Interrelationship between COVID-19 and Coagulopathy: Pathophysiological and Clinical Evidence.

Since the first description of COVID-19 infection, among clinical manifestations of the disease, including fever, dyspnea, cough, and fatigue, it was observed a high incidence of thromboembolic events potentially evolving towards acute respiratory distress syndrome (ARDS) and COVID-19-associated-coagulopathy (CAC). The hypercoagulation state is based on an interaction between thrombosis and inflammation. The so-called CAC represents a key aspect in the genesis of organ damage from SARS-CoV-2. The prothrombotic status of COVID-19 can be explained by the increase in coagulation levels of D-dimer, lymphocytes, fibrinogen, interleukin 6 (IL-6), and prothrombin time. Several mechanisms have been hypothesized to explain this hypercoagulable process such as inflammatory cytokine storm, platelet activation, endothelial dysfunction, and stasis for a long time. The purpose of this narrative review is to provide an overview of the current knowledge on the pathogenic mechanisms of coagulopathy that may characterize COVID-19 infection and inform on new areas of research. New vascular therapeutic strategies are also reviewed.

Potential role of diacylglycerol kinases in immune-mediated diseases.

The mechanism promoting exacerbated immune responses in allergy and autoimmunity as well as those blunting the immune control of cancer cells are of primary interest in medicine. Diacylglycerol kinases (DGKs) are key modulators of signal transduction, which blunt diacylglycerol (DAG) signals and produce phosphatidic acid (PA). By modulating lipid second messengers, DGK modulate the activity of downstream signaling proteins, vesicle trafficking and membrane shape. The biological role of the DGK α and ζ isoforms in immune cells differentiation and effector function was subjected to in deep investigations. DGK α and ζ resulted in negatively regulating synergistic way basal and receptor induced DAG signals in T cells as well as leukocytes. In this way, they contributed to keep under control the immune response but also downmodulate immune response against tumors. Alteration in DGKα activity is also implicated in the pathogenesis of genetic perturbations of the immune function such as the X-linked lymphoproliferative disease 1 and localized juvenile periodontitis. These findings suggested a participation of DGK to the pathogenetic mechanisms underlying several immune-mediated diseases and prompted several researches aiming to target DGK with pharmacologic and molecular strategies. Those findings are discussed inhere together with experimental applications in tumors as well as in other immune-mediated diseases such as asthma.

Association of FEF25-75% Impairment with Bronchial Hyperresponsiveness and Airway Inflammation in Subjects with Asthma-Like Symptoms.

BACKGROUND: Forced expiratory flow at 25 and 75% of the pulmonary volume (FEF25-75%) might be considered as a marker of early airway obstruction. FEF25-75% impairment might suggest earlier asthma recognition in symptomatic subjects even in the absence of other abnormal spirometry values. OBJECTIVES: The study was designed in order to verify whether FEF25-75% impairment in a cohort of subjects with asthma-like symptoms could be associated with the risk of bronchial hyperresponsiveness (BHR) and with airway inflammation expressed as fractional exhaled nitric oxide (FeNO) and eosinophil counts in induced sputum. METHODS: Four hundred adults with a history of asthma-like symptoms (10.5% allergic) underwent spirometry, determination of BHR to methacholine (PD20FEV1), FeNO analysis and sputum induction. FEF25-75% <65% of predicted or <-1.64 z-score was considered abnormal. RESULTS: All subjects had normal FVC, FEV1 and FEV1/FVC, while FEF25-75% was abnormal in 27.5% of them. FEF25-75% (z-score) was associated with PD20FEV1 (p < 0.001), FeNO (p < 0.001) and sputum eosinophils (p < 0.001). Patients with abnormal FEF25-75% showed higher levels of FeNO and eosinophils in induced sputum than did patients with normal FEF25-75% (p < 0.01 and p < 0.01, respectively). Subjects with abnormal FEF25-75% had an increased probability of being BHR positive (OR = 13.38; 95% CI: 6.7-26.7; p < 0.001). CONCLUSIONS: Our data show that abnormal FEF25-75% might be considered an early marker of airflow limitation associated with eosinophilic inflammation and BHR in subjects with asthma-like symptoms, indicating a role for FEF25-75% as a predictive marker of newly diagnosed asthma.

Lung Involvement in Patients with Ulcerative Colitis: Relationship between Exhaled Nitric Oxide and Lung Function.

Ulcerative colitis (UC) is characterized by immune system dysregulation with frequent extraintestinal manifestations, including airway involvement. A reduction in CO diffusing capacity and functional alterations in small airways have been described. An extended analysis of fractional exhaled nitric oxide (FeNO) may distinguish the sites of production, and the presence of small airway inflammation may be a useful, non-invasive marker for patient follow-up. The aim of our study was to compare the PFTs as well as FeNO and CANO values of UC patients with different clinical disease activities and healthy subjects to reveal lung function abnormalities and the presence of subclinical airway inflammation. We enrolled 42 adult outpatients at different clinical activity stages of UC (39 ± 13 years) and a healthy control group of 41 subjects (29 ± 3 years). C-reactive protein (CRP) and FeNO values at different flows (50,100, and 200 mL/s) were collected. All patients performed pulmonary function tests (PFTs) with static volumes and diffusing capacity (DLCO). FeNO and CANO values were significantly increased in UC patients when compared with controls (p = 0.0008 and p < 0.0001, respectively) and were proportional to disease activity (FeNO class 3: 28.1 ppb vs. classes 1-2: 7.7 ppb; CANO values class 3: 8.6 ppb vs. classes 1-2: 2.7 ppb (p < 0.0001)). TLC and DLCO were significantly reduced in severe (Mayo 3) UC patients (p = 0.010 and p = 0.003, respectively). The results of this study show significant lung functional abnormalities in UC patients and suggest the presence of airway inflammation directly correlated with disease activity, suggesting the need for an integrated approach in routine assessment.

Bronchial Progenitor Cells in Obstructive and Neoplastic Lung Disease: A Pilot Study.

The alteration of progenitor/stem cells present in the airway epithelium has been observed in patients with COPD. Smoking exposure induces remodeling patterns in bronchial progenitor cells (BPCs), encompassing squamous metaplasia, hyperplasia of basal and of mucus-secreting cells, and the depletion of ciliated and non-mucous secretory cells. Our aim was to assess the expression of p63 and vimentin as potential markers of airway remodeling and the regulation of stem cell populations in obstructive and neoplastic lung disease patients. A retrospective single-center observational study was conducted, including patients undergoing bronchoscopy with bronchial biopsies for suspected lung cancer. p63 and vimentin expression were evaluated via immunohistochemical analysis. There were 25 patients, of which 21 with COPD were included, and 17 were diagnosed with lung cancer. We observed that FEV1% was negatively correlated with p63+ basal cell number (r = -0.614, p = 0.019) and positively correlated with vimentin expression (r = 0.670; p = 0.008). p63 was significantly higher in biopsies from the trachea and main bronchi compared to more distal areas (p = 0.040), whereas vimentin was prevalent in the more distal areas (p = 0.042). Our preliminary data suggest the initial evidence of structural changes in BPCs among patients with COPD and lung cancer. Further research efforts are warranted to investigate additional morphologic and functional respiratory parameters in these patients.

Effect of high flow nasal oxygen on inspiratory effort of patients with acute hypoxic respiratory failure and do not intubate orders.

High flow nasal oxygen (HFNO) is recommended as a first-line respiratory support during acute hypoxic respiratory failure (AHRF) and represents a proportionate treatment option for patients with do not intubate (DNI) orders. The aim of the study is to assess the effect of HFNO on inspiratory effort as assessed by esophageal manometry in a population of DNI patients suffering from AHRF. Patients with AHRF and DNI orders admitted to Respiratory intermediate Care Unit between January 1st, 2018 and May 31st, 2023 to receive HFNO and subjected to esophageal manometry were enrolled. Esophageal pressure swing (ΔPes), clinical variables before and after 2 h of HFNO and clinical outcome (including HFNO failure) were collected and compared as appropriate. The change in physiological and clinical parameters according to the intensity of baseline breathing effort was assessed and the correlation between baseline ΔPes values and the relative change in breathing effort and clinical variables after 2 h of HFNO was explored. Eighty-two consecutive patients were enrolled according to sample size calculation. Two hours after HFNO start, patients presented significant improvement in ΔPes (12 VS 16 cmH2O, p < 0.0001), respiratory rate (RR) (22 VS 28 bpm, p < 0.0001), PaO2/FiO2 (133 VS 126 mmHg, p < 0.0001), Heart rate, Acidosis, Consciousness, Oxygenation and respiratory rate (HACOR) score, (4 VS 6, p < 0.0001), Respiratory rate Oxygenation (ROX) index (8.5 VS 6.1, p < 0.0001) and BORG (1 VS 4, p < 000.1). Patients with baseline ΔPes below 20 cmH2O where those who improved all the explored variables, while patients with baseline ΔPes above 30 cmH2O did not report significant changes in physiological or clinical features. A significant correlation was found between baseline ΔPes values and after 2 h of HFNO (R2 = 0.9, p < 0.0001). ΔPes change 2 h after HFNO significantly correlated with change in BORG (p < 0.0001), ROX index (p < 0.0001), HACOR score (p < 0.001) and RR (p < 0.001). In DNI patients with AHRF, HFNO was effective in reducing breathing effort and improving respiratory and clinical variables only for those patients with not excessive inspiratory effort.

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.

Circulating Peptidome Is Strongly Altered in COVID-19 Patients.

Whilst the impact of coronavirus disease 2019 (COVID-19) on the host proteome, metabolome, and lipidome has been largely investigated in different bio-fluids, to date, the circulating peptidome remains unexplored. Thus, the present study aimed to apply an untargeted peptidomic approach to provide insight into alterations of circulating peptides in the development and severity of SARS-CoV-2 infection. The circulating peptidome from COVID-19 severe and mildly symptomatic patients and negative controls was characterized using LC-MS/MS analysis for identification and quantification purposes. Database search and statistical analysis allowed a complete characterization of the plasma peptidome and the detection of the most significant modulated peptides that were impacted by the infection. Our results highlighted not only that peptide abundance inversely correlates with disease severity, but also the involvement of biomolecules belonging to inflammatory, immune-response, and coagulation proteins/processes. Moreover, our data suggested a possible involvement of changes in protein degradation patterns. In the present research, for the first time, the untargeted peptidomic approach enabled the identification of circulating peptides potentially playing a crucial role in the progression of COVID-19.

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.

Sleep Deprivation, Immune Suppression and SARS-CoV-2 Infection.

Sleep health and its adaptation to individual and environmental factors are crucial to promote physical and mental well-being across animal species. In recent years, increasing evidence has been reported regarding the relationship between sleep and the immune system and how sleep disturbances may perturb the delicate balance with severe repercussions on health outcomes. For instance, experimental sleep deprivation studies in vivo have reported several major detrimental effects on immune health, including induced failure of host defense in rats and increased risk for metabolic syndrome (MetS) and immune suppression in humans. In addition, two novel risk factors for dysregulated metabolic physiology have recently been identified: sleep disruption and circadian misalignment. In light of these recent findings about the interplay between sleep and the immune system, in this review, we focus on the relationship between sleep deprivation and immunity against viruses, with a special interest in SARS-CoV-2 infection.

Interrelationship Between Obstructive Sleep Apnea Syndrome and Severe Asthma: From Endo-Phenotype to Clinical Aspects.

Sleep-related breathing disorders (SBDs) are characterized by abnormal respiration during sleep. Obstructive sleep apnea (OSA), a common SBD increasingly recognized by physicians, is characterized by recurrent episodes of partial or complete closure of the upper airway resulting in disturbed breathing during sleep. OSA syndrome (OSAS) is associated with decreased patients' quality of life (QoL) and the presence of significant comorbidities, such as daytime sleepiness. Similarly to what seen for OSAS, the prevalence of asthma has been steadily rising in recent years. Interestingly, severe asthma (SA) patients are also affected by poor sleep quality-often attributed to nocturnal worsening of their asthma-and increased daytime sleepiness and snoring compared to the general population. The fact that such symptoms are also found in OSAS, and that these two conditions share common risk factors, such as obesity, rhinitis, and gastroesophageal reflux, has led many to postulate an association between these two conditions. Specifically, it has been proposed a bidirectional correlation between SA and OSAS, with a mutual negative effect in term of disease severity. According to this model, OSAS not only acts as an independent risk factor of asthma exacerbations, but its co-existence can also worsen asthma symptoms, and the same is true for asthma with respect to OSAS. In this comprehensive review, we summarize past and present studies on the interrelationship between OSAS and SA, from endo-phenotype to clinical aspects, highlighting possible implications for clinical practice and future research directions.

Comorbid Insomnia and Obstructive Sleep Apnea (COMISA): Current Concepts of Patient Management.

Obstructive sleep apnea (OSA) and insomnia are the two most common sleep disorders among the general population, and they may often coexist in patients with sleep-disordered breathing (SDB). The higher prevalence of insomnia symptoms in patients with OSA (40-60%) compared to that observed in the general population has thus led researchers to identify a new disorder named comorbid insomnia and OSA (COMISA), whose true burden has been so far largely underestimated. The combined treatment of COMISA patients with positive-airway pressure ventilation (PAP) with cognitive behavioral therapy for insomnia (CBTi) has shown a better patient outcome compared to that obtained with a single treatment. Furthermore, recent evidence has shown that an innovative patient-centered approach taking into consideration patient characteristics, treatment preferences and accessibility to treatment is recommended to optimize clinical management of COMISA patients. However, in this complex mosaic, many other sleep disorders may overlap with COMISA, so there is an urgent need for further research to fully understand the impact of these therapies on outcomes for OSA patients with comorbidity. In light of this need, this review focuses on the major sleep disorders comorbid with OSA and the recent advances in the management of these insomniac patients.

Exosomes in chronic respiratory diseases.

Exosomes are nano-sized vesicles released by almost all cell types, with a central role as mediators of intercellular communication. In addition to physiological conditions, these extracellular vesicles seem to play a pivotal role in inflammatory processes. This assumption offers the opportunity to study exosomes as promising biomarkers and therapeutic tools for chronic respiratory disorders. Indeed, although it is well-known that at the basis of conditions like asthma, chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency and idiopathic pulmonary fibrosis there is a dysregulated inflammatory process, an unequivocal correlation between different phenotypes and their pathophysiological mechanisms has not been established yet. In this review, we report and discuss some of the most significant studies on exosomes from body fluids of subjects affected by airway diseases. Furthermore, the most widespread techniques for exosome isolation and characterization are described. Further studies are needed to answer the unresolved questions about the functional link between exosomes and chronic respiratory diseases.

Predictive Markers of Bronchial Hyperreactivity in a Large Cohort of Young Adults With Cough Variant Asthma.

Cough variant asthma (CVA), a common asthma phenotype characterized by nonproductive cough and bronchial hyperreactivity (BHR), is usually detected by bronchial provocation tests (BPTs) which are time-consuming, expensive, and unsafe. The primary study objective was to provide proof of concept for the use of fractional exhaled nitric oxide (FENO), eosinophil count percentage in induced sputum (sEOS%), forced expiratory flow between 25 and 75% of forced vital capacity (FEF25-75%) % predicted value, and FEF25-75% z-scores as surrogate markers predicting BHR in young adults with suspected CVA; the secondary objective was to compare the diagnostic performance of the various techniques. Three hundred and ten subjects (median age 24 years) were included in a cross-sectional study. Subjects were characterized as BHR positive (POS) (n = 147) or BHR negative (NEG) (n = 163) according to methacholine BPT. Classification accuracies were expressed as areas under the receiver operator characteristic curves (AUC). Compared with BHR NEG, FEF25-75% % predicted value and FEF25-75% z-scores were lower in the BHR POS group (p < 0.001), whereas FENO (p < 0.001) and sEOS% were higher (p < 0.001). AUC values for detecting BHR were as follows: FENO, 0.98 (SD = 0.02); sEOS%, 0.98 (SD = 0.02); FEF25-75% % pred, 0.93 (SD = 0.05); FEF25-75% z scores, 0.92 (SD = 0.05). Optimal cutoff values (OCV) for BHR prediction were as follows: FENO, 32.7 ppb (sensitivity = 0.93, specificity = 0.96), sEOS%, 3.80% (sensitivity = 0.94, specificity = 0.94), FEF25-75% % predicted value, 80.0% (sensitivity = 0.90, specificity = 0.87), and FEF25-75% z-score, -0.87 (sensitivity = 0.89, specificity = 0.87). Non-invasive/semi-invasive airway inflammatory or small airway functional measures might be used as surrogate markers predicting BHR in young adults with suspected CVA.

Identification of Key Phospholipids That Bind and Activate Atypical PKCs.

PKCζ and PKCι/λ form the atypical protein kinase C subgroup, characterised by a lack of regulation by calcium and the neutral lipid diacylglycerol. To better understand the regulation of these kinases, we systematically explored their interactions with various purified phospholipids using the lipid overlay assays, followed by kinase activity assays to evaluate the lipid effects on their enzymatic activity. We observed that both PKCζ and PKCι interact with phosphatidic acid and phosphatidylserine. Conversely, PKCι is unique in binding also to phosphatidylinositol-monophosphates (e.g., phosphatidylinositol 3-phosphate, 4-phosphate, and 5-phosphate). Moreover, we observed that phosphatidylinositol 4-phosphate specifically activates PKCι, while both isoforms are responsive to phosphatidic acid and phosphatidylserine. Overall, our results suggest that atypical Protein kinase C (PKC) localisation and activity are regulated by membrane lipids distinct from those involved in conventional PKCs and unveil a specific regulation of PKCι by phosphatidylinositol-monophosphates.

Focus on the Potential Role of Lung Ultrasound in COVID-19 Pandemic: What More to Do?

COVID-19, a novel severe acute respiratory syndrome (SARS) emerging in China's Hubei province in late 2019, due to a new coronavirus (SARS-CoV-2), is causing a global pandemic involving many areas of the world, which so far counts more than 43 million cases and more than 1,155,000 deaths worldwide [...].

Supporting healthcare workers on front lines of the Covid-19 fight.

Un unexpected infection by a novel coronavirus (SAR CoV-2) started by the end of December in Wuhan, China, spreading all over other countries, and Italy was one of the most affected ones. WHO declared the pandemic on 11th March, 2020. Despite the numerous unknown aspects of this infection, the healthcare system had to face a multidimensional emergency. Albania, a small country with a geographical, historical and cultural relationship with Italy was one of the first countries giving support and starting a profitable collaboration focusing on the mission to provide the necessary help for the health care workers. In order to help the Italian healthcare system to face up to the situation two medical teams firstly (in March) and a group of 60 health care workers later in April were sent to Italy (Brescia Hospital) to support clinical activities in departments with COVID-19 patients. This important contribution showed the great solidarity and helped to strengthen the partnership between the two countries.

Interrelationship among Obstructive Sleep Apnea, Renal Function and Survival: A Cohort Study.

Previous studies showed a bidirectional relationship between renal function decline and obstructive sleep apnea (OSA) syndrome. Continuous Positive Airway Pressure (C-PAP) treatment was shown to preserve the kidney function in OSA patients. This study aims to investigate the progression of long-term renal function in OSA patients treated with different PAP strategies (patients were divided into two groups, fixed C-PAP or other PAP-automatic and bilevel pressure). Comorbidities and 10-years survival were also evaluated. We performed a retrospective, observational, single-center, cohort study, including the first 40 consecutive patients enrolled from 2009 in the Respiratory disease Unit at the Vercelli University Hospital database. The patient inclusion criteria were: age ≥ 18 years with OSA syndrome according to AASM (American Academy of Sleep Medicine) guidelines. Creatinine serum levels (mg/dL) and the estimated Glomerular Filtration Rate (eGFR, mL/min calculated by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration equation)) were measured at 3 different time points: at baseline, 3 years and 8 years after PAP treatment. The Kaplan-Meier survival curves stratified according to PAP treatment and compliance have been reported together with log-rank test estimation. In our study, we found a significant creatinine serum level reduction after 3 years of fixed C-PAP treatment (p value = 0.006) when compared to baseline values. However, we observed that the long-term C-PAP benefit was not significant (p value = 0.060). Our data confirmed the progressive renal function decline in OSA patients, especially in those using other-PAP treatments; nevertheless, OSA treatment with a fixed C-PAP device has shown, in the short term, a significant improvement in renal function. By contrast, in our study, long-term benefits after 8 years are not been demonstrated probably because of the lack of compliance of the patients and the aging effect.

Usefulness of exhaled nitric oxide and sputum eosinophils in the long-term control of eosinophilic asthma.

BACKGROUND: The aim of the present study was to treat unstable asthma according to exhaled nitric oxide (eNO) and induced-sputum eosinophils (sEos) levels to assess if this strategy is better than the conventional approach based on symptoms and function to achieve asthma control. METHODS: Fourteen patients with mild-to-moderate persistent asthma (6 men, 8 women) were recruited. During the recruitment visit, the patients, previously treated for asthma following Global Initiative for Asthma recommendations, underwent clinical evaluation and pulmonary function tests (PFTs). Then, after 4 weeks of washout from inhaled antiinflammatory treatment, the patients underwent a basal visit performing PFTs, challenge test to methacholine, and determination of eNO and sEos counts. These procedures were repeated after 3, 6, and 12 months while the patients were treated with inhaled steroids in a stepwise fashion according to eNO and sEos values. RESULTS: At the end of the study, a significant decrease in eNO and sEos was observed (57.2 +/- 32.8 parts per billion [ppb] vs 22.1 +/- 10.8 ppb, p < 0.01; and 27.1 +/- 27.1% vs 3.7 +/- 3.5%, p < 0.01, respectively). A close correlation (r2 = 0.41, p < 0.01) between the percentage change of eNO and sEos was observed only after 6 months. Patients treated according to the levels of these inflammatory markers had fewer symptoms and fewer exacerbations compared to those the year before when they were conventionally treated. CONCLUSIONS: Our results show the usefulness of eNO and sEos for titrating treatment in asthmatic patients in order to achieve better long-term control of the disease. The eNO decrease reflects adequately the reduction of sEos only after 6 months.

Ambroxol in the 21st century: pharmacological and clinical update.

BACKGROUND: Belonging to the group of expectorants, ambroxol is an active substance with a long history that influences parameters considered to be the basis for the physiological production and the transport of the bronchial mucus. Therefore, ambroxol's indication is 'secretolytic therapy in acute and chronic bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport'. OBJECTIVE: The aim of this review is to evaluate the pharmacological and clinical data on the mucokinetic compound ambroxol. METHODS: The existing database that covers >40 years of pharmacological research and clinical development was analysed. Only studies with adequate study design were evaluated. CONCLUSION: Ambroxol is shown to exert several activities: i) secretolytic activity (i.e., promotes mucus clearance, facilitates expectoration, and eases productive cough); ii) anti-inflammatory and antioxidant activity; and iii) a local anaesthetic effect through sodium channel blocking at the level of the cell membrane. The reduction on chronic obstructive pulmonary disease exacerbations is consistent and clinically relevant. The anaesthetic effect is a new pharmacological action that could be beneficial in the management of acute respiratory tract infections. The efficacy and safety of ambroxol is well established.