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:m810Read our latest coverage of the Coronavirus outbreak
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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
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).
Dear Editor
It’s well established that the Sars-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE2) as its host cell receptor (1). Because we see an increased risk of death in patients who are likely to take angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACE-I), Sommerstein suggested that the overexpression of the ACE2 receptors associated with these drugs might play a role in the severity of the Coronavirus disease 2019 (Covid-19) (2). While cardiologists have already advised against the discontinuation of ACE-I or ARB 2 based on the lack of evidence, there are other pathways to regulate the expression of ACE2 receptors.
Albumin downregulates the expression of the ACE2 receptors (3) and has been shown to improve the ratio of arterial partial pressure of oxygen/fraction of inspired oxygen in patients with acute respiratory distress syndrome as soon as 24 hours after treatment and with an effect that persisted for at least seven days (4). Moreover, researchers who have studied the clinical characteristics of Covid-19 patients have reported again and again that lower serum albumin levels were associated with an increased risk of death, even to suggest that “albumin therapy might be a potential remedy”(5).
In spite of these facts, currently, there are no clinical trials registered in ClinicalTrials.gov looking at the effect of albumin in Covid-19 patients nor indications of the use of albumin in the general guidelines developed by most countries to deal with the infection. The purpose of this letter is to emphasize the importance of studying the potential effects of albumin in the clinical outcomes of Covid-19 patients.
References
1. Hoffmann M, Kleine-Weber H, Krüger N, Mueller MA, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv. 2020;(368:m810).
2. Sommerstein R. Re: Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19 | The BMJ [Internet]. BMJ. 2020 [cited 2020 Mar 30]. p. 368:m810. Available from: https://www.bmj.com/content/368/bmj.m810/rr-2
3. Liu BC, Gao J, Li Q, Xu LM. Albumin caused the increasing production of angiotensin II due to the dysregulation of ACE/ACE2 expression in HK2 cells. Clin Chim Acta. 2009 May 1;403(1–2):23–30.
4. Uhlig C, Silva PL, Deckert S, Schmitt J, De Abreu MG. Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: A systematic review and meta-analysis. Crit Care [Internet]. 2014 Jan 9 [cited 2020 Mar 30];18(1):R10. Available from: http://ccforum.biomedcentral.com/articles/10.1186/cc13187
5. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364–74.
Competing interests: No competing interests
To use or not to use Renin Angiotensin Aldosterone System blocking agents in the setting of COVID-19 pandemic
Dear Editor,
Use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been suggested as likely hazardous and predisposing to CoVID-19 infection [1]. On the other hand, some other studies suggested somewhat the opposite and proposed that ARBs maybe beneficial for controlling COVID-19 infection [2].
The SARS-CoV-2 enters the cell via the angiotensin-converting enzyme 2 (ACE2) [3] and ACE2 facilitates the invasion of SARS virus for rapid replication [4]. Administration of ACEIs and ARBs causes increases in ACE2 expression [5]. Hence, it is plausible that use of ACEIs and ARBs may ease internalization and thus the virulence of the SARS-CoV-2.
In the course of SARS-CoV-2 infection, ACE2 is depleted with its internalization into the host cell with the virus and by also the decreased ACE2 expression with the virus effect [4]. This causes shift of the ACE/ACE2 balance to a predominant ACE/Angiotensin (Ang)II/AT1 axis signaling. Physiologically, angiotensinogen is mainly synthesized in the liver and renin converts angiotensinogen to the decapetide AngI. AngI is either converted to the octapeptide AngII by ACE or to Ang (1-9) by ACE2 through clevage of one aminoacid. ACE2 also acts to cleave an amino acid from AngII to form angiotensin (1-7) [6]. The Ang1-9 produced by ACE2 is also converted to Ang (1-7) with the action of ACE [7]. Thus, the ultimate product of ACE2 system is Ang (1-7) and it exerts its effect throgh Mas signaling/activation causing the anti-inflammatory, vasodilatory effects of ACE2.
With infection with the SARS-CoV-2 virus, as a shift occurs from the ACE/ACE2 balance to predominant ACE/AngII/AT1 axis signaling, Ang (1-7) decreases and the environment is left available for the deleterious effects of AngII through the AT1 receptor. AngII causes pulmonary vasoconstriction, and inflammatory, oxidative organ damage, ultimately progressing towards acute lung injury and acute respiratory distress sydrome [8]. Moreover, ACE is under promoter regulation by hypoxia-inducing factor 1α that upregulates the ACE expression under hypoxic conditions, resulting in an increase in Ang II concentration during the respiratory distress [4]. Hence, hypoxia induces ACE while decreases ACE2.
The utilization of the expressed ACE2 with the COVID-19 virus, reduced ACE2 cellular expression and also the hypoxia induced changes, they, all cause depletion of ACE2 and its effects in the COVID-19 infection and augment the effects of AngII. In this setting, ACEIs would decrease AngII levels by inhibiting production of AngII from AngI and ARBs would decrease the deleterious effect of AngII by blocking the AT1 receptors. Therefore, ACEIs and ARBs maybe beneficial either by decreasing the production or effect of AngII, respectively. Of note, ACEIs decrease breakdown of the bradykinin and result in increased levels of bradykinin. Bradykinin is known as one of the actors that potentiate the systemic inflammation response syndrome causing some detrimental consequences of the COVID-19 infection [9,10]. Therefore, accumulation of bradykinin by the effect of ACEIs may be hazardous at this point. Therefore, blocking the AngII effect by ARBs without increasing the amount of bradykinin may be advantageous over the ACEIs in the infection setting.
As an overview, ARBs may increase susceptibility for SARS-CoV-2 infection in naive individuals by increasing ACE2 expression whilst in the course of infection ARBs could mitigate the pathophysiological deleterious effects of the disease by blocking the harmful effects of Ang II. It is currently unknown whether decreasing the effects of Ang II while still possibly augmenting SARS-CoV-2 entry and infectivity on the host cell could be beneficial to the host or not. This point is much debatable. It is known that ACE2 is also the cellular receptor for SARS-CoV [11]. The comparative and adjusted analyses of the individuals that had and had not been infected with SARS-CoV may provide insight if ACEIs and ARBs makes susceptibility for the SARS-CoV and SARS-CoV-2 infections. Similar analyses for outcome measures of the SARS-CoV infection among the patients with and without ACEIs and ARBs can aid the clinicians in the COVID-19 disease setting.
Strikingly, there is a moving on pandemic over the globe with an increasingly high death toll [12]. Therefore, taking the risk of possible greater infectivity by ARBs should be compared and considered with the possible favourable effects of ARBs on the COVID-19 disease’s pathophysiological course. ACEIs/ ARBs may be used for the treatment of hypertension only or for some additional/other strong cardiovascular indications. It may be suggested that in the non-infected individuals without strong cardiovascular indications for ARBs or ACEIs, preference for not using ARBs or ACEIs, may perhaps be a better and leery choice in order to prevent susceptibility to this deadly infection especially in patients with higher risk of COVID-19 associated adverse outcomes.
References
1.https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext?fbclid=IwAR2rsO78vs1dezPxYwVsXf4LiAQKGKAo_HKcor4h5vc-Ukup2SLS-c4tbsQ
2. https://www.bmj.com/content/368/bmj.m406/rr-19
3. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-273.
4. Wong M. Angiotensin Converting Enzymes. Handbook of Hormones. Comparative Endocrinology for Basic and Clinical Research. 2016, 263-265, e29D-1-e29D-4. https://doi.org/10.1016/B978-0-12-801028-0.00254-3
5. Sukumaran V, Veeraveedu PT, Gurusamy N, Yamaguchi K, Lakshmanan AP, Ma M, Suzuki K, Kodama M, Watanabe K. Cardioprotective effects of telmisartan against heart failure in rats induced by experimental autoimmune myocarditis through the modulation of angiotensin-converting enzyme-2/angiotensin 1-7/mas receptor axis. Int J Biol Sci. 2011;7:1077-92.
6. Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002; 277:14838.
7. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87:E1-9.
8. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit Care. 2017;21:305.
9. Nicola H. The role of contact system in septic shock: the next target? An overview of the current evidence. J Intensive Care. 2017;5:31.
10. https://www.bmj.com/content/368/bmj.m406/rr-23
11. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450-4.
12. https://www.who.int/docs/default-source/coronaviruse/situation-reports/2...
Competing interests: No competing interests
Dear Editor,
The implementation of Angiotensin II - AT1R axis in COVID-19 treatment: a potentially promising approach
The COVID-19 outbreak with an increasing mortality and an enormous socioeconomic impact calls for immediate action. Below we propose an evidence-based approach that is based on taking into consideration Angiotensin II – Angiotensin II Receptor I (AT1R) axis in handling COVID-19 patients.
First, the novel SARS-coronavirus 2 (SARS-CoV-2) which is the etiologic agent of COVID-19 shares the same cell receptor with SARS-CoV. The 2019-nCoV spike (S) glycoprotein binds to the host’s cell membrane protein called angiotensin converting enzyme 2 (ACE2)(1). ACE2 is a negative regulator of renin-angiotensin axis, by diminishing angiotensin II levels.
Second, it has been shown that blocking renin-angiotensin axis protects from acute lung injury due to SARS-CoV infection (2). Infection with SARS-CoV reduced ACE2 levels in the lung that in turn was associated with severe lung injury. Pharmacologic inhibition of AT1R attenuated lung failure in ACE2 knockout mice, suggesting that Angiotensin II drives lung injury through AT1R. Exogenous administration of recombinant ACE2 ameliorated acute lung injury in ACE2 knockout mice. Within this context, there is an ongoing phase II clinical trial phase by APEIRON Biologics AG, employing a recombinant human ACE2 to treat Coronavirus infected patients in the Republic of China: https://pipelinereview.com/index.php/2020022673884/Proteins-and-Peptides...
Third, ACE2 deficiency could protect from lung injury due to RSV infection mainly via its action on AT1R (3). Interestingly, RSV pediatric patients exhibited increased plasma angiotensin II levels versus healthy children. Along this line H7N9-infected patients exhibited significantly elevated plasma angiotensin II levels versus matched uninfected normal and individuals with coronary heart disease and hypertension (4). The kinetics of angiotensin II levels revealed a sharp decrease in patients hospitalized less than 28 days, whereas the levels of angiotensin II rise both in patients hospitalized for a longer period and patients that died. To provide a mechanistic insight the same group demonstrated in vivo that ACE2 deficiency worsened H7N9-induced lung injury through angiotensin II – AT1R axis (5). These data come in line with the fact that circulating angiotensin peptides have a prognostic value in Acute Respiratory Distress Syndrome (ARDS) patients (6). Of note, it was recently demonstrated that COVID-19 patients exhibited elevated angiotensin II levels and this is correlated with reduced PaO2/FiO2 levels and elevated viral load (7).
Fourth, a meta-analysis concluded that treatment with angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) is related to a decreased risk of pneumonia associated mortality (8). Along this line, a retrospective analysis including 215,225 patients with hypertension highlights the protective effect of prolonged treatment with ARB and ACEi, by delaying or reducing the infectious, inflammatory and structural pulmonary outcomes (9).
Fifth, men have higher levels of renin than women in a normotensive population (10). Given that renin up-regulates angiotensin II – AT1R axis, this finding may be relevant with the recently described higher crude fatality ratio in men versus women (4.7% versus 2.8%) among COVID-19 patients (11).
Altogether the above evidence underline the important role of Angiotensin II – AT1R axis in lung injury due to lethal viral infections. Hence this route in COVID-19 treatment may have an added value both predictively and therapeutically. Based on initial screening of plasma angiotensin II levels in COVID-19 patients, high plasma angiotensin II status could provide a strong rationale to block angiotensin II – AT1R axis in order to ameliorate lung injury.
Assessment of plasma levels of angiotensin II in individuals tested positive for SARS-CoV-2 could rapidly stratify patients according to disease severity. To define the cut-off level for decision making we should take into consideration the following: a) a significant percentage of hospitalized COVID-19 patients are elderly with accompanying cardiovascular diseases, b) a rise of plasma angiotensin II levels at week 2 in H7N9 patients predicts worse prognosis, c) the respiratory symptoms may worsen suddenly; this often occurs in the second week of COVID-19. Besides, regular clinical evaluation of COVID-19 patients could help determine at which levels of plasma angiotensin II levels ARB administration would be of critical importance. Importantly, the kinetics of plasma angiotensin II during hospitalization should be taken into account, since a constant rise of plasma angiotensin II levels should be considered a dismal prognostic sign. Additionally monitoring plasma angiotensin II levels on a regular basis is important to foresee the sudden worsening of COVID-19 patients with rapid respiratory deterioration.
To dampen angiotensin II – AT1R axis the administration of ARB is an approved approach for over 20 years. ARB are highly selective for AT1R. Importantly, ARB beyond lowering blood pressure have rapid anti-inflammatory properties. In the context of increased CRP levels as a common finding in patients with confirmed COVID-19 pneumonia (12) ARB administration has an additive value.
At the time of writing this brief response two commentaries related to angiotensin II - AT1R axis and COVID-19 infection were published. The first one by Gurwitz D (13) supports the implementation of ARB as tentative therapeutic strategy. This study raises the necessity to look into clinical patient records and examine whether COVID-19 patients treated with ARB prior to diagnosis have a better outcome. The second one suggested that individuals treated with drugs raising ACE2 levels including ARB may be at a higher risk for COVID-19 infection since COVID-19 uses ACE2 to enter host cells (14). Along this line, there are limited data demonstrating that ACE2 expression patterns vary among the general population (15,16). RNAseq analysis in the human lung depicted that Asian males have higher levels of ACE2-expressing cells than white and African-America donors; however, the small sample number and the absence of protein examination are major limitations (15). Whether ACE2 expression levels may define different susceptibility groups remains to be clarified. However, in our case angiotensin II screening and ARB repurposing refers only to COVID-19 hospitalized patients and does not apply to the general population despite the potential prophylactic effect of ARB in pneumonia-associated pathology (9).
Altogether, given that the number of COVID-19 patients is rising quickly across the world, an efficient biomarker for risk-stratification allowing also a lung injury minimizing therapeutic approach would be of significant value. Besides we should not underestimate that the COVID-19 outbreak is stretching healthcare systems beyond their limit, providing an additional argument for such an approach. Hence we propose that, angiotensin II screening and ARB repurposing in COVID-19 hospitalized patients should be seriously taken into consideration in this critical situation.
Ioannis S Pateras 1 and Agis D Tsouros 2,3
1 Laboratory of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi 11527, Athens, Greece (ipateras@med.uoa.gr); 2 Centre for Health Leadership and Practice, Thiras 4, Athens 11257, Greece; 3 Laboratory of Health Economics & Management (LabHEM), Economics Dept., University of Piraeus (tsouros@gmail.com).
Conflict of interest
The authors declare no conflict of interest.
References
(1) Walls AC, Park YJ, Tortorici MA, Wall A, McGuirre AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020 DOI: 10.1016/j.cell.2020.02.058.
(2) 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: 875-879.
(3) Gu H, Xie Z, Li T, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep. 2016; 6: 19840. DOI: 10.1038/srep19840.
(4) Huang F, Guo J, Zou Z, et al. Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients. Nat Commun. 2014; 5:3595. Doi: 10.1038/ncomms4595.
(5) Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep 2014; 4: 7027.
(6) Reddy R, Asante I, Liu S, Parikh P, Liebler J, Borok Z, Rodgers K, Baydur A, Louie SG Circulating angiotensin peptides levels in Acute Respiratory Distress Syndrome correlate with clinical outcomes: A pilot study. PLoS One. 2019 Mar 7;14(3):e0213096. doi: 10.1371/journal.pone.0213096. eCollection 2019.
(7) Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, Wang Z, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Science China Life Sciences 2020; 63: 363-374.
(8) Caldeira D, Alarcão J, Vaz-Carneiro A, Costa J. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis BMJ 2012; 345:e4260.
(9) Soto M, Bang SI, McCombs J, Rodgers KE. Renin-angiotensin system-modifying therapies are associated with improved pulmonary health. Clin Diabetes Endocrinol 2017; 3: DOI: 10.1186/s40842-017-0044-1.
(10) James GD, Sealey JE, Müller F, Alderman M, Madhavan S, Laragh JH. Renin relationship to sex, race and age in a normotensive population. J Hypertens Suppl. 1986 Dec;4(5):S387-9.
(11) Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19), 2020. P12
(12) Zhou S, Wang Y, Zhu T, Xia L. CT features of coronavirus disease 2019 (COVID-19) pneumonia in 62 patients in Wuhan, China, AJR Am J Roentgenol. 2020:1-8. DOI: 10.2214/AJR.20.22975. [Epub ahead of print]
(13) Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Disc Res 2020 DOI: 10.1002/ddr.21656.
(14) Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Resp Med 2020 https://doi.org/10.1016/PII.
(15) Zhao Y, Zhao Z, Wang Y, et al. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov bioRxiv; DOI: https://doi.org/10.1101/2020.01.26.919985.
(16) Cao Y, Li L, Feng Z, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020; 6: Doi: 10.1038/s41421-020-0147-1. eCollection 2020.
Competing interests: No competing interests
Dear Editor,
Older age and cardiovascular (CV) diseases are very common among patients admitted to intensive care units or dying from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). Many of these patients are treated with angiotensin-converting-enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB), very effective in reducing blood pressure and CV events. The ACE2, a metallocarboxypeptidase with homology to ACE, is the receptor for SARS-CoV-2 [1] and, thus, ACE-I and ARB, given their capacity to increase ACE2 levels, have been accused to possibly increase the likelihood of lung infection.
Indeed, some authors [2] speculated that the increased ACE2 expression, linked to ACE-I and ARB treatment, could promote the spread and severity of COVID-19 and they even hypothesized to replace such drugs with other anti-hypertensive agents. We think that this simple deduction is not supported by experimental data and could even be dangerous, leading to higher rates of CV deaths, especially in older COVID-19 patients with acute medical conditions, in which CV comorbidities are likely to strongly affect mortality [3].
On the contrary, a protective role of ACE-I and ARB against the aggressiveness and mortality from SARS-CoV-2 infection might be hypothesized, given the peculiar protective action of the ACE2-Angiotensin (Ang) 1-7-Mas axis on the lung. ACE2 cleaves Ang I into a nonapeptide (Ang 1–9), that binds Ang II type 2 receptor (AT2R), and Ang II into Ang 1–7, that binds an endogenous orphan receptor (MasR), thus playing a central role in counterbalancing renin-angiotensin-aldosterone-system (RAAS) activation. While the activation of ACE-Ang II-Ang II type 1 receptor (AT1R) axis induces vascular permeability, inflammation and lung fibrosis, previous studies found that ACE2-Ang 1-7-MasR axis can protect lungs from the development of acute respiratory distress syndrome (ARDS) in several animal models, through opposite mechanisms [4]. The binding of the viral surface-spike protein to ACE2 leads to its downregulation with a consequent hyperactivation of RAAS, which contributes to lung injury.
This process is attenuated by RAAS blockers, especially ARB, through reduction of Ang II-AT1R stimulation, increase in Ang II substrate, and increase in ACE2, leading to a larger increase in Ang 1-7 [5]. Therefore, CV patients should safely continue to take these drugs also in the context of the pandemic COVID-19 outbreak, as also recently stated by several Scientific Societies (ESC council on Hypertension and HFSA/ACC/AHA).
REFERENCES
1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020 doi: 10.1016/j.cell.2020.02.052
2. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory medicine 2020 doi: 10.1016/S2213-2600(20)30116-8
3. Spannella F, Giulietti F, Balietti P, et al. Renin-Angiotensin System Blockers and Statins Are Associated With Lower In-Hospital Mortality in Very Elderly Hypertensives. Journal of the American Medical Directors Association 2018;19(4):342-47. doi: 10.1016/j.jamda.2017.09.023
4. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436(7047):112-6. doi: 10.1038/nature03712
5. Shen L, Mo H, Cai L, et al. Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases. Shock 2009;31(5):500-6. doi: 10.1097/SHK.0b013e318189017a
Competing interests: No competing interests
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@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
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Competing interests: No competing interests
Dear Editor
A remarkable percentage of patients who initially died in Wuhan from Coronavirus (COVID-19) infection with lung injury had been treated for arterial hypertension.
There is no effective treatment strategy for COVID-19 available.
Recently, it was published, that inhibition of clathrin-mediated endocytosis (inhibition of viral infection) and compounds targeting the numb-associated kinase (NAK)-family, as well as JAK-STAT signalling inhibitors (baricitinib, fedratinib, ruxolitinib) for attenuation of inflammation, might be beneficial (1). Recently, ACE inhibitors were hypothesized as a potential risk factor for fatal COVID-19 (2).
Retrospective analysis of SARS-Coronavirus patients suggested that inhibition of the renin-angiotensin system may reduce mortality (3).
It has also been demonstrated that the SARS-Coronavirus binds to the angiotensin converting enzyme 2 (ACE2, a monocarboxypeptidase) to be internalized into the cells where it replicates; the ACE2 expression on the cell surface is downregulated (4).
Since ACE2 normally cleaves angiotensin I (Ang I, decapeptide 1-10) into Ang-(1-9) nonapeptide, this downregulation of ACE2 leaves more Ang I available to the main metabolisation pathway catalysed by the angiotensin converting enzyme 1 (ACE1 or simply ACE, a dicarboxypeptidase) (Fig. 1 http://covid-19-and-ras.ch/ReninSystemCOVID-19-Figure1f.pdf ). ACE 1 converts Ang I into Ang II [octapeptide-(1-8)] and Ang II is a substrate to build smaller Ang peptides (1-7, 3-8,…). Lung injury in SARS is specifically mediated by ACE2, and increased Ang II levels were measured in the lungs of SARS-challenged mice (5). Several Ang peptides and receptors may contribute to this lung injury: Ang II via AT1 and AT2 receptors or Ang-(1-7) via the Mas receptor that forms a heterodimer ("sibling receptor") with the bradykinin BK2 receptor well known for causing angioedema including considerable vascular leakage. Signaling of the heterodimer is activated by both specific ligands i.e. by Ang-(1-7) for MasR and by bradykinin nonapeptide for BK2R (6).
The clinically used ACE1-inhibitors (type captopril, enalapril,…) not only cumulate bradykinin but also enhance renin activity and therefore Ang I and Ang-(1-7) levels. The latter is also true for angiotensin receptor blockers like losartan. Any lowering of blood pressure itself also stimulates renin activity. It is unknown which Ang peptide may do harm in the Coronavirus patients, but it would necessarily be a metabolite of Ang I.
Therefore, we propose for COVID-19 patients to prevent Ang I formation by direct blockade of renin with the specific inhibitor aliskiren. This avoids any harmfully increased angiotensin levels and takes care of hypertension.
Paul Mohacsi; CardioVascular Center Zurich, Clinic im Parc (Hirslanden), Seestrasse 247, CH-8038 Zurich, Switzerland; email: paul.mohacsi@hirslanden.ch
Jürg Nussberger; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
References
1) Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, Richardson P.COVID-19: combining antiviral and anti-inflammatory treatments : thelancet.com/infection PublishedonlineFebruary27,2020 https://doi.org/10.1016/S1473-3099(20)30132-8
2) Sommerstein R, Gräni C. Preventing a Covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ 2020; 368 doi: https://www.bmj.com/content/368/bmj.m810/rr-2
3) Kim J, Choi SM, Lee J, Park YS, Lee CH, et al. Effect of renin-angiotensin system blockade in patients with acute respiratory distress syndrome: a retrospective case control study. Korean J Crit Care Med 2017; 32: 154-63
4) Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, et al. Angiotensin-converting enzyme 2 is a functional receptor for SARS coronavirus. Nature 2003; 426: Nov 27 2003, https://doi:10.1038/nature02145
5) Kuba K, Imai Y, Rao S, Gao H, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Medicine 2005; 11: 875-79
6) Cerrato BD, Carretero OA, Janic B, Grecco HE, Gironacci MM. Heteromerization between the bradycinin B2 receptor and the angiotensin-(1-7) Mas receptor: functional consequences. Hypertension 2016; 68: 1039-48
Competing interests: No competing interests
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
Covid 19, Vitamin D deficiency, Smoking, Age and Lack of Masks Equals the Perfect Storm
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.
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