≤10 ppm) at week-24 was observed in 18/50 (36%) participants, with 15/18 (83.3%) still using their PVs at the end of the study. Combined 50% reduction and smoking abstinence was shown in 33/50 (66%) participants. Throat/mouth irritation (35.6%), dry throat/mouth (28.9%), headache (26.7%) and dry cough (22.2%) were frequently reported early in the study, but waned substantially by week-24. Participants' perception and acceptance of the products was very good. CONCLUSION: The use of second generation PVs substantially decreased cigarette consumption without causing significant adverse effects in smokers not intending to quit. TRIAL REGISTRATION: (ClinicalTrials.gov Identifier: NCT02124200).

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.

Chemokine receptor 4 plays a key role in T cell recruitment into the airways of asthmatic patients.

T lymphocytes of the Th2 type are central orchestrators of airway inflammation in asthma. The mechanisms that regulate their accumulation in the asthmatic airways remains poorly understood. We tested the hypothesis that CCR4, preferentially expressed on T lymphocytes of the Th2 type, plays a critical role in this process. We enumerated by flow cytometry the CCR4-expressing T cells from blood, induced sputum, and biopsy samples of patients with asthma and control subjects. We showed a positive correlation between the numbers of peripheral blood CCR4+ T cells and asthma severity, provided evidence of preferential accumulation of CCR4+ T cells in asthmatic airways, and demonstrated that CCR4+ but not CCR4- cells from patients with asthma produce Th2 cytokines. Explanted airway mucosal biopsy specimens, acquired by bronchoscopy from subjects with asthma, were challenged with allergen and the explant supernatants assayed for T cell chemotactic activity. Allergen-induced ex vivo production of the CCR4 ligand, CCL17 was raised in explants from patients with asthma when compared with healthy controls. Using chemotaxis assays, we showed that the T cell chemotactic activity generated by bronchial explants can be blocked with a selective CCR4 antagonist or by depleting CCR4+ cells from responder cells. These results provide evidence that CCR4 might play a role in allergen-driven Th2 cell accumulation in asthmatic airways. Targeting this chemokine receptor in patients with asthma might reduce Th2 cell-driven airway inflammation; therefore, CCR4 antagonists could be an effective new therapy for asthma. This study also provides wider proof of concept for using tissue explants to study immunomodulatory drugs for asthma.

Associations between procalcitonin and markers of bacterial sepsis.

BACKGROUND: Bacterial sepsis with no bacterial isolates can be a difficult clinical conundrum, where other markers like C-reactive protein (CRP), white cell count (WCC), and neutrophilia are helpful to arrive at a diagnosis. Procalcitonin (PCT) has been shown to be a useful biomarker in bacterial sepsis. The aim of the study was to look at the association of PCT with bacterial cultures and compare this to currently used markers of bacterial sepsis. MATERIAL AND METHODS: WCC, neutrophil count, and CRP with PCT were compared in patients with a positive bacterial culture from blood/body fluid. The specificity and sensitivity of PCT were compared with those of CRP. RESULTS: Of the 99 paired samples obtained, 25 cultures were positive for bacteria. There was a significant difference in CRP (P=0.04) and PCT (P<0.001) levels between culture-positive and culture-negative samples. PCT had a better sensitivity and specificity than CRP (84% and 64.9% vs. 69.6% and 52.9%, respectively), with a combined specificity (CRP and PCT) of 83.5%. CONCLUSIONS: PCT has a better association with bacterial sepsis and is superior to currently available biomarkers in the clinical setting. The rapid pharmacodynamics of PCT can serve as an early predictor of the diagnosis of bacterial sepsis while awaiting the bacterial culture results avoiding undue delay in the institution of antibiotics, hence, potentially improving the prognosis of patients with bacterial sepsis.

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.

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.

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.

Circulating endothelial-coagulative activation markers after smoking cessation: a 12-month observational study.

BACKGROUND: Cigarette smoking is associated with cardiovascular morbidity and mortality. Exposure to cigarette smoke can cause endothelial dysfunction with impaired endothelium-dependent vasodilation and 'endothelial activation', which predispose to atherothrombosis. The effects of continued smoking and smoking cessation on the level of endothelial, platelet and clotting activation have not been described previously. Here, we prospectively monitored changes in circulating endothelial-coagulative activation markers in smokers undertaking smoking cessation. METHOD: This 12-month prospective study of 174 smokers with no commonly acquired atherothrombotic risk factors underwent an intensive smoking-cessation programme investigating the effect of quitting on circulating levels of von Willebrand's Factor Antigen (vWF:Ag), soluble Thrombomodulin (sTM), d-Dimer (d-D), prothrombin fragment F1+2 (F1+2), platelet factor-4 (PF4) and ß-Thromboglobulin (ß-TG). Blood samples and study measures were collected and compared at baseline and at 2, 6 and 12months after smoking cessation from quitters and relapsers'. RESULTS: No significant differences in demographic or laboratory parameters at baseline were observed between the study groups. Significant changes in von Willebrand's Factor activity were observed at 2months after smoking cessation, with levels decreasing from 141·8% to 113·6%. Substantial modifications in d-Dimer, prothrombin fragment F1 +2, platelet factor-4 and ß-thromboglobulin concentrations were observed only at 6 and 12months after smoking cessation. Positive associations between baseline levels of these biomarkers and number of pack per years have been demonstrated. CONCLUSIONS: Chronic exposure to cigarette smoke sustains the activation of the endothelial-coagulative system and abstinence may result in the improvement of several endothelial-coagulative abnormalities in regular smokers. This may translate into an overall decline in cardiovascular risk.

Monoclonal antibodies for the treatment of severe asthma.

Patients with severe asthma have a significant unmet need with persistent symptoms and/or frequent exacerbations despite treatment with high-dose steroid and other currently available therapies. These patients are also at risk of developing steroid-related side effects, and their severe, unrelenting symptoms have a huge impact on health care resources due to frequent hospital admissions and requirement for intensive medication use. Consequently, a compelling need exists for more effective and safer pharmacotherapies to help them achieve adequate disease control. Recent novel therapies for severe asthma are now emerging, some of the most promising of which are monoclonal antibodies. Monoclonal antibodies represent a form of immunotherapy used in a wide variety of therapeutic roles. The spectrum of disease states in which monoclonal antibodies have been approved for therapeutic use now includes respiratory and allergic diseases. At present, only one drug is licensed for allergic asthmatics with severe disease, omalizumab. We review some of the currently available biologics that are approved or under investigation for use in severe asthma. Some have shown to be useful in specifically targeted subpopulations of patients with severe asthma, whereas other have proven to be unsafe and/or unsuccessful. Despite these developments, more effort should be devoted to identifying new molecular targets, testing innovative approaches, and establishing the best use of what is available. Regarding this latter point, identifying individual characteristics that predict successful responses to these treatments is highly desirable.