Over the past year, scientists across the globe have conducted extensive research to try and understand the pathophysiology of COVID-19. At present, we do not have an effective cure, but our knowledge continues to grow regarding potential genetic factors, lifestyle choices or exposures that may influence our likelihood of becoming infected with SARS-CoV-2 and the severity of the subsequent COVID-19 disease.
Researchers from the University of Edinburgh have been exploring the role that the sun's rays may play. Dr Richard Weller – consultant dermatologist and reader at the university – is part of the research team behind a new observational study. Published in the British Journal of Dermatology this study investigated whether sunlight might affect COVID-19 mortality, using a sample incorporating several different countries: The United States, Italy and England.
The researchers found that sunnier areas are associated with fewer deaths from COVID-19. The reduction in risk of death observed in the study was found to be completely independent from vitamin D levels; the work only incorporated countries in which the level of UVB light was not high enough to form vitamin D in the timeframes analyzed.
Technology Networks interviewed Weller to learn more about the rationale behind the study and how its data can be utilized for public health. Weller acknowledges that the study is observational and thus has associated limitations, but he is certain there is more work to be done in this area to unravel this apparent relationship.
Molly Campbell (MC): Why did you decide to investigate whether a link exists between sunlight and COVID-19 deaths?
Richard Weller (RW): Chris Dibben and I have previously studied the effects of sunlight on cardiovascular disease and, working independently, have both shown that higher sunlight levels correlate with lower blood pressure and rates of myocardial infarction. This effect is independent of temperature and vitamin D, which have usually been used to explain such things, as the well-known summer reduction in population blood pressure and myocardial infarctions. As data became available showing that cardiovascular disease was an adverse risk factor for dying from COVID-19, and also knowing that many respiratory diseases such as influenza are seasonal, we wondered if sunlight might affect COVID-19 mortality.
MC: Can you talk about the covariates that had to be assessed in the study, and why it was important to consider them?
RW: This is an observational study, and robust correction for covariates is essential for it to be valid. The greatest part of the work involved was to ensure that this had been done.
To die of COVID-19 a number of steps must occur. You must encounter someone with COVID-19, catch it, become unwell, not respond to treatment and ultimately die. Each of these steps will be affected by different confounders and was handled by different parts of our model.
Our first study was performed in the contiguous US, where data is collected at county level (just over 3,000 counties). We could cross reference all our data at county level and corrected for risks of catching COVID-19 by including factors such as population density, proportion of population with COVID-19 infections and the use of public transport.
Your risk of dying from COVID-19 is then heavily influenced by age and ethnicity, but also by socio-economic factors (for example, poverty) and environmental factors for air pollution. These were thus also included in the model.
We then included a random effect for higher level administratively important factors. In our American analysis this was done at state level to account for any bias that might occur due to state level policy, funding or health care delivery factors. The study was repeated in Italy and England. These confounders are recorded in different ways in each country, so we ran independent analyses. In effect, this is three different studies. Our units of analysis (small area and higher level) also varied by each country: USA, County/State; Italy, Municipality/Province; England, Middle Layer Super Output Area/Upper Tier Local Authority). We measured UV from satellite data, recording both energy and wavelength of UV, but also included temperature and humidity in the model.
MC: What biological factors might be behind the reduction in mortality observed?
RW: This is a vitamin D-independent effect. Vitamin D is made by UVB wavelength of sunlight, and we excluded from the study counties where there was UVB of high enough energy to form vitamin D. Our American analysis (from January to April 2020) was thus restricted to the 2,474 out of 3,143.
As the study is observational, other than saying that this is not a vitamin D effect we can only speculate as to biological mechanisms. One possibility, however, is that this is a nitric oxide (NO) effect. We have previously shown that UVA releases NO from stores in the skin to the circulation (accounting for the fall in blood pressure and cardiovascular disease with sunlight).
Laboratory studies have shown that NO prevents the replication of SARS-CoV-2, and also prevents the post-translational modifications (myristolation) needed for the SARS-CoV spike protein to bind to the angiotensin-converting enzyme 2 (ACE2) receptor. There are over 20 trials of NO for the treatment of COVID-19 currently registered on clinicaltrials.gov, and we suspect that sunlight might deliver this environmentally. There may also be a non-specific benefit of sunlight, as it reduces cardiovascular risk factors. Unfortunately, the dermatology world has been so fixated on the adverse effects of sunlight (skin cancer) that very little work has been done looking at other UV driven mechanisms which I am sure remain to be discovered.
MC: For our readers that may be unfamiliar, can you talk about how UVA radiation induces the release of nitric oxide, and why this is relevant to the study findings?
RW: The classical method of NO production involves the oxidation of L-arginine to citrulline with release of NO, catalyzed by one of the NO synthase enzymes. The alternative, and more recently described pathway, is via reduction of nitrate to nitrite and then NO. Nitrate is very stable, but nitrate reductases can carry out the first step of this reduction. Nitrite is more readily reduced to NO in anoxic or low pH conditions. Professor Martin Feelisch made the important discovery that, in the presence of thiols, UV radiation can photochemically reduce nitrate to NO without any enzymes. I had previously shown that the skin contains large stores of nitrate, nitrite and also nitrosothiols and the skin thus brings together these NO storage forms, thiols (in structural proteins) and also UV. Working in parallel, myself and Professor Christoph Suschek in Germany then showed that UV irradiation of skin releases NO to the systemic circulation, where it lowers blood pressure.
MC: Are there any limitations to the study that you wish to highlight?
RW: This is an observational study and carries the same warnings as any other observational study. In all observational studies you need to think about confounders which were not accounted for. We think we have covered all the main bases here and have also – in effect –repeated the study three times with the same finding.
One important point, which could be missed on a quick read through, is that the effect was more marked at low UV levels. We thus had a halving of mortality with a rise from 350 to 450 kJ/m2 UVA in England (a rise of 100kJ/m2), but in Italy and America the halving of mortality occurred with a 200 kJ/m2 rise of UVA (600 to 800). We thus suspect that there is a ceiling to this effect and just cranking up UV exposure to higher and higher levels will not continue to produce the same degree of benefit.
MC: The study is observational and therefore cannot prove cause and effect. How can the study findings be harnessed?
RW: This is a starting point. I think an important message is that there is more to sunlight than vitamin D alone. The unfortunate fixation on vitamin D in the press and even the medical world is that so little consideration has been given to, or research performed on, other beneficial mechanisms of action of sunlight. I hope that this will start to change. Our study suggests benefit from sunlight and if we could work out the mechanism, that would lead to new treatments. The second consideration is public health. We are currently advising (correctly) that people should meet outside to benefit from ventilation reducing COVID-19 transmission. Our data suggests that there are further benefits to being outside, in that you also get more sunlight. I hope that our data thus feeds into public health policy and advice.
MC: Are there other research methods that could be used to demonstrate cause and effect, based on your work?
RW: Nearly every dermatology department in Britain has a phototherapy department. Use of UV is a mainstay of dermatology treatment. I think we should be considering clinical trials of phototherapy, although at the moment we do not know where in the pathway from health to COVID-19 mortality the benefits of UV occur. We thus do not know whether this is a prophylactic or therapeutic benefit. I am now trying to raise research funding to study this.
MC: What are your next steps in this research area?
RW: Get funding. I then want to do more work on the UV-NO-COVID pathway.
Reference: Cherrie M, Clemens T, Colandrea C, et al. Ultraviolet A Radiation and COVID-19 Deaths in the USA with replication studies in England and Italy. British Journal of Dermatology. 2021. doi:10.1111/bjd.20093.
Richard Weller was speaking to Molly Campbell, Science Writer for Technology Networks.