CALL FOR COOPERATION - COVID-19

By Tamás Kókai, inventor and manufacturer of the LibAirator salt therapy device. This writing is work in progress.

Redefining hyponatremia could be necessary for successful COVID-19 prevention and treatment

 

ABSTRACT

Inhaled NaCl (common salt) may help in preventing SARS-Cov-2 coronavirus infection (COVID-19) and relieving respiratory symptoms:

• In vivo, NaCl has shown an antiviral effect in the airways.

• In vivo, elevated extracellular NaCl concentration has been shown to reduce cellular ACE2 expression by up to 60 percent. ACE2 is considered to be the binding site for SARS-CoV2. 

• Elevated extracellular NaCl has been shown in vitro to block intracellular viral replication by nearly 100 percent

• Inhaled NaCl has been shown to help mucociliary clearance.

• There is a strong correlation between the negative deviation of serum Na+ levels from the median at patient admission, especially 141 mmol / L and below and the later severity of the disease. 

The current study hypothesizes that inhaled NaCl reduces ACE-2 expression in airway epithelial cells, reducing virus binding, and blocks viral replication within infected cells. Improved mucociliary clearance helps in preventing infection and a milder course of the disease in the lungs. A clinical trial is considered necessary.

A related hypothesis of the current study is that salt deficiency, and therefore low sNa+ (and ultimately, low intercellular Na+) due to heavy sweating may explain why people doing exhausting high-profile sports are infected by the virus at an unexpectedly high proportion. Low sNa+ may also play a key role in obese people because of a combination of factors, including sweating and elevated urine Na+ excretion. The high prevalence of fatalities among patients with hypertension may also be explained by a low-salt diet and the use of (thiazide) diuretics. 

The current study also hypothesizes that serum Na-levels - because of the ACE2-expression downregulating role of NaCl/Na+ - should be regarded as a key factor in the prevention and treatment of COVID-19 and that the elevated ACE2-expression caused by lower than average sNa+ explains most COVID-19 phenomena experienced. Consequently, it would be essential to look at sNa+ levels of 141 mmol / L and below as hyponatremia, at least as a work hypothesis for further investigation, and to consider sNa+ levels of 142-145 mmol / L as ideal in terms of coronavirus prevention and treatment.

Pre-COVID-19 normals may have to be overridden by new normals for a successful COVID-19 management, especially in the light that the virus is most probably of zoonotic - bat - origin where the virus is essentially non-lethal, and healthy bat sNa+- levels are 146 ± 5 mmol / L, just outside of the range in patients with elevated danger of serious or lethal complications.

 

INTRODUCTION

COVID-19 has become a pandemic since its first outbreak in Wuhan, China in 2019. This writing was started in March, 2020, concentrating on the potential applicability of inhaled NaCl in the prevention and treatment of a SARS-CoV-2 infection. During the course of writing, so many pieces of the puzzle pointing to a (relative) salt deficiency have emerged, that it was extended to cover the role of Na(Cl) related to COVID-19 in general, in order to provide a consistent explanation.

 

INTEREST

The author refers to experience with LibAirator, a salt therapy device invented and developed by himself. It generates dry salt nanoparticles, which can arguably be the most suitable solution for the purpose of COVID-19 prevention and alleviation of symptoms in the airways, provided the present hypothesis is valid. However, the author also suggests an alternative device (LibAirNose) which is simple, easy to make in a home-made version, and easily applicable anywhere. It is arguably more efficient than known solutions based on wet aerosolization and safer as far as potential virus transmission is concerned, and can be used in a clinical setting.

The author also declares that his thoughts on the necessity of maintaining higher serum Na+-levels and the eventual suspension of a low-salt diet do not serve any business interest.

 

APPLIED DEVICE AND METHOD

LibAirator is a device that has been used successfully to prevent and alleviate respiratory symptoms by inhalation of dry salt nanoparticles (of about 1 nm size) released into the immediate environment of the user. LibAirator is a Class I medical device (OGYÉI HU / CA01 / 12001/2018), a European patent (EP3240530), patent pending in the United States, and has been on the market since 2018 with nearly 10,000 users. The device is not based on conventional wet aerosol generation, therefore, there is no risk of virus transmission by the emitted particles. It only requires natural inhalation and exhalation; it moves less air than human respiration (315 liters / hour), so any concerns about the device extensively moving air in a clinical environment are unfounded. The inlet side of the device can be hermetically sealed with a HEPA filter to prevent internal contamination. Its effect depends on the user’s distance from the device. In everyday use, the device is placed within arm's reach, with a typical duration of 8 hours per day. In addition, intensive use (“shock therapy”) from close for up to 30 minutes is recommended, as needed. Based on the results of study cited in point 2 below which  describes how NaCl reduces / blocks intracellular replication of SARS-Cov2 virus, this shock therapy may be particularly effective.

 

SUGGESTED ALTERNATIVE DEVICE AND METHOD USABLE WIDELY AND IMMEDIATELY

The device is a small container held or fixed with a strap under the nose containing salt grains wrapped in a thin absorbent material. It is to be moistened with a few drops of water before the first use, so that it acts as a single salty block afterward. The salt(bag) is cyclically wetted by exhalation and desorbed by inhalation, resulting in the inhaled air being enriched with salt. The dose is comparable to that of a bather sitting up to their neck in the Dead Sea, therefore, it can be considered safe. The device is patent pending and is expected to be marketed as LibAirNose, but the idea can be freely used for non-commercial purposes with non-industrial manufacturing methods (a homemade version can be a beverage cap deformed oval). Suggested application: 3x60 or 6x15 minutes per day; additional maintenance application depending on the effect experienced. (The taste of sputum should taste at least as salty as a 1.5% NaCl solution).

 

RESEARCH RESULTS TO DATE

1. NaCl has an antiviral effect in the airways, as confirmed and theoretically substantiated by ELVIS (Edinburgh & Lothians Viral Intervention Study ([1] Ramalingam et al., Sci Rep 9, 1015 (2019)) :  [2] Ramalingam et al., Sci Rep 8, 13630 (2018). In this clinical trial, although only regular saline gargling and saline nasal rinsing were applied, significant improvement in viral upper respiratory tract infection (URTI) indicators could be achieved compared to the control group: 1.9 days sooner recovery, 36% lower OTC drug use. It was further experienced that people living in the same household were 35 % less likely to get infected, meaning the antiviral effect works both ways. in 2020, a re-analysis of the data collected in the study revealed that those infected with coronaviruses causing common cold recovered 2.5 days sooner (5.6 days instead of 8.1 days), based on which the authors considered it necessary to repeat the trial as soon as possible, focusing on COVID-19: [3] Ramalingam et al., J Glob Health. 2020, which has started. 

As the dry salt nanoparticles emitted by LibAirator reach the airways and sinuses entirely , it can be assumed that the device can be used to achieve even better results than those found in the ELVIS study. Our questionnaire survey on infectious respiratory diseases (see later) is consistent with the hypothesis. A further supporting evidence which can be considered objective, is that according to user feedback on LibAirator use, among preschoolers, the number of days spent at home with respiratory illnesses is typically reduced by half or to a third.
 

2. The study by [4] Rafael et al., BioRxiv, 2020 shows in detail how NaCl reduces intracellular replication of the SARS-Cov2 virus in vitro in Vero cells, depending on extracellular salt concentration. Above the concentration of 0.8%, intracellular viral replication is significantly reduced, and at 1.5%, it is practically blocked. This concentration can presumably be achieved on the surface of the airways using inhaled NaCl. Based on the article, regular shock therapy appears to be the most suitable for blocking viral replication, given that a high-concentration shock causes depolarization in airway epithelial cells for a day, presumably in close association with viral replication blocking. The authors suggest that inhaled NaCl may be suitable for both prophylaxis and therapy, and therefore a clinical trial is considered necessary.
    

3. Inhaled NaCl may be suitable for reducing ACE2 expression in airway epithelial cells, reducing the possibility and pace of an infection. The expression of ACE2, which is considered to be the binding site for SARS-CoV-2, can be reduced by NaCl, which has been demonstrated in kidney in vivo: [5] Guy et al., Biochemistry 2003, [6]  Elased et al., Hypertension, 2006, [7]  Bernardi et al., Nephrology Dialysis Transplantation, 2012. In the latter study, a diet containing 1.2% salt reduced ACE2 gene expression in the glomeruli of the experimental animals by 60%. The discussion of the study [4] Rafael et al., BioRxiv, 2020 cited above analyzes in detail the relevant similarities between kidneys and the lungs, suggesting that the effect is similar in airway epithelial cells.
    

4. A  very strong negative correlation can be observed between serum Na+ levels measured at admission and the later severity of the disease, as demonstrated by [8] Yi Luo et al., MedRxiv, 2020, analyzing data of thousands of Chinese and more than 2,000 American patients. Of all ions, only Na+ showed a prominent (negative) correlation. The correlation is particularly striking if we examine not the averaged data of a region but the data of a particular institution where the laboratory tests have been likely made under the same conditions.
   A typical data set:
   - average serum sodium level at time of admission of patients with the most severe progress is 137 mmol / l or below
   - average level of patients with moderately serious progress  is 138.7 mmol / L
   - average level of patients with mild progress  is 140.8 mmol / L
   - while the healthy average is 142 mmol / L and that of asymptomatic bats is 146 mmol / L.
   
   It may be assumed that low Na+ level is a consequence of the disease, but according to the authors this is unlikely and they find it much more associated with a low-salt diet or age. The close association with disease severity is attributed to the effect of salt (deficiency) on ACE-2 expression. According to the authors, the revealed interrelation may serve as a basis for the development of new COVID-19 prevention and therapeutic procedures.
   
   In their opinion piece [9] Post et al., EJIM, 2020 suggest increasing salt intake at the onset of symptoms and pausing a low-salt diet for the duration of the COVID-19 epidemic. In September, in the possession of more data, many of them referred to in this writing, suggest that sodium intake and status should be monitored carefully during severe COVID-19 infections and low sodium intake be treated early in its course, despite a potential conflict regarding common dietary recommendations: [10] Post et al. ., VirusRes, 2020.
   
   Several other publications also deal with the correlation between electrolyte levels in severe vs. non-severe coronavirus patients, but only in relation to the systematic discrepancy experienced, and only with the conclusion that it is worth paying attention to electrolyte levels, such as [11] Lippi et al., Ann. Clin. Biochem., 2020. This study, summarizing data from 36 studies and tested for bias, obtained a WMD of -0.91 mmol / L [95% CI: –1.33 to –0.50 mmol / L] by comparing severe vs.  non-severe cases. Analyzing the data, it is apparent that above the median value of 142 mmol / L, hardly any patients became seriously ill. For other electrolytes, no such strong correlation can be found.
   
   Low Na+ levels may also explain why people in top-class strenuous sports, especially athletes can get unexpectedly easily infected. It is well known that heavy sweating due to strenuous exercising for several hours can cause a serious drop in serum Na+ level. The phenomenon even has a name: Exercise Associated Hyponatremia (EAH) [12]. Overweight people tend to have elevated urine Na+ excretion and also sweat excessively, which may partly explain their high vulnerability on top of the extra risk posed by the high ACE2-expression level of the adipose tissue. The high prevalence of fatalities among patients with hypertension may also be explained by keeping a recommended low-salt diet and possibly the use of (thiazide) diuretics.
   
   Pieces of information in 1-4. on COVID-19 seem to fit together:
   - ACE2 is considered to be the binding site for SARS-CoV2
   - Organs with high ACE2 expression ([13] Lei et al., Infect Dis Poverty 9, 45 ,2020) seem to be the most affected.
   - High NaCl salt intake is known to downregulate ACE2, but the exact relationship is not known
   - However, there is convincing evidence that 141 (or 142, for that matter) mmol / L serum Na+ is a critical level in this respect, no matter the underlying reason.
   - Therefore, it can be concluded that “sufficient” dowregulation of ACE2 takes place above 141 mmol / L, and that by maintaining serum Na+ levels above 141 mmol / L, serious complications related to COVID-19 could likely be avoided.
   
   It can be assumed that by a reasonable increase of salt intake or other measures (e.g. giving up a low salt diet, replacing - suspected - thiazide diuretics with other substances, stopping overconsumption of water, etc.), and thus an increase in serum Na+ to at least 142 mmol / L, which corresponds to the healthy average, a significant potential risk factor could be eliminated. The risk is negligible on the population scale: statistically, the cost of health care for patients with too low serum Na+ levels is much higher than for those with too high serum Na+ levels ([14] Shea et al., J Am Soc Nephrol. 2008,  Corona et al., AJM, 2016).
    

5. Mucociliary clearance is the number one antiviral defense mechanism of the airways ([15] Li et al., FEBS J., 2020). If self-cleansing is inadequate, the infection can get easier deep in the airways. In the worst case, the infection destroys the cilia of the ciliated epithelium responsible for mucociliary clearance ([14] Li et al., FEBS J., 2020) and surfactant production of type 2 pneumocytes ([16] Mason, AJP-Lung, 2020), therefore, it may be particularly important to aid in the removal of secretion, especially the hyaluronic acid based hydrogel accumulating in the alveolar region [17] Garvin et al., eLIfe, 2020, [18] Hellman et al., J. of Biochem., 2020  

Efficient support of mucociliary clearance can be a key factor behind the positive experiences with LibAirator in the treatment of other respiratory diseases. During the development of LibAirator, it was concluded* that the NaCl particles produced by LibAirator partly act as an exogenous surfactant, more precisely, as "patcher" of the existing surfactant layer. This may be explained by the fact that one Na+ ion binds to the carbonyl oxygen of an average of 3 lipids with a strong bond, leading to larger complexes ([19] Böckmann et al., Biophys. J., 2003). In addition to improving mucociliary clearance, this "surfactant-patching" effect may play a key role in preventing alveolar surfactant deficiency in severe (ARDS) cases.

 

QUESTIONNAIRE RESULTS

To put the idea of potential suitability of the LibAirator to the test, in March 2020, we asked users to complete a targeted online questionnaire on respiratory infections in order to find out how the incidence and course of infectious respiratory diseases had changed by using LibAirator. A brief summary of the first 108 responses that have been processed: 

Changes in general but relevant respiratory problems:

• Secretion clearance: 28.7% “It has become much easier”, 36.1% “It has become easier”, even with limited compliance. The proportion of a positive change can be approx. 80% because unfortunately there was no “I’m not involved” answer. (The effect can be significantly increased in a short time with intensive use.)

• Dry cough: 10.7% “Completely gone”, 34.7% “Became much rarer”, 29.3% “Became rarer”. The share of positive change is 74.7%.

• Respiratory allergy symptoms: 4.8% “They are completely gone”, 39.7% “They have become much rarer”, 25.4% “They have become rarer”. The proportion of a positive change is 69.9%. A similar positive change in the duration and severity of symptoms has been reported.

Changes in viral respiratory infections:

• Common cold symptoms: 5.3% “Completely gone”, 29.8% “Much rarer”, 37.2% “Rarer”. The proportion of a positive change is 72.3%. A similar positive change in the duration and severity of symptoms has been reported.

• Influenza symptoms: 33.3% “They have not been since”, 13.7% “They have become much rarer”, 17.6% “They have become rarer”. The proportion of a positive change is 64.6%. A positive change in the duration and severity of symptoms has also been reported. 

• Since the device has been on the market only since 2018 and the flu is not an everyday disease, there is more uncertainty, it is more difficult to compare with previous periods.

• Croup: It does not affect the most vulnerable age groups in terms of coronavirus, but since it is of viral origin, we asked about it under 14 years of age. The sample is small, but in most cases the symptoms were completely gone or have become less frequent. A similar positive change in the duration and severity of symptoms has been reported.

• COVID-19: There was no one diagnosed with coronavirus among the respondents (March 2020). Those who chose “Maybe” or “I don’t know” as an answer, reported “More severe” or “I don’t know”, but not “Much more severe” conditions compared to an average flu. Feedback from confirmed coronavirus patients came as a message from the United States stating that, despite severe other symptoms, no severe respiratory symptoms were experienced. The devices were only used after the diagnosis.

Detailed questionnaire results are available here: [20] LibAirator_Infectious_Airway_Diseases_Questionnaire_March_2020_Results.pdf

 

CONCLUSION

Inhalation of NaCl may provide a combined effect that can prevent or significantly reduce the severity of respiratory disease caused by SARS-CoV-2.

• It has an antiviral effect, reducing the possibility and pace of infection (see 1. and 2.)

• It has an ACE2 expression downregulating effect, reducing the possibility and pace of infection (see 2. and 3.)

• As a result of the above two effects, it helps to prevent a decrease in surfactant production (see 5.)

• By improving mucociliary clearance, it slows down the pace of infection spreading through the airways, leaving time for the build-up defense (see 5 .)

• It helps in the removal of hyaluronic acid-based hydrogels that are difficult to release from the alveolar region, which can be critical. (see 5.)

• It helps to prevent surfactant deficiency in the alveolar region by "patching" the existing surfactant layer. (see 5.) 

A related hypothesis is that the risks of COVID-19 to other organs, especially the kidney, can be greatly reduced by setting the recommended serum Na+ level at 142-145 mmol / L at least for the duration of the COVID-19 epidemic, with consideration of individual risks and appropriate control. (see 4.)

Also knowing that the virus is most probably of zoonotic - bat - origin where the virus is essentially non-lethal, and healthy bat serum Na+- levels are 146 ± 5 mmol / L, just outside of the range in patients with elevated risk of serious or lethal complications, it is hypothesized that serum Na+- levels considered healthy and the definition of hyponatremia set in pre-COVID-19 times are invalid, and an immediate revision is to be considered for a successful COVID-19 management. 

 

EXPECTED RESULTS

Based on the research results and our questionnaire survey on respiratory infections, the presumed effect of prophylactic use of inhaled NaCl against COVID-19 is 50 to 60 percent less frequent and significantly milder respiratory symptoms. If treatment is started only after diagnosis but as soon as possible, the presumed effect is a significantly milder course of respiratory symptoms, a less than 50 percent reduction in surfactant production due to the infection, effective removal of the hydrogel from the alveolar region, and thus the avoidance of mechanical ventilation.

The effect expected from increased dietary sodium intake or other measures (e.g. giving up a low salt diet, replacing - suspected - thiazide diuretics with other substances, stopping overconsumption of water, etc.), and thus an increase in serum Na+ to at least 142 mmol / L, a much milder course can be expected in other affected organs, especially the kidneys.

 

SUGGESTED TEST PROTOCOLS

The effect of inhaled (dry) NaCl must be tested under conditions that allow a clear assessment of its suitability for the purpose. It must be noted that the LibAirator was designed to be placed within arm's length from the patient,  it emits only dry salt particles, moves air only as much as (approximately) human breathing does, therefore, there is no conceivable risk for the device to foster the spread of viruses within an institution, and the internal contamination of the device can be prevented by placing a HEPA pre-filter on the backplate. The sterilization procedure to which the device can be subjected is being examined. Gamma, UV and ozone sterilization appear to be trouble-free; it is also possible to blow the inside of the device with 96% alcohol after removing the removable front plate. The simple device proposed as an alternative is disposable or can be disinfected by any sterilization procedure.

In a study suitable for testing the alleviation of the course of the disease, it would be advisable to use the devices as part of home / hospital therapy in patients newly diagnosed with COVID-19, and to compare their experience and course with those who do not use the devices. The test protocol is an adapted version of the aforementioned [21] Hypertonic Saline Nasal Irrigation and Gargling in Suspected or Confirmed COVID-19 (ELVIS COVID-19), which is largely based on the validated Wisconsin Upper Respiratory Symptom Survey-24 (WURSS-24 ) questionnaire and patient diary, and a record of other indicators.

As an indicator of a reduction in the risk of infection, changes in airway ACE2 levels can also be examined in healthy individuals based on airway samples if we accept that a decrease in ACE2 levels is closely correlated (negatively) with the risk of disease. Endobronchial biopsy is required for execution ([22] Wark et al, medRxiv, 2020), but nasal mucosa sampling may be sufficient for a first estimate. A small sample size (10 people) would be sufficient, no control group is required. Selection criteria: no inhaled NaCl use, serum Na+ under141, COVID-19 infection negativity. Exclusion criteria: Inhaled or systemic corticosteroid use. Protocol: 2 samples prior to treatment followed by daily samples for 5 consecutive days. LibAirator use: normal use + 3x15 minutes per day shock therapy application; possibly 5 people 3x15 minutes, 5 people 3x30 minutes. Use of the device attached under the nose: 6x30 or 3x60 minutes per day.

 

RESEARCH IDEA

A simple - although not conclusive - test of the concept would be to observe if asymptomatic, COVID-19 infected bats would show serious symptoms experienced in humans if they are kept on a low-salt diet so that their serum Na+ decreases to 135 mmol / L, which is the lower end of the range labelled as healthy in humans. 

 

DISCUSSION

If the presumed effect is confirmed, the suggested NaCl inhalation methods can be used for therapeutic purposes in both clinical and non-clinical settings, and for preventive purposes especially in places where the risk of respiratory infection is always present, such as hospitals and nursing homes. 

According to the author’s experience, there seems to be a mental block in the way of thinking beyond protocols and healthy levels set under pre-COVID-19 circumstances. A critical revision may help in fulfilling the immediate need for more efficient COVID-19 treatment practices. 

With the emergence of more and more viruses of zoonotic origin, it may be worth further consideration if the change in our chemical composition due to dietary and medication practices of the past decades is a factor that makes us more vulnerable to the new viral challenges of the present.

 

* Logical steps:

 

• The effect of improved secretion clearance is known (see questionnaire, effective in cystic fibrosis, etc.)

• It is known that the amount of inhaled NaCl is on a scale of micrograms per hour (the emission of the LibAirator device measured by absorption followed by laboratory Na+ measurement is approx. 10 micrograms / hour)

• The question is how a few micrograms can be sufficient on a surface as big as a tennis court  ⟹ most probably acts in a very thin layer

• It is known that surfactants are only present in a layer of molecular thickness and improve clearance

• What amount of NaCl is sufficient to cover the surface of airways as big as a tennis court with a saturated (36%) saline solution (as an extreme) in a nanometer-thick layer? - only 2 micrograms

• Can NaCl influence the behaviour of surfactants? - yes

• Is there a more precise explanation? Yes: An Na+ ion binds to the carbonyl oxygen of an average of 3 lipids with a strong bond, creating larger contiguous lipid groups ([19] Böckmann et al., Biophys. J., 2003). Within the lipid-protein ratio range of ¼ to 4/1, the respiratory surfactant represents 4/1 of the lipid-protein complexes in favour of lipids, therefore NaCl can particularly influence its behaviour.

• Conclusion: this is probably the mechanism of the mucociliary-clearance-helping effect of inhaled NaCl

 

REFERENCES

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[12] Hew-Butler, T., Loi, V., Pani, A., & Rosner, M. H. (2017). Exercise-Associated Hyponatremia: 2017 Update. Frontiers in medicine, 4, 21. https://doi.org/10.3389/fmed.2017.00021

[13] Li, MY., Li, L., Zhang, Y. et al.: Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty 9, 45 (2020). https://doi.org/10.1186/s40249-020-00662-x

 

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[15] Li, W., Li, M. and Ou, G.:COVID‐19, cilia, and smell. FEBS J (2020), 287: 3672-3676. https://doi.org/10.1111/febs.15491

[16] Robert J. Mason: Thoughts on the alveolar phase of COVID-19 American Journal of Physiology-Lung Cellular and Molecular Physiology 2020 319:1, L115-L120 https://doi.org/10.1152/ajplung.00126.2020

[17] Michael R Garvin, Christiane Alvarez, J Izaak Miller, Erica T Prates, Angelica M Walker, B Kirtley Amos, Alan E Mast, Amy Justice, Bruce Aronow, Daniel Jacobson A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm eLife 2020;9:e59177 DOI: https://doi.org/10.7554/eLife.59177

[18] Urban Hellman, Mats G. Karlsson, Anna Engström-Laurent, Sara Cajander, Luiza Dorofte, Clas Ahlm, Claude Laurent, and Anders Blomberg: Presence of hyaluronan in lung alveoli in severe Covid-19: An opening for new treatment options? J. Biol. Chem. 2020 295: 15418-. doi: https://doi.org/10.1074/jbc.AC120.015967

[19] Rainer A. Böckmann, Agnieszka Hac, Thomas Heimburg, and Helmut Grubmüller Effect of Sodium Chloride on a Lipid Bilayer, Biophysical journal, Volume 85, Issue 3, P1647-1655, September 01, 2003 DOI:https://doi.org/10.1016/S0006-3495(03)74594-9

[20] Tamás Kókai LibAirator_Infectious_Airway_Diseases_Questionnaire_March_2020_Results.pdf March 2020 https://www.libairator.com/custom/liblib/image/data/Kerdoiv2020mar/LibAirator_Infectious_Airway_Diseases_Questionnaire_March_2020_Results.pdf

[21] Hypertonic Saline Nasal Irrigation and Gargling in Suspected or Confirmed COVID-19 (ELVIS COVID-19) https://clinicaltrials.gov/ct2/show/NCT04382131