SARS-CoV-2 and sodium transport: a diabolical strategy.

The Covid 19 pandemic remains a serious public health problem until effective drugs and/or vaccines are available. Can we explain why so many people remain asymptomatic but nevertheless highly contagious explaining the speed with which the pandemic has spread around the world? Can we explain why the acute respiratory distress syndrome (ARDS) appears late but can so quickly have a fatal outcome? In the lung, mucociliary clearance (CMC) and alveolar clearance (CA) depend on the transport of sodium through the plasma membrane of epithelial cells. This transport is mediated by a highly selective sodium channel (Epithelial Sodium Channel = ENaC) which could be a key element in the pulmonary pathophysiology of SARS-CoV-2 infection.Copyright © 2020 Editions Medecine et Hygiene. All rights reserved.

Tolerance of ETD001, a long-acting inhaled epithelial sodium channel blocker, in humans

Background: To assess the safety, tolerability, and pharmacokinetic (PK) profile in humans of the novel inhaled epithelial sodium channel blocker ETD001. Method(s): Inhaled ETD001 or placebo, delivered via nebulizer, have been administered in a 3:1 ratio to 96 healthy subjects in a blinded, first-inhuman clinical trial (ClinicalTrials.gov Identifier: NCT04926701). The study consisted of two parts. Part A evaluated single ascending doses (SADs) up to 10.8 mg, and Part B evaluated multiple ascending doses (MADs) up to 3.1 mg once daily (QD) for 7 days and 4.65 mg twice daily (BID) for 14 days. Safety was assessed by monitoring for adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG), and spirometry. Systemic exposurewas assessed using serial pharmacokinetic blood draws. Result(s): Therewere no serious AEs. Twenty-four subjects reported 38 AEs, all of mild to moderate intensity and all resolved. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs, or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B;all withdrawals were considered unrelated to study drug: one on day 6 from the 3.1-mg QD cohort for personal reasons, one after the first dose of the 3.1-mg BID cohort because of vasovagal syncope at time of venipuncture triggering atrial fibrillation that spontaneously resolved, and one on Day 4 of the 3.1- mg BID cohort because of a positive COVID-19 test. Pharmacokinetic parameters were approximately dose proportional in Part A, with peak concentrations 1 to 2 hours after dose and exposure out to 12 to 24 hours at all doses, indicating good lung retention. Part B plasma concentrations displayed dose-independent kinetics and showed minimal accumulation, with a mean of 1.11-fold observed over 14 days. Conclusion(s): ETD001 was well tolerated at single doses up to 10.8 mg and multiple doses of 3.1 mg QD for 7 days and 4.65 mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Impact of elexacaftor/tezacaftor/ivacaftor on Pseudomonas aeruginosa acquisition and chronic infection at a single pediatric cystic fibrosis center

Background: As cystic fibrosis (CF) lung disease progresses, the airways become colonized with opportunistic pathogens such as Pseudomonas aeruginosa secondary to airway surface liquid depletion. Acquisition of P. aeruginosa is associated with decline in lung function and increase in treatment burden and mortality. In October 2019, the Food and Drug Administration approved elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), a highly effective modulator therapy (HEMT) for individuals aged 12 and older with one copy of the F508del CFTR mutation. ELX/TEZ/IVA increases the amount of and function of CF transmembrane conductance regulator (CFTR) in the respiratory epithelium, increasing mucociliary clearance (MCC) and reducing static airway mucous, a major trigger for chronic infection and inflammation. Method(s): A retrospective analysis of inhaled tobramycin (iTOB) prescriptions prescribed between January 1, 2016, and December 31, 2021, was performed. This captured data before and after ELX/TEZ/IVA approval at Children's Mercy Kansas City (CMKC). The number of individuals with new P. aeruginosa acquisition was determined by identifying electronic prescriptions for iTOB eradication courses. An eradication course was defined as a first lifetime prescription for iTOB or a new prescription for iTOB submitted at least 1 year after a previous prescription. The number of individuals considered chronically infected with P. aeruginosa was determined by identifying individuals receiving chronic iTOB prescriptions and confirmed by respiratory cultures indicating chronic infection based on the Leeds criteria (P. aeruginosa recovered in >=50% of airway cultures in the previous 12 months). Result(s): Eradication courseswere prescribed to 34 individuals in 2016 (15% of people receiving care at CMKC). The number of eradication prescriptions declined in 2020 and 2021, with only 15 (7%) individuals prescribed eradication therapy in 2020 and 12 (5%) in 2021. A similar pattern was observed for prescriptions for chronic infection. In 2016, 57 individuals (25% of our patient population) were receiving iTOB for chronic P. aeruginosa infection. Reductions were seen in 2020 and 2021, with 28 (13%) and 20 (9%) individuals prescribed chronic therapy, respectively. The number of individuals prescribed iTOB for P. aeruginosa eradication and chronic infection per year is represented in Figure 1.(Figure Presented)Conclusions: CMKC experienced a decrease in the number of courses of iTOB prescribed over the last 6 years. HEMT use is associated with greater MCC and anti-inflammatory effects affecting the airway microbiome. The decrease in respiratory cultures growing P. aeruginosa likely reflects these phenomena. A confounding factor is the SARS-CoV-2 pandemic and widespread use of HEMT. Clinic closures and implementation of telemedicine limited in-person patient visits during 2020 and 2021. Despite limited in-person visits, the average number of respiratory cultures per individual at CMKC in 2020 was 3.5, which is consistent with previous years.Wewere able to obtain frequent surveillance cultures through implementation of a drive-through respiratory specimen collection process. Hence, the decrease in number of iTOB courses cannot be attributed to a decrease in frequency of respiratory cultures, although we cannot assess the impact of school closures and a decrease in social gatherings on new P. aeruginosa acquisition or chronic infection. Looking at all these variables, the widespread use of HEMT likely played a significant role in reducing new P. aeruginosa acquisition and chronic P. aeruginosa infection.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

A Comparison of Nasal Mucociliary Clearance Time in COVID-19 and Variant COVID-19 Patients

Objective: The aim of this study was to compare nasal mucociliary clearance times in coronavirus disease 2019 and variant coronavirus disease 2019 patients and a control group. Methods: The study was conducted in Karaman Training and Research Hospital between April 2021 and June 2021. Three groups were formed. Group 1 included 41 coronavirus disease 2019 patients, group 2 included 41 patients diagnosed with variant coronavirus disease 2019, and group 3 included 42 patients from the ear, nose, and throat polyclinic with no nasal symptoms. The primary outcome was nasal mucociliary clearance time and sinonasal outcome test-22 scores. Results: The mean nasal mucociliary clearance time was 12.87 +/- 2.46 minutes in group 1, 14.02 +/- 2.95 minutes in group 2, and 8.57 +/- 1.25 minutes in group 3. Nasal mucociliary clearance time was significantly different between groups 1 and 3 and between groups 2 and 3 but not between groups 1 and 2 (P =.07). The nasal mucociliary clearance times of group 2 were determined to be higher than those of group 1. The mean sinonasal outcome test-22 score was 24.70 +/- 6.65 in group 1 and 23.92 +/- 7.01 in group 2, with no significant difference determined between the groups (P >.05). Conclusion: Nasal mucociliary clearance time was higher in coronavirus disease 2019 and variant coronavirus disease 2019 patients than in the control group. There is a need for further studies to be able to understand the underlying pathophysiology of prolonged nasal mucociliary clearance time.

Inhalation of virus-loaded droplets as a clinically plausible pathway to deep lung infection.

Respiratory viruses, such as SARS-CoV-2, preliminarily infect the nasopharyngeal mucosa. The mechanism of infection spread from the nasopharynx to the deep lung-which may cause a severe infection-is, however, still unclear. We propose a clinically plausible mechanism of infection spread to the deep lung through droplets, present in the nasopharynx, inhaled and transported into the lower respiratory tract. A coupled mathematical model of droplet, virus transport and virus infection kinetics is exercised to demonstrate clinically observed times to deep lung infection. The model predicts, in agreement with clinical observations, that severe infection can develop in the deep lung within 2.5-7 days of initial symptom onset. Results indicate that while fluid dynamics plays an important role in transporting the droplets, infection kinetics and immune responses determine infection growth and resolution. Immune responses, particularly antibodies and T-lymphocytes, are observed to be critically important for preventing infection severity. This reinforces the role of vaccination in preventing severe infection. Managing aerosolization of infected nasopharyngeal mucosa is additionally suggested as a strategy for minimizing infection spread and severity.

Upper Airway Mucociliary Clearance is Impaired in Dyspneic COVID-19 Patients.

Covid-19 is transmitted mainly by respiratory droplets and as the upper airway mucosa is the first innate immune barrier, it is crucial to understand the effects of SARS-CoV-2 on this system. In the current study, we aimed to evaluate the nasal mucociliary clearance in patients with SARS-CoV-2 infection and their symptom development. Observational cross-sectional study. The nasal mucociliary clearance (NMC) time was evaluated by the saccharin test and the results were compared between patients with SARS-CoV-2 infection (group 1) and controls (group 2, asymptomatic patients with a negative polymerase chain reaction test). We also compared the NMC time for each specific symptom suffered by participants in group 1 with the NMC time of the control group as well as with the patients in group 1 who were asymptomatic. There was a significant increase in NMC time in group 1 with dyspnea when compared to the control group (p = 0.032) and also when compared to patients who were infected were not dyspneic (p = 0.04). There were no differences in the clearance times when considering other symptoms. COVID-19 patients with dyspnea present with altered nasal mucociliary clearance.

Warmer ambient air temperatures reduce nasal turbinate and brain infection, but increase lung inflammation in the K18-hACE2 mouse model of COVID-19.

Warmer climatic conditions have been associated with fewer COVID-19 cases. Herein we infected K18-hACE2 mice housed at the standard animal house temperature of ∼22 °C, or at ∼31 °C, which is considered to be thermoneutral for mice. On day 2 post infection, RNA-Seq analyses showed no significant differential gene expression lung in lungs of mice housed at the two temperatures, with almost identical viral loads and type I interferon responses. There was also no significant difference in viral loads in lungs on day 5, but RNA-Seq and histology analyses showed clearly elevated inflammatory signatures and infiltrates. Thermoneutrality thus promoted lung inflammation. On day 2 post infection mice housed at 31 °C showed reduced viral loads in nasal turbinates, consistent with increased mucociliary clearance at the warmer ambient temperature. These mice also had reduced virus levels in the brain, and an ensuing amelioration of weight loss and a delay in mortality. Warmer air temperatures may thus reduce infection of the upper respiratory track and the olfactory epithelium, resulting in reduced brain infection. Potential relevance for anosmia and neurological sequelae in COVID-19 patients is discussed.

The Effect of Nasal Irrigation on COVID-19 Patient’s Mild Symptoms of Respiratory Tract

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus-2 is a virus that causes COVID-19. The initial symptoms put forward by the WHO since 2020 is fever accompanied by cough and shortness of breath. Currently, the loss of smell and taste, accompanied by other symptoms, tends to be a strong predictor of COVID-19. The nose is the entrance for air, that’s why the nose has an important role in the breathing process. In addition to warming, humidifying, and filtering incoming air, the nose can also maintain respiratory tract homeostasis. The use of nasal irrigation with isotonic saline solution (NaCl 0.9%) is a way to improve mucociliary clearance function by activating cilia as an olfactory sensory system. AIM: This study aims to evaluate the effect of nasal irrigation on COVID patients who have mild symptoms in the upper respiratory tract. METHODS: The purpose of this study was to see the effectiveness of nasal irrigation using 0.9% NaCl in COVID-19 patients with mild symptoms by looking at the average duration of time complaints felt by patients compared to those without nasal irrigation intervention. RESULTS: This study found a significant difference (p = 0.000) between the control group and the intervention group, where the mean duration of symptoms in the intervention group was shorter than the control group. CONCLUSION: Anosmia is a symptom in COVID-19 which is almost always accompanied by symptoms of loss of taste, various theories on the cause of anosmia have been put forward since the COVID-19 pandemic broke out. Improvements in symptom duration were found to be shorter in COVID-19 patients who performed nasal irrigation using 0.9% NaCl independently for 10 days so that in the future, it is hoped that nasal irrigation will become part of the comprehensive management of COVID-19 patients who have mild symptoms, especially symptoms related to nasal and upper respiratory complaints.

Rapidly Progressive Disseminated Aspergillosis in a Diabetic Patient

Invasive aspergillosis is a rapidly progressive, fatal infection that usually occurs in immunocompromised patients. The spectrum of clinical presentation ranges from non-invasive, invasive, destructive and allergic aspergillosis. It is rare to see overwhelming aspergillosis in an immunocompetent host. Nevertheless, certain risk factors such as underlying fibrotic lung disease, suppurative infection, long-term corticosteroid use and uncontrolled diabetes mellitus (DM) have been described. We hereby present a case of invasive pulmonary aspergillosis in a patient with uncontrolled DM. A 60-year-old man with a history of heavy smoking (50- pack-year), poorly controlled DM presented to the hospital with a large area of erythema with eschar over his left posterior thigh. Clinical examination and CT abdomen pelvis confirmed necrotizing fasciitis involving his perineum and left thigh. Admission CT abdomen showed a small left lower lobe infiltrate (Day 1, Panel A). He underwent urgent debridement and intraoperative tissue cultures grew coagulase-negative staphylococcus, Proteus Vulgaris and anaerobic gram-positive rods. He received piperacillintazobactam, vancomycin, and clindamycin for 16 days which was subsequently narrowed to ceftriaxone and metronidazole. He had worsening leukocytosis but all his blood cultures have been negative. Tracheal aspirate gram stain on day 5 showed moderate yeast, and cultures grew Candida albicans and Aspergillus fumigatus. CT scan of his chest showed bilateral reticulonodular opacities with a new loculated right pleural effusion (Day 16, Panel B). Trans-esophageal echocardiogram did not show any right-sided heart valve vegetation. He received intravenous voriconazole for disseminated aspergillosis. Despite of new prophylactic antifungal strategies, more sensitive and rapid diagnostic tests, as well as various efficacious treatments, survival of invasive disseminated aspergillosis remains poor. High clinical suspicion with a proactive investigation approach is the key to minimizing mortality. Various risk factors such as hematopoietic-cell transplantation, neutropenia, solid-organ transplantation, chemotherapy, prolonged ICU stay, structural lung disease, impaired mucociliary clearance after a recent pulmonary infection (including SARS-CoV-2) have been well described. Our case highlights the importance of recognizing uncontrolled DM as a crucial risk factor for disseminated aspergillosis. (Figure Presented).

Aerosol Transport Modeling: The Key Link Between Lung Infections of Individuals and Populations.

The recent COVID-19 pandemic has propelled the field of aerosol science to the forefront, particularly the central role of virus-laden respiratory droplets and aerosols. The pandemic has also highlighted the critical need, and value for, an information bridge between epidemiological models (that inform policymakers to develop public health responses) and within-host models (that inform the public and health care providers how individuals develop respiratory infections). Here, we review existing data and models of generation of respiratory droplets and aerosols, their exhalation and inhalation, and the fate of infectious droplet transport and deposition throughout the respiratory tract. We then articulate how aerosol transport modeling can serve as a bridge between and guide calibration of within-host and epidemiological models, forming a comprehensive tool to formulate and test hypotheses about respiratory tract exposure and infection within and between individuals.

The residual effect of coronovirus disease 2019 on olfactory acuity and mucociliary clearance time: a cross-sectional, controlled study.

OBJECTIVE: This study evaluated the olfactory, sinonasal and mucociliary functions of patients with post-coronavirus disease 2019 long-term persistent olfactory dysfunction. METHOD: Three groups of 30 patients each were formed: patients with a history of coronavirus disease 2019 infection with self-reported, persistent, sudden-onset olfactory dysfunction (group 1), patients with a history of coronavirus disease 2019 infection without any self-reported olfactory dysfunction (group 2) and healthy controls with no history of coronavirus disease 2019 infection (group 3). Saccharin time, Sniffin' Sticks, Turkish Nasal Obstruction Symptom Evaluation and Sino-Nasal Outcome Test 22 scores were compared. RESULTS: Turkish Nasal Obstruction Symptom Evaluation scores were similar between groups (p = 0.252). Sino-Nasal Outcome Test-22 scores were higher in group 1 than groups 2 and 3 (p < 0.01 and p < 0.001, respectively). Saccharin time was significantly longer in group 1 than groups 2 and 3 (p < 0.05 and p < 0.01, respectively). Group 1 had lower olfactory scores than groups 2 and 3 (p < 0.001 and p < 0.001, respectively). CONCLUSION: Mucociliary clearance time was significantly prolonged in patients with post-coronavirus disease 2019 persistent olfactory dysfunction. Coronavirus disease 2019 infection was likely to cause asymptomatic olfactory dysfunction.

SARS-CoV-2 and sodium transport: a diabolical strategy

The Covid 19 pandemic remains a serious public health problem until effective drugs and/or vaccines are available. Can we explain why so many people remain asymptomatic but nevertheless highly contagious explaining the speed with which the pandemic has spread around the world? Can we explain why the acute respiratory distress syndrome (ARDS) appears late but can so quickly have a fatal outcome? In the lung, mucociliary clearance (CMC) and alveolar clearance (CA) depend on the transport of sodium through the plasma membrane of epithelial cells. This transport is mediated by a highly selective sodium channel (Epithelial Sodium Channel = ENaC) which could be a key element in the pulmonary pathophysiology of SARS-CoV-2 infection.

Non-Cellular Layers of the Respiratory Tract: Protection against Pathogens and Target for Drug Delivery.

Epithelial barriers separate the human body from the environment to maintain homeostasis. Compared to the skin and gastrointestinal tract, the respiratory barrier is the thinnest and least protective. The properties of the epithelial cells (height, number of layers, intercellular junctions) and non-cellular layers, mucus in the conducting airways and surfactant in the respiratory parts determine the permeability of the barrier. The review focuses on the non-cellular layers and describes the architecture of the mucus and surfactant followed by interaction with gases and pathogens. While the penetration of gases into the respiratory tract is mainly determined by their hydrophobicity, pathogens use different mechanisms to invade the respiratory tract. Often, the combination of mucus adhesion and subsequent permeation of the mucus mesh is used. Similar mechanisms are also employed to improve drug delivery across the respiratory barrier. Depending on the payload and target region, various mucus-targeting delivery systems have been developed. It appears that the mucus-targeting strategy has to be selected according to the planned application.

Versatility of Intermittent Abdominal Pressure Ventilation in a Case of Complicated Restrictive Respiratory Failure and COVID-19.

BACKGROUND: The intermittent abdominal pressure ventilation (IAPV) is a non-invasive ventilation (NIV) technique that avoids facial interfaces and is a diurnal ventilatory support alternative for neuromuscular patients during stable chronic phases of the disease. Coronavirus disease 2019 (COVID-19) is a novel infection possibly causing acute respiratory distress syndrome (ARDS). Neuromuscular diseases (NMD) and preexisting respiratory failure can be exacerbated by respiratory infection and progress to severe disease and ICU admission with a poor prognosis. AIM: To report on the versatility and feasibility of IAPV in acute restrictive respiratory failure exacerbated by COVID-19. PATIENT: We describe the case of a 33-year-old man with spastic tetraparesis, kyphoscoliosis, and impaired cough, eventually leading to a restrictive ventilation pattern. COVID-19 exacerbated respiratory failure and seizures. An NIV trial failed because of inadequate interface adhesion and intolerance. During NIV, dyspnea and seizures worsened. He underwent a high flow nasal cannula (HFNC) with a fluctuating benefit on gas exchange. IAPV was initiated and although there was a lack of cooperation and inability to sit; the compliance was good and a progressive improvement of gas exchange, respiratory rate, and dyspnea was observed. CONCLUSIONS: IAPV is a versatile type of NIV that can be adopted in complicated restrictive respiratory failure. COVID-19 exacerbates preexisting conditions and is destined to be a disease of frailty. COVID-19 is not a contraindication to IAPV and this kind of ventilation can be employed in selected cases in a specialistic setting. Moreover, this report suggests that IAPV is safe when used in combination with HFNC. This hybrid approach provides the opportunity to benefit from both therapies, and, in this particular case, prevented the intubation with all connected risks.

Nasal Mucociliary Clearance and Sinonasal Symptoms in Healthcare Professionals Wearing FFP3 Respirators: A Prospective Cross-Sectional Study.

INTRODUCTION: The purpose of the present study was to assess nasal mucociliary clearance (NMC) and sinonasal symptoms of healthcare professionals wearing filtering facepiece-3 (FFP3) respirators. METHODS: This prospective cross-sectional study was conducted at a large tertiary care academic center. Thirty-four healthcare professionals working at a coronavirus disease-19 patient care unit were included in the study. Visual analog scale (VAS) scores of sinonasal symptoms (nasal discharge, postnasal discharge, nasal blockage, hyposmia, facial pain/pressure, facial fullness, headache, fatigue, halitosis, cough) and the NMC times of the participants were assessed immediately before wearing FFP3 respirators and after 4 h of work with FFP3 respirators. RESULTS: The mean age of the participants was 28.82 ± 4.95 (range, 26-31) years. Twenty participants were female and 14 were male. After wearing the FFP3 respirators for 4 h, a statistically significant increase was observed in total VAS scores for all sinonasal symptoms and NMC times (p < 0.001). When the VAS score of each sinonasal symptom was evaluated separately, a statistically significant increase was found for VAS scores of nasal discharge, postnasal discharge, nasal blockage, hyposmia, facial pain/pressure, and facial fullness (p < 0.05). CONCLUSION: The present study shows that nasal mucosal functions might be affected significantly after 4 h of using FFP3 respirators. The long-term effects and clinical significance of these short-term changes should be investigated on healthcare professionals in further studies.

Efficacy and Safety of ELOM-080 as Add-On Therapy in COVID-19 Patients with Acute Respiratory Insufficiency: Exploratory Data from the Prospective Placebo-Controlled COVARI Trial.

INTRODUCTION: Enhancement of mucociliary clearance (MCC) might be a potential target in treating COVID-19. The phytomedicine ELOM-080 is an MCC enhancer that is used to treat inflammatory respiratory diseases. PATIENTS/METHODS: This randomised, double-blind exploratory study (EudraCT number 2020-003779-17) evaluated 14 days' add-on therapy with ELOM-080 versus placebo in patients with COVID-19 hospitalised with acute respiratory insufficiency. RESULTS: The trial was terminated early after enrolment of 47 patients as a result of poor recruitment. Twelve patients discontinued prematurely, leaving 35 in the per-protocol set (PPS). Treatment with ELOM-080 had no significant effect on overall clinical status versus placebo (p = 0.49). However, compared with the placebo group, patients treated with ELOM-080 had less dyspnoea in the second week of hospitalisation (p = 0.0035), required less supplemental oxygen (p = 0.0229), and were more often without dyspnoea when climbing stairs at home (p < 0.0001). CONCLUSION: These exploratory data suggest the potential for ELOM-080 to improve respiratory status during and after hospitalisation in patients with COVID-19.

The effect of COVID-19 on nasal mucociliary clearance.

BACKGROUND: The impacts of coronavirus disease-2019 (COVID-19) on nasal mucociliary clearance (MCC) have shown conflicting results. OBJECTIVES: The aim of this study was to determine whether COVID-19 infections affect nasal mucociliary activity using the saccharin test to measure nasal MCC time. MATERIAL AND METHODS: This prospective comparative investigation included 25 patients with COVID-19 infection and 25 healthy controls. The nasal MCC time was assessed using the saccharin test. Saccharin test was applied to COVID-19 patients between the 10th and 20th days of COVID-19 test positivity. Patients admitted to the otolaryngology outpatient clinic with non-nasal symptoms and no history of COVID-19 infection served as the control subjects. RESULTS: Age, gender distribution, smoking, and alcohol usage, and the existence of other systemic disorders had no statistically significant differences between the groups (p = 0.25, p = 0.77, p = 1.00, p = 0.28, p = 0.54, respectively). The COVID-19 group had a mean nasal MCC time of 12.00 ± 2.51 min, compared to 9.77 ± 2.51 min in the control group. The nasal MCC time in the COVID-19 group was statistically significantly longer (p = 0.043). CONCLUSIONS AND SIGNIFICANCE: The COVID-19 infection negatively affects mucociliary activity and causes prolongation of MCC. As the nasal defense mechanism weakens in the early period after COVID-19 infection, susceptibility to respiratory infections may occur.

Models using native tracheobronchial mucus in the context of pulmonary drug delivery research: Composition, structure and barrier properties.

Mucus covers all wet epithelia and acts as a protective barrier. In the airways of the lungs, the viscoelastic mucus meshwork entraps and clears inhaled materials and efficiently removes them by mucociliary escalation. In addition to physical and chemical interaction mechanisms, the role of macromolecular glycoproteins (mucins) and antimicrobial constituents in innate immune defense are receiving increasing attention. Collectively, mucus displays a major barrier for inhaled aerosols, also including therapeutics. This review discusses the origin and composition of tracheobronchial mucus in relation to its (barrier) function, as well as some pathophysiological changes in the context of pulmonary diseases. Mucus models that contemplate key features such as elastic-dominant rheology, composition, filtering mechanisms and microbial interactions are critically reviewed in the context of health and disease considering different collection methods of native human pulmonary mucus. Finally, the prerequisites towards a standardization of mucus models in a regulatory context and their role in drug delivery research are addressed.

Nasally inhaled therapeutics and vaccination for COVID-19: Developments and challenges.

The nose is the initial site of viral infection, replication, and transmission in the human body. Nasally inhaled vaccines may act as a promising alternative for COVID-19 management in addition to intramuscular vaccination. In this review, the latest developments of nasal sprays either as repurposed or antiviral formulations were presented. Nasal vaccines based on traditional medicines, such as grapefruit seed extract, algae-isolated carrageenan, and Yogurt-fermenting Lactobacillus, are promising and under active investigations. Inherent challenges that hinder effective intranasal delivery were discussed in detail, which included nasal device issues and human nose physiological complexities. We examined factors related to nasal spray administration, including the nasal angiotensin I converting enzyme 2 (ACE2) locations as the delivery target, nasal devices, medication translocation after application, delivery methods, safety issues, and other nasal delivery options. The effects of human factors on nasal spray efficacy, such as nasal physiology, disease-induced physiological modifications, intersubject variability, and mucociliary clearance, were also examined. Finally, the potential impact of nasal vaccines on COVID-19 management in the developing world was discussed. It is concluded that effective delivery of nasal sprays to ACE2-rich regions is urgently needed, especially in the context that new variants may become unresponsive to current vaccines and more refractory to existing therapies.