Saline nasal irrigation and gargling in COVID-19: a multidisciplinary review of effects on viral load, mucosal dynamics, and patient outcomes.

With unrelenting SARS-CoV-2 variants, additional COVID-19 mitigation strategies are needed. Oral and nasal saline irrigation (SI) is a traditional approach for respiratory infections/diseases. As a multidisciplinary network with expertise/experience with saline, we conducted a narrative review to examine mechanisms of action and clinical outcomes associated with nasal SI, gargling, spray, or nebulization in COVID-19. SI was found to reduce SARS-CoV-2 nasopharyngeal loads and hasten viral clearance. Other mechanisms may involve inhibition of viral replication, bioaerosol reduction, improved mucociliary clearance, modulation of ENaC, and neutrophil responses. Prophylaxis was documented adjunctive to personal protective equipment. COVID-19 patients experienced significant symptom relief, while overall data suggest lower hospitalization risk. We found no harm and hence recommend SI use, as safe, inexpensive, and easy-to-use hygiene measure, complementary to hand washing or mask-wearing. In view of mainly small studies, large well-controlled or surveillance studies can help to further validate the outcomes and to implement its use.

Reply to Davison, G. Comment on "Huijghebaert et al. Does Trypsin Oral Spray (Viruprotect®/ColdZyme®) Protect against COVID-19 and Common Colds or Induce Mutation? Caveats in Medical Device Regulations in the European Union. Int. J. Environ. Res. Public Health 2021, 18, 5066".

We have read the comment from Davison with great interest [...].

Does Trypsin Oral Spray (Viruprotect®/ColdZyme®) Protect against COVID-19 and Common Colds or Induce Mutation? Caveats in Medical Device Regulations in the European Union.

BACKGROUND: nasal or oral sprays are often marketed as medical devices (MDs) in the European Union to prevent common cold (CC), with ColdZyme®/Viruprotect® (trypsin/glycerol) mouth spray claiming to prevent colds and the COVID-19 virus from infecting host cells and to shorten/reduce CC symptoms as an example. We analyzed the published (pre)-clinical evidence. METHODS: preclinical: comparison of in vitro tests with validated host cell models to determine viral infectivity. Clinical: efficacy, proportion of users protected against virus (compared with non-users) and safety associated with trypsin/glycerol. RESULTS: preclinical data showed that exogenous trypsin enhances SARS-CoV-2 infectivity and syncytia formation in host models, while culture passages in trypsin presence induce spike protein mutants. The manufacturer claims >98% SARS-CoV-2 deactivation, although clinically irrelevant as based on a tryptic viral digest, inserting trypsin inactivation before host cells exposure. Efficacy and safety were not adequately addressed in clinical studies or leaflets (no COVID-19 data). Protection was obtained among 9-39% of users, comparable to or lower than placebo-treated or non-users. Several potential safety risks (tissue digestion, bronchoconstriction) were identified. CONCLUSIONS: the current European MD regulations may result in insufficient exploration of (pre)clinical proof of action. Exogenous trypsin exposure even raises concerns (higher SARS-CoV-2 infectivity, mutations), whereas its clinical protective performance against respiratory viruses as published remains poor and substandard.

Essentials in saline pharmacology for nasal or respiratory hygiene in times of COVID-19.

PURPOSE: Nasal irrigation or nebulizing aerosol of isotonic or hypertonic saline is a traditional method for respiratory or nasal care. A recent small study in outpatients with COVID-19 without acute respiratory distress syndrome suggests substantial symptom resolution. We therefore analyzed pharmacological/pharmacodynamic effects of isotonic or hypertonic saline, relevant to SARS-CoV-2 infection and respiratory care. METHODS: Mixed search method. RESULTS: Due to its wetting properties, saline achieves an improved spreading of alveolar lining fluid and has been shown to reduce bio-aerosols and viral load. Saline provides moisture to respiratory epithelia and gels mucus, promotes ciliary beating, and improves mucociliary clearance. Coronaviruses and SARS-CoV-2 damage ciliated epithelium in the nose and airways. Saline inhibits SARS-CoV-2 replication in Vero cells; possible interactions involve the viral ACE2-entry mechanism (chloride-dependent ACE2 configuration), furin and 3CLpro (inhibition by NaCl), and the sodium channel ENaC. Saline shifts myeloperoxidase activity in epithelial or phagocytic cells to produce hypochlorous acid. Clinically, nasal or respiratory airway care with saline reduces symptoms of seasonal coronaviruses and other common cold viruses. Its use as aerosol reduces hospitalization rates for bronchiolitis in children. Preliminary data suggest symptom reduction in symptomatic COVID-19 patients if saline is initiated within 48 h of symptom onset. CONCLUSIONS: Saline interacts at various levels relevant to nasal or respiratory hygiene (nasal irrigation, gargling or aerosol). If used from the onset of common cold symptoms, it may represent a useful add-on to first-line interventions for COVID-19. Formal evaluation in mild COVID-19 is desirable as to establish efficacy and optimal treatment regimens.

Medical devices that look like medicines: safety and regulatory concerns for children in Europe.

INTRODUCTION: Medical devices (MedDevs) and medicines are assessed (and monitored) differently before and after launch. There are products for repeated oral ingestion that are marketed in the European Union as MedDevs. OBJECTIVES AND METHODS: To illustrate the consequences of these differences in assessment, we compared the leaflet information of three MedDevs with the standards for medicines and with published evidence at launch. As examples, gelatin tannate (GT), its combination with tyndalised probiotics (TP) (GTTP) for diarrhoea and a gel containing hyaluronic acid (HA)/chondroitin sulfate (CS)/poloxamer (Pol407) (HACSPol) for gastro-oesophageal reflux disease were examined. RESULTS: Applying standards for medicines, product composition is insufficiently defined in the MedDev leaflet (eg, plant origin, polymerisation grade, dose and ratio of the relevant constituents). As no age limit is mentioned in the leaflets, all 3 products allow use in children from birth onwards, although published clinical documentation in children was poor (GT) or lacking (GTTP and HACSPol). MedDev leaflets do not mention adverse events (AEs), while literature search suggests safety concerns such as tannic acid (TA) cytotoxicity, potentially more diarrhoea/AEs with TP, use of doses higher than established safe (TA and HA) and lack of chronic toxicity studies for oral Pol407. None refers to interactions with medicines, although some ingredients may affect medicine absorption. CONCLUSION: Although these MedDevs require repeated oral intake as do medicines, their assessment and monitoring differ significantly from the standards for medicines. Compared with medicines, MedDevs for repeated oral use are poorly labelled and rely on very limited clinical information at market release.

Influence of food intake on the QT and QT/RR relation.

BACKGROUND: There are conflicting data on the influence of meal intake on the QT interval. METHODS: Ten healthy subjects were studied before and after a standardized breakfast and lunch with a sequence of supine resting, standing and exercise. Data collection was performed using a 12-lead Holter with semi-automated analysis. QT correction was performed using Fridericia (QTcF) correction formula and a subject-specific method based on individual QT/RR-regression (QTcI). RESULTS: Meal intake induced significant changes in HR (p<0.001), but not in QTcF (p=0.512) or QTcI (p=0.739). Postural analysis showed only significant differences in supine position for HR (p=0.010), not when standing or during exercise. CONCLUSION: Food intake induced an increase in heart rate limited to supine position. Using QTcF and QTcI no QTc changes were found.