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Many doctors believe that high dose vitamin D can fight COVID-19 – BMJ April 2020

Potential direct therapeutic role for Vitamin D – Silberstein

Dear Editor,

Vitamin D may directly prevent COVID-19 from entering lung epithelial cells; this means that Vitamin D might be a specific treatment (in addition to its potential role in prophylaxis). Here is the rationale:
1. COVID-19 enters lung cells by binding to ACE2 receptors [1].
2. ACE2 receptors utilize a specific interleukin (IL-6) when normally activated [2].
3. Blockade of IL-6 by tocilizumab may be an effective treatment for COVID-19 [3].
4. Vitamin D reduces IL-6 production in monocytes (and, presumably, macrophages) [4].

This provides a rationale for administration of Vitamin D (eg by intramuscular injection) as treatment in acutely ill patients with COVID-19.

REFERENCES

  • 1. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(8):875–879. doi:10.1038/nm1267
  • 2. Senchenkova EY, Russell J, Yildirim A, Granger DN, Gavins FNE. Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II-Induced Microvascular Dysfunction. Hypertension. 2019;73(4):829–838. doi:10.1161/HYPERTENSIONAHA.118.12286
  • 3. Michot JM, Albiges L, Chaput N, et al.Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report. Annals Oncology. 2020. doi: https://doi.org/10.1016/j.annonc.2020.03.300.
  • 4. Sadeghi K1, Wessner B, Laggner U, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 2006;36(2):361-70. doi:10.1002/eji.200425995


Competing interests: No competing interests

09 April 2020
Morry Silberstein
Associate Professor, MB BS MD
School of Molecular & Life Sciences, Curtin University, Perth WA, Australia

Response to Maestri – Schaffeler

Dear Editor

I'm responding to the response made by Emilio Maestri (endocrinologist) on 12 March 2020 regarding contradictory studies using 'vitamin' D supplementation.

I have not read the references he has cited but, although I am not a nutritionist, I have read enough over the years to know that supplementation of just one micronutrient in large doses is not necessarily advisable and may well give poor results. In the case of 'vitamin/hormone' D, I am aware that a deficiency of magnesium, said to be rife in developed countries (due to modern farming methods and depletion through what we call "stress"), can manifest also as a vitamin D deficiency so that increasing supplemental dose of vitamin D will not have the desired effect precisely because the deficiency concerned is magnesium (which is needed to 'activate' vitamin D.)

Furthermore, in the case of trying to improve osteoporosis with supplemental vitamin D, there is the necessity of vitamin K (in the form of K2) which 'directs' dietary calcium in the presence of vitamin D to the bone rather than soft tissues. Vitamin K is found, for example, in dark green leafy vegetables in the form of K1, but is not always easily converted to K2 in the body and therefore animal sources are preferable, a factor which may produce even more health problems in the future with the increasing popularity of a vegan diet.

As I have said, I am not a nutritionist and may have simplified my explanations somewhat, but merely wished to point out that micronutrients work in harmony with one another and studies focusing on just one discrete micronutrient are likely to have already failed at the outset.

Competing interests: No competing interests

08 April 2020
Vanessa J Schaffeler
Homemaker
Chard

Re: Preventing a covid-19 pandemic – Smith

Dear Editor

Prevention and Cure of Covid 19? – A Discussion about Vitamin D Deficiency.
Fiona Smith 7th April 2020

Let’s be clear about this please, I’m not a doctor… But, with years of experience of being a loving mother and registered manager in charge of care for thousands of our older generation, I have had to live with the constant spur of an enquiring mind, especially in relation to procuring best care and support for the people I had responsibility for…

Having recently taken early retirement, my partner and I spent much of February 2020 travelling the Far East; we lived and breathed the emergence of Covid 19 through news and internet. Hand washing and mask wearing was a daily, minute by minute duty. But, on our travels through the heat and sunlight of Cambodia, Lao and Thailand, not only did we learn from locals that the Chinese were their most frequent visitors, but it was also evident they have close economic ties – widespread Chinese, housing and road construction work was heavily in progress; if Covid 19 was going to come knocking on any door, these three Countries would likely be the first to experience a pandemic. But, no pandemic appeared then, or even now. So, WHY?

Sunlight brings the benefit of vitamin D through its interaction and chemical synthesis with our epidermis – the benefits of which go far beyond the production of vitamin D. But, ‘cutting to the chase’, we theorised back then in February, that optimum levels of vitamin D, not only make you feel great, but medical studies (Martineau 2017) suggest it can help prevent respiratory tract infections; we also wondered whether optimum levels of vitamin D could make symptoms of Covid 19, asymptomatic or just extremely mild?

It is known that the death rate from Covid 19 is higher in men than women. It is also known that obesity, diabetes, high blood pressure and old age make your chances of survival more difficult too. It is my opinion that vitamin D deficiency is likely to be the reason, firstly that those with obesity, diabetes and the elderly have suffered more severe conditions related to Covid 19, but that others who don’t have known underlying conditions have suffered such terrible fates too, and these are my reasons:

  • 1. Vitamin D deficiency is prevalent in people with high blood pressure, diabetes and obesity
  • 2. Vitamin D deficiency is prevalent in the winter months due to lack of therapeutic levels of sunshine.
  • 3. The overuse of sunscreens has reduced vitamin D absorption in summer months.
  • 4. Women generally have higher vitamin D levels than men because oestrogen encourages the uptake of this vitamin into the body.
  • 5. Older people don’t absorb vitamin D as effectively as younger people, and are often severely deficient. Generally older people who regularly sunbathe, not only live longer, but are much healthier, suffer less obesity and blood pressure problems and are less likely to suffer bone fractures – I have made this observation from 15 years of caring for the elderly.


I therefore suggest the following measures be taken:

  • 1. Every new suspected case of Covid 19 be tested for vitamin D deficiency, and treated bringing vitamin D status to optimum levels. This would require several measured therapeutic doses of vitamin D, or several doses of full body UVB exposure.
  • 2. Government advice be updated to encourage the UK population to take sensible levels of sunshine therapy and/or vitamin D supplementation at higher levels (4000iu – the upper level recommendation on the NHS website). People who live in flats should be allowed a permit to sunbathe in public areas.
  • 3. Therapeutic vitamin D supplementation be provided to frontline staff and the most vulnerable.
  • 4. Medical trials be actioned immediately, with results available within weeks regarding the value of therapeutic levels of vitamin D supplementation.

Competing interests: No competing interests

08 April 2020
Fiona Smith
Writer
None
fiona at travel2paradise.co.uk

Stay rational during an urgent epidemic outbreak – Luo

Dear Editor

In the prevention of COVID-19 pandemic, Robert A Brown suggests that vitamin D may contribute to the prevention of COVID-19 and should be applied in a wider clinical practice immediately. The reason was that the higher mortality rates in Spain and Italy in comparison with northern European Countries may arise from vitamin D deficiency. [1] However, I have the same concerns as George Trovas. [2] Although there is probably a correlation between the level of vitamin D and the epidemiological data of COVID-19, it may be caused by other underlying risk factors.

A meta-analysis reported that vitamin D supplementation alone had no connection with the mortality in adults. [3] Another study demonstrated that sufficient vitamin D supplementation (≥ 25 nmol/L) did not improve the condition of patients with chronic obstructive pulmonary disease (COPD), compared with patients taking a placebo. Thus the NICE 2018 guideline does not suggest vitamin D. [4]

The data of global incidence and deaths from the World Health Organization showed that the morbidity of COVID-19 in developed countries is obviously higher than that in developing countries. The data of Max Roser and colleagues indicated that total tests for COVID-19 in Germany was 918 460, which was 454 030 in Italy as of 29 March 2020. [5] Although Germany has more people than Italy, total tests for COVID-19 per thousand people was 11.13 in Germany, 48.03 in Iceland, and only 7.68 in Italy. On 5 April 2020, daily COVID-19 tests per thousand people in Iceland were 7.24, Italy was 0.58, South Africa was 0.0.5, and India was less than 0.01. [5] Mild cases took up a major part of the COVID-19 in Germany. Therefore, the high mortality rates in Italy may because many mild COVID-19 patients were not detected. And the most notable point is that low incidence does not mean a mild epidemic: on the contrary, there may be a large number of undetected COVID-19 patients which could make the outbreak worse in developing countries.

In conclusion, vitamin D should not be used blindly in wider clinical trials because of the urgent epidemic. If not, it may cause people to miss more effective treatments, and more valuable research may lose subject resources. Researchers should confront COVID-19 rationally and scientifically, especially when the epidemic is serious.

References

  • 1. Robert A Brown. (7th April 2020). BMJ 2020;368:m810 doi: https://doi.org/10.1136/bmj.m810
  • 2. George Trovas. (2nd April 2020). BMJ 2020;368:m810 doi: https://doi.org/10.1136/bmj.m810
  • 3. Yu Zhang, Fang Fang, Jingjing Tang, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ 2019;366: l4673.
  • 4. Cook R, Thomas V, Martin R. Can treating vitamin D deficiency reduce exacerbations of chronic obstructive pulmonary disease? BMJ. 2019;364:l1025. doi: 10.1136/bmj.l1025.
  • 5. Max Roser, Hannah Ritchie, Esteban Ortiz-Ospina. Coronavirus Disease (COVID-19) – Statistics and Research. Our World In Data. 2020. Retrieved from: https://ourworldindata.org/coronavirus. [Online Resource]

Competing interests: No competing interests

08 April 2020
Qiankun Luo
doctoral candidate
Tao Qin, Department of Scientific Research and Discipline Construction, Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, 450003, China.
Zhengzhou University People's Hospital, Henan Provincial People's Hospital
No 7, Weiwu Road, Zhengzhou 450003, China

Try first with health care workers and first responders.– Grant

Dear Editor,

There is reasonable evidence that higher 25-hydroxyvitamin D [25(OH)D] concentrations reduce the risk of respiratory tract infections. A meta-analysis of vitamin D supplementation trials found an inverse relationship between vitamin D supplementation and incidence of acute respiratory tract infections, especially for those with 25(OH)D concentrations below 25 nmol/l [1]. Several mechanisms by which vitamin D reduces risk of respiratory tract infections have been identified. One is that cathelicidens and defensins are induced that have antimicrobial and antiendotoxin properties [2]. Another is that vitamin D reduces the production of pro-inflammatory cytokines and increases production of anti-inflammatory cytokines 2. The innate immune system often goes into overdrive during respiratory tract infections, resulting in the cytokine storm that can damage the lining of the lungs [3]. Serum 25(OH)D concentrations have been found to be inversely correlated with development of acute respiratory distress syndrome [4].

An article tying this and other information together suggests that raising serum 25(OH)D concentrations to 100 – 150 nmol/l should be able to reduce the risk of COVID-19 infection and death [5]. To reach those concentrations rapidly would take large doses of vitamin D for a week or two, followed by several thousand IU/d vitamin D for the duration of the COVID-19 pandemic. Such doses have been found not to have adverse health effects [6]. In addition, vitamin D reduces risk of many chronic diseases such as cancer and diabetes mellitus in secondary analyses of large clinical trials [7], and observational studies have found inverse correlations between serum 25(OH)D concentration and all-cause mortality rate up to 100 nmol/l [8].

No results of clinical trials regarding vitamin D supplementation for prevention or treatment of COVID-19 have been reported. Thus, an important question is whether making a public health announcement that taking enough vitamin D to raise serum 25(OH)D concentrations is a good idea. On the pro side, high-dose vitamin D supplementation and 25(OH)D concentrations have very few adverse side effects [6, 9]. It is also very inexpensive in markets that are not regulated, such as in the United States. Also, high 25(OH)D concentrations are associated with many health benefits [10] (see, also, information at vitaminDWiki.com and Grassrootshealth.net). On the anti side, physicians and health policy makers are reluctant to recommend health interventions that have not been rigorously tested and approved.

In my opinion, supplementation with substantial vitamin D doses is justified based on the enormous health and economic magnitude of the COVID-19 pandemic, the likely benefit in reducing risk of COVID-19 infection incidence and severity, and the preponderance of other health benefits from vitamin D supplementation and higher 25(OH)D concentrations with minimal adverse effects.

In terms of rolling out this recommendation, it is proposed that health care providers and first responders might try it first. Many of them lack adequate personal protective equipment and are contracting COVID-19 as a result. They have the training and motivation to lead the way in evaluating the benefit of vitamin D supplementation to help stem the COVID-19 pandemic. Measuring serum 25(OH)D concentrations at baseline and after supplementing for some time would be useful, especially in terms of evaluating the results in a field study rather than a randomized controlled trial [5].

References

  • 1. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583. doi: 10.1136/bmj.i6583
  • 2. Gombart AF, Pierre A, Maggini S. A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection. Nutrients 2020;12(1):E236. doi: 10.3390/nu12010236
  • 3. Guo XJ, Thomas PG. New fronts emerge in the influenza cytokine storm. Semin Immunopathol 2017;39(5):541-50. doi: 10.1007/s00281-017-0636-y
  • 4. Dancer RC, Parekh D, Lax S, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax 2015;70(7):617-24. doi: 10.1136/thoraxjnl-2014-206680
  • 5. Grant WB, Lahore H, McDonnell SL, et al. Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020 doi: 10.20944/preprints202003.0235.v2 [published Online First: 30 March 2020]
  • 6. McCullough PJ, Lehrer DS, Amend J. Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol 2019;189:228-39. doi: 10.1016/j.jsbmb.2018.12.010
  • 7. Grant WB, Boucher BJ. Why Secondary Analyses in Vitamin D Clinical Trials Are Important and How to Improve Vitamin D Clinical Trial Outcome Analyses-A Comment on "Extra-Skeletal Effects of Vitamin D, Nutrients 2019, 11, 1460". Nutrients 2019;11(9) doi: 10.3390/nu11092182
  • 8. Garland CF, Kim JJ, Mohr SB, et al. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Public Health 2014;104(8):e43-50. doi: 10.2105/AJPH.2014.302034
  • 9. Grant WB, Karras SN, Bischoff-Ferrari HA, et al. Do studies reporting 'U'-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects? Dermatoendocrinol 2016;8(1):e1187349. doi: 10.1080/19381980.2016.1187349
  • 10. Charoenngam N, Shirvani A, Holick MF. Vitamin D for skeletal and non-skeletal health: What we should know. J Clin Orthop Trauma 2019;10(6):1082-93. doi: 10.1016/j.jcot.2019.07.004

Competing interests: Disclosure: I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR).

01 April 2020
William B. Grant
Research
Sunlight, Nutrition and Health Research Center
PO Box 641603, San Francisco, CA 94164-1603
@wbgrant2

COVID-19: Vitamin D deficiency; and, death rates; are both disproportionately higher in
elderly Italians, Spanish, Swedish Somali, and African Americans? A connection? Research urgently required! – Brown

Dear Editor

It is posited by contributors [1, 2, 3, 4, 5] to BMJ, ‘Preventing a covid-19 pandemic’, others, [6, 7, 8] and myself, [9] that vitamin D, and particularly vitamin D deficiency, is a likely factor in the progression, and/ or severity, and/ or mortality of COVID-19; and also may present clinical treatment opportunities.

My preprint, ‘Vitamin D deficiency: a factor in COVID-19, progression, severity and mortality? – An urgent call for research’, [9] posits, greater vitamin D deficiency <25nmol/L in southern (E.g. Spain and Italy), than northern European Countries (E.g. Germany, Norway, Finland, Iceland), may help account for differentials, in mortality rates per million. Consistent with this, Northern Europeans have higher vitamin D food intakes, food fortification, and supplement more. This is an easily testable posit.

Northerly resident; Europeans with darker skins; BAME, and African Americans; as well as more southerly elderly Spanish and Italians; are often vitamin D deficient. IF, vitamin D deficiency, increases the risk of COVID-19 related; infection, hospitalisation and mortality; one would expect, and indeed sees, higher COVID-19 hospitalisation and mortality, in; dark-skinned (Fitzpatrick scale) northerly residents; those with dress codes that inhibit sunlight; and generally in groups likely to include the ‘D’ deficient.

Whilst data is still sparse, it supports the above contention; albeit lack of distancing, and vitamin D deficiency, may both be contributing factors; for example: “40 % of the reported COVID-19 related deaths occurring in Stockholm involve the Somali diaspora communities”; yet they only represent 0.84% of the population] [10, 11, 12, 13] Data clearly shows, Somalis, and wider immigrant groups, are D deficient, for example, “Vitamin D deficiency ( < 25 nmol/l) was found in 73% of the Somali women and in 1% of the controls” [14, 15, 16]

In respect of African Americans, a headline, April 3rd, 2020, states, ‘Early Data Shows African Americans Have Contracted and Died of Coronavirus at an Alarming Rate [17] “In Chicago, 70% of COVID-19 Deaths Are Black,” [18] The review, APHA ‘Call for Education and Research Into Vitamin D Deficiency/Insufficiency’, in 2008, noted, “84% of African American men and women (over 65) were vitamin D deficient.” [19, 20, 21] (‘D’ deficiency definitions vary).

In contrast, in continental Africa, whilst Vitamin D deficiency exists, it does not appear to be as widespread as in the United States: “one in five people living in Africa had a low 25(OH)D concentration with use of a less than 30 nmol/L.” [22] COVID-19 data for Somalia is limited. Tests are done externally: current data; 7 cases, 1 recovered, no deaths. [23] The first recorded case was confirmed on the 16th of March. Twenty volunteer doctors from Somali National University went to Italy to help fight COVID-19 there. [24, 25] Case numbers in wider Africa are currently relatively low, compared to the most infected countries, but arguably there is insufficient data, or certainty, as to initial infection dates, to, at this point, even postulate as to future COVID-19 infection, or mortality rates, in Africa. [26]

Differences appear to exist in the metabolism of Vitamin D; ‘The D paradox’; [27] between Caucasians and African Americans, particularly in terms of bone density. However, the metabolism of vitamin D is complex, and pathways impacting COVID-19 likely differ from those regulating bone densities.

The COVID-19 mortality rate, has very sadly, been high in Italy (15,887 as at 5th April 2020). [28] A rapid response to the BMJ titled ‘Re: Preventing a covid-19 pandemic Can high prevalence of severe hypovitaminosis D play a role in the high impact of Covid infection in Italy? ’[29] notes, “700 women aged 60-80 yrs in Italy had values of 25OH vitamin D lower than 5 ng/ml in 27% of the women and lower than 12 ng/ml in as many as 76%.” [29]

BAME (Black, Asian, Minority Ethnic) persons in the United Kingdom, may be more susceptible. A UK study of 2,249 patients by the ‘Intensive Care National Audit and Research Centre’, noted “Despite making up just 13 per cent of the UK population, a third of patients who fall critically ill with COVID-19 are from black, Asian or minority ethnic (BME) groups.” [30] Further, sadly, 6 out of 8, UK COVID-19 medical staff deaths, were British Muslims.[31] Hasidic Jews in Israel may also be at higher COVID-19 risk, due to failure to isolate[32] and/ or greater risk of vitamin D deficiency.[33, 34]

Arguably it is urgent, that research is done, to determine if vitamin D deficiency factors in COVID-19, infection, progression, severity and mortality. Vitamin D blood spot tests are cheap. Patient records have to be maintained in any event. The additional work, and risk burden, in taking vitamin D measurements are limited. However, the reward could be very significant, even a ‘game changer’.

Further, any determination that vitamin D factors in COVID-19, incidence progression and outcome, would point to the likelihood of COVID-19 following a seasonal pattern in populations, which would require factoring into determination of Governmental COVID-19 forward planning policies; mortality risk modelling; social distancing polices; and population vitamin D optimisation, including access to outside spaces, to facilitate sensible, ethnicity appropriate, exposure to UVB in sunlight; and/ or free ‘D’ supplementation, at least for the most vulnerable and financially insecure.

COVID-19 studies might comprise:
• Test all COVID-19 patients in hospital/s at a given point in time for Vit D, follow, and report results.
• Take finger prick samples at the same time as COVID-19 test – follow through with laboratory vitamin D tests on the samples of all positives, and an equal number of controls; report results.
• A study using Vit D clinically – test for low vit D – where low supplement with vitamin D3, and/ or as an alternative to above, try a 1,25-active form; [35] report results.

Vitamin D, could usefully be immediately incorporated into wider clinical nutritional COVID-19 protocols, [36, 37] but, to better understand the role of vitamin D in COVID-19; for the formulation of; treatment, prevention, and wider, policies; the above studies would still be urgently required.
References

Competing interests: No competing interests

07 April 2020
Robert A Brown
Researcher
McCarrison Society
St Lawrence, Jersey. C.I.

Covid 19, Vitamin D deficiency, Smoking, Age and Lack of Masks Equals the Perfect Storm – Schwalfenberg

Dear Editor

Covid 19 was introduced to the northern hemisphere during the winter of 2019/2020. It is well known that vitamin D levels are significantly lower at the end of winter than in the summer. More than 40% of Canadians have low levels of vitamin D (less than 50nmol/l)[1] at this time of year. Solar radiation is a major contributor to vitamin D levels. Regions in China (Wuhan)[2](and Italy (northern areas)[3] and parts of Spain again have noticeably less solar radiation annually as well as more air pollution. These areas with high air pollution[4] block ultraviolet frequencies that result in vitamin D production in the skin[5] .
Vitamin D has a significant impact on our immune system[6] being important in barrier function maintaining tight junctions, gap junctions and adherens junctions. Recent evidence shows that vitamin D down regulates the DDP/CD26 binding site of the COVID-19 spike glycoprotein thus reducing the virulence of this virus.[7]. As well it is important for the production of cathelicidins and other antimicrobial compounds. Vitamin D also reduces the cytokine storm by reducing the expression of pro-inflammatory cytokines and improving anti inflammatory cytokines[8] such as LL 17, thus attenuating the risk of cascading responses in the immune system that may lead to death.
In order to correct the vitamin D winter low, rapid supplementation with 10,000IU of vitamin D3 can be safely employed as suggested in a most recent article[9]. Another approach would be the employ the” vitamin D hammer” as a one time 50,000IU dose of vitamin D3 when one becomes ill[10]. Of course this one time dose should be followed by a reasonable daily dose of at least 5000IU until vitamin D levels are at 100nmol/l.
Smoking reduces vitamin D levels[11], increases inflammation and slows resolution of viral infections[12]. Vitamin D may have a protective effect on lung function[13] and reduce infections of the lung in both adults and children[14].
Those that are older[15] have an increased likelihood of being vitamin D deficient and the skin with increasing age becomes less efficient at producing vitamin D[16]. Thus supplementation of vitamin D is more important as we age.
Wearing a mask has been shown to reduce infection in clinical situations and may be another protective measure[17]. A rational approach needs to be taken[18]. It appears as this pandemic is unfolding that countries that adopt wearing masks early on (even home made cloth masks) are faring much better than those that do not. Certainly wearing masks is not a panacea without all the other public health measures, but are useful for everyone within a population to wear when public as asymptomatic individuals can transmit this virus[19].
Modifiable risk factors for covid 19 infections would include discontinuing smoking, normalizing vitamin D levels quickly, and using universal mask protection.

References

  • 1. Vitamin D levels of Canadians, 2012 to 2013 [https://www150.statcan.gc.ca/n1/pub/82-625-x/2014001/inf-eng.htm]
  • 2. Ehsanul Kabira PK, Sandeep Kumarc, Adedeji A Adelodun, Ki-Hyun Kim: Solar energy: Potential and future prospects. Renewable and Sustainable Energy Reviews 2018, February, 82:894-900.
  • 3. Annual solar radiation in Italy [http://www.eniscuola.net/en/mediateca/annual-solar-radiation-in-italy/]
  • 4. Additional Renewable Maps - Spain [http://www.geni.org/globalenergy/library/energy-issues/spain/additional-...
  • 5. Hosseinpanah F, Pour SH, Heibatollahi M, Moghbel N, Asefzade S, Azizi F: The effects of air pollution on vitamin D status in healthy women: a cross sectional study. BMC Public Health 2010, 10:519.
  • 6. Schwalfenberg GK: A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res 2011, 55:96-108.
  • 7. Mccartney DM, Bryne D.G.: Optimisation of Vitamin D Status for Enhanced Immuno-protection Against Covid-19. Irish Mediical Journal 2020, 113:58.
  • 8. Svensson D, Nebel D, Nilsson BO: Vitamin D3 modulates the innate immune response through regulation of the hCAP-18/LL-37 gene expression and cytokine production. Inflamm Res 2016, 65:25-32.
  • 9. Grant WBL, H.; McDonnell, S.L.; Baggerly, C.A.; French, C.B.; Aliano, J.L.; Bhattoa, H.P.: Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020, 12.
  • 10. Schwalfenberg G: Vitamin D for influenza. Can Fam Physician 2015, 61:507.
  • 11. Brot C, Jorgensen NR, Sorensen OH: The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr 1999, 53:920-926.
  • 12. Gualano RC, Hansen MJ, Vlahos R, Jones JE, Park-Jones RA, Deliyannis G, Turner SJ, Duca KA, Anderson GP: Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice. Respir Res 2008, 9:53.
  • 13. Lange NE, Sparrow D, Vokonas P, Litonjua AA: Vitamin D deficiency, smoking, and lung function in the Normative Aging Study. Am J Respir Crit Care Med 2012, 186:616-621.
  • 14. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, et al: Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017, 356:i6583.
  • 15. Gallagher JC: Vitamin D and aging. Endocrinol Metab Clin North Am 2013, 42:319-332.
  • 16. Boucher BJ: The problems of vitamin d insufficiency in older people. Aging Dis 2012, 3:313-329.
  • 17. Sung AD, Sung JAM, Thomas S, Hyslop T, Gasparetto C, Long G, Rizzieri D, Sullivan KM, Corbet K, Broadwater G, et al: Universal Mask Usage for Reduction of Respiratory Viral Infections After Stem Cell Transplant: A Prospective Trial. Clin Infect Dis 2016, 63:999-1006.
  • 18. Shuo Feng CS, Nan Xia, Wei Song, Mengzhen Fan, Benjamin J Cowling: Rational use of face masks in the COVID-19 pandemic. wwwthelancetcom/respiratory March 20,2020.
  • 19. Klompas M, Morris CA, Sinclair J, Pearson M, Shenoy ES: Universal Masking in Hospitals in the Covid-19 Era. N Engl J Med 2020.

Competing interests: No competing interests

05 April 2020
Gerry K Schwalfenberg
Family Physician
University of Alberta

  1. 301,9509-156 St

Re: Preventing a covid-19 pandemic and the role of vitamin D – Trovas

Dear Editor

I have read with interest the rapid response recently posted on bmj.com by Professor A.Giustina et al related to prevalence of severe hypovitaminosis D and covid-19 infection in Italy.

In this manuscript is discussed reasonably the possible role of vitamin D in the prevention of human response to covid-19 pandemic. Although I agree that there are several epidemiological data which hypothesized that low vitamin D levels could be a link between susceptibility to infection to covid-19 in northern Italy, on the other hand, Greece is a country where old (1) and new data (2) report very low vitamin levels in a vast range of ages and at the same time it is among the countries with low numbers of confirmed cases (1415) and deaths (51) in the last report 2/4/20 (Coronavirus covid-19 global cases at John Hopkins Center for Health Security), underlying the fact that other factors are more important in this terrible nightmare we are facing.

References

  • 1. Van der Wielen RPJ, Lowik MRH, van der Berg H, de Groot LCPGM, Haller J, Moreiras O, van Staveren WA(1995) Serum vitamin D concentrations among elderly people in Europe. Lancet 346:207210.
  • 2. Effimia V. Grigoriou , George Trovas,Nikolaos Papaioannou, Polyzois Makras,Panagiotis Kokkoris,Ismene Dontas,Konstantinos Makris,Symeon Tournis George V. Dedoussis Serum 25-hydroxyvitamin D status, quantitative ultrasound parameters, and their determinants in Greek population Archives of Osteoporosis (2018) 13:111.

Competing interests: No competing interests

02 April 2020
George Trovas
ENDOCRINOLOGIST
LABORATORY FOR THE RESEARCH OF MUSCULOSKELETAL SYSTEM,UNIVERSITY OF ATHENS
MITHIMNIS 37, PL AMERIKIS

Can high prevalence of severe hypovitaminosis D play a role in the high impact of Covid infection in Italy? - Giustina

Dear Editor,
We have read with interest the Editorial recently published in BMJ by Watkins and related rapid responses by Cobbold, Garami, Maestri and Rhein. In most of these comments a possible helpful role of vitamin D in the prevention or the response to Covid19 pandemic has been proposed or discussed-. In particular, vitamin D deficiency has been reported to increase predisposition to systemic infections and impaired immune response or even autoimmune diseases (1). Moreover, an interesting metaanalysis has shown that vitamin D supplementation can prevent respiratory infections (2)
Italy is the Country that is paying the highest death toll to Covid19 infection in the whole world (reaching today the impressive number of 4000 in less than four weeks and exceeding already by far the number of deaths of slightly more than 3.200 so far reported in China) ) (3).
From the analysis of epidemiological data available particularly in the Chinese Literature but also in the reports of the Italian Ministry of Health the majority of deaths is concentrated in the elderly with common, although not necessarily deadly per se , comorbidities such as hypertension, diabetes or obesity(4). In fact, it has been suggested that the elevated mean age of the Italian population (5) could be a predisposing factor to the severity and elevated mortality related to Covid infection. This has led to the hypothesis that Italians may die with Coronavirus infection rather than for Coronavirus infection,
Nevertheless, a convincing explanation on the reason(s) of this so far anomalous and deadly impact of Covid in Italy and particularly in the Northern Regions has not so far been provided.
Interestingly, epidemiological data report that Italy is one of the Countries with the highest prevalence of hypovitaminosis D in Europe. A study from Isaia et al on 700 women aged 60-80 yrs in Italy found values of 25OH vitaminD lower than 5 ng/ml in 27% of the women and lower than 12 ng/ml in as many as 76%. (6) Moreover, the same group found a very high prevalence of hypovitaminosis D in elderly women with diabetes (7). Finally, another Italian study found a winter prevalence of hypovitaminosis D up to 32% of healthy postmenopausal women and to 82% in patients engaged in long-term rehabilitation programmes because of various neurological disorders.(8). Obesity has also been suggested to be linked to low vitamin D and higher vitamin D requirements (9)
Vitamin D status largely depends on sun exposure since at odds with all other vitamins (in fact it is a steroid hormone) the amount introduced with diet is far from being sufficient (1). The huge amount of the population with low circulating vitamin D levels in Italy is due to the historical lack of a program of food fortification with vitamin D ( at odds with what has been done since several decades in many European countries leading to what is known as the Scandinavian paradox, i.e. the highest level of vitamin D in northern european Countries at low sunshine exposure vs the Southern Countries at higher sunshine exposure) as well as the change in lifestyle with more sedentary type of working and living plus the different climate conditions in the Northern vs Southern regions of the Country (10).
Therefore, based on the previous considerations it could be hypothesized that low vitamin D could be the link between age, comorbidities and increased susceptibility to complications and mortality due to Covid19 infection in the northern regions in Italy.
Two other further general considerations may contribute to the argument of contribution of low vitamin D to the impact of Covid19: a) in severely compromised patients: patients with acute illness, whether they are in the intensive care unit or not, have very low levels of 25(OH)vitaminD (11) Moreover, some authors think that poor vitamin D status may aggravate the health outcome of ICU patients and correction with (high doses) of vitamin D of poor vitamin D status could decrease morbidity and mortality (12); b) in general population: home confinement is the most used preventive measure against the spreading of Covid19 infection in many Countries and in Italy in particular. Total absence of sunlight exposure may cause in large part also of the younger population a decrease or worsening in the vitamin D status. (13)
In order to corroborate our hypothesis it should be necessary to look at 25OH vitamin D levels in hospitalized patients with Covid19 infection and in different stages of the disease. However, even in absence of a proof of our concept, in an era of restrictive mesures of Health authorities concerning the reimbursability of vitamin D (14) we think reasonable a message reinforcing the importance of maintaining vitamin D treatment in those already diagnosed with hypovitaminosis D and considering the supplementation with vitamin D of elderly comorbid persons at home confinement (15). Issue of universal supplementation with vitamin D due to high risk of complicated Covid19 infection in Italy or in other Countries including the hospitalized, in and not in ICU, patients remains open.

REFERENCES
1. Bouillon R, Marcocci C, Carmeliet G, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019 Aug 1;40(4):1109-1151.
2. Martineau AR,Jolliffe DA, Hooper RL et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583
3. covid19 at gimbe.org March 20 2020
4. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China. JAMA. Published online February 07, 2020. doi:10.1001/jama.2020.1585
5. www.istat.org February 11 2020
6. Isaia G, Giorgino R, Rini GB, Bevilacqua M, Maugeri D, Adami S. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors Osteoporos Int. 2003 Jul;14(7):577-82
7. Isaia G, Giorgino R, Adami S. High prevalence of hypovitaminosis D in female type 2 diabetic population
Diabetes Care. 2001 Aug;24(8):1496
8. Romagnoli E, Caravella P, Scarnecchia L, Martinez P, Minisola S. Hypovitaminosis D in an Italian population of healthy subjects and hospitalized patients.Br J Nutr. 1999 Feb;81(2):133-7.
9. Formenti AM, Tecilazich F, Frara S, Giubbini R, De Luca H, Giustina A. Body mass index predicts resistance to active vitamin D in patients with hypoparathyroidism Endocrine. 2019 Dec;66(3):699-700
10. Giustina A, Adler RA, Binkley N, et al. Controversies in Vitamin D: Summary Statement From an International Conference. J Clin Endocrinol Metab. 2019 Feb 1;104(2):234-240.
11. . Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care 2012;15(2):188–193.
12. Christopher KB. Vitamin D and critical illness outcomes. Curr Opin Crit Care 2016;22(4):332–338.
13. Nota 96. Gazzetta Ufficiale Serie Generale n. 252 del 26/10/2019.
14. Giustina A, Adler RA, Binkley N, et al. Consensus statement from 2nd International Conference on Controversies in Vitamin D. Rev Endocrinol Metab Dis 2020 ] Mar 17. doi: 10.1007/s11154-019-09532-w. [Epub ahead of print]
15. Ebeling PR, Adler RA, Jones G, et al. MANAGEMENT OF ENDOCRINE DISEASE: Therapeutics of Vitamin D. Eur J Endocrinol. 2018 Oct 12;179(5):R239-R259
Competing interests: No competing interests

20 March 2020
Andrea Giustina
Professor of Endocrinology
Anna Maria Formenti
Vita-Salute San Raffaele University, Milano
IRCCS San Raffaele Hospital, via Olgettina 60, 20132 Milano, Italy
@EsePresident

Re: Preventing a covid-19 pandemic – Michely

Dear Editor

I read with quite some excitement the original article and the related responses.

R. Sommerstein’s and M.Phadke’s letters indeed led to some questioning among emergency physicians and internists.

Angiotensin-converting enzymes (ACE) 1 and 2 are key factors in the renin-angiotensin system (RAS) and act as a counterbalance. (1, 2). Angiotensin (AT) 2, resulting from the enzymatic cleavage of AT1 from ACE1, via activating AT2-type 1 receptors, and besides its actions on the RAS system, plays a role as bronchoconstrictive, pro-inflammatory and proliferative actor (via different signaling pathways implicating NFkB, Toll 4, free radicals and others), resulting in inflammatory lung injuries. AT 1-7, resulting from the cleavage of AT2 by ACE2 has opposite actions, namely anti-inflammatory and anti-proliferative. (1, 2) ACE2 is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. It is increased / upregulated in patients treated chronically with AT2-type 1 receptor blockers (1, 3, 4). ACE2 is also increased by ibuprofen and ACE inhibitors (5). SARS-CoV-2 uses ACE2 for target cell entry by fixing on it via its viral spike glycoprotein (1, 2, 6). Hence stems the idea that ACE2 stimulating drugs would increase the risk of developing severe and fatal COVID-19. (1)

However, SARS-CoV-2 downregulates ACE2 (4) after binding and internalisation, hence diminishing the formation of AT 1-7 (and 1-9), thereby diminishing AT 1-7’s action as an anti-inflammatory and anti-proliferative actor, leading to inflammatory lung injury, and increasing AT2 (4), thus favoring its action on AT2-type 1 receptors with subsequent proliferation, apoptosis and inflammation of pulmonary cells, bronchoconstriction and increased pulmonary vascular permeability. By blocking these receptors via losartan or an analogous compound, we diminish proliferation, inflammation and apoptosis in pneumocytes together with upregulating ACE2 due to excess in AT2 (shift), and favour again the formation of AT 1-7. (7)

Angiotensin receptor 1 inhibitors could be used as a novel therapy in SARS-CoV-2 Covid 19 pneumonia. (7) But instead of preventing viral entry into target cell, as suggested by Phadke and al., it would be through its anti-inflammatory actions on lung tissue.

  • 1. Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci. 2004 Jun;25(6):291-4.
  • 2. Rella M, Rushworth CA, Guy JL, Turner AJ, Langer T, Jackson RM. Structure-based pharmacophore design and virtual screening for novel angiotensin converting enzyme 2 inhibitors. J Chem Inf Model. 2006 Mar-Apr;46(2):708-16.
  • 3. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virology 2020; published online Jan 29. DOI:10.1128/JVI.00127-20.
  • 4. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656. [Epub ahead of print]
  • 5. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11. pii: S2213-2600(20)30116-8. doi: 10.1016/S2213-2600(20)30116-8. [Epub ahead of print]
  • 6. Wan Y#, Shang J#, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020 Mar 17;94(7). pii: e00127-20. doi: 10.1128/JVI.00127-20. Print 2020 Mar 17.
  • 7. Sun ML, Yang JM, Sun YP, Su GH. [Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):219-222. doi: 10.3760/cma.j.issn.1001-0939.2020.03.016.

Competing interests: No competing interests

19 March 2020
David Michely
Resident in internal and emergency medicine
Hôpital Neuchâtelois, Switzerland
rue de la Maladière, 2000 Neuchâtel, Switzerland

Vitamin D against COVID 19: Clinicians need more than observations and hope – Maestri

Dear Editor

As the war against COV 19 is declared we see proposal of new (old) weapons sustained by microbiology and observations.

Among many putative functions, a role for Vitamin D in the modulation of the immune response to infectious agents is based on laboratory findings and observational studies; randomized clinical trials gave controversial results, so more is required to recommend Vitamin D in this clinical setting (1).

We respect fears and hopes to find that golden bullet needed to protect against COV 19 but we need to avoid premature believes which could lower the attention or the adherence to unpopular means like mobility-restriction and quarantine as imposed in Italy.

The scientific basis of the employ of cholecalciferol in prevention and therapy of COVID 19 described by Professor Cobbold may be respectable and the citation from Doctor Rhein of Vitamin D in preventing pulmonary acute infections (principally for people with 25OH D < 10 ng/mL) (2) could be suggestive but the history of the last decades should have stated the need for randomized clinical trials before considering an intervention as useful in prevention and/or therapy.

The same history tells about interventions claimed as safe and potentially useful in reducing the risk of diseases (for example, alpha-tocopherol and beta-carotene against lung cancer in smokers) which instead were found to increase the risk .(3)

The recent failures to demonstrate benefits from vitamin D administration against cancer and cardiovascular disease (4) and many other pathologic conditions should alert physicians to be cautious in considering observational studies as sufficient evidence to encourage a widespread diffusion of Vitamin D supplementation. The hurry to obtain “safe” vitamin D levels can be quite dangerous.(5)

As healthcare professionals we hope to have weapons to fight against diseases but we think it very dangerous to transform hopes and observations into scientific evidence.
References

  • 1 Gruber B Vitamin D and Influenza-Prevention or Therapy? Int J Mol Sci. 2018;19. pii: E2419. doi: 10.3390/ijms19082419.
  • 2 Martineau AR, Jolliffe DA, Hooper RL et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583
  • 3 Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35.
  • 4 Manson JE, Cook N, Lee i-M, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. New Engl J Med 2019;380:33-44.
  • 5 Sanders KM Stuart AL, Williamson EJ. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303:1815-1822.

Competing interests: No competing interests

12 March 2020
Emilio Maestri
clinical endocrinologist
Giulio Formoso, Roberto Da Cas, Federica Mammarella, Francesco Trotta
Clinical Governance Unit, Local Health Authority - IRCCS of Reggio Emilia, Italy ISS - Italian National Institute of Health, Rome, Italy AIFA – Italian Medicines Agency, Rome, Italy
Via G. Amendola 2, 42122, Reggio Emilia, Italy

Preventing a covid-19 pandemic

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m810 (Published 28 February 2020)
Cite this as: BMJ 2020;368:m810
Read our latest coverage of the Coronavirus outbreak
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Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles.

Re: Preventing a covid-19 pandemic - Anand

Dear Editor

1. According to a BBC report this morning, the Deputy Chief Medical Officer says thst closing down major events such as football matches will not be necessarily supported by science.
It is incumbent on her to cite the science on which she relies.

2. The same officer also says that the Virus is reported not to survive outside very long.
Could she please tell us how long it will survive? And what is the evidence on which she relies?

3. What is the scientific evidence on which she is relying in keeping theatres and cinemas open?

Can her Department answer the questions, please? Thank you.

Competing interests: No competing interests

10 March 2020
JK Anand
Retired doctor
Free spirit
Peterborough

United efforts to win the anti-coronavirus campaign: moving from discrimination to cooperation

Dear Editor

As a highly contagious pathogen, the COVID-19 virus has caused serious threat to the whole world. When positive trends have been seen in China after more than a month of relentless efforts, the virus is rapidly spreading in other countries worldwide. The World Health Organization (WHO) has increased the risk assessment to very high at the global level. Eighty-eight countries/territories/areas have reported 17,481 confirmed cases and 335 deaths outside China by Mar 6, 2020, [1] while three weeks ago, only 447 cases and one death were reported in 24 countries outside China. [2] The number of newly reported cases in the past 24 hours outside China far exceeds that in China. [1]

With enough attention, effective measures, and timely correction of decisions, China has set a good example for combating the outbreak. Nonetheless, the situations of countries outside China including Italy and South Korea deteriorate rapidly and catch the eyes of the world. Meanwhile, racism and xenophobia toward Chinese communities originally, has been transferred to new epicenter of COVID-19, such as Italy and South Korea, etc., fuelled by the heightened fear of infection. This epidemic is a public health issue. People from China, Italy and other countries at high epidemic level have been blamed rather than being treated as victims, and those living oversea are facing discrimination. Some racist people and even the media refer to this novel coronavirus as the “China virus” or “Chinese virus”. Some shops and clinics refuse to provide service for Chinese customers. Moreover, innocent Chinese have been harassed or attacked in some countries for wearing a mask, and sometimes the discrimination has even spread to their local people who wear a mask, the purpose of which is an effort to protect oneself and others from person-to-person transmission.

A key reason for this emerging discrimination is fear caused by this novel virus, and outright fear is based on distrust regarding the competence of authorities and health officials. [3] If a population cannot receive reliable information about the spread of the virus from trustworthy sources, then they have a tendency to blame individuals from infected areas. Similar situations occurred during the outbreak of H1N1 swine flu and 2014 Ebola, in which Latinos and Africans were scapegoated. However, what does not match the threat and fear people are facing is the lack of government attention, commitment and effective actions in some countries. Absence of cooperation with and even quarantining countries at high epidemic level increases the fear of the public and cuts off valuable sources of information about the outbreak.

United efforts are needed to win the worldwide battle against COVID-19. Governments need to work closely with health professionals and the public to disseminate reliable information about the epidemic, including the mode of transmission, susceptible populations, protection tips for individuals, and effective control measures. Less discrimination occurs when more accurate and transparent information is released, which gives the public confidence to cope with the epidemic while mitigating fear, panic, stigma, and discrimination in an effort to achieve disease control. The WHO opposes the imposition of travel and trade restrictions against countries reporting cases. More evidence-based approaches should be taken rather than quarantining these countries with travel bans, which violates the International Health Regulations. [4]

In the era of globalization, attempts to isolate a country fighting against epidemic are irrational. Instead, coordinated and comprehensive approaches that are proved to have effectively contained the outbreak should be learned and credits should be given to countries including China. Most countries, their populations, and international organizations, including the WHO, appreciate China’s efforts and experiences to contain the virus. With the dramatic spread of COVID-19 in the world, China has donated protective equipment and diagnostic kits to some countries that are severely affected, and the updated Chinese guidelines for diagnosis and treatment of COVID-19 have been translated to other languages like Farsi to help Iran and other countries in need.

The war against COVID-19 is ongoing. Collaborations should be established between countries at different stages of the outbreak, with mutual support on medical supplies and joint efforts on scientific research. International communities need to pull together to eliminate discrimination and enhance international cooperation among countries, governments, officials, and professionals to fight the epidemic.

Shiqiu Meng 1, Yanping Bao 1, Yankun Sun 2, Jie Shi 1, Lin Lu 1,2*

1 Peking University Health Science Center, Peking University, Beijing 100191, China
2 Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China
3 Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100191, China

Corresponding author: Prof. Lin Lu, email: linlu at bjmu.edu.cn

References

Competing interests: No competing interests

09 March 2020
Shiqiu Meng
Assistant Professor
Yanping Bao, Yankun Sun, Jie Shi, Lin Lu
Peking University Health Science Center
38 Xueyuan Road, Haidian District, Beijing 100191, China
Re: Preventing a covid-19 pandemic
Dear Editor

I read with interest the article by J. Watkins [1], which presents a point of importance towards the need of “catch and isolate” for people who may be suspected of having contracted covid-19. There appears to be increasing fear among people that the chance of being severely unwell if they caught the virus is rapidly increasing. Whilst the spread is showing little signs of slowing down, people are taking precautionary measures to maintain their own self-protection. These measures include actively practicing improved handwashing techniques, the wearing of protective equipment (such as face masks) and limiting their contact with other people while outside their own homes. However, there are instances where people are taking these protective measures against covid-19 to an extreme level. As a student in a secondary school, I have witnessed debate by students and their families around school closure, or whether children should be taken out of school in order to limit their contact with other students. However, with the exams season rapidly approaching, such drastic action would severely affect students who are due to take GCSE, A-level or other academic exams, all of which will have huge impacts on their future opportunities. Students self-isolating themselves from school will most likely result in poor performance in their exams as a result. All this is despite the fact that most schools have increased measures in place to monitor the health of students as a result of this virus, raise awareness of the need for regular handwashing and self-protection, and of the importance of notifying the school if they begin to feel unwell. Parents and students need to realise that covid-19 only has a 1% chance of death according to some authorities [2] and that, provided their children are fit and healthy, they are highly likely to only experience flu-like symptoms if they contract it [3]. As a result, the consequences of students performing poorer in their exams due to self-isolation or the closure of schools will likely be worse than the consequences of remaining in school, especially as poor exam results will turn into denied opportunities to universities and reduced options for future careers. Therefore, awareness of this needs to be presented to parents and students in school to allow them to make a reasoned decision on whether the needs of self-isolation are necessary or not.

[1] Watkins, J. Preventing a covid-19 pandemic. BMJ 2020, 368:m810
[2] https://www.bbc.co.uk/news/health-51674743 - “Researchers currently think that between five and 40 coronavirus cases in 1,000 will result in death, with a best guess of nine in 1,000 or about 1%.”
[3] https://www.health.harvard.edu/blog/as-coronavirus-spreads-many-question...
- Most people who get sick will recover from COVID-19. Recovery time varies and, for people who are not severely ill, may be similar to the aftermath of a flulike illness.

Competing interests: No competing interests

08 March 2020
Rhys Thornett
Student
United Kingdom
Re: Preventing a covid-19 pandemic
Dear Editor,

John Watkin's editorial is timely and on the money. His description of responses to previous outbreaks of viral disease overlooks one piece of evidence, which I think could help in focusing mass-containment strategies (such as in Northern Italy just now) and in monitoring diseases in which so many people have sub-clinical disease. I refer to the polio outbreak in 2014 in Israel(1). There was only one clinical case, but by detecting polio virus in sewage outfalls, the authorities were able to determine that there was an outbreak among the Bedouins and eradicate it by carrying out mass vaccination in just that area, without any paralytic sequelae.

As Covid-19, in common with polio and many other viruses, is excreted in faeces, couldn't our authorities monitor sewage outfalls for Covid-19 virus RNA. It would become apparent if and when containment had failed, well before waiting for 'sporadic' clinical disease to come to their attention and if containment is still deemed feasible, it would help determine where to draw lines when determining exactly which areas would need restricted movement. It has the potential to be a sensitive advanced indicator of when the disease is responding or not to measures instituted and when to change strategy from containing the outbreak to delaying spread. It would do so requiring many fewer tests than mass screening.

1. Epidemiology of the silent polio outbreak in Rahat, Israel, based on modeling of environmental surveillance data. Brouwer AF, Eisenberg JNS, Pomeroy CD, Shulman LM, Hindiyeh M, Manor Y, Grotto I, Koopman JS, and Eisenberg MC. PNAS 2018; 115 (45): E10625-E10633.

Competing interests: No competing interests

08 March 2020
Wayne Sunman
Consultant Physician
Nottingham University Hospitals NHS Trust
Ivy Cottage, Main Street, Epperstone, Nottingham NG14 6AU

Re: Preventing a covid-19 pandemic – Cobbold

Dear Editor,
As we approach a time when retired health professionals are invited to rejoin their younger colleagues would it not be wise to offer them protection from the novel corona virus ? Dr Rhein highlights the 2017 BMJ study on D3 by Martineau et al and the safety of dosing with 100ug D3 per day (=4000 IU). The text below has been submitted to a national broadsheet paper. Supplies of D3 are likely limited and D2 may not be an effective subsittute. The vast majoriity of UK elderly fail to reach physiological levels of 25(OH)D3 so bolus dosing may be needed by those older volunteers to endow them with an effective defense form the virus.
COVID-19 and D3
As a 75 year old cell biologist with impaired health I know I have an unacceptable existential risk from COVID-19. I supplement with vitamin D3. To understand why, we need to look into the biology of this hugely important hormone.
Amongst the 5000 research articles published annually on vitamin D3 is one common feature, for the past decade they mostly begin with “The secosteroid hormone D3.....”. As a hormone D3's natural, physiological blood level can be defined scientifically. There is interminable debate by health bodies globally about the correct blood level and how much D3 is needed in diet and from sunlight. The overarching importance of the physiological level of this hormone is still being lost to the persisting, out of date, assumption that D3 is a vitamin whose dosage can be determined as if D3 were a drug. D3 is not a drug whose minimally effective dose governs the debate. That approach risks advising too little, leaving us deficient. D3 is a hormone with a 400 million year evolutionary history which exerts a broadly defensive role in almost every cell in our body by controlling the expression of 2000 genes, one in ten of our genome. The physiological blood level of D3, which is measured routinely as 25(OH)D3, has been determined by several criteria to be 100 to 125 nmol/l (“ nano moles per litre”, a unit of concentration). This talk by the late Professor Robert Heaney MD describes how he and a committee of experts defined the physiological level:
https://ucsd.tv/search-details.aspx?showID=29077
There are key pointers in the literature that I am raising my blood D3 level high enough to protect from the corona virus that causes COVID-19. There are many clinical trials of supplementing with D3 that have failed to influence 'flu. I place especial emphasis on two 'flu studies in which serum 25(OH)D3 met the physiological criterion of 100 to 125 nmol/L.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463890/
“A colleague of mine and I have introduced vitamin D at doses that have achieved greater than 100 nmol/L in most of our patients for the past number of years, and we now see very few patients in our clinics with the flu or influenza like illness.”
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011088
“Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections significantly....”
(38 ng/ml is 100 nmol/L and physiological )
We have a pretty good idea of how D3 combats microbes. One action is to promote production of anti-microbial peptides, including cathelicidin and defensins, that attack the membranes of bacteria, fungi and enveloped viruses, and kill them. Influenza and corona viruses are enveloped. The COVID-19 virus is unlikely to avoid these defences, but the lack of lab' data on this new virus offers a loophole to cautious authorities.
My remaining question was: am I taking enough D3 supplements to reach that physiological blood level? The literature points to around 2000 International Units per day of D3, or maybe 4000 IU pd for the elderly who take it up less well from the gut. Sunbathing before May in UK wont make significant D3. Dietary intake in UK averages merely 200 IU pd. A tin of sardines including the oil contains about 2000 IU. Unfortunately there is a snag: it takes 2 to 3 months for the blood level to fully stabilise after boosting uptake. So blood D3 rises too slowly to help anyone infected in the next month, even if supplements started now. Bolus administration is feasible under medical advice. Of course, supplementing D3 is not a substitute for the hygiene and social measures advised by the governments.

Competing interests: No competing interests

08 March 2020
Peter H Cobbold
Emeritus Professor, Cell Biology
University of Liverpool, UK
North Wales

individuals' defence better if supplied with sufficient vitamin D – Rhein

Dear Editor

In this interesting collection of rapid responses others have already pointed out, that vitamin D could be helpful, I can only agree.

If avoiding vitamin D deficiency can prevent respiratory infections, as shown by a meticulous meta-analysis, published in the BMJ in 2017 (1) , which was called “magic bullet” by a reviewer (2), then, wouldn’t there be a realistic chance that sufficient vitamin D could also help in the Corvid-19 pandemic? Maybe more people could be in the mild category, less in the severe. Indeed there is ample opportunity in the UK to treat vitamin D deficient people, as we have a very high prevalence, worst in Scotland, due to latitude, one third of the population here has severe deficiency, in some areas nearly 50% (3). I encountered many vitamin D deficient patients in our GP practice (4).

I think everyone would be wise to take a supplement, as has been advised by the UK health authorities anyway, although only for bone health reasons. It might be wise to take a slightly larger dose than the NHS recommended 10 mcg (good for babies, but not for a much larger adult). It is safe, cheap, up to 100 mcg daily is acceptable. Others, in Finland, have implemented population wide food fortification in recent years.

Shouldn’t we remind the public of taking a vitamin D supplement now?

  • 1. Martineau AR,Jolliffe DA, Hooper RL et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583
  • 2. Mellis C. Journal of Paediatrics and Child Health 53 (2017) 722–723 723 © 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
  • 3. Food Standards Agency in Scotland. Vitamin D status of Scottish adults: Results from the 2010 & 2011 Scottish Health Surveys . Purdon G, Comrie F, Rutherford L, Marcinkiewicz A. September 2013
  • 4. Rhein HM. Vitamin D deficiency is widespread in Scotland. BMJ 2008;336 June 28

Competing interests: No competing interests
06 March 2020
Helga M Rhein
retired GP
previous Sighthill HC, 380 Calder Road, Edinburgh EH11 4AU


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