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

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Would serum sodium levels below 141 mmol/L looked at and treated as hyponatremia, maybe called "COVID-19-specific hyponatremia", it could significantly improve survival rates. A similar effect is hypothesized for intensive salt inhalation. To date, the suggested inhalation methods have been voluntarily tested by 26 COVID-19 positive patients (some combining it with higher salt intake). No serious problems breathing was experienced. Hospital treatment was not necessary except 1 immunodeficient person, who needed hospitalization because of prolonged fever and pneumonia, but recovered without oxygenisation. One 90+ patient already with pneumonia at the start of using the "simple" method also recovered without hospitalization.
Redefining hyponatremia could be
necessary for successful COVID-19
prevention and treatment
Tamás Kókai,
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
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.
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.
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.
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.
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).
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
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
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.
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
Detailed questionnaire results are available here: [20]
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.
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.
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.
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
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,
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
[1] Ramalingam, S., Graham, C., Dove, J. et al.: A pilot, open labelled, randomised controlled trial of
hypertonic saline nasal irrigation and gargling for the common cold. Sci Rep 9, 1015 (2019).
[2] Ramalingam, S., Cai, B., Wong, J. et al.: Antiviral innate immune response in non-myeloid cells is
augmented by chloride ions via an increase in intracellular hypochlorous acid levels. Sci Rep 8, 13630
[3] Ramalingam S, Graham C, Dove J, Morrice L, Sheikh A.: Hypertonic saline nasal irrigation and gargling
should be considered as a treatment option for COVID-19. J Glob Health 2020;10(1):010332. doi:
[4] Rafael R. G. Machado, Talita Glaser, Danielle B. Araujo, Lyvia Lintzmaier Petiz, Danielle B. L. Oliveira,
Giuliana S. Durigon, Alessandra L. Leal, João Renato R. Pinho, Luis Carlos S. Ferreira, Henning Ulrich,
Edison L. Durigon, Cristiane R. Guzzo: Hypertonic saline solution inhibits SARS-CoV-2 in vitro assay bioRxiv
2020.08.04.235549; doi:
[5] Jodie L. Guy, Richard M. Jackson, K. Ravi Acharya, Edward D. Sturrock, Nigel M. Hooper, and Anthony
J. Turner Angiotensin-Converting Enzyme-2 (ACE2):Comparative Modeling of the Active Site, Specificity
Requirements, and Chloride Dependence. Biochemistry 2003 42 (45), 13185-13192
[6] Khalid M. Elased, Tatiana S. Cunha, Susan B. Gurley, Thomas M. Coffman, and Mariana Morris: New
Mass Spectrometric Assay for Angiotensin-Converting Enzyme 2 Activity. Hypertension 2006;47:1010–1017
[7] Stella Bernardi, Barbara Toffoli, Cristina Zennaro, Christos Tikellis, Silvia Monticone, Pasquale Losurdo,
Giuseppe Bellini, Merlin C. Thomas, Francesco Fallo, Franco Veglio, Colin I. Johnston, Bruno Fabris,
High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage,
Nephrology Dialysis Transplantation, Volume 27, Issue 5, May 2012, Pages 1793–1800,
[8] Low blood sodium increases risk and severity of COVID-19: a systematic review, meta-analysis and
retrospective cohort study. Yi Luo, Yirong Li, Jiapei Dai medRxiv 2020.05.18.20102509; doi:
[9] Adrian Post, Robin P.F. Dullaart, Stephan J.L. Bakker: Letter to the Editor, Is low sodium intake a risk
factor for severe and fatal COVID-19 infection? European Journal of Internal Medicine, 08 April 2020,
[10] Adrian Post, Robin P.F. Dullaart, Stephan J.L. Bakker: Sodium status and kidney involvement during
COVID-19 infection, Virus Research, Volume 286, 2020, 198034, ISSN 0168-1702,
[11] Lippi G, South AM, Henry BM.: Electrolyte imbalances in patients with severe coronavirus disease 2019
(COVID-19). Annals of Clinical Biochemistry. 2020;57(3):262-265. doi:
[12] Hew-Butler, T., Loi, V., Pani, A., & Rosner, M. H. (2017). Exercise-Associated Hyponatremia: 2017
Update. Frontiers in medicine, 4, 21.
[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).
[14] Corona G, Giuliani C, Parenti G, Colombo GL, Sforza A, Maggi M, Forti G, Peri A.: The Economic
Burden of Hyponatremia: Systematic Review and Meta-Analysis. Am J Med. 2016 Aug;129(8):823-835.e4.
Epub 2016 Apr 5. PMID: 27059386 doi:
[15] Li, W., Li, M. and Ou, G.:COVID19, cilia, and smell. FEBS J (2020), 287: 3672-3676.
[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
[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:
[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:
[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
[20] Tamás Kókai LibAirator_Infectious_Airway_Diseases_Questionnaire_March_2020_Results.pdf March
[21] Hypertonic Saline Nasal Irrigation and Gargling in Suspected or Confirmed COVID-19 (ELVIS
ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Severe corona virus disease 2019 (Covid-19) is characterized by inflammation of the lungs with increasing respiratory impairment. In fatal Covid-19, lungs at autopsy have been filled with a clear liquid jelly. However, the nature of this finding has not yet been determined.The aim of the study was to demonstrate if the lungs of fatal Covid-19 contain hyaluronan as it is associated with inflammation and acute respiratory distress syndrome (ARDS) and may have the appearance of liquid jelly.Lung tissue obtained at autopsy from three deceased Covid-19 patients was processed for hyaluronan histochemistry using a direct staining method and compared with staining in normal lung tissue.Stainings confirmed that hyaluronan is obstructing alveoli with presence in exudate and plugs, as well as in thickened perialveolar interstitium. In contrast, normal lungs only showed hyaluronan in intact alveolar walls and perivascular tissue. This is the first study to confirm prominent hyaluronan exudates in the alveolar spaces of Covid-19 lungs, supporting the notion that the macromolecule is involved in ARDS caused by SARS-CoV-2. The present finding may open up for new treatment options in severe Covid-19, aiming at reducing the presence and production of hyaluronan in the lungs.
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We are facing an unprecedented global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At this date more than 680 thousand people have died due to coronavirus disease 2019 (COVID-19). Unfortunately, until now no effective treatment to combat the virus and vaccine are available. We performed experiments to test if hypertonic saline solution is able to inhibit virus replication in vitro. Our data shows that 260 mM NaCl (1.5%) inhibits 100% SARS-CoV-2 replication in Vero cells. Furthermore, our results suggest that the virus replication inhibition is due to an intracellular mechanism and not due to the dissociation between spike SARS-CoV-2 protein and its human receptor angiotensin-converting enzyme 2 interaction. NaCl depolarizes the plasma membrane supposedly associated with the inhibition of the SARS-CoV-2 life cycle. This observation could lead to simple, safe and low cost interventions at various stages of COVID-19 treatment, improving the prognosis of infected patients, thereby mitigating the social and economic costs of the pandemic.
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The angiotensin-converting enzyme 2 receptor (ACE2) is expressed in epithelial cells of many tissues including the kidney, and has been identified to interact with human pathogenic coronaviruses, including SARS-CoV-2. Although diffuse alveolar damage and acute respiratory failure are the main features of COVID-19 infection, two recent studies demonstrate that kidney impairment in hospitalized COVID-19 patients is common, and that kidney involvement is associated with high risk of in-hospital death. Interestingly, studies in rats have demonstrated that high dietary sodium intake results in down-regulation of the ACE2 expression in kidney tissue. We hypothesize that low sodium status makes renal involvement during the course of COVID-19 infection more likely due to upregulation of membrane bound ACE2 in the kidneys. We propose that sodium intake and status should be monitored carefully during severe COVID-19 infections, and that low sodium intake be corrected early in its course, despite a potential conflict regarding common dietary recommendations to restrict dietary sodium intake in patients with hypertension, diabetes, and kidney disease.
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Background: Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection. Methods: We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student’s t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson’s correlation test. Results: ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively. Conclusions: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.
The novel coronavirus SARS‐CoV‐2 is the causative agent of the global COVID‐19 outbreak. In addition to pneumonia, other COVID‐19‐associated symptoms have been reported, including loss of smell (anosmia). However, the connection between infection with coronavirus and anosmia remains enigmatic. It has been reported that defects in olfactory cilia lead to anosmia. In this Viewpoint, we summarize transmission electron microscopic studies of cilia in virus‐infected cells. In the human nasal epithelium, coronavirus infects the ciliated cells and causes deciliation. Research has shown that viruses such as Influenza and Sendai attach to the ciliary membrane. The Sendai virus enters cilia by fusing its viral membrane with the ciliary membrane. A recent study on SARS‐CoV‐2‐human protein‐protein interactions revealed that the viral non‐structural protein Nsp13 interacts with the centrosome components, providing a potential molecular link. The mucociliary escalator removes inhaled pathogenic particles and functions as the first line of protection mechanism against viral infection in the human airway. Thus, future investigation into the virus‐cilium interface will help further the battle against COVID‐19.
COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the infection mostly resides in the nose where it elicits a minimal innate immune response. For the mildly symptomatic phase, the infection is mostly in the psuedostatified stratified epithelium of the larger airways and is accompanied by a more vigorous innate immune response. In the conducting airways, the epithelium can recover from the infection, because the keratin V basal cells are spared and they are the progenitor cells for the bronchial epithelium. There may be more severe disease in the respiratory bronchioles where the club cells are likely infected. The devastating third phase is in the gas exchange units of the lung, where ACE2 expressing alveolar type II cells and perhaps type I cells are infected. The loss of type II cells results in respiratory insufficiency due to the loss of pulmonary surfactant, alveolar flooding, and loss of normal repair, since type II cells are the progenitors of type I cells. The loss of type I and type II cells will also block normal active resorption of alveolar fluid. Subsequent endothelial damage leads to transudation of plasma proteins, formation of hyaline membranes, and an inflammatory exudate, characteristic of ARDS. Repair might be normal, but if the type II cells are severely damaged, alternative pathways for epithelial repair may be activated, which would result in some residual lung disease.
Background Novel coronavirus (SARS-CoV-2) infects human lung tissue cells through angiotensin-converting enzyme-2 (ACE2), and the body sodium is an important factor for regulating the expression of ACE2. Through a systematic review, meta-analysis and retrospective cohort study, we found that the low blood sodium population may significantly increase the risk and severity of SARS-CoV-2 infection. Methods We extracted the data of serum sodium concentrations of patients with COVID-19 on admission from the articles published between Jan 1 and April 28, 2020, and analyzed the relationship between the serum sodium concentrations and the illness severity of patients. Then we used a cohort of 244 patients with COVID-19 for a retrospective analysis. Results We identified 36 studies, one of which comprised 2736 patients.The mean serum sodium concentration in patients with COVID-19 was 138.6 mmol/L, which was much lower than the median level in population (142.0). The mean serum sodium concentration in severe/critical patients (137.0) was significantly lower than those in mild and moderate patients (140.8 and 138.7, respectively). Such findings were confirmed in a retrospective cohort study, of which the mean serum sodium concentration in all patients was 137.5 mmol/L, and the significant differences were found between the mild (139.2) and moderate (137.2) patients, and the mild and severe/critical (136.6) patients. Interestingly, such changes were not obvious in the serum chlorine and potassium concentrations. Conclusions The low sodium state of patients with COVID-19 may not be the consequence of virus infection, but could be a physiological state possibly caused by living habits such as low salt diet and during aging process, which may result in ACE2 overexpression, and increase the risk and severity of COVID-19. These findings may provide a new idea for the prevention and treatment of COVID-19.
Background: Early studies have reported various electrolyte abnormalities at admission in patients who progress to the severe form of coronavirus disease 2019 (COVID-19). As electrolyte imbalance may not only impact patient care, but provide insight into the pathophysiology of COVID-19, we aimed to analyze all early data reported on electrolytes in COVID-19 patients with and without severe form. Methods: An electronic search of Medline (PubMed interface), Scopus, and Web of Science was performed for articles comparing electrolytes (sodium, potassium, chloride, and calcium) between COVID-19 patients with and without severe disease. A pooled analysis was performed to estimate the weighted mean difference (WMD) with 95% confidence interval. Results: Five studies with a total sample size of 1415 COVID-19 patients. Sodium was significantly lower in patients with severe COVID-19 (WMD: -0.91 mmol/L [95% CI: -1.33 to -0.50 mmol/L]). Similarly, potassium was also significantly lower in COVID-19 patients with severe disease (WMD: -0.12 mmol/L [95%CI: -0.18 to -0.07 mmol/L], I2=33%). For chloride, no statistical differences were observed between patients with severe and non-severe COVID-19 (WMD: 0.30 mmol/L [95%CI: -0.41 to 1.01 mmol/L]). For calcium, a statistically significant lower concentration was noted in patients with severe COVID-19 (WMD: -0.20 mmol/L [95% CI: -0.25 to -0.20 mmol/L]). Conclusions: This pooled analysis confirms that COVID-19 severity is associated with lower serum concentrations of sodium, potassium, and calcium. We recommend electrolytes be measured at initial presentation and serially monitored during hospitalization in order to establish timely and appropriate corrective actions.