Inhaled Drug Therapy-Associated Adverse Reactions in Obstructive Respiratory Diseases: A Review of a Decade of Reporting to the Portuguese Pharmacovigilance System

Inhaled medication used for treatment of chronic obstructive lung diseases (asthma, chronic obstructive pulmonary disease-COPD, and Asthma-COPD overlap) may be associated with adverse drug reactions (ADRs). The aim of this study was to characterise spontaneous reports (SRs) of suspected ADRs received by the Portuguese Pharmacovigilance System (PPS), from 2007 to 2017. Methods: Retrospective observational study of SRs associated with single substance and combination inhalers, analysed in terms of pharmacological class of the involved drugs, sex and age range of the involved patients, and seriousness and type of ADRs. Results: 230 SRs were analysed, accounting for a total of 599 suspected ADRs. Inhaled corticosteroid/long-acting beta-2 agonist combination had the highest frequency in SRs (32.2%) and in ADRs (32.7%). There was a slight predominance in men (51.3%) and non-elderly adults were the most affected age group (39.1%). Most SRs were serious (70.4%). In total, “respiratory, thoracic and mediastinal diseases” ADRs were the most reported (19.5%), with “dyspnea” being the most frequent (4.8%). Conclusions: Most SRs were associated with controller medications and were expected. Most ADRs involved non-elderly adults, were serious and of respiratory nature and many were due to overuse of reliever medication.

Data Analytical Approach for Regional Variation of Incidence Rates for Asthma and Other Chronic Obstructive Lung Diseases in Oman

Background This study aimed to examine regional differences for asthma and other chronic obstructive lung diseases. Information pertaining influence of region on asthma is not well established. Method The study was based on data collected from annual reports produced by the Ministry of Health over a ten-year period beginning from 2010 to 2019. Incidence rates per 10000 populations for the eleven regions in the Sultanate of Oman were analyzed using statistical tools including; analysis of variance and binary logistic regression model to determine the effect of region on asthma and other chronic obstructive lung diseases. Results The incident rates were found to be significantly different by region (F-value=27.07, p=0.00). There was no significant variation by year (F-value=1.05, p>0.407). Overall over the ten-year period the incidence rates stagnated between 250 and 300 per 10000 of the population, but showed a reducing trend between 2016 and 2019. The logistic regression model shows that compared to the Muscat region, all the other regions had significant increased odd ratios. Conclusion There is a significant evidence of regional variation in the incidence of asthma and other chronic obstructive lung diseases. This implies probable characteristics in geographical regions that are associated with asthma and other chronic obstructive lung diseases’ exacerbation. Five asthma-region classifications were identified from our analysis. Findings of this study may be used to guide decision making towards the management and control of asthma and chronic obstructive lung diseases.

Assembly and organization of the N-terminal region of mucin MUC5AC: Indications for structural and functional distinction from MUC5B

Elevated levels of MUC5AC, one of the major gel-forming mucins in the lungs, are closely associated with chronic obstructive lung diseases such as chronic bronchitis and asthma. It is not known, however, how the structure and/or gel-making properties of MUC5AC contribute to innate lung defense in health and drive the formation of stagnant mucus in disease. To understand this, here we studied the biophysical properties and macromolecular assembly of MUC5AC compared to MUC5B. To study each native mucin, we used Calu3 monomucin cultures that produced MUC5AC or MUC5B. To understand the macromolecular assembly of MUC5AC through N-terminal oligomerization, we expressed a recombinant whole N-terminal domain (5ACNT). Scanning electron microscopy and atomic force microscopy imaging indicated that the two mucins formed distinct networks on epithelial and experimental surfaces; MUC5B formed linear, infrequently branched multimers, whereas MUC5AC formed tightly organized networks with a high degree of branching. Quartz crystal microbalance-dissipation monitoring experiments indicated that MUC5AC bound significantly more to hydrophobic surfaces and was stiffer and more viscoelastic as compared to MUC5B. Light scattering analysis determined that 5ACNT primarily forms disulfide-linked covalent dimers and higher-order oligomers (i.e., trimers and tetramers). Selective proteolytic digestion of the central glycosylated region of the full-length molecule confirmed that MUC5AC forms dimers and higher-order oligomers through its N terminus. Collectively, the distinct N-terminal organization of MUC5AC may explain the more adhesive and unique viscoelastic properties of branched, highly networked MUC5AC gels. These properties may generate insight into why/how MUC5AC forms a static, “tethered” mucus layer in chronic muco-obstructive lung diseases.

Association between lung function and future risks of diabetes, asthma, myocardial infarction, hypertension and all-cause mortality

BackgroundWhile forced expiratory volume in 1 s (FEV1) is a hallmark of disease progression in chronic obstructive lung diseases, little is known about the relationship between baseline FEV1 and future risks of other medical conditions.ObjectiveTo study the association between baseline FEV1 and future risks of diabetes, asthma, myocardial infarction, hypertension and all-cause mortality.MethodsWe used data from the National Health and Nutrition Examination Survey and its Epidemiological Follow-Up Study. Our data provided longitudinal follow-up of the original cohort for up to 12 years. We used two competing risks approaches, the cause-specific hazard model and the Fine-Gray sub-distribution hazard model, to measure the associations between baseline FEV1 and future risks of the outcomes of interest. All models adjusted for major confounding factors.ResultsThe final sample included 3020 participants (mean baseline age: 44.64 years, standard deviation: 13.44). In the cause-specific hazard model, for every percent increase in the baseline percent predicted FEV1, the hazard of the event reduced by 2.5% (HR: 0.975 (95% Confidence Interval [CI]: 0.958, 0.994)) for diabetes, 4.3% (HR: 0.957 (95%CI: 0.932, 0.983)) for asthma, and 1.8% (HR: 0.982 (95%CI: 0.971, 0.992)) for all-cause mortality. There was no statistically significant association between baseline percent predicted FEV1 and future risks of myocardial infarction (HR: 0.987 (95%CI: 0.970, 1.004)) and hypertension (HR: 0.998 (95%CI: 0.992, 1.005)). Consistent results were observed for the Fine-Gray sub-distribution hazard model.ConclusionOur data suggests that lower percent predicted FEV1 values at baseline were significantly associated with higher future risks of diabetes, asthma, and all-cause mortality.

Red Blood Cell Distribution Width in Patients with Chronic Obstructive Lung Diseases: Alteration due to Severity of Exacerbation

Background: Elevated red blood cell distribution width (RDW) levels were associated with mortality in patients with stable chronic obstructive lung diseases (COPD). There are limited data about RDW levels in COPD exacerbation. Aim/Objective: The association of the RDW levels with the severity of the acute exacerbation of COPD (AECOPD) were evaluated according to admission location, (outpatient-clinic, ward and intensive care unit (ICU). Methods: Cross sectional retrospective study designed in tertiary chest dieases hospital. COPD patients admitted to hospital outpatiens-clinic, ward and ICU due to AECOPD were included. Patients demographics, RDW, C-reactive protein (CRP), biochemistry values were recorded. RDW values were subdivided below 0.11% (low), above and equal 0.15% (high) and between 0.11-0.15% (normal). Neutrophile to lymphocyte ratio (NLR) and platelet to mean platelet volume (PLT-MPV) were also calculated. Recorded values were compared according to where AECOPD was treated. Results: 2771 COPD patients (33% female) and 1429 outpatients-clinic, 1156 ward and 186 ICU were enrolled in the study. The median RWD values in outpatients-clinic, ward and ICU were 0.16 (0.09-0.26), 0.07 (0.01-0.14) and 0.01 (0.00-0.07) respectively (p<0.001). In outpatient to ward and ICU, low RDW values were significantly increased (31%, 66%, 83% respectively) and high RDW values significantly decreased (54%, 24%, 10%) (p<0.001). According to attack severity, low RDW values were determined. Conclusion: Patients with AECOPD, lower RDW values should be considered carefully. Lower RDW can be used for decision of COPD exacerbation severity and follow up treatment response. What is already known about this topic; In current studies, elevated RDW levels were associated with mortality in patients with stable COPD. What does this article add; Currently , there are limited data about RDW levels in COPD exacerbation. In the present study, the association of the RDW levels according to the severity of AECOPD were evaluated due to admission location.

Modeling Incidence Rate by Region: Analysis of Asthma and Other Chronic Obstructive Lung Diseases

This study aimed to examine regional differences for asthma and other chronic obstructive lung diseases. The study was based on data collected from annual reports produced by the Ministry of Health over a ten-year period beginning from 2010 to 2019. Incidence rates for eleven regions in the Sultanate of Oman were analyzed using statistical tools including; analysis of variance and binary logistic regression model to determine the effect of region on asthma and other chronic obstructive lung diseases. The incident rates were found to be significantly different by region (F-value=27.07, p=0.00). There was no significant variation by year (F-value=1.05, p>0.407). Overall over the ten-year period the incidence rates stagnated between 250 and 300 per 10000 of the population, but showed a reducing trend between 2016 and 2019. The logistic regression model shows that compared to the Muscat region, all the other regions had significant increased odd ratios. There is a significant evidence of regional variation in the incidence of asthma and other chronic obstructive lung diseases. This implies probable characteristics in geographical regions that are associated with asthma and other chronic obstructive lung diseases’ exacerbation. Five asthma-region classifications were identified from our analysis. Findings of this study may be used to guide decision making towards the management and control of asthma and chronic obstructive lung diseases.

Airway Epithelial Nucleotide Release Contributes to Mucociliary Clearance

Mucociliary clearance (MCC) is a dominant component of pulmonary host defense. In health, the periciliary layer (PCL) is optimally hydrated, thus acting as an efficient lubricant layer over which the mucus layer moves by ciliary force. Airway surface dehydration and production of hyperconcentrated mucus is a common feature of chronic obstructive lung diseases such as cystic fibrosis (CF) and chronic bronchitis (CB). Mucus hydration is driven by electrolyte transport activities, which in turn are regulated by airway epithelial purinergic receptors. The activity of these receptors is controlled by the extracellular concentrations of ATP and its metabolite adenosine. Vesicular and conducted pathways contribute to ATP release from airway epithelial cells. In this study, we review the evidence leading to the identification of major components of these pathways: (a) the vesicular nucleotide transporter VNUT (the product of the SLC17A9 gene), the ATP transporter mediating ATP storage in (and release from) mucin granules and secretory vesicles; and (b) the ATP conduit pannexin 1 expressed in non-mucous airway epithelial cells. We further illustrate that ablation of pannexin 1 reduces, at least in part, airway surface liquid (ASL) volume production, ciliary beating, and MCC rates.

Modeling Incidence Rate by Region: Analysis of Asthma and Other Chronic Obstructive Lung Diseases

This study aimed to examine regional differences for asthma and other chronic obstructive lung diseases. The study was based on data collected from annual reports produced by the Ministry of Health over a ten-year period beginning from 2010 to 2019. Incidence rates for eleven regions in the Sultanate of Oman were analyzed using statistical tools including; analysis of variance and binary logistic regression model to determine the effect of region on asthma and other chronic obstructive lung diseases. The incident rates were found to be significantly different by region (F-value = 27.07, p = 0.00). There was no significant variation by year (F-value = 1.05, p > 0.407). Overall over the ten-year period the incidence rates stagnated between 250 and 300 per 10000 of the population, but showed a reducing trend between 2016 and 2019. The logistic regression model shows that compared to the Muscat region, all the other regions had significant increased odd ratios. There is a significant evidence of regional variation in the incidence of asthma and other chronic obstructive lung diseases. This implies probable characteristics in geographical regions that are associated with asthma and other chronic obstructive lung diseases’ exacerbation. Five asthma-region classifications were identified from our analysis. Findings of this study may be used to guide decision making towards the management and control of asthma and chronic obstructive lung diseases.