New drugs targeting Th2 lymphocytes in asthma

Asthma represents a profound worldwide public health problem. The most effective anti-asthmatic drugs currently available include inhaled β2-agonists and glucocorticoids and control asthma in about 90-95% of patients. The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term therapy. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the lower airway remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses. The development of novel drugs may allow resolution of these changes. In addition, severe glucocorticoid-dependent and resistant asthma presents a great clinical burden and reducing the side-effects of glucocorticoids using novel steroid-sparing agents is needed. Furthermore, the mechanisms involved in the persistence of inflammation are poorly understood and the reasons why some patients have severe life threatening asthma and others have very mild disease are still unknown. Drug development for asthma has been directed at improving currently available drugs and findings new compounds that usually target the Th2-driven airway inflammatory response. Considering the apparently central role of T lymphocytes in the pathogenesis of asthma, drugs targeting disease-inducing Th2 cells are promising therapeutic strategies. However, although animal models of asthma suggest that this is feasible, the translation of these types of studies for the treatment of human asthma remains poor due to the limitations of the models currently used. The myriad of new compounds that are in development directed to modulate Th2 cells recruitment and/or activation will clarify in the near future the relative importance of these cells and their mediators in the complex interactions with the other pro-inflammatory/anti-inflammatory cells and mediators responsible of the different asthmatic phenotypes. Some of these new Th2-oriented strategies may in the future not only control symptoms and modify the natural course of asthma, but also potentially prevent or cure the disease

Azithromycin in COVID-19 Patients: Pharmacological Mechanism, Clinical Evidence and Prescribing Guidelines

The global COVID-19 pandemic has led to a race to find medications that can improve the prognosis of the disease. Azithromycin, in association with hydroxychloroquine or chloroquine, has been proposed as one such medication. The aim of this review is to describe the pharmacological mechanism, clinical evidence and prescribing guidelines concerning azithromycin in COVID-19 patients. There is weak evidence on the antiviral and immunomodulating effects of azithromycin, which in addition is not based on results from COVID-19 patients specifically. Therefore, this antibacterial should be considered only as empirical treatment of community-acquired pneumonia (CAP), although not all current treatment guidelines are in agreement. After the initial expectations raised by a small trial, more recent evidence has raised serious safety concerns on the use of hydroxychloroquine or chloroquine with azithromycin to treat COVID-19 patients, as all these drugs have arrhythmogenic potential. The World Health Organization has not made recommendations suggesting the use of azithromycin with hydroxychloroquine or chloroquine as treatment for COVID-19, but some national organisations have taken a different position, recommending this as first-line treatment. Several scientific societies, including the American College of Cardiology, have cautioned about the risks of this treatment in view of the lack of evidence concerning its benefits

Hereditary hyperhomocysteinemia associated with nephrotic syndrome complicated by artery thrombosis and chronic thromboembolic pulmonary hypertension: A case report.

We present here the case of a 30-year-old man with a long term history of nephrotic syndrome (NS) who developed an episode of acute left main pulmonary artery thrombosis complicated by a lung abscess. During the hospital admission was also identified a concomitant hyperhomocysteinemia. After an atypical resection of the left upper pulmonary lobe and the starting of long term anticoagulation the patient was discharged but did not attend the planned follow up visits until one year later when he was seen again for severe dyspnea and exercise intolerance. At this time chronic thromboembolic pulmonary hypertension (CTEPH) was diagnosed by lung perfusion scintigraphy and right heart catheterization. He initially refused the surgical treatment but, after six months, for the presence of worsening dyspnea was referred for bilateral pulmonary endarterectomy followed by a cardio-thoracic rehabilitation program. After a follow-up of seven years the patient is alive and in stable conditions. NS and hyperhomocysteinemia are both known risk factors for pulmonary embolism (PE), but their association with CTEPH is extremely rare. We discuss here the possible mechanisms linking these conditions. CTEPH must be suspected in any patient with NS, with or without hyperhomocysteinemia, and unexplained dyspnea

A middle-age non-smoking woman with uncontrolled persistent bronchial asthma

A 51 year-old female was referred to our attention in our outpatient clinic for persistent dyspnea on exertion and cough. Her past medical history was characterized, in the last 7 years, by atopic uncontrolled persistent bronchial asthma and bronchiectasis. The patient was only using affixed dose combination of inhaled glucocorticoid and long-acting beta2 agonist as needed. The presence of comorbidities that may influence asthma control and the response to the antiasthma drugs were excluded. The patient was educated to using correctly her drug devices and on the fundamental relevance of adhering a regular asthma treatment, according to the medical recommendations. Within one month of regular antiasthma therapy, her asthma was well controlled. Bronchial Asthma is a chronic inflammatory disease of the lower airways whose management needs long-term adherence to the prescribed anti-inflammatory therapy. Despite the clinical efficacy of current asthmatherapies, a low level of adherence is a frequent issue in clinical practice. Before defining a patient as affected by severe asthma, it is mandatory to carefully evaluate its long-term adherence to the asthma treatment and to exclude the presence of comorbidities that may cause asthma like-symptoms and/or reduce the efficacy of antiasthma dru

The anti-proliferative and anti-inflammatory response of COPD airway smooth muscle cells to hydrogen sulfide

BACKBROUND: COPD is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease caused, in part, by the aberrant function of airway smooth muscle (ASM). We have previously demonstrated that hydrogen sulfide (H2S) can inhibit ASM cell proliferation and CXCL8 release, from cells isolated from non-smokers. METHODS: We examined the effect of H2S upon ASM cells from COPD patients. ASM cells were isolated from non-smokers, smokers and patients with COPD (n = 9). Proliferation and cytokine release (IL-6 and CXCL8) of ASM was induced by FCS, and measured by bromodeoxyuridine incorporation and ELISA, respectively. RESULTS: Exposure of ASM to H2S donors inhibited FCS-induced proliferation and cytokine release, but was less effective upon COPD ASM cells compared to the non-smokers and smokers. The mRNA and protein expression of the enzymes responsible for endogenous H2S production (cystathionine-β-synthase [CBS] and 3-mercaptopyruvate sulphur transferase [MPST]) were inhibited by H2S donors. Finally, we report that exogenous H2S inhibited FCS-stimulated phosphorylation of ERK-1/2 and p38 mitogen activated protein kinases (MAPKs), in the non-smoker and smoker ASM cells, with little effect in COPD cells. CONCLUSIONS: H2S production provides a novel mechanism for the repression of ASM proliferation and cytokine release. The ability of COPD ASM cells to respond to H2S is attenuated in COPD ASM cells despite the presence of the enzymes responsible for H2S production

Overlap and common correlates between depression and COPD: a narrative review

Background: Chronic obstructive pulmonary disease (COPD) is characterized by a burden of comorbid conditions, including depression, that has been related with an increased risk of exacerbations, low adherence to pharmacological treatments and behavioral interventions, and overall mortality rates. The aim of the present review was to explore the comorbidity between depression and COPD by examining epidemiological and etiopathogenetic perspectives, along with shared risk factors including the potential role of hypoxia, systemic inflammation, and drugs for COPD treatment. Methods: the aim of this work was to review studies published in the last eleven years, using Medline/PubMed, Scopus, and Google Scholar as search engines and the following terms “Mood Disorders", "Hypoxia "Pulmonary Disease, Chronic Obstructive", “Chronic obstructive pulmonary disease”, linked by the Boolean operator “AND”. Articles were included in the review if written in English and containing quantitative and qualitative information on Depression, Chronic Obstructive Pulmonary Disease, and Hypoxia.  Exclusion criteria were studies in languages other than English, irrelevant articles to the examined topic reviews, case reports, case series, and articles on animal models. Results: The present review has confirmed the increased risk of depression onset in COPD patients, suggesting a strong multifactorial and bidirectional correlation between the two conditions. Hypoxia has been emphasized as a key mechanism in both diseases, whereas evidence on shared inflammatory and molecular pathways is still limited.  Conclusions: The multifactorial nature of the bidirectional correlation between COPD and depression is far from being entirely understood. Comorbid depression negatively affects COPD course and severity, along with patients’ functioning, psychological well-being and quality of life. Well-designed pre-clinical and clinical studies on the genetic, molecular, and neurobiological pathways which underlie the comorbidity between COPD and depression are needed for addressing the clinical implications and treatment options. needs more research efforts to be clarified. Further studies are mandatory to improve our knowledge on the co-presence of these two widespread diseases

Primary Pulmonary Epithelioid Hemangioendothelioma: A Rare Cause of PET-Negative Pulmonary Nodules

We report here a case of primary pulmonary epithelioid hemangioendothelioma diagnosed in a 67-year-old Caucasian man, presenting with exertion dyspnoea, dry cough, and multiple bilateral pulmonary nodules revealed by computed tomography. At the 18F-fluorodeoxyglucose positron emission tomography, these nodules were negative. The histopathological diagnosis was made on a pulmonary wedge resection (performed during video-thoracoscopic surgery)

STAT6 expression in T cells, alveolar macrophages and bronchial biopsies of normal and asthmatic subjects

<p>Abstract</p> <p>Background</p> <p>Asthma is characterised by increased numbers of Th2-like cells in the airways and IgE secretion. Generation of Th2 cells requires interleukin (IL)-4 and IL-13 acting through their specific receptors and activating the transcription factor, signal transducer and activator of transcription 6 (STAT6). STAT6 knockout mice fail to produce IgE, airway hyperresponsiveness and bronchoalveolar lavage eosinophilia after allergen sensitisation, suggesting a critical role for STAT6 in allergic responses.</p> <p>Methods</p> <p>We have investigated the expression of STAT6 in peripheral blood T-lymphocytes, alveolar macrophages and bronchial biopsies from 17 normal subjects and 18 mild-moderate steroid-naïve stable asthmatic patients.</p> <p>Results</p> <p>STAT6 expression was variable and was detected in T-lymphocytes, macrophages and bronchial epithelial cells from all subjects with no difference between normal and stable asthmatic subjects.</p> <p>Conclusions</p> <p>STAT6 expression in different cells suggests that it may be important in regulating the expression of not only Th2-like cytokines in T cells of man, but may also regulate STAT-inducible genes in alveolar macrophages and airway epithelial cells.</p

A case of lung injury resembling diffuse pulmonary hemorrhage after the first administration of alemtuzumab in a patient with multiple sclerosis. Role of the HRCT

Diffuse pulmonary hemorrhage (DPH) is an uncommon, acute condition characterized by a variable combination of hemoptysis, dyspnoea, anemia, hypoxernia, and an initial nonspecific imaging features such as diffuse and bilateral ground glass pulmonary opacities that can be induced by different causes. DPH is a rare manifestation of adverse drug reactions. We report here the case of a 25-year-old woman that has been admitted to our pulmonary clinic for the onset of chest pain, cough and haemoptysis, started one week after her first treatment with alemtuzumab for multiple sclerosis. Computed tomography (CT) scan of the chest at the admission showed diffuse and bilateral ground glass pulmonary opacities. Her symptoms resolved completely without any treatment, after the interruption of alemtuzumab, and a CT scan of the chest performed one month later showed total disappearance of the pulmonary opacities