Nasal Lavage Research Articles

Optimal thresholds and key parameters for predicting influenza A virus transmission events in ferrets

Although assessments of influenza A virus transmissibility in the ferret model play a critical role in pandemic risk evaluations, few studies have investigated which virological data collected from virus-inoculated animals are most predictive of subsequent virus transmission to naïve contacts. We compiled viral titer data from >475 ferrets inoculated with 97 contemporary IAV (including high- and low-pathogenicity avian, swine-origin, and human viruses of multiple HA subtypes) that served as donors for assessments of virus transmission in the presence of direct contact (DCT) or via respiratory droplets (RDT). A diversity of molecular determinants, clinical parameters, and infectious titer measurements and derived quantities were examined to identify which metrics were most statistically supported with transmission outcome. Higher viral loads in nasal wash (NW) specimens were strongly associated with higher transmission frequencies in DCT, but not RDT models. However, viruses that reached peak titers in NW specimens early (day 1 p.i.) were strongly associated with higher transmission in both models. Interestingly, viruses with ‘intermediate’ transmission outcomes (33–66%) had NW titers and derived quantities more similar to non-transmissible viruses (<33%) in a DCT setting, but with efficiently transmissible viruses (>67%) in a RDT setting. Machine learning was employed to further assess the predictive role of summary measures and varied interpretation of intermediate transmission outcomes in both DCT and RDT models, with models employing these different thresholds yielding high performance metrics against both internal and external datasets. Collectively, these findings suggest that higher viral load in inoculated animals can be predictive of DCT outcomes, whereas the timing of when peak titers are detected in inoculated animals can inform RDT outcomes. Identification that intermediate transmission outcomes should be contextualized relative to the transmission mode assessed provides needed refinement towards improving interpretation of ferret transmission studies in the context of pandemic risk assessment.

Feasibility analysis of the treatment of rhinitis diseases by subcutaneous injection of phenol in nasal cavity

Rhinitis is a very common disease that can be roughly divided into allergic and non-allergic rhinitis. Treatments for rhinitis include medication, nasal irrigation, and immunotherapy, all of which have been tested by doctors at various times, but none of which reach the target or work quickly enough. After in-depth analysis of the specific advantages and disadvantages of rhinitis and current rhinitis treatment methods, the use of subcutaneous injection of phenol in the treatment of rhinitis is proposed, and its process is preliminarily determined and its feasibility is verified. Subcutaneous injection has the advantages of rapid efficacy, proximity to the lesion, high bioavailability of the drug and stable rate of subcutaneous tissue absorption of the drug. Phenol is a strong-smelling compound that is highly soluble and volatile and is commonly used to relieve inflammation and reduce secretions. The subcutaneous injection of phenol proposed in this research is a combination of subcutaneous injection therapy and the theory of human acupoints of Chinese medicine, and subcutaneous injection of phenol at six points in the nose for a period of time to achieve the effect of treating rhinitis with half the effort and twice the result.

Inter-societal Survey on the topical nasal treatments in Italy.

Topical nasal therapy represents a widespread opportunity to treat upper airway diseases. As a result, specialists in different areas (mainly ENT, pediatrics, and allergology) and general practitioners prescribe intranasal compounds. However, a myriad of products and devices are available, as well as respiratory disorders. Consequently, this matter is debatable, and no guideline organically addresses this issue. Considering these premises, a restricted panel of qualified experts promoted an initial multidisciplinary survey involving only Fellows of some Scientific Societies belonging to ENT, pediatrics, and allergology areas. The survey included a series of queries concerning practical aspects of topical nasal therapy (treated disease, devices, and agents). A web platform served to participate in this survey. Each participant anonymously completed the questionnaire. Four hundred and forty-five doctors participated in the survey. There was a homogeneous distribution in Italy. Most participants were pediatricians (37%), followed by allergologists (31%) and ENT specialists (24%). Almost all doctors (95%) used topical nasal therapy. The most common diseases topically treated were allergic rhinitis (79%), chronic rhinosinusitis (73%), and non-allergic rhinitis. The most popular devices were pre-dosed spray both for nasal irrigation (67%) and nebulization (66%). Corticosteroids (67%), isotonic saline (63%), hyaluronic acid, hypertonic saline, and antihistamines (39%) were the most common agents used for intranasal therapy. Combined antihistamine/corticosteroids were also commonly used (38%). The most frequent schedule was the cyclic treatment. Most doctors (89%) claim they adequately spend time educating patients on this matter. In conclusion, topical nasal therapy is commonly used to manage upper respiratory diseases. However, the disagreement about some issues requires greater knowledge of the topics and the need to develop new studies, including pragmatic ones.

Otolaryngologist surgical preferences for orbital decompression in thyroid eye disease: A North American survey.

Orbital decompression is recommended for TED especially in the treatment of severe, refractory cases yet there are no clear guidelines regarding the optimal surgical approach. Previously conducted surveys assessed variations in the management of TED but only amongst ophthalmologists. Our study attempts to better characterize surgical and perioperative preferences amongst otolaryngologists in the management of TED. A survey was administered to the American Rhinologic Society and Canadian Society of Otolaryngology - Head and Neck Surgery via REDCap with 52 total respondents. Respondent demographic information and pre-operative management, procedural specifics, and post-operative management preferences were collected. The majority of respondents practiced in a metropolitan (82.7%), academic setting (73.1%) and received subspecialty training in Rhinology & Skull Base Surgery (88.9%). Most elected for corticosteroids (63.5%) and medical management (69.2%) prior to orbital decompression but did not use any classification system (86.5%). Orbital decompression was most often done with ophthalmology collaboration (71.2%). Removal of two bony walls (55.8%) via medial wall (97.9%) and orbital floor (72.3%) removal was most preferred. Removal of one orbital fat aspect (60.6%) via the medial fat pad was most preferred. Combined bone and fat removal (59.6%) completed via an endoscopic approach (71.2% and 97.0%, respectively) was most common. Post-operatively, most patients were not admitted (88.4%) with saline nasal rinses (92.3%) utilized by most respondents. This survey completed by otolaryngologists highlights several key distinctions in the preferred surgical approach during orbital decompression and the perioperative management of TED when compared to ophthalmologists and current recommendations. Level 4.

Adapted retrograde rhinopharyngeal clearance versus high-volume nasal lavage and the impact on sleep in children and adolescents with allergic rhinitis

Adapted retrograde rhinopharyngeal clearance versus high-volume nasal lavage and the impact on sleep in children and adolescents with allergic rhinitis

Nasal effects of environmental tobacco smoke exposure in children with allergic rhinitis

ObjectivesTobacco smoke exposure is associated with inflammatory changes in the respiratory system including nasal mucosa. Our aim was to demonstrate nasal mucosal inflammation such as neutrophilic activation and epithelial permeability in patients with allergic rhinitis with exposure to environmental tobacco smoke (ETS) and reveal its effect on allergic rhinitis symptoms. MethodsWe enrolled 204 subjects with allergic rhinitis to this cross-sectional study. Sociodemographic and AR clinical characteristics were recorded. Urinary cotinine levels >50 ng/ml were defined as exposure to secondhand tobacco smoke. Club cell 16 (CC16) and myeloperoxidase (MPO) levels were measured in the nasal lavage fluid. Levels of these biomarkers and clinical severity were compared between ETS exposed and non-exposed children with AR. ResultsAmong 204 children enrolled, 53 (26 %) had ETS exposure. Mean age of the ETS exposed group was significantly higher than the unexposed group (12.1 ± 3.5 and 10.7 ± 3.6 years respectively, (p = 0.02). Similarly, T5SS score was significantly higher in ETS exposure group (9.3 vs 8.3, p = 0.03) but this significance was lost when corrected for age. Age and T5SS were inversely correlated with MPO levels (r = −0,24, p < 0.001 and r = −0,14, p = 0.04). Nasal lavage CC-16 and MPO levels were not found to be significantly different among subjects with and without ETS exposure (p = 0.13 and p = 0.26 respectively). ConclusionOur results demonstrated that ETS exposure is associated with more persistent AR in children. However, it is not related to severity or nasal lavage MPO or CC16 levels. Rhinitis symptoms beyond allergen period suggests isolated smoke exposure effect.

Effects of intranasal administration with a symbiotic strain of Bacillus velezensis NSV2 on nasal cavity mucosal barrier in lambs.

The nasal mucosa is composed of multiple layers of barrier structures and is the first line of defense against infection by respiratory pathogenic microorganisms. A large number of commensal microorganisms are present in the nasal mucosa that mediate and regulate nasal mucosal barrier function. The objective of this research was to investigate the effects of commensal microorganisms on the nasal mucosal barrier. The results revealed that the strain of Bacillus velezensis (B. velezensis) NSV2 from the nasal cavity has good probiotic abilities to resist Pasteurella multocida, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium. Lambs were subsequently administered intranasally with B. velezensis NSV2 at 3, 12, 21, and 26 days old, respectively. For the microbial barrier, although B. velezensis NSV2 reduces the diversity of nasal microbiota, it significantly increased the relative abundance of beneficial bacteria in the nasal cavity, and reduced the abundance of potential pathogenic bacteria. For the mucus barrier, the number of goblet cells in the nasal mucosa significantly increased after B. velezensis NSV2 treatment. For the immune barrier, B. velezensis NSV2 also significantly increased the number of IgA+ B cells, CD3+ T cells and dendritic cells in the nasal mucosa, as well as the mRNA expression of interleukin (IL) 6, IL11, CCL2, and CCL20 (P < 0.05). The protein level of CCL20 also significantly raised in nasal washings (P < 0.05). Moreover, the heat-inactivated and culture products of B. velezensis NSV2 also drastically induced the expression of CCL20 in nasal mucosa explants (P < 0.05), but lower than that of the live bacteria. This study demonstrated that a symbiotic strain of B. velezensis NSV2 could improve the nasal mucosal barrier, and emphasized the important role of nasal symbiotic microbiota.

Adjunctive Saline Nasal Irrigation for Acute Rhinosinusitis: Results of a Randomized Pilot Study

Adjunctive Saline Nasal Irrigation for Acute Rhinosinusitis: Results of a Randomized Pilot Study

Infectivity and Immunogenicity of Live-Attenuated Respiratory Syncytial Virus Vaccines in Human Immunodeficiency Virus-Exposed Uninfected Children.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory illness among young children. Human immunodeficiency virus (HIV)-exposed, uninfected (HEU) children experience a higher burden of RSV disease and have immune abnormalities that may influence their responses to live-attenuated RSV vaccines. In a pooled analysis of clinical trials of 7 live-attenuated, intranasal RSV vaccines conducted by the IMPAACT Network among children 6 to <25 months of age with serum RSV-neutralizing titers of <1:40, the infectivity and immunogenicity of these vaccines were compared among HEU and HIV-unexposed, uninfected (HUU) children. Nasal washes were collected during the first 28 days after vaccination. Serum RSV-neutralizing and anti-RSV F glycoprotein immunoglobulin G (IgG) antibodies were measured prior to and 56 days after vaccination, and before and after the following winter season. Of 156 children, 90 (58%) were HUU and 66 (42%) were HEU. Seventy-six (84%) HUU and 63 (95%) HEU participants were infected with vaccine (shed vaccine virus and/or had a ≥4-fold rise in serum RSV antibodies at 56 days after vaccination). HUU children had higher serum RSV-neutralizing and anti-RSV F IgG titers prior to vaccination. Compared to HEU children, lower percentages of HUU children had ≥4-fold rises in RSV-neutralizing (67% vs 88%) and anti-RSV F IgG (70% vs 89%) titers at 56 days after vaccination. Live-attenuated RSV vaccines are highly immunogenic in HEU children. Given their increased burden of RSV disease and higher early childhood mortality in some settings, HEU children should be prioritized for vaccination against RSV as these vaccines become available.

The essential oils from Asarum sieboldii Miq. Alleviate allergic rhinitis by regulating tight junction and inflammation; Network analysis and preclinical validation

Ethnopharmacological relevanceEssential oils from herbs, including those from Asarum sieboldii Miq., are readily absorbed through mucous membranes, explaining their widespread use in inhalation formulations. Asarum sieboldii Miq. has a long history of traditional use for various medicinal purposes, attributed to its anti-inflammatory, antiallergic, and antioxidant properties. Despite research on Asarum sieboldii Miq. for allergic inflammation in respiratory diseases, detailed mechanistic studies are still lacking. Aim of the studyWe utilized bioinformatics and network pharmacology to identify the effectiveness of Asarum sieboldii Miq. in treating allergic rhinitis (AR). Our aim is to elucidate the potential therapeutic effects of essential oil derived from Asarum sieboldii Miq. (ASO), which is recognized for its diverse pharmacological properties, on AR. Materials and methodsCommon genes associated with the active compounds of ASO and AR were utilized to construct a related network and predict their mode of action. AR was induced in BALB/c mice by exposing them to ovalbumin (OVA) and particulate matter 10 (PM10; airborne particles <10 μm). With induction, aerosolized ASO (0.0002% and 0.02%) were administered via nebulizer for 5 min per day, three times a week for 7 weeks. Mice were examined for histopathological changes in the nasal tissue, nasal epithelial inflammation, the production of allergen-specific cytokine response in vitro and in vivo. ResultsThe common genes of ASO and AR were predicted to include 'Tight junction', 'Apoptosis', and 'TGF-beta signaling', which are the main pathways of pathogenesis in AR. Consistent with network prediction, nebulized ASO treatment effectively improved the expression of tight junction-related factors, zonula occludens-1, claudin-1, occludin and junction adhesion molecule A, in OVA + PM10 induced mice. Additionally, it reduced hyperplasia of nasal epithelial thickness, goblet cell counts, and inflammatory cell infiltration (eosinophils, neutrophils, macrophages, and lymphocytes) in nasal lavage fluid, while also alleviating allergic symptoms such as sneezing, rubbing, and serum IgE level when compared to the AR-induced group. The levels of mRNA and protein expression related to tight junctions were restored to normal levels by ASO, as confirmed in immunofluorescence analysis in nasal epithelial cells RPMI2650. Furthermore, treatment of ASO on PM10-treated nasal epithelial cells significantly reduced ROS production, recovered mitochondria membrane potential, and inhibition of the production of proinflammatory cytokines (TNF-α, IL-4, and IL-13) and inflammatory mediators linked to the MAPK/NF-κB signaling pathways. ConclusionIntranasal nebulization of ASO improves TJs and alleviates allergic nasal inflammation in AR. It supports the potential pharmaceutical application of ASO treatment for AR.

Characterization of H5N1 avian influenza virus isolated from bird in Russia with the E627K mutation in the PB2 protein

Currently A(H5Nx) avian influenza viruses are globally widespread and continue to evolve. Since their emergence in 2020 novel highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b reassortant viruses have become predominant in the world and caused multiple infections in mammals. It was shown that some of A(H5N1) viruses mostly isolated from mammals contain an E627K mutation in the PB2 protein which can lead to adaptation of influenza viruses to mammalian cells. In 2023 in Russia we have isolated two highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b viruses from birds one of which contained an E627K mutation in the PB2 protein. This virus had increased virulence in mice. Limited airborne transmission of the virus with the PB2-E627K mutation was observed between ferrets, in which infectious virus was detected in the nasal washings of the three of the twelve recipient ferrets, and clinical symptoms of the disease were observed in one case. Both viruses showed dominant binding to avian-type sialoside receptors, which was most likely the reason for the limited transmissibility. Thus, this study indicates a possible limited increase in the pandemic potential of A(H5N1) 2.3.4.4b viruses and highlights the importance of continuous avian influenza surveillance for pandemic preparedness and response.

Contemporary practice patterns for chronic rhinosinusitis with nasal polyps.

Data on current practice patterns for the management of chronic rhinosinusitis with nasal polyps, including which medications are deemed by otolaryngologists to better manage patient symptoms, are limited. This study demonstrated that contemporary practice patterns are largely consistent with published clinical consensus statements. Off-label nasal steroid irrigations and dupilumab are the most commonly used topical and systemic therapies for chronic rhinosinusitis with nasal polyps, respectively.

Effectiveness and safety of addition binahong extract 2.5% on saline nasal irrigation for allergic rhinitis patients: protocol for randomized controlled trial investigator-blinded

Effectiveness and safety of addition binahong extract 2.5% on saline nasal irrigation for allergic rhinitis patients: protocol for randomized controlled trial investigator-blinded

Profile of immune response during nasal challenge with dermatophagoides pteronyssinus in subjects with allergic airway diseases

BackgroundT lymphocyte helper (Th) 2 plays the main role in pathogenesis of allergic airway diseases (AAD). Recent studies showed that interleukin (IL) 33, Th17 and Th22 also may be involved in allergic inflammation. The aim is to evaluate cytokine level before and after nasal challenge with Dermatophagoides pteronyssinus in patients with AAD.MethodsPatients with persistent allergic rhinitis (AR) with or without allergic asthma (AA) allergic to house dust mite and healthy individuals underwent nasal challenge with Dermatophagoides pteronyssinus. Measurements of IL-13, IL-17, IL-22 and IL-33 in serum and nasal lavage were performed before, 2 and 22 h after nasal challenge by ELISA.Results. Ten patients with AR only, 6 patients with AR and AA and 7 healthy individuals were involved in the study. Serum IL-22 level significantly increased in patients with AR and AA and nasal lavage IL-22 tended to increase in patients with AAD after nasal challenge. Serum IL-13 level tended to increase in patients with AR and AA. IL-13 level in nasal lavage fluid decreased at 22 h after nasal challenge in patients with AR only. IL-17 level in serum and nasal lavage decreased in patients with AAD. Serum IL-33 tended to increase after nasal challenge whereas IL-33 in nasal lavage significantly decreased.ConclusionCytokine profile differs between local and systemic compartments and between patients with allergic rhinitis only and patients with allergic rhinitis and asthma after nasal challenge.

The role of epithelial alarmins and Th2 cytokines in the inflammatory response in allergic rhinitis

Allergic rhinitis (AR) occupies a leading position among the causes of morbidity throughout the world, to date, it has been diagnosed in 400 million people. In the formation and progression of AR, a significant role is assigned to cytokines associated with the second type of immune response, in particular, IL-4, IL-5, IL-9, IL-13, IL-25, IL-33, thymic stromal lymphopoietin (TSLP). This literature review provides information on the influence of the listed mediators on the structural cells of the nasal cavity and blood immune cells (T- and B-lymphocytes, eosinophils, macrophages, dendritic cells), and discusses their association with the manifestation of AR symptoms and the severity of the disease. The results of studies aimed at establishing the level of IL-4, IL-5, IL-9, IL-13, IL-25, IL-33 and TSLP in biological fluids (blood serum, nasal lavage) and their expression in nasal epithelial cells in patients with AR compared to healthy people are assessed.

Ameliorative Potency of Iridoid Glucoside Compound Catalpol on Inhibiting NF-κB-mediated Inflammation in Allergic Rhinitis-induced Mice

Background Over time, the prevalence of allergic rhinitis (AR) has surged due to various risk factors, notably attributed to global urbanization, rendering heightened levels of pollutants, including traffic-related emissions and particulate matter. About 25% of the global children population and 40% of the adult population were reported with AR. Even though AR is recognized as a systemic inflammatory disease, it often results in diverse other comorbidities, such as dermatitis, sinusitis, conjunctivitis, and otitis, requiring extensive and expensive treatment. Purpose We assessed the effectiveness of iridoid glucoside catalpol against AR in a mouse model. Catalpol is recommended in traditional Chinese medicine to treat diverse acute and chronic diseases. Methods AR was induced in mice with an ovalbumin-sensitized AR model and treated with 10 and 20 mg of catalpol. Nasal severity scoring was performed to confirm the AR induction in mice. Allergic mediators immunoglobulin E (IgE) and histamine were quantified in the serum to assess the anti-allergic response of catalpol. In nasal lavage fluid (NALF), the inflammatory mediators IgE Ab, prostaglandin D2, leukotriene C4, eosinophil cationic protein (ECP), and pro-inflammatory cytokines were measured to analyze the anti-inflammatory potency of catalpol. The binding capacity of nuclear factor-kappa B (NF-κB) to DNA was evaluated to assess the catalpol inhibitory potency against NF-κB-mediated inflammation in AR mice. To confirm the ameliorative potency of catalpol in AR mice, a histopathological analysis of nasal mucosa was performed. Results Catalpol treatment significantly decreased the nasal symptoms and reduced the allergic mediators in the serum of experimental animals. It effectively inhibited the synthesis of inflammatory mediators, ECP, and pro-inflammatory cytokines in the NALF, and also suppressed the NF-κB DNA-binding activity in AR mice. The decrease in ciliary loss, goblet cells, eosinophil infiltration, and vascular congestion observed with our nasal mucosa histopathological analysis confirmed the ameliorative potency of catalpol. Conclusion Our findings have proven catalpol inhibits NF-κB-mediated inflammatory response in AR mice. With further analysis, a potent natural compound, catalpol, can be formulated as a drug to treat AR.

Intranasal M2SR and BM2SR Vaccine Viruses Do Not Shed or Transmit in Ferrets.

Live influenza vaccines are considered to stimulate better overall immune responses but are associated with safety concerns regarding shedding and the potential for transmission or reassortment with wild-type influenza viruses. Intranasal M2SR and BM2SR (M2- and BM2-deficient single replication), intranasal influenza viruses, have shown promise as broadly cross-reactive next-generation influenza vaccines. The replication deficiency, shedding, and transmissibility of M2SR/BM2SR viruses were evaluated in a ferret model. Wild-type influenza A and B control viruses replicated in upper respiratory organs and transmitted to both direct and aerosol contact ferrets, whereas M2SR and BM2SR influenza vaccine viruses were not detected in any tissues or in nasal washes after inoculation and were not recovered from any direct or aerosol contact ferrets. Mice were simultaneously infected with wild-type influenza A and M2SR viruses to assess reassortment potential. Sequence and PCR analyses of the genome recovered from individual virus plaques isolated from lung homogenates identified the origin of the segments as exclusively from the replicating wild-type virus. These results indicate that M2SR and BM2SR influenza vaccine viruses are attenuated, do not shed or transmit, and have a low probability for reassortment after coinfection. Absence of shedding was further demonstrated in nasal swabs taken from subjects who were inoculated with H3N2 M2SR in a previously described Phase 1 clinical study. These results indicate that M2SR/BM2SR viruses have the potential to be used in a broader population range than current live influenza vaccines.

Protection of Rabbits Against Colonization and Morbidity Associated With Toxigenic Pasteurella multocida by Immunization With Inactivated Heat-labile Toxin.

Pasteurella multocida is a significant cause of morbidity and mortality in rabbits, as well as other species. Some isolates elaborate a heat-labile toxin (PMT) that has been shown to be an important virulence factor. Though previous studies have demonstrated protective immunity can be conferred via immunization of rabbits with heat-inactivated PMT (IPMT), we investigated the ability of immunization to impact colonization of P. multocida. Rabbits were immunized at days 0, 7 and 14 with either phosphate buffered saline (PBS), the mucosal adjuvant cholera toxin (CT), IMPT or IPMT + CT. Male New Zealand white rabbits were used and confirmed to be free of P. multocida prior to experimentation. Serum IgG and nasal lavage fluid IgA responses directed against PMT were found in rabbits immunized with IPMT, with or without CT, but not in those immunized with only PBS or CT; and the addition of CT to IPMT enhanced the response. Significantly more P. multocida CFUs (p≤0.05) were cultured from the lungs of rabbits immunized with IPMT, with or without CT, compared to those administered only PBS or CT, although no differences were observed in nasal lavage fluid samples. Further, immunization IPMT, with or without CT, conferred protection against pleuritis and pneumonia. PMT, in addition to its role as a virulence factor, may serve as a colonization factor for P. multocida in the lungs of rabbits.

EDP-938 Has a High Barrier to Resistance in Healthy Adults Experimentally Infected with Respiratory Syncytial Virus.

EDP-938 is an oral once-daily RSV nucleoprotein (N) inhibitor with potent antiviral activity. In a human RSV challenge trial, EDP-938 significantly reduced viral load and symptom severity. During antiviral development, it is critical to understand the propensity for resistance to develop. In vitro studies of EDP-938 suggest a higher barrier to resistance as compared to RSV fusion inhibitors. We evaluated the development of viral resistance to EDP-938 in a human challenge trial. A subset of the 124 participants with RSV infection were chosen for genetic analysis; 159 nasal wash samples from 48 participants were analyzed using next-generation sequencing of the N gene of RSV. Of the 48 participant sampled, 37 were from EDP-938-treated and 11 were placebo-treated participants, representing 45% and 26% of the participants, respectively. The effects of treatment-emergent mutations on viral load, EDP-938 efficacy, and viral fitness were evaluated. Two of the 37 EDP-938-treated participants with samples sequenced had treatment-emergent mutations: N:L139I and N:E112G. From in vitro analysis, N:L139I reduced sensitivity to EDP-938 by approximately 10-fold, while N:E112G had no effect. However, N:L139I was associated with a reduction in viral fitness, suggesting clinical resistance is associated with fitness costs. Neither of these variants were associated with reduced viral clearance. In human RSV infections treated with EDP-938, emergence of RSV variants with reduced sensitivity to EDP-938 occurred in only 1 participant and was associated with reduced viral fitness. EDP-938's high barrier to resistance highlights its robust mechanism of action. NCT03691623.

Hypertonic Saline Nasal Rinse Intervention: Immunomodulatory Effects in Dairy Workers

ABSTRACT Objective Increased risk of occupational exposure to bioaerosols has long been recognized in livestock operations including dairy facilities. Spanning the inhalable fraction (0–100 μm), dairy bioaerosols comprise a wide variety of inflammatory components that deposit in the nasopharyngeal region. The resultant inflammatory response from bioaerosol exposure is likely driving the increased prevalence of respiratory disease observed in dairy workers. It is also thought the microbiome of the upper respiratory system may help mediate this inflammation. We investigated the viability of a low-cost hypertonic saline nasal rinse intervention in modulating inflammatory responses in bioaerosol exposed dairy workers and its impact on microbial diversity. Methods Pre- and post-shift nasal rinses were administered and collected alongside full shift inhalable personal breathing zone (PBZ) samples for each participant for up to 5 consecutive days. Treatment group participants (n = 23) received hypertonic saline rinses while control group participants (n = 22) received normotonic saline rinses. Particulate matter (PM) and endotoxin concentrations were quantified from PBZ samples using gravimetric and enzymatic analytical methods, respectively. Pre- and post-shift rinses were analyzed for pro- and anti-inflammatory markers and microbial diversity using a multiplex assay and 16S rRNA sequencing, respectively. Results PM and endotoxin concentrations were comparable between groups indicating similar exposures. Post-shift pro-inflammatory markers were significantly higher than pre-shift for IL-13 (p = .047), IL-1β (p < .001), IL-6 (p < .001), IL-8 (p < .001), and TNF-α (p = .024). There was no evidence of a difference in log concentrations between intervention group or day among any of the measured inflammatory markers. Anti-inflammatory IL-10 concentrations increased across the 5 sample days, independent of treatment group suggesting tonicity may not be driving the change. However, this result was not significant (p = .217). Nasal microbiome alpha (within sample) and beta (between sample) diversity metrics did not differ significantly between group or day demonstrating no adverse washout intervention effects. Conclusion This study provided encouraging results that warrant future research to further evaluate saline nasal rinses as a workplace intervention.