ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

In silico modelling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. MaVie16 induced profound pathology in BALB/c and C57BL/6 mice and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNg and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo.

Evaluating the technique of using MDI and DPI in patients with respiratory disease

Inhalation therapy plays a major role in treatment of respiratory diseases. Correct inhalation technique is crucial for effective clinical outcomes. The aim of this study was to evaluate and analyse technique of use of Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) in patients with respiratory disease. This observational study was conducted at pulmonary outpatient department of a tertiary care hospital. 30 patients were enrolled using convenience sampling. Participants’ demographic and disease specific data was recorded. Participants were asked to use their inhaler just as they would at home. The technique of device use was observed and recorded using inhaler specific checklists. Data collected was analyzed using descriptive statistics. Out of 30 patients 26 were using MDI, 23 of which (92%) performed at least 1 error. Among 4 patients using DPI, 3 (75%) performed at least 1 error. Patients using MDI for more than 1 year performed less errors compared to those who had been using MDI for less than 1 year, however the difference observed was not significant (n=26, p= 0.304). 29 patients (96%) received education about inhaler device use. The most common incorrectly performed steps were “complete exhalation” and “breath hold.” 92% of MDI and 75% of DPI users made at least one error during the inhalation maneuver despite majority being educated about inhaler technique. The most frequently performed incorrect steps for MDI and DPI were “Complete exhalation” and “Breath hold”.

Effects of Vibration Characteristics on the Atomization Performance in the Medical Piezoelectric Atomization Device Induced by Intra-Hole Fluctuation

Oral inhalation of aerosolized drugs has be widely applied in healing the affected body organs including lesions of the throat and lungs and it is more efficient than those conventional therapies, such as intravenous drip, intramuscular injection and external topical administration in the aspects of the dosage reduction and side effects of drugs. Nevertheless, the traditional atomization devices always exhibit many drawbacks. For example, non-uniformed atomization particle distribution, the instability of transient atomization quantity and difficulties in precise energy control would seriously restrict an extensive use of atomization inhalation therapy. In this study, the principle of intra-hole fluctuation phenomenon occurred in the hole is fully explained, and the produced volume change is also estimated. Additionally, the mathematical expression of the atomization rate of the atomizing device is well established. The mechanism of the micro-pump is further clarified, and the influence of the vibration characteristics of the atomizing film on the atomization behavior is analyzed theoretically. The curves of sweep frequency against the velocity and amplitude of the piezoelectric vibrator are obtained by the Doppler laser vibrometer, and the corresponding mode shapes of the resonance point are achieved. The influence of vibration characteristics on atomization rate, atomization height and atomization particle size are also verified by experiments, respectively. Both the experimental results and theoretical calculation are expected to provide a guidance for the design of this kind of atomization device in the future.

Management of patients with severe asthma: results from a survey among allergists and clinical immunologists of the Central Italy Inter-Regional Section of SIAAIC

Background Asthma, and severe asthma in particular, is often managed within a specialized field with allergists and clinical immunologists playing a leading role. In this respect, the National Scientific Society SIAAIC (Società Italiana di Allergologia, Asma ed Immunologia Clinica), structured in Regional and Inter-Regional sections, interviewed a large number of specialists involved in the management of this respiratory disease. Methods A survey entitled “Management of patients with asthma and severe asthma” based on 17 questions was conducted through the SIAAIC newsletter in 2019 thanks to the collaboration between GlaxoSmithKline S.p.A. and the Inter-Regional Section of SIAAIC of Central Italy. Results Fifty-nine allergists and clinical immunologists participated to the survey, and 40 of them completed the entire questionnaire. Almost all of the specialists (88%) reported that asthma control was achieved in above 50% of their patients, even if only one third (32%) actually used validated clinical tools such as asthma control test (ACT). Poor adherence to inhaled therapy was recognized as the main cause of asthma control failure by 60% of respondents, and 2–5 min on average is dedicated to the patient inhaler technique training by two-thirds of the experts (65%). Maintenance and as-needed therapy (SMART/MART) is considered an appropriate approach in only a minority of the patients (25%) by one half of the respondents (52%). A high number of exacerbations despite the maximum inhalation therapy were recognized as highly suspicious of severe asthma. Patients eligible for biological therapies are 3–5% of the patients, and almost all the responders (95%) agreed that patients affected by severe asthma need to be managed in specialized centers with dedicated settings. Biological drugs are generally prescribed after 3–6 months from the initial access to the center, and once started, the follow-up is initially programmed monthly, and then every 3–6 months after the first year of treatment (96% of responders). After phenotyping and severity assessment, comorbidities (urticaria, chronic rhinosinusitis with or without nasal polyps, vasculitis, etc.) are the drivers of choice among the different biological drugs. In the management of severe asthma, general practitioners (GPs) should play a central role in selecting patients and referring them to specialized centers while Scientific Societies should train GPs to appropriately recognize difficult asthma and promote public disease awareness campaigns. Conclusions This survey which collects the point of view of allergists and clinical immunologists from Central Italy highlights that asthma control is still not measured with validated instruments. There is a general consensus that severe asthma should be managed only in dedicated centers and to this aim it is essential to encourage patient selection from a primary care setting and develop disease awareness campaigns for patients.

LITERATURE REVIEW INHALASI AROMATERAPI PADA PASIEN HEMODIALISIS YANG MENGALAMI KECEMASAN

Background: In hemodial therapy can cause various kinds of problems, one of which is anxiety. Anxiety becomes a common problem, the results of studies in patients undergoing hemodialysis showed 183 patients (100%) experienced anxiety. One therapy for overcoming anxiety is aromatherapy inhalation therapy. Purpose: The study of this literature aims to determine the effect of aromatherapy inhalation on hemodialysis patients with anxiety problems. Method: In this scientific paper is a literature review search using electronic databases namely google schoolar and pubmed. The keywords used with search are hemodialysis or hemodialysis, aromatherapy or aromatherapy and anxiety or anxiety. inclusion criteria used in the article are accessible full text, no pay available in English and Indonesian. The number of journals used is limited to the last 10 years, results are found 1 journal from google schoolar and 4 pubmed, of 5 articles discussing the effectiveness of inhalation aromatherapy for decreased anxiety in hemodialysis patients. Results: From the literature review results from the 5 articles show that inhalation aromatherapy is effective in reducing anxiety levels in hemodialysis patients. Conclusion: the results of a literature review review show that aromatherapy inhalation can reduce anxiety in hemodialysis patients.

Excipient-Free Inhalable Microparticles of Azithromycin Produced by Electrospray: A Novel Approach to Direct Pulmonary Delivery of Antibiotics

Inhalation therapy offers several advantages in respiratory disease treatment. Azithromycin is a macrolide antibiotic with poor solubility and bioavailability but with a high potential to be used to fight lung infections. The main objective of this study was to generate a new inhalable dry powder azithromycin formulation. To this end, an electrospray was used, yielding a particle size around 2.5 µm, which is considered suitable to achieve total deposition in the respiratory system. The physicochemical properties and morphology of the obtained microparticles were analysed with a battery of characterization techniques. In vitro deposition assays were evaluated after aerosolization of the powder at constant flow rate (100 L/min) and the consideration of the simulation of two different realistic breathing profiles (healthy and chronic obstructive pulmonary disease (COPD) patients) into a next generation impactor (NGI). The formulation was effective in vitro against two types of bacteria, Staphylococcus aureus and Pseudomonas aeruginosa. Finally, the particles were biocompatible, as evidenced by tests on the alveolar cell line (A549) and bronchial cell line (Calu-3).

The Potential Use of Cyclosporine Ultrafine Solution Pressurised Metered-Dose Inhaler in the Treatment of COVID-19 Patients

Introduction: Serious COVID-19 respiratory problems start when the virus reaches the alveolar level, where type II cells get infected and die. Therefore, virus inhibition at the alveolar level would help prevent these respiratory complications. Method: A literature search was conducted to collect physicochemical properties of small molecule compounds that could be used for the COVID-19 treatment. Compounds with a low melting point were selected along with those soluble in ethanol, hydrogen-bond donors, and acceptors. Results : There are severe acute respiratory syndrome coronavirus inhibitors with physicochemical properties suitable for the formulation as an ultrafine pressurised metered-dose inhaler (pMDI). Mycophenolic acid, Debio 025, and cyclosporine A are prime candidates among these compounds. Cyclosporine A (hereafter cyclosporine) is a potent SARS-CoV-2 inhibitor, and it has been used for the treatment of COVID-19 patients, demonstrating an improved survival rate. Also, inhalation therapy of nebulised cyclosporine was tolerated, which was used for patients with lung transplants. Finally, cyclosporine has been formulated as a solution ultrafine pMDI. Although vaccine therapy has been started in most countries, inhalation therapies with non-immunological activities could minimise the spread of the disease and be used in vaccine-hesitant individuals. Conclusion: Ultrafine pMDI formulation of cyclosporine or Debio 025 should be investigated for the inhalation therapy of COVID-19.

Effect of Salbutamol on Lung Ventilation in Children with Cystic Fibrosis: Comprehensive Assessment Using Spirometry, Multiple-Breath Washout, and Functional Lung Magnetic Resonance Imaging

<b><i>Background:</i></b> Inhalation therapy is one of the cornerstones of the daily treatment regimen in patients with cystic fibrosis (CF). Recommendations regarding the addition of bronchodilators, especially salbutamol are conflicting due to the lack of evidence. New diagnostic measures such as multiple-breath washout (<underline>MBW)</underline> and functional magnetic resonance imaging (MRI) have the potential to reveal new insights into bronchodilator effects in patients with CF. <b><i>Objective:</i></b> The objective of the study was to comprehensively assess the functional response to nebulized inhalation with salbutamol in children with CF. <b><i>Methods:</i></b> Thirty children aged 6–18 years with stable CF performed pulmonary function tests, MBW, and matrix pencil-MRI before and after standardized nebulized inhalation of salbutamol. <b><i>Results:</i></b> Lung clearance index decreased (improved) by −0.24 turnover (95% confidence interval [CI]: −0.53 to 0.06; <i>p</i> = 0.111). Percentage of the lung volume with impaired fractional ventilation and relative perfusion decreased (improved) by −0.79% (CI: −1.99 to 0.42; <i>p</i> = 0.194) and −1.31% (CI: −2.28 to −0.35; <i>p</i> = 0.009), respectively. Forced expiratory volume (FEV₁) increased (improved) by 0.41 z-score (CI: 0.24–0.58; <i>p</i> &#x3c; 0.0001). We could not identify specific clinical factors associated with a more pronounced effect of salbutamol. <b><i>Conclusions:</i></b> There is a positive short-term effect of bronchodilator inhalation on FEV₁ in patients with CF, which is independent of ventilation inhomogeneity. Heterogeneous response between patients suggests that for prediction of a therapeutic effect this should be tested by spirometry in every patient individually.