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How to strengthen immunity and protect against SARS and, probably, COVID-19. Science Proof

The most scientifically-confirmed popular article in Runet. From here you will learn specific ways to effectively prevent acute respiratory viral infections and, probably, COVID-19, based on the most reliable information - meta-analyzes of clinical trials.  


Hello, my name is Yaroslav, I graduated from the bachelor's program in the biology department of the Ural Federal University, graduate school at the Department of Molecular Biology of Moscow State University, I am currently in the last postgraduate course at the Institute of Bioorganic Chemistry of the Russian Academy of Sciences and am engaged in science.

At the moment, on the Internet in Russian there is a lot of information about what will help strengthen immunity (somewhere it is even mentioned what part of immunity it can affect). However, it is difficult to find an article where there would be at least some links to scientific sources.

How can information be trusted without reference to research? In the information age, anyone can create a website and write anything. Well, if the article is written by a person who understands something in this area, but without reference to research, the big question is how much can this be trusted. Do we have confidence that this person is familiar with the latest clinical studies and meta-analyzes on this topic that could change ideas in this area?

Meta-analysis - combines the results of several studies to test one or more interrelated scientific hypotheses (quantitative combination). May be part of a systematic review (63).

In order to understand what you can really trust, you should take a look at the pyramid of evidence-based medicine (Fig. 1) (59, 60, 63). In it you can see that the expert opinion has the lowest degree of reliability. Prior to human studies, studies are carried out on cells ( in vitro ) and animals. If in science something happened on the cells, then it is not a fact that this will work on animals; and if it happened on animals (for example, mice), then it is not a fact that it will work in humans.




Fig. 1. Pyramid of evidence-based medicine: hierarchy of evidence (63). Two levels were added - animal studies and in vitro from an article in Lancet (60)

From the pyramid, we see that the most reliable information is in systematic reviews and meta-analyzes (59, 63). A little lower are randomized controlled trials (see the help below), which, however, cannot be blindly trusted (60). Non-randomized and placebo-controlled studies, like retrospective and epidemiological studies, are found below.

Systematic review- scientific research (analysis) of all published individual medical studies on a specific topic with a view to their critical analysis and evaluation. The task is to minimize possible random or systematic errors that can affect the results of individual studies and distort them (63).

Most of the studies that are mentioned here deal with respiratory viral infections and effects on immunity. 

Why can it be assumed that something that helps treat other viral respiratory infections will help with COVID-19?

  • To get to the lung cells, the virus goes the same way as respiratory viruses. It also leads to inflammation and the formation of reactive oxygen species, causing similar symptoms.
  • The prevention methods proposed here strengthen the barrier functions of the body, have an immunostimulating, anti-inflammatory, antioxidant effect on the body, which are independent of the pathogen.

It will be possible to claim that something is effective against COVID-19 only after a series of clinical studies and meta-analyzes. However, conducting clinical trials, like creating a vaccine, can take a lot more time. 

Ways to strengthen the immune system


Based on the information from all the articles, the following table was compiled:


Sleep


Studies have found that people who get enough sleep (have enough quality sleep for them) have less risk of getting a cold and the flu (1, 2, 3, 4).

In addition, poor sleep, lack of sleep, insomnia lead to a decrease in immunity. It has been shown that people with insomnia after vaccination had fewer antibodies against the influenza virus compared to people without insomnia, which means that they had weaker protection against the virus after vaccination (5). 

An interesting study was conducted that showed that people with normally normal sleep who did not sleep the night before hepatitis A vaccination had half the antibodies to the virus after 4 weeks compared with those who slept that night (6) .

Physical exercises


People involved in moderate exercise have a 40-50% lower risk of upper respiratory tract infections (a simple review, no meta-analysis, took into account epidemiological studies, not only randomized controlled trials). Heavy exercise can increase this risk (7).

Medium-intensity aerobic exercises (walking, cycling, treadmill exercises, or a combination of them, in most studies at least three times a week for 30–45 minutes) did not reduce the risk of acute respiratory infection, but they also reduced the duration of acute respiratory infections and the severity of symptoms (Cochrane systematic review (meta-analysis), only randomized controlled trials). In the article, the authors mention that epidemiological data confirm a reduced risk of ARI (8). In this systematic review, in most (8 out of 14) studies, the intensity was 60-80% (average 70%) of maximum heart rate. In two studies (2 out of 14), intensity was assessed according to the Borg scale (12-16 points) (8, 79). 

13-14 points on the Borg scale. Walking fast or other activities that require moderate effort and speed up your heartbeat and breathing but don't make you breathless (79).

15-16 points. Cycling, swimming or other activities that require vigorous effort and lead to rapid heartbeat and breathing (79).

About how to determine the maximum and target heart rate, as well as a more detailed Borg scale, you can see at the bottom of the article.

The benefits for immunity are not only in regular, but also in one-time sports. A one-time aerobic exercise of medium and high intensity lasting less than 60 minutes increases the activity and number of NK cells and CD8 + T lymphocytes in the blood and reduces systemic inflammation. Stress hormones, which can suppress the function of immune cells, and pro-inflammatory cytokines, do not reach high levels during short, moderate workouts (7, 67).

In addition to influencing the number of immune cells in the blood and the severity of symptoms of acute respiratory infections, exercise also affects the effectiveness of vaccination. Single or regular moderate-intensity exercises significantly increase the immune response to vaccination. Interestingly, most of these studies reported that exercise reinforced the response against those vaccine strains that caused the weakest response in the control group, indicating that immune responses to these low immunogenicity vaccine antigens are likely to be enhanced by exercise (68). This means that, for example, if there is some kind of virus for which antibodies are poorly developed, people involved in sports will have a stronger and longer lasting immunity after vaccination / infection with such a virus than those who do not engage in sports. 

Stress


It has been established that psychological stress reduces immunity (9). This is manifested in the fact that the risk of developing respiratory infections and colds increases with the level of psychological stress (10, 62), as well as in the fact that psychological stress reduces the production of antibodies in response to vaccination against influenza virus (11). For those who want to learn more about the relationship of stress and immunity, you can see the article at this link (61).

Vitamin D


Daily (12 studies) or weekly (3 studies) intake of vitamin D 3 reduces the risk of acute respiratory infections. The greatest effect of vitamin D 3 supplementation  was on people with deficiency. If you look at the doses used in the studies, it turns out that on average the daily dose for adults was 43 mcg, for children (<18 years old) 25 mcg (12).

Vitamin D deficiency (25 (OH) D <50 nmol / L or 20 ng / ml) is common among the population in Europe and the Middle East (78):
· Eastern, Western, Southern Europe 30–60%
· Middle East up to 80%
· Northern Europe <20% (take supplements, cod liver oil, fortified foods)
Severe deficiency (serum 25 (OH) D <30 nmol / L or 12 ng / ml) is found in> 10% of Europeans (78).

You can see the recommended doses and the content of vitamin D in the products at the bottom of the article.  

Recently, an article was published in which scientists suggest that vitamin D 3 may be useful for treating people infected with COVID-19 (13).

In addition, a series of preprints of articles on Vitamin D and COVID-19 were published:

Preprint- This is a manuscript that saw the light before official publication in a scientific journal (without peer review, editing and publishing). According to the representative of the preprint servers BioRxiv and MedRxiv, peer review involves answering the question “Are the statements in this article true?”, While the preprint moderator asks the question “Is the preprint a reasonable report on the original work carried out in the relevant subject area?”. The credibility of the information in them is lower by default than the credibility of the article (66).  

  1. A retrospective multicenter study of 212 laboratory-confirmed patients with COVID-19 showed that increasing vitamin D levels in the body can prevent the onset of severe symptoms or reduce the severity of symptoms in severe or critical patients, and lowering vitamin D levels can lead to more severe symptoms. (14).

On the website of the non-profit public health research organization GrassrootsHealth, according to the article described above, a graph was constructed that illustrates the number of patients with different levels of vitamin D in the body in groups according to the severity of symptoms of COVID-19 (Fig. . 2) (15).


Fig. 2. The number of patients with different levels of vitamin D in the body in groups according to the severity of symptoms of COVID-19 (15)

Cases of COVID-19 were grouped as follows (15): 

  • Mild - With mild clinical symptoms and no diagnosis of pneumonia
  • Ordinary (Normal) - with fever, respiratory symptoms and a confirmed diagnosis of pneumonia
  • Severe (Severe) - Cases of hypoxia and respiratory failure
  • Critical - cases of respiratory failure requiring intensive care

Vitamin D levels were grouped as follows (15):

  • Normal - Vitamin D level 30 ng / ml (75 nmol / L) or higher
  • Insufficient - insufficient vitamin D levels between 21-29 ng / ml (51-74 nmol / l)
  • Deficient (deficiency) - Vitamin D levels below 20 ng / ml (50 nmol / L)

  1. COVID-19 (16).
  2. 25(OH) D ( ) 50 /  (40–60 / — ) 25(OH) D <20 / () 27% , (17).
  3. COVID-19 15,6% (18).
  4. D SARS-CoV-2 (19).
  5. D , COVID-19 (20). 

In the comments there is a link to another article and 5 preprints of observational studies with patients with confirmed COVID-19 from different countries about the relationship of vitamin D deficiency, mortality, and severity of COVID-19. There is also a link to another 2 meta-analyzes about the relationship of vitamin D status with respiratory diseases.
Possible mechanisms of the effect of vitamin D on the immune system can be found in the following articles (21, 22). 

Out of 120 people (age from 20 to 60 years) with fair skin from the UK, 62.5% had a level of 25 (OH) D (vitamin D) <20 ng / ml, 37.5% ≥20 ng / ml, 2.9% ≥32ng / ml. After 6 weeks in the summer on a cloudless day at noon (maximum amount of ultraviolet radiation) for 13 minutes 3 times a week under the sun in shorts and a T-shirt (35% of the skin surface is open), 90% had a level of 25 (OH) D (vitamin D) ≥20 ng / ml, and in 26% ≥32 ng / ml (73). 

The risk group for vitamin D deficiency includes elderly people, since they do not form vitamin D effectively in the sun, as well as people with dark skin who also have less effective vitamin D formation in the sun (75). 

Given the data in these articles, it can be assumed that if a person with fair skin is in the sun for a long time in the summer in a T-shirt and shorts, then the need for additional intake of vitamin D may not be great. However, with a short duration of exposure to the sun, it may be worth consuming vitamin D from additional sources in the summer, not to mention the rest of the year.  

Zinc


Taking zinc within 24 hours of the onset of symptoms reduces the duration of the common cold. Zinc intake (in one study 10 mg for 5 months, in another 15 mg of zinc daily for 7 months, two doses of 15 mg per day for symptoms of a cold) reduces the risk of getting a cold in children (26).

Taking zinc in doses of 80–92 mg per day in the form of lozenges reduces the duration of the common cold by 33% in adults. These doses should not be interpreted as minimally effective. In studies with lower doses that failed, there were problems that hindered the assessment of the effective dose. Assessing the effectiveness of doses less than 80 mg per day requires further research. Studies with doses above 80–92 mg were not effective in reducing the duration of the common cold. Properly formulated zinc gluconate lozenges can be as effective as zinc acetate lozenges. The optimal composition of the lozenges and the dosage regimen require further study (27). 

It is not clear how the effectiveness of zinc depends on how many lozenges break the daily dose of zinc, fewer lozenges, but with a higher dose of zinc or more lozenges, but with a lower dose. It is unlikely that taking one lozenge with 80 mg of zinc will be as effective as taking 8 lozenges of 10 mg all day long (27).

It is suggested that taking 80 mg of zinc per day for 1-2 weeks, starting with the early symptoms of a cold, is unlikely to lead to long-term side effects (27, 28). This statement is also confirmed in the protocol of the organization "Cochrane cooperation" (certificate of organization at the bottom of the text). The use of high doses for a long time can lead to copper deficiency, which is reversible (69).

You can see the recommended doses and zinc content in the products at the bottom of the article.  

When choosing a lozenge with zinc, you should pay attention to the composition, since effectiveness depends on it. Citric and tartaric acids, sodium bicarbonate, sorbitol, and mannitol bind zinc in lozenges and prevent its release; therefore, they are ineffective (27).

Zinc can have a protective effect as a preventive and adjuvant therapy (additional to the main one) COVID-19 by reducing inflammation, improving mucociliary clearance, preventing lung damage, modulating antiviral and antibacterial immunity (Fig. 3) (29).


Fig. 3. Proposed mechanisms by which zinc can protect against COVID ‑ 19 (29)

Zinc has been shown to inhibit SARS-CoV coronavirus RNA polymerase activity in vitro , and zinc ionophores block virus replication in cell culture (30). In addition, it has been shown in humans that zinc has antiviral activity against certain viruses (31). 

Vitamin C


Regular intake of vitamin C does not reduce the risk of getting a cold in the general population. However, taking vitamin C regularly (before taking the disease) reduces the duration and severity of cold symptoms. In adults, taking ≥ 0.2 g / day of vitamin C reduces the duration of the common cold by 8%, and in children by 14%; Moreover, in children, taking 1 to 2 g of vitamin C per day reduces the duration of the common cold by 18%. The minimum doses tested in adult studies were 0.5–0.6 g / day (32). You can see the recommended doses and vitamin C content in the products at the bottom of the article. 

Vitamin A


The intake of vitamin A shortened the period with high fever and cough, accelerated the cleaning of the lungs, and reduced the time spent in the hospital in children with pneumonia (33). You can read about the role of vitamin A in the immune system in an article at this link (81). You can see the recommended doses and vitamin A content in the products at the bottom of the article.  

Probiotics


The use of probiotics reduces the risk of contracting respiratory infections and reduces the duration of respiratory illness (34, 35, 36). In most studies in (34, 35), Lactobacillus casei or Lactobacillus rhamnosus were used as probiotics, and milk-based probiotics (of the Actimel type) were used. All strains used in (34, 35) can be found at the bottom of the article.

When taking probiotics in response to vaccination against influenza virus, an increased amount of antibodies is produced and the duration of protection against the virus is increased compared to the control (37, 38).

mushroom β-glucans


β-glucans from fungi have immunostimulating activity. fungal β-glucans have the potential for use in therapy and prevention (reduce the risk of getting sick) of recurrent respiratory infections in children (mainly β-glucans from Pleurotus ostreatus (Oyster mushroom) were studied) and adults (mainly β-yeast glucans were studied) ( 39, 40, 41, 42, 43). Children usually took about 100 mg, while adults took 250-500 mg of β-glucans (39). 

Champignon β-glucans also have an immunostimulating effect (42, 43). An interesting study was conducted in which it was shown that after eating 100 g of champignons every day for a week, the level of secretion of immunoglobulin A (IgA) in saliva increased by 50% and remained elevated for two weeks after the end of consumption of champignons (70). An increased IgA secretion rate enhances mucosal immunity and protects against infections. Other studies have also shown that β-glucans increase the level of immunoglobulins (41).

Since β-glucans are a component of the cell wall of fungi, β-glucans from other fungi may also have a certain immunostimulating activity.

There are 3 times more β-glucans in oyster mushroom than in mushrooms. After boiling mushrooms, the content of β-glucans increased slightly, and after frying it decreased (71). 

Melatonin


Melatonin can reduce oxidative stress and inhibit increased levels of proinflammatory cytokines and chemokines in lung tissues and thereby reduce the severity of pulmonary infections (44).

Recently, several articles have been published about melatonin and COVID-19. The articles urge the use of melatonin right now. Melatonin can prevent the development of severe symptoms of the disease in patients with coronavirus, reduce the severity of symptoms, reduce mortality due to antioxidant, anti-inflammatory activities, reduce anxiety, normalize sleep, which contributes to the normal functioning of the immune system, prevent fibrosis, reduce vascular permeability, and suppress an excessive immune response (Fig. 4) (45, 46, 47, 48).


Fig. 4. Pathogenesis of COVID-19 and potential adjuvant use of melatonin

Coronavirus and interferons



SARS-CoV-2 (COVID-19) is more sensitive to interferon-α pretreatment than SARS-CoV (see help below). When interferon-α was added to the cells 18 hours before infection after 48 hours, the amount of SARS-CoV was as in the control, and the amount of SARS-CoV-2 was significantly lower than the control (49) (preprint). Another article also reports that SARS-CoV-2 is more sensitive to IFNα / β than SARS-CoV (50). In addition, SARS-CoV-2 induces much weaker expression of interferons than SARS-CoV (51). The weaker the production of interferons, the more virus can form. 

Plasma IFNα2 concentration was significantly lower in critical than in patients with mild to moderate severity. The activity of interferons in blood serum was significantly lower in patients in a serious and critical condition than in patients in a moderate and mild condition (52) (Fig. 5).


Fig. 5. Violation of the IFN type I response in patients with severe SARS-CoV-2

In a retrospective study, 77 adults showed that treatment with IFN-α2b significantly reduced the period during which the virus was detected in the upper respiratory tract and the period of elevated levels markers of inflammation (IL-6 and CRP) in the blood (53).

Interferon Inductors



There is insufficient evidence in reliable sources about the effectiveness and / or safety of interferon inducers.

Based on the information in the articles, it can be assumed that the following methods will strengthen the immune system and contribute to the effective prevention of acute respiratory viral infections and, probably, COVID-19:

  1. Get enough sleep
  2. Engage in medium-intensity aerobic exercises (60-80% heart rate) (running, cycling, walking)
  3. Less stress
  4. 40 3 . : , , , ; ( )
  5. 25 : , , ,  
  6. 90 :  , , , , ,
  7. 900  . .: , , , , , ,
  8. : Lactobacillus casei (), Lactobacillus rhamnosus (), Lactobacillus paracasei (), Lactobacillus acidophilus (), Lactobacillus plantarum ( ), , ,
  9. β–: , ,
  10. Promote the development of a normal amount of melatonin: before going to bed, turn off gadgets or turn on programs that remove the blue part of the spectrum of screens, sleep in complete darkness


reference Information


Borg Scale (79).

The target heart rate is the range between inadequate exercise and overstrain (80).

The target heart rate is usually expressed as a percentage (usually 50 to 85%) of your maximum safe heart rate. The maximum frequency depends on age and is calculated as 220 - age (this option is offered by one link, not the fact that it can suit everyone). For a 50-year-old, the maximum heart rate is 170, the target frequency is 85-145 (50-85%) beats per minute. An easier way to determine the target heart rate is to use a fitness gadget or simulator (80).




Data on the content of vitamins and trace elements in food was taken from the website of the U.S. National Institute of Health (25).






Probiotics used in meta-analyzes (34.35) and some products containing probiotics





Methods for preparing mushrooms used in the study (71):

1. Boiling: sliced ​​mushrooms (300 g per serving) were boiled in a pan containing 3 l of bottled water for 10 minutes.

2. Deep frying: slices of mushrooms (150 g per serving) were fried in a pan with 500 ml of olive oil (160 ° C) for 3 minutes.

3. Microwave: mushroom slices (100 g per serving) were placed in a dish and cooked in a home microwave at 1000 watts for 1.5 minutes.

4. Grill: slices of mushrooms (180 g per serving) were cooked on an electric grill at 100 ° C for 6 minutes (3 minutes on each side). 

reference


On February 11, 2020, the World Health Organization (WHO) assigned the official name for the infection caused by the new coronavirus, COVID-19 (“Coronavirus disease 2019”). On February 11, 2020, the International Committee on Virus Taxonomy assigned the official name to the pathogen - SARS-CoV-2 (72). 

At the end of 2002, coronavirus ( SARS-CoV ) appeared, a causative agent of SARS that caused SARS in humans. In total, over the period of the epidemic, more than 8,000 cases were recorded in 37 countries around the world, of which 774 were fatal. Since 2004, no new cases of SARS-CoV-associated SARS have been reported (72).

In 2012, the world faced the new MERS coronavirus (MERS-CoV), a causative agent of the Middle East respiratory syndrome, also belonging to the genus Betacoronavirus. From 2012 to January 31, 2020, 2519 cases of coronavirus infection caused by the MERS-CoV virus were recorded, of which 866 were fatal. Currently, MERS-CoV continues to circulate and cause new cases (72).

Double-blind, randomized, placebo-controlled method(randomized controlled trial) - a method of clinical research of drugs in which subjects are not dedicated to the important details of the study. “Double blind” means that neither subjects nor experimenters know who is being treated with what, “randomized” means that the distribution into groups is random, and placebo is used to show that the effect of the drug is not based on auto-suggestion and that This medicine helps better than a tablet without an active substance. This method prevents subjective distortion of the results. Sometimes the control group is given another drug with already proven efficacy, rather than a placebo, to show that the drug not only treats better than nothing, but also surpasses analogues (64).

Cochrane Library- The database of the international non-profit organization Cochrane Collaboration, which is involved in the development of guidelines for the World Health Organization. The name of the organization comes from the name of its founder, the 20th century Scottish medical scientist Archibald Cochrane, who defended the need for evidence-based medicine and competent clinical trials and wrote the book “Efficiency and Effectiveness: Random Thoughts on Health Care”. Medical scientists and pharmacists consider the Cochrane database one of the most authoritative sources of such information: the publications included in it were selected according to the standards of evidence-based medicine and talk about the results of randomized double-blind, placebo-controlled clinical trials (64).This article has links to systematic reviews of the Cochrane library about sports, probiotics, zinc, and vitamin C. 

Impact factor (IF) - an indicator that reflects the frequency of citation of articles in a scientific journal for a certain period (usually two years). For example, for one of the largest medical journals The Lancet, the impact factor is 44.0, and on average for good journals it is 4 (64). 

Quartile (quarter) Q is a category of scientific journals, which is determined by bibliometric indicators that reflect the level of citation, i.e., the demand for the journal by the scientific community (65).

Narrative subject journals are ranked in descending order by impact factor in the Web of Science database. The resulting list is divided into 4 equal parts. As a result of ranking, each magazine falls into one of four quartiles: from Q1 (the highest, to which the most authoritative foreign magazines belong) to Q4 (the lowest). The quartile system allows the most objective assessment of quality - the level of the journal, regardless of the subject area (65).

Quartile helps to compare the authority of a magazine in different subject areas. For example, in one region the maximum impact factor is 100, in another 10, if in the first region the journal with the impact factor 10 will be in the last quartile, then in the second region it will be in the first quartile. 

Bibliography


Impact Factor (IF) data taken over 5 years from Web of science

Bibliography
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