Asthma as a protective factor against COVID-19 infection: a narrative literature review

Asthma and COPD comorbidities are expected to exacerbate the clinical manifestations of COVID-19. However, many reported studies show that asthmatic patients infected with COVID-19 do not show severe clinical manifestations, and some are asymptomatic. This literature review aimed to describe COVID-19 in asthmatic patients along with the hypothesis that asthma is a protective factor against COVID-19 infection. Systemic corticosteroids have been shown to reduce the death/mortality rate in patients who are hospitalized due to COVID-19 infection. This is possibly due to the suppression of the immune system against a hyperinflammatory state which can result in further damage from SARS-CoV-2 infection. Mucus hypersecretion, which is one of the hallmarks of asthma, can prevent the SARS-CoV-2 virus from reaching the distal lung and can protect the lungs from pathological processes. The secreted mucus is rich in glycoproteins, such as MUC5AC, which act as the first line of defense against infection. Mucus hypersecretion in asthmatic patients may prevent SARS-CoV-2 from penetrating far enough to gain access to type-2 alveolar cells, which are the cells that predominantly express ACE2 in the lungs. In conclusion, comorbid asthma in patients infected with COVID-19 does not cause adverse clinical manifestations to appear, but on the contrary, it will have a protective effect on patients.

Visual prediction and parameter optimization of viral dynamics in the mucus milieu of the upper airway based on CFPD-HCD analysis.

BACKGROUND AND OBJECTIVE: Respiratory diseases caused by viruses are a major human health problem. To better control the infection and understand the pathogenesis of these diseases, this paper studied SARS-CoV-2, a novel coronavirus outbreak, as an example. METHODS: Based on coupled computational fluid and particle dynamics (CFPD) and host-cell dynamics (HCD) analyses, we studied the viral dynamics in the mucus layer of the human nasal cavity-nasopharynx. To reproduce the effect of mucociliary movement on the diffusive and convective transport of viruses in the mucus layer, a 3D-shell model was constructed using CT data of the upper respiratory tract (URT) of volunteers. Considering the mucus environment, the HCD model was established by coupling the target cell-limited model with the convection-diffusion term. Parameter optimization of the HCD model is the key problem in the simulation. Therefore, this study focused on the parameter optimization of the viral dynamics model, divided the geometric model into multiple compartments, and used Monolix to perform the nonlinear mixed effects (NLME) of pharmacometrics to discuss the influence of factors such as the number of mucus layers, number of compartments, diffusion rate, and mucus flow velocity on the prediction results. RESULTS: The findings showed that sufficient experimental data can be used to estimate the corresponding parameters of the HCD model. The optimized convection-diffusion case with a two-layer multi-compartment low-velocity model could accurately predict the viral dynamics. CONCLUSIONS: Its visualization process could explain the symptoms of the disease in the nose and contribute to the prevention and targeted treatment of respiratory diseases.

Tracheoesophageal Fistula Presenting With Gastrostomy Tube Pressurization

Introduction: Patients with COVID pneumonia who require intubation and prolonged mechanical ventilation are at risk for complications such as recurrent infection, tracheomalacia, tracheal stenosis, and the development of tracheoesophageal fistula (TEF). TEF is a devastating complication where the trachea and esophagus develop an abnormal connection in the lower airway that dramatically increases the mortality of critically ill patients by recurrent aspiration and pneumonias. Though commonly associated with neoplasms another risk is pressure induced ischemia of the common wall between the trachea and esophagus. This can occur due to overinflation of the endotracheal (ET) cuff, especially with concomitant use of a nasogastric tube (NGT). Definitive management requires surgical repair. Case Description/Methods: A 69-year-old male patient presented with acute hypoxemic respiratory failure secondary to COVID pneumonia requiring intubation and insertion of an NGT. On day 29 the patient underwent percutaneous enterogastrostomy (PEG) placement and tracheostomy;it was noted intraoperatively that the tracheal mucosa was inflamed and friable. On day 36 bronchoscopy was performed through the tracheostomy tube due to concerns for mucus plugging. Friable mucosa with granulation tissue was seen at the distal end of the tube, so an extra-long tracheostomy tube was exchanged to bypass the granulation tissue. Later that night the ventilator measured a 50% discrepancy between the delivered and exhaled tidal volumes, triggering an alarm. Exam noted distension of the PEG-bag with a fluid meniscus in the tubing moving in sync with each respiration. TEF was considered and bronchoscopic evaluation confirmed a 1-centimeter TEF. The patient underwent successful TEF repair and is slowly recovering (Figure). Discussion(s): Critically ill patients who require prolonged support are at high risk of complications and device related injury. With each device-day there is an increased risk of complications, such as infection, dislodgement, and pressure-related injuries. This case highlights the importance of serial physical examinations as well as understanding possible device related complications. An unexpected finding, such as a persistent air leak, air in a PEG bag, or a fluctuating meniscus should raise suspicion for the development of a serious complication and would warrant prompt confirmatory testing. Our literature review revealed no reports of a PEG tube abnormalities as a presenting finding for TEF.

Longitudinal improvements in clinical and functional outcomes following initiation of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis

Background: The advent of highly effective modulator therapies (HEMTs), including elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), for treatment of cystic fibrosis (CF) has resulted in remarkable clinical improvement for modulator-naive patients and for those who have been treated with prior modulator therapies. Intranasal micro-optical coherence tomography (muOCT) has detected functional abnormalities in the mucociliary apparatus of people with CF. The objectivewas to characterize the effects of ELX/TEZ/ IVA on nasal mucociliary clearance by muOCT and monitor the clinical changes conferred as a way to understand the effects. Method(s): Of 26 individuals aged 12 and older with at least one F508del mutation recruited, 24 were enrolled and followed over three visits: baseline and 1 (visit 2) and 6 months (visit 4) after initiation of ELX/TEZ/IVA therapy;the COVID-19 pandemic affected visit windows. Intranasal muOCT imaging was conducted at baseline and visit 2 as previously described;additional imaging for 18 months (visit 5) is in progress. Clinical outcomes, including percentage predicted forced expiratory volume in 1 second (FEV1pp) and sweat chloride levels were computed as part of the parent Prospective Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function (PROMISE study). A blinded investigator team analyzed in vivo muOCT parameters including mucociliary transport (MCT) rate, ciliary beat frequency (CBF), and periciliary liquid depth (PCL) after devising an improved stabilization algorithm. Analysis of airway surface liquid (ASL) depthswas excluded because of the limited number of cases in which the necessary condition for measurement,which is preservation of a clear air layer between the mucus layer and the probe, was satisfied. Result(s): Twenty-three subjects completed visits 1 and 2, and 18 completed visits 1, 2, and 4. Average age at baselinewas 27 +/- 8.7, 69% were female, and 43% were on prior two-drug modulator therapy. No significant change in body mass index was found between the visits. FEV1pp increased significantly (10.9%, 95% CI, 76.1-98.4%) by visit 2 and persisted at visit 4 (10.6%, 95% CI, 87.7-107.0;p < 0.001). Sweat chloride levels decreased significantly at visit 2 (-36.6 mmol/L, 95% CI, 40.9-54.9 mmol/L) and visit 4 (-41.3 mmol/L, 95% CI, 34.9-51.8 mmol/L) at visit 4 ( p < 0.001). Analysis of muOCT images revealed significant improvement in MCT rate (2.8 +/- 1.5 mm/ min at baseline vs 4.0 +/- 1.5 mm/min at visit 2, p = 0.048), although no discernable changes were noted in CBF or PCL. When stratified based on use of prior modulator therapy, no significant differences were found for any muOCT metric. No significant correlations between change in MCT rates and change in FEV1pp or sweat chloride from baseline to visit 2were found. Conclusion(s): Treatment with ELX/TEZ/IVA in people with CF, including those that were treatment naive and those on prior modulator therapy, resulted in significant, sustained improvement in lung function and decreases in sweat chloride levels at ~10 months, consistent with recently published reports. Functional improvements in MCTratewere evident after initiation of ELX/TEZ/IVA therapy, which may partially explain the findings of better whole-lung mucus clearance and reduction in chronic infections reported previously. muOCT imaging in people with CF is sensitive to the treatment effect of HEMT and suggests better mucociliary transport as a mechanism of action underlying the clinical benefits for lung health. Acknowledgements: On behalf of the PROMISE investigatorsCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

PHASE 1 CLINICAL TRIALS OF A Q-GRIFFITHSIN NASAL SPRAY FOR SARS-CoV-2 PROPHYLAXIS

Background: The currently approved vaccines do not induce sterilizing immunity against SAR-CoV-2 infection, and immunity wanes over time. A robust broad spectrum topical prophylaxis strategy could protect vulnerable populations in the face of continuous evolution of SARS-CoV-2. The algal antiviral lectin Griffithsin (GRFT), and an engineered oxidation-resistant variant Q-GRFT have robust entry inhibitory activity against SARS-CoV variants of concern, in addition to other respiratory viruses with pandemic potential. We designed a nasal spray to deliver Q-GRFT to the upper respiratory tract mucosa for on-demand use as a broad-spectrum prophylactic. Two clinical trials (Phase 1a and 1b) were conducted to assess safety, tolerability, and pharmacokinetics of Q-GRFT nasal spray in healthy adults. Method(s): Healthy adult volunteers were enrolled in a Phase 1a double blinded, randomized study to receive a single dose of either intranasal Q-GRFT (3.0 mg, 2 sprays per nostril) or placebo at 2:1 ratio. Following a safety review, the Phase 1b study was initiated. Eleven volunteers in Group 1 received 3.0 mg dose once daily, for 7 days. After a safety review, 11 volunteers in Group 2 received a total of 6.0 mg Q-GRFT (3.0 mg twice daily for 7 days). Topical Q-GRFT concentrations were measured by ELISA in collected nasal and nasopharyngeal fluids. Drug levels in plasma were assayed to determine systemic exposure. Viral microneutralization cytopathic effect (CPE) assays were performed against SARS-CoV-2 Omicron BA-5 and MERS-CoV. Result(s): Eighteen adults (24-54 years;Males 58.3%, Females 41.7%;12 Q-GRFT, 6 Placebo), and 22 adults (aged 23-59 years;Males 52.4%, Females 47.6%) were enrolled in Phase 1a and 1b, respectively. In Phase 1a, a single dose of Q-GRFT maintained quantifiable levels in nasal passages and nasopharynx for up to 24 hours. Similarly, Q-GRFT was quantifiable in nasal and nasopharyngeal regions in the Phase 1b study. No dose accumulation effect or systemic exposure was observed. Nasal and nasopharyngeal swab eluates inhibited SARS-CoV-2 Omicron BA.5 and MERS-CoV in CPE assays. Q-GRFT did not modify olfactory sensation. No severe adverse events were reported. Thus, the nasal spray was deemed safe. Conclusion(s): Intranasal Q-GRFT was safe and enhanced mucosal SARSCoV-2 inhibitory activity in human volunteers. The results support further development of Q-GRFT as a broad-spectrum prophylactic against coronaviruses to curb ongoing infections, and for future pandemic preparedness.

Outpatient Child Life: Integrating play, coping strategies, and diagnosis education into a Pediatric Cystic Fibrosis Center

Background: A small Midwest cystic fibrosis (CF) center gained child life support in fall of 2016, but availability was limited due to sharing full-time equivalents (FTEs) between 31 outpatient subspecialty clinics. Child life involvementwas often restricted to immediate stressors (e.g., throat swabs, blood draws, first pulmonary function tests) in a reactive approach, but in the summer of 2020, the child life team added FTEs, increasing the ability for a primary child life specialist (CLS) to be more integrated into the clinic workflow. Partnering with the nurse care coordinators, a comprehensive, proactive approach to the integration of child life was formed, focusing on full scope of practice. Method(s): CFregistered nurse care coordinators collaborated with the CLSto discuss the goal of integration while understanding knownpatient stressors and optimal developmental and coping goals for patients younger than 19 and their siblings. We also determined ways to reduce disruption to clinic workflowwhile leveraging scheduling and increasing awareness of scope of practice of the interdisciplinary team, patients, and families. The CLS also obtained feedback from the family advisory committee engrained in clinic along with hosting a booth at the center's annual CF familyevent that targets caregivers of children with CF. Throughout each of these formative actions,(Figure Presented) Figure 1. : Child life integration protocol the primary focus was on collaboration with the interdisciplinary team, employing the full scope of practice of the CLS, mitigating logistical barriers, and optimizing patient experience and satisfaction. Result(s): The current plan (Figure 1) is based on identified time points where developmentally appropriate interventions and resources are implemented in a stepwise fashion, building upon itself. Interventions are individualized for each patient or family member based on coping and learning needs or developmental differences and are completed by the CLS based on professional judgment and after assessment and rapport is built. The scope of practice includes preparation for procedures or changes in the plan of care, procedural support, creation of coping plans for in-clinic and at-home care routines or events, educational activities and resources (e.g., making slime to learn about mucus, word searches about medications), therapeutic activities to support emotional processing of chronic illness, providing information on typical growth and development to caregivers, and facilitating developmentally appropriate transition-readiness goals through CF R.I.S.E. materials. During the COVID global pandemic, changes to outpatient clinic, including addition of virtual appointments, allowed the CLS to expand practice further. In these video appointments, teen patients appear to be more engaging and talkative, allowing the CLS to better assess coping, adherence, and transition readiness in a relaxed Table 1. Two-way table depicting concordance between substance use and mental health screening results at same encounter. General Anxiety Disorder (GAD7) and Patient Health Questionnaire (PHQ9) results were aggregated such that a positive screening result on either was compared with neither being positive.(Table Presented) environment more suited to their developmental needs. Based on the success of having video appointments with adolescent patients without caregivers present, the CLS and the registered nurse care coordinators agreed to include these moving forward. Conclusion(s): The integration of the CLS at full scope of practice benefits not only patients and families, but also the interdisciplinary team and clinic as a whole. By taking a proactive and preventative approach, coping and psychosocial concerns can be navigated throughout the developmental stages with greater stability and emotional safety for patients and their familiesCopyright © 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

Long-Term High Flow Nasal Cannula Therapy in Primary and Secondary Bronchiectasis.

BACKGROUND: Bronchiectasis is the consequence of chronic bronchial inflammation, inappropriate mucus clearance, bacterial colonization, and recurrent or chronic infection. High flow therapy (HFT) is a type of non-invasive respiratory therapy, usually delivered through a nasal cannula interface (HFNC). It delivers heated and humidified air with a stable fraction of inspired oxygen and a wide range of possible flow rates. AIM OF THE STUDY: Determine the effectiveness of HFNC as add-on therapy in adult primary and secondary bronchiectasis with frequent acute exacerbations (AEs) and/or hospitalizations. METHODS: This is a single-center crossover study on long-term home therapy with HFNC in adult bronchiectasis. Pharmacological therapy included pulse therapy with mucolytics and bronchodilators. After one year, all patients were switched to additional HFNC. The temperature range was 31-37 °C. The flow range was 35-60 L/m. FiO2 was 0.21. RESULTS: Seventy-eight patients completed the follow-up; 54% were females; the median age was 70 years (IQR 60-76). The etiology of bronchiectasis was mainly post-infective (51%), COPD related (26%), and congenital (11%). AEs at baseline were 2.81 (±2.15). A significant reduction in AEs was observed after 24 months with a mean of 0.45 (±0.66) (f-ratio value 79.703. p-value < 0.00001). No significant difference was observed after HFNC therapy on FEV1 (2.39 ± 0.87 vs. 2.55 ± 0.82; f-ratio 0.79. p-value 0.45) and FVC (2.73 ± 0.88 vs. 2.84 ± 0.90; f-ratio 0.411. p-value 0.66). A significant reduction in mMRC score was observed after HFNC therapy (2.40 ± 0.81 vs. 0.97 ± 0.97 at 2 months vs. 0.60 ± 0.78 at 24 months; f-ratio value 95.512. p-value < 0.00001). CONCLUSIONS: HFNC is a well-tolerated add-on therapy for adult bronchiectasis. Dyspnea improved after 2 months and further after 2 years. The exacerbation rate decreased during the 2 years follow-up. No significant difference was observed in lung function.

Purification and characterisation of heparin-like sulfated polysaccharides with potent anti-SARS-CoV-2 activity from snail mucus of Achatina fulica.

Heparin-like sulfated polysaccharide, acharan sulfate, was purified from the mucus of an African giant snail with unique sulfated glycosaminoglycans (GAGs). This study reported on finding novel and safe heparin resources from Achatina fulica for further use as well as easy isolation and purification of the active fraction from the initial raw material. Its structure was characterised by a strong-anion exchange combined with high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy. The results indicated that the potential acharan sulfate fraction is a glycosaminoglycan composed of several repeating disaccharide units, namely, of →4)-α-IdoA(2S)(1→4)-α-GlcNAc/GlcNAc(6S)/GlcNSO3(6S)(1→, and hence, presents heterogeneity regarding negative net charge density. Furthermore, the heparinase digests inhibit the binding of SARS-CoV-2 spike protein to the ACE2 receptor. In summary, the acharan sulfate presented in this work has shown its great potential for application in the preparation of sulfated polysaccharides as an alternative to heparin with important biological activity.

Seroconversion in nasal lining fluid antibodies after Covid19 infection in a health professional cohort

Background: The novel coronavirus SARS-CoV- 2 has caused far-reaching consequences world-wide. Lack of immunity in human, severe airway disease based on a high virulence and its airborne transmission pointed to a significant role of the airways. To investigate immune responses and antibody seroconversion in nasal lining fluid and in serum we examined a cohort of health professionals at the university hospital Klinikum rechts der Isar in Munich. By long-term follow-up of infected and non-infected participants, we were able to investigate the development of local and systemic immunity against SARS-CoV- 2. Method(s): To learn about nasal antibody production we reached out for hospital staff with estimated high risk of a possible Covid19 infection due to their working conditions and staff members suffering from symptoms like fever, cough, loss of smell and taste or sore throat. To detect current infections, we performed SARS-CoV- 2 PCR testing at visit one (V1) and asked our participants to rate possible Covid19 symptoms by filling a questionnaire before every sampling. We eventually included participants, who had been tested positive for SARS-CoV- 2 before (n = 22), as well as people without detected infection, including high-risk contact persons of Covid19 patients and individuals with no Covid-19 infection so far (n = 85). The cohort included 107 hospital staff members, who were sampled six times overall between March and September 2020. Each of the six visits V1 -V6 contained the sampling of serum and nasal fluid to measure IgG, IgM, and IgA rates using immunoassay technique. Result(s): We were able to show the increase of IgA and IgG in the nasal mucosa after recent Covid19 infection. In infected individuals the levels of SARS-CoV- 2 specific nasal IgA increased until V2 with a mean of 4,81 +/- 1,92 mug/l compared to a mean of 0,13 mug/l in non-infected participants, followed by a plateau until V4 and decreased again until V6. Nasal IgG showed a similar trend, apart from a steeper decline after reaching a peak on V2 with a mean of 7,39 +/- 1,63 mug/l, which correlated to the antibody responses in serum. Non-infected individuals showed a mean level of 0,03 mug/l nasal IgG on V2. Serum IgA declined from V1 onwards and hereby showed a quicker drop of systemic antibody levels compared to the nasal lining fluid. Nasal antibody rates reached peaks of 40,00 mug/l (nasal IgA) and 25,74 mug/l (nasal IgG). However, these counts will need further confirmation by a vaccinated control group. Conclusion(s): Nasal measurement of SARS-CoV- 2 specific antibodies provides deeper understanding of mucosal processes while facing inflammation, which may pave the way to less invasive diagnostic possibilities in the future. Furthermore, nasal antibodies built-up after an infection with Covid19 may be protective features concerning a possible re-infection with the virus.

Scientific Connotation and Clinical Value of Traditional Chinese Medicine Lianhua Qingke Improving Ventilation Function Through "Reducing Phlegm".

[] Airway mucus is an important part of the defense barrier function of the airway. Abnormal secretion of airway mucus is closely related to recurrent attacks,delay or aggravation of respiratory infectious or infectious diseases such as chronic obstructive pulmonary disease(COPD),community-acquired pneumonia, and coronavirus disease 2019(COVID-19). Lianhua Qingke tablets,an innovative traditional Chinese medicine (TCM)developed under the guidance of the theory of collateral disease of TCM,has the function of reducing phlegm and relieving cough,which can reduce the generation and viscosity of sputum and promote sputum excretion. Clinical studies have shown that it can significantly improve the symptoms of expectoration and cough in patients with acute bronchitis or COVID-19,confirming its scientific connotation and clinical value of reducing phlegm and relieving cough to improve ventilation and exchanging function.Copyright © 2021, China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica. All rights reserved.

Changes in intestinal morphology, number of mucus-producing cells and expression of coronavirus receptors APN, DPP4, ACE2 and TMPRSS2 in pigs with aging.

Porcine enteric viral infections cause high morbidity and mortality in young piglets (<3 weeks). Later, these rates decrease with age. This age-dependent infectivity remains largely unexplored. This study investigated the changes in intestinal morphology, number of mucus-producing cells and expression level of coronavirus receptors in three age groups of pigs. Villus height and crypt depth increased with age from 3 days to 3 months in duodenum and ileum but not in mid-jejunum, where the villus height decreased from 580 µm at 3 days to 430 µm at 3 months. Enterocyte length-to-width ratio increased from 3 days to 3 months in all intestinal regions. The number of mucus-producing cells increased with age in the intestinal villi and crypts. The Brunner's glands of the duodenum contained the highest concentration of mucus-producing cells. The expression of coronavirus receptor APN was highest in the small intestinal villi at all ages. DPP4 expression slightly decreased over time in jejunum and ileum; it was highest in the ileal villi of 3-day-old piglets (70.2% of cells). ACE2 and TMPRSS2 positive cells increased with age in jejunal and ileal crypts and were particularly dominant in the ileal crypts (> 45% of cells). Except for the expression of DPP4 in the jejunum and ileum of young pigs, the expression pattern of the selected coronavirus receptors was very different and not correlated with the age-dependent susceptibility to viral infections. In contrast, the number of mucus-producing cells increased over time and may play an essential role in protecting enteric mucosae against intestinal viruses.

Airway obstruction in respiratory viral infections due to impaired mucociliary clearance.

Respiratory viral infections, such as SARS-CoV-2 or influenza, can lead to impaired mucociliary clearance in the bronchial tree due to increased mucus viscosity and its hyper-secretion. We develop in this work a mathematical model to study the interplay between viral infection and mucus motion. The results of numerical simulations show that infection progression can be characterized by three main stages. At the first stage, infection spreads through the most part of mucus producing airways (about 90% of the length) without significant changes in mucus velocity and thickness layer. During the second stage, when it passes through the remaining generations, mucus viscosity increases, its velocity drops down, and it forms a plug. At the last stage, the thickness of the mucus layer gradually increases because mucus is still produced but not removed by the flow. After some time, the thickness of the mucus layer in the small airways becomes comparable with their diameter leading to their complete obstruction.

mRNA vaccine boosts the SARS-CoV-2 specific mucosal antibody in recipients of inactivated and mRNA vaccines

Background: Little is known about the induction of mucosal Ab after the 3rd dose. We reported that two doses of BNT162b2 induced mucosal Abs as early as 14-days after the 1st dose. As BNT162b2 only provides the RNA encoding a full-length spike (S) protein, a mixed-vaccine regime with a vaccine that provides inactivated but intact viral particles was executed in some countries to expand the diversity of SARS-CoV-2 Abs. Aim and objectives: To examine the mucosal and plasma Ab induction in vaccine recipients receiving their 3rd vaccine dose with single or mixed vaccine type. Method(s): 46 healthy subjects who had BNT162b2 (B) or CoronaVac (C) in a sequence of either BBB, BBC, CCC or CCB were recruited for a longitudinal sampling of nasal fluid and blood. The S1-specific Ab and neutralizing Ab against SARS-CoV-2 VOCs were measured. Result(s): All BBB recipients (n=28) had nasal specific S1-IgA and IgG after two doses, and the Abs lasted six months and were readily induced after the 3rd dose. In BBC recipients (n=4), though they had prior induction of nasal Abs after two doses of B, the inactivated vaccine did not boost their nasal Abs. In CCC recipients (n=5), there was no induction on nasal Abs. If they adopted the CCB regime (CCB, n=11), they acquired nasal Ab after the 3rd dose. The nasal neutralizing antibodies against the wild type were boosted in 20/28 of the BBB recipients and induced in 8/11 of the CCB recipients but not in CCC or BBC recipients. Lastly, all 46 subjects had a boosted specific S1-IgA and S1IgG in plasma. Conclusion(s): Our findings highlighted the uniqueness of BNT162b2 in induing nasal Ab regardless of the vaccination history.

Vaccination after recovery from COVID-19 affects nasal antibody levels

Introduction: Vaccines prevent severe disease, but to prevent viral transmission and lessen the risk of new variants emerging they need to also enhance mucosal protection. Intramuscular (IM) vaccines induce systemic antibody and appear to transiently reduce transmission, but their effect on nasal antibody in previously infected subjects has not been studied. Aim(s): To study durability of local and systemic antibody responses after COVID-19 in those subsequently vaccinated. Method(s): Nasal fluid and plasma were collected from 448 hospitalised COVID-19 cases during admission and convalescence via the ISARIC4C/PHOSP-COVID studies. IgA/G to wildtype SARS-CoV-2 S, NP and to receptor binding domain (RBD) of Delta and Omicron variants were measured by ELISA. Result(s): Nasal IgA/G anti-S/RBD responses appeared within 28 days and remained high for 1 year(figure 1). Plasma IgA/G responses to S also remained elevated at 1 year(P<0.001). 87% of those with complete data were vaccinated between 6-12 months after infection;when nasal and plasma anti-NP IgA/G waned, whilst anti-S/RBD responses to Delta and Omicron were maintained or increased. Conclusion(s): This is the first study to demonstrate that IM vaccination may boost nasal antibody 1 year after COVID19. This may explain why IM vaccination reduces transmission, adding to the evidence for booster vaccines in COVID-19 recoverees. (Figure Presented).

Case study: Manual respiratory physiotherapy manoeuvres facilitating fibroscopy in an intubated and sedated ICU patient

Introduction: The interest of respiratory physiotherapy maneuvers during a difficult fibroscopy in the intubated patient, sedated in a context of Covid-19 has not been reported so far. Case presentation: A 50-years-old patient with a severe form of Covid-19, requiring an endotracheal intubation, complicated by a ventilator-associated pneumonia and a complete atelectasis of the left lung. Because of adherent and purulent mucus, chest physiotherapy techniques and fiberoptic bronchoscopy conducted separately showed low effectiveness to remove the atelectasis. Chest physiotherapy manual techniques used during fiberoptic bronchoscopy allowed extracting easier the mucus;they helped to remove the atelectasis and to improve the hematosis as well as the prognosis for survival of the patient. Conclusion(s): Manual maneuvers of respiratory physiotherapy during the fibroscopy procedure could improve the efficiency of aspiration of very adherent secretions. Level of Evidence: 5.Copyright © 2022 Elsevier Masson SAS

Induction and maintenance of mucosal healing in Crohn's disease with ustekinumab in clinical practice - Results of a nationwide, prospective, multicenter study in Germany (MUCUS)

Background: Ustekinumab (UST) is a fully human IgG1k monoclonal antibody to human IL-12/23p40 approved in several jurisdictions for the treatment of adult patients with moderately to severely active Crohn's disease (CD). UST's impact on induction and maintenance of mucosal healing, fistula healing and extraintestinal manifestations were not fully elucidated in the registration trial program. Method(s): In this prospective, multicenter study (EudraCT number: 2017-005151-83) across all care levels in Germany, we evaluated the real-world effectiveness of UST prescribed within its German label to achieve the primary endpoint of combined clinical (Harvey Bradshaw Index (HBI) score reduction >= 3 points from baseline) and endoscopic (50% reduction of the simple Endoscopic Score for Crohn Disease (SES-CD) from baseline) response in week 52 and a variety of secondary endpoints including mucosal healing defined as the complete absence of mucosal ulcerations in any ileocolonic segment and endoscopic remission defined as an SES-CD score of 0 - 2. Result(s): We recruited 52 CD patients (female n=28, bionaive n=13, bioexposed n=39). See Table 1 for baseline demographics and pertinent history details. At week 52, 50% (n=12/24) of patients achieved the primary endpoint [50% (n=3/6) in the bionaive, 45.5% (n=5/11) bioexposed to one and 57.1% (n=4/7) bioexposed to multiple biologics cohorts, respectively], 58.3% (n=14/24) of patients achieved endoscopic response [50% (n=3/6) in the bionaive, 54.5% (n=6/11) bioexposed to one and 71.4% (n=5/7) bioexposed to multiple biologics cohorts, respectively], 33.3% (n=8/24) of patients achieved endoscopic remission [50% (n=3/6) in the bionaive, 27.3% (n=3/11) bioexposed to one and 28.6% (n=2/7) bioexposed to multiple biologics cohorts, respectively], 45.8% (n=11/24) of patients achieved mucosal healing [50% (n=3/6) in the bionaive, 36.4% (n=4/11) bioexposed to one and 57.1% (n=4/7) bioexposed to multiple biologics cohorts, respectively]. 36 patients (69.2%) experienced >= 1 treatment emergent adverse event (TEAE), in 8 (15.4%) cases rated as severe and in 5 (9.6%) leading to discontinuation of UST, but no very severe events or deaths (Table 2). Conclusion(s): UST reliably induces endoscopic response and mucosal clinical practice. The limited samples size is a direct result from the Covid-19 pandemic. No new safety signals were recorded.

Single cell mRNA sequencing of nasal swabs indicate an impaired ciliated cell function in COVID-19 convalescents with persisting dyspnea

COVID-19 convalescents often experience persistent symptoms such as fatigue, neurologic complications or dyspnea, often referred to as "long COVID". To elucidate molecular mechanisms underlying ongoing dyspnea in COVID-19 convalescents, we analyzed single-cell RNA sequencing data from nasal swabs collected during acute infection, and three, six and twelve months post infection together with matching healthy controls. Patients with and without persisting symptoms and with varying severity during the acute phase were included. Post infection, we observed a time-dependent decrease in immune cells. Transcriptional analysis of nasal epithelial cells provided evidence of an impaired cilia assembly, organization and function in COVID-19 convalescents with dyspnea compared to healthy controls and convalescents without ongoing respiratory symptoms. Moreover, differences in the differentiation trajectories of ciliated cells were evident between patients with and without dyspnea, with less diverse differentiation endpoints in the dyspnea patients than in healthy controls or convalescents without respiratory impairment. Overall, our analyses revealed a potential deficiency of ciliated cells in COVID-19 convalescents with dyspnea compared to convalescents without ongoing respiratory symptoms or compared with healthy controls. Ciliated cells clear the lung from particles and mucus. If these cells are functionally impaired, pathogens remain in the airways, causing respiratory problems and infections. Thus, it is reasonable to assume, that impaired ciliated cell function contributes to the persistent respiratory symptoms seen in COVID-19 convalescents.

The Role of Labacs in Long COVID-19 Patients in Pringsewu,Indonesia

Background: Severe covid-19 disease has led to many death. Some post mortem study has investigated the cause. The autopsy revealed occurrence of DVT and postmortem lung CT showed reticular infiltration, dense consolidation, while histologically showed diffuse alveolar damage. Through FOB conducted In mechanically ventilated COVID-19 patient, airway obstruction was seen due to hypersecretion and mucus plug in the bronchi. Inhaled budesonide in COVID-19 patient has showed faster recovery and the research focus in the administration of ICS is limited. Objective(s): This study aims to investigate the benefit of LABACS treatment in LONG COVID-19 patients in Pringsewu Indonesia. Method(s): The method of this research was cross sectional. Total subjects included in this study were 276 patients. 168 subjects were treated with Beclomethasone-Formoterol (61%), 49 subjects were treated with FluticasoneSalmeterol (17%), 59 subjects were treated with Budesonide-Formoterol (22%) during 3 months period. We assessed symptoms improvement, mMRC score and chest X-ray imaging. Spirometry of 34 subjects were measured. Result(s): There was a significant correlation between the incidence of lung obstruction and persistent symptom of long covid patients according to spirometry measurement (P value = 0.000). There was a significant correlation between symptoms improvement, mMRC score and chest X-ray imaging after treatment with Beclomethasoneformoterol (p-value = <0.05) Fluticasone-Salmeterol (P value = <0.05) Budesonide-Formoterol (P value = 0.002, P value = 0.007, P value = 0.049). Conclusion(s): LABACS treatment improved lung function and clinically benefit in managing obstruction due to COVID-19.

Scientific Connotation and Clinical Value of Traditional Chinese Medicine Lianhua Qingke Improving Ventilation Function Through "Reducing Phlegm".

[] Airway mucus is an important part of the defense barrier function of the airway. Abnormal secretion of airway mucus is closely related to recurrent attacks,delay or aggravation of respiratory infectious or infectious diseases such as chronic obstructive pulmonary disease(COPD),community-acquired pneumonia, and coronavirus disease 2019(COVID-19). Lianhua Qingke tablets,an innovative traditional Chinese medicine (TCM)developed under the guidance of the theory of collateral disease of TCM,has the function of reducing phlegm and relieving cough,which can reduce the generation and viscosity of sputum and promote sputum excretion. Clinical studies have shown that it can significantly improve the symptoms of expectoration and cough in patients with acute bronchitis or COVID-19,confirming its scientific connotation and clinical value of reducing phlegm and relieving cough to improve ventilation and exchanging function.Copyright © 2021, China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica. All rights reserved.