Considering photodynamic therapy to combat COVID19.
Could photodynamic therapy be a new tool to fight the COVID19 pandemic? Light-based technology can be used to prevent and treat viral infections and is indicated as a method to decontaminate humans that have already received exposure to biological agents, without causing undue harm to host tissue.
When we consider the apparent seasonal differences in the recent COVID19 spread throughout the global hemisphere and the global possibility of viral transmission throughout the world as a result of international travel and globalisation, the apparent low infection rate in the southern hemisphere with apparent seasonal influence on COVID19 spread may be explained by the atmospheric UV levels in those regions. Currently the UK has UV index of 1-2 and Australia has a UV index of 5-12, South Africa maximum 12, several times that of the UK. Seasonal flu epidemics in the Middle East occur at relatively high global temperatures but reduced UV indexes, indicating that UV levels may be a factor in these seasonal epidemics.
Germicidal UV (UVC) light from monochromatic or polychromatic light sources destroys many viruses and research data suggests that UVC has a high selectivity over host mammalian cells and tissues. Further Near Infra Red (NIR) has been shown to cause damage to the protein coat of a virus or bacteria, thus inactivating it using NIR femtosecond laser. This process targets the mechanical or vibrational properties of microorganisms.
If low-level UV emitters from light sources equivalent to safe summer values were placed in public places or where people frequent could this affect the transmission of the virus in the most affected countries?
Light is non-polluting and environmentally friendly, and when containment of the virus is accomplished and the bio-threat has been neutralized photodynamic means will leave no lasting pollution or drug reactions.
Using a very low power visible femtosecond laser to selectively inactivate viruses and other microorganisms has been found to leave sensitive materials unharmed by manipulating and controlling with the femtosecond laser system in experiments.
Obviously, consideration should be made for individuals as UV light is a mutagen to microbes and humans alike and people who are susceptible to UV DNA damage (eg P53 mutations, Li–Fraumeni) should be warned about exposure but if levels are well within safe values similar to safe levels of natural sunlight exposure for unaffected individuals then clearly this is a strategy well worth considering in countries affected by the COVID19 virus. Antimicrobial germicidal sterilisation lamps are already available commercially to effectively inactivate viruses.
References
McDevitt JJ, Milton DK, Rudnick SN, First MW. Inactivation of poxviruses by upper-room UVC light in a simulated hospital room environment. PLoS One. 2008;3:e3186. doi: 10.1371/journal.pone.0003186.
Sagripanti JL, Lytle CD. Sensitivity to ultraviolet radiation of Lassa, vaccinia, and Ebola viruses dried on surfaces. Arch Virol. 2011;156:489–94.
Fatma Vatansever, Cleber Ferraresi, Marcelo Victor Pires de Sousa, Rui Yin, Ardeshir Rineh, Sulbha K Sharma, and Michael R Hamblin, Can biowarfare agents be defeated with light? Virulence. 2013 Nov 15; 4(8): 796–825.
Dai T, Vrahas MS, Murray CK, Hamblin MR. Ultraviolet C irradiation: an alternative antimicrobial approach to localized infections? Expert Rev Anti Infect Ther. 2012;10:185–95. doi: 10.1586/eri.11.166
Pinna D, Sampson-Johannes A, Clementi M, Poli G, Rossini S, Lin L, Vicenzi E. Amotosalen photochemical inactivation of severe acute respiratory syndrome coronavirus in human platelet concentrates. Transfus Med. 2005;15:269–76. doi: 10.1111/j.0958-7578.2005.00588.x.
Costa L, Faustino MA, Neves MG, Cunha A, Almeida A. Photodynamic inactivation of mammalian viruses and bacteriophages. Viruses. 2012;4:1034–74. doi: 10.3390/v4071034.
Tsen K, Tsen S, Chang C, Hung C, Wu T, Kiang J. Inactivation of viruses with a very low power visible femtosecond laser. J Phys Condens Matter. 2007;19:322102. doi: 10.1088/0953-8984/19/32/322102
Think the argument is not compelling. You might identify a specific application and, for discussion, offer in silico analysis. e.g. - if public space, what level of exposure would be required for a representative area?.
Inactivation is studied under conditions of controlled exposure - direct (close) line of sight exposure for sufficient time with sufficient energy. Didn't see citations offering confidence for efficacy to " decontaminate humans that have already received exposure to biological agents,...". How would that be tested?
One could assume efficacy for public spaces with limitations, esp. intensity necessary to address distance from there source. The last citation's "femtosecond' referred to the laser - not efficacy. They reported ~ 2 log reduction after "about 10 hours" exposure - pretty casual timing..
Not sure one could effect UV intensity necessary for open spaces - esp. without human impact - eye damage to potential skin cancer.
Think there are not sufficient data or sufficient time to assume seasonal exposure parameters. The 1st case was reportedly just last November and WHO didn't call it an public health emergency until end Jan. Dynamics in australia are just now being seen https://www.abc.net.au/news/2020-03-17/coronavirus-data-reveals-how-covid-19-is-spreading-in-australia/12060704 .
Other viral diseases have been associated with seasonal mitigation and that involved many environmental parameters - not just UV exposure.
Thank you Phil for your thoughtful contribution to this rather shallow suggestion. We do know that UV does inactivate some coronaviruses and that humans can tolerate moderate amounts of UV light (3-5 UV index).
Would it be possible to change the lighting source of one facility relative to UV index equivalent to UK index on a safe summer exposure and assess the virion count on surfaces and air samples before and after exposure? Agreed that outside spaces are far more complicated to contemplate.
Clinicians do use blue light for patients with seasonal affective disorder with some success, thinking quite laterally, of course.
Australia is approaching winter months now, with reduced UV index and increased contagion of COVID19 is anticipated as a response to lower UV levels.
Please tell me about the UK index and its basis. Think we'd review the lit 1st, incl UK index (I do not know that) for relevant studies to the question - is there a basis to presume clinically significant efficacy? - and for design.
As you suggest, think I'd plan around reasonable context and paths of infection. Aerosol, exposed surfaces - and if respiratory sourced - in what is the inoculum to be dispersed? Likely not as single virions - so how is that simulated and to what titer? What reduction would be clinically significant?
" Australia ....increased contagion of COVID19 is anticipated as a response to lower UV levels.
Is this your thinking or are there relevant data?
You might want investigate this publication Article The mechanism of low-intensity laser irradiation effects on virus
The mechanism of low-intensity laser irradiation effects on virus.
Sorry for the delay in answering, Phil, currently relocating in UK.
The UV Index is an international standard measurement of the strength of sunburn-producing ultraviolet (UV) radiation at a particular place and time designed as an open ended linear scale and was developed by Canadian scientists in 1992. The scale was then adopted and standardized by the UN's WHO and World Meteorological Organization in 1994. It is primarily used in daily forecasts aimed at the general public, and is increasingly available as an hourly forecast as well.
The UV Index scale is directly proportional to the intensity of UV radiation that causes sunburn on human skin. For example, if a light-skinned individual (without sunscreen) begins to sunburn in 30 minutes at UV Index 6, then that individual should expect to sunburn in about 15 minutes at UV Index 12 – twice the UV, twice as fast.
Not wishing to be too optimistic and looking at this very cautiously, the attached maps and graphs look at the global spread of COVID 19 and the UV index. As an example, Australia's start of the contagion was in the Southern territories and when compared to the UV map at low UV index. The graphs of Australia contagion align to the UV decrease as autumn reduced the UV index.
my name is prof. Dr. Mohammadreza Saboktakin from Germany. I am a nanomedicine specialist. I have testes my new nanophotosensitizers with under 100 nm size by Photodynamic Laser Therapy Technique to fight COVID-19 virus. The initial experiments have positive results, but we need more information. We have gotten the positive results on two pateints in Germany. I would like to cooperate with your center about developing this technique.
Many thanks for contributing this, Mohammadreza, this sounds extremely hopeful and so exciting. Are there any other centres out there that can cooperate with this?
As a confounding factor to the UV index influence on COVID 19 viability, it was suggested that vitamin D may influence the outcome of COVID 19 infection and contagion but another aspect to this subject could be the synthesis of vitamin D in different ethnicities.
Here are a few thoughts that may influence our thinking about the demographics of COVID 19 fatalities in the healthcare worker population in the UK-
Ethnicity, skin colour, melanin and vitamin D and relative COVID 19 immune responses
A marked increase of non-Caucasian ethnicities has been observed of healthcare workers who have succumbed fatally to the COVID 19 virus. With this in mind, a second genetic factor could be considered regarding skin colour and melanin content. Skin type influences vitamin D levels where darker skin has greater amounts of melanin, which competes for UVB photons with 7-dehydrocholesterol (vitamin D making substrate). Several epidemiological studies link higher susceptibility to immune mediated disorders with vitamin D deficiency.
The non-skeletal effects of vitamin D have been of increasing interest with regard to its association with several diseases and, in particular, its role in regulating the immune system at the cellular level. 1,25-dihydoxyvitamin D3, the active form of vitamin D, has a physiological role in immunomodulation targeting several cells of the immune system and is a key factor linking innate and adaptive immunity and both are compromised with vitamin D deficiency. Hypovitaminosis D is associated with several immune and autoimmune disorders in addition to the classical association with osteomalacia.
Several immune cells have the cellular ability to convert 25-hydroxyvitamin D to active 1,25-duhydroxyvitamin D, which promote responses to pathogens in macrophages. Another antimicrobial response is in regulating the maturation of antigen-presenting dendritic cells and this pathway controls T-lymphocyte function. T cells also responds directly to activated vitamin D. Another immunomodulatory function is that cells of the immune system express vitamin D-activating enzymes also enabling the conversion of vitamin D into its active form.
The amount of UV exposure is related to the global UV index is also associated with vitamin D synthesis in skin and thus undergoes activation via a binding protein in the liver and kidney.
As higher levels of melanin inhibit vitamin D synthesis from UV exposure and the currently low UV index in the UK, this may influence the demographic findings of healthcare workers that have succumbed to the virus.
References
· Vitamin D levels, for instance, are associated with thyroid nodule size, which is commented in the paper to influence MIBI uptake by parathyroid cells. Vitamin D receptor (VDR) polymorphisms also alter vitamin D levels and can influence disease.
· Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012;71(1):50–61. doi:10.1017/S0029665111001650
· Hewison M. Vitamin D and the immune system: new perspectives on an old theme.Endocrinol Metab Clin North Am. 2010;39(2):365–379. doi:10.1016/j.ecl.2010.02.010
· Glass D, Lens M, Swaminathan R, Spector TD, Bataille V. Pigmentation and vitamin D metabolism in Caucasians: low vitamin D serum levels in fair skin types in the UK. PLoS One. 2009;4(8):e6477. Published 2009 Aug 3. doi:10.1371/journal.pone.0006477
· Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet. 1982;1(8263):74–76. doi:10.1016/s0140-6736(82)90214-8
· Jones P, Lucock M, Chaplin G, et al. Distribution of variants in multiple vitamin D-related loci (DHCR7/NADSYN1, GC, CYP2R1, CYP11A1, CYP24A1, VDR, RXRα and RXRγ) vary between European, East-Asian and Sub-Saharan African-ancestry populations. Genes Nutr. 2020;15(1):5. Published 2020 Mar 13. doi:10.1186/s12263-020-00663-3
· Rockell JE, Skeaff CM, Williams SM, Green TJ. Association between quantitative measures of skin color and plasma 25-hydroxyvitamin D. Osteoporos Int. 2008;19(11):1639–1642. doi:10.1007/s00198-008-0620-4
Alternatively, Genotype of vitamin D receptor influencing severity of COVID 19 infection
Having already established that genetic factors determining skin colour may influence disease outcomes to COVID 19 infection, it should also be considered that genetic differences in vitamin D receptor genes (VDR) might influence disease outcomes.
Located on chromosome 12q13.11 in humans, the VDR gene consists of eleven exons. Several polymorphisms of the VDR gene have been identified, but four single-nucleotide polymorphisms (SNPs) of this gene are the ones that have been most studied, namely, BsmI (rs1544410), ApaI (rs7975232), TaqI (T> C; rs731236), and FokI (C> T; rs2228570, formerly known as rs10735810).
Dear Annwyne Houldsworth
Thank you for asking this question. The role of environmental factors mentioned in this discussion should certainly not be overlooked. There is a significant body of research indicating that UV radiation from the sun is a main factor controlling viruses and bacterias. This knowledge should be successively included in our models used for prediction of the epidemic outbreak.
If the premise that COVID 19 is seasonal is correct and the virus possibly affected by the environmental UV index, should we be planning for a repeat peak of cases when the summer season has ended in the UK, and other countries from the northern hemisphere? Complacency may set in as cases decrease over the summer.
Based on existing experimental data, the group of viruses known as Coronaviridae is deactivated by their exposure to UV in sunlight. It is too early to speculate about the seasonality of COVID-19 although this working hypothesis is plausible. For this reason, planning for the second outbreak is essential and should include greater attention to hygiene, sustainable social separation, more emphasis on teleworking for all knowledge-based professions and a drastic reduction of “packing density” in transportation systems, including aircrafts.
According to the models used for the simulation of epidemic diseases with environmental factors, we can hope that the approaching summer can lead to the isolation of the current pandemics in several hotspots and to a possible elimination of the virus.
The main concern I have right now is that we are currently in the solar minimum phase. Some researchers speculate that the viral mutation may be correlated with the 11-year cycle of solar activity. The most interesting observation is described in the attached document stating that the pandemic warning was given last year.
Even if this claim is not yet substantiated, it shows that virus epidemics are caused by imbalances created in the complex earth system including solar radiation, chemical pollution and changing the habitats of some species.
This is a fascinating turn in the discussion venturing into cosmic biology in astrophysics and space science, quite beyond my remit, so many thanks for the new perspective.
Nalin Chandra Wickramasinghe certainly has a recognised track record in this field.
Thank you for this interesting article. It is certain that in order to understand how viruses encroach on a territory of human activities, we need to use the knowledge from many disciplines (from virology and ecology to astrophysics). Only after realizing the need for such interdisciplinary knowledge, we can build better models to predict the future evolution of this pandemic.
Janusz - thanks for the article. It offers a tentative prediction to emergence of viral strains but limited retrospective consideration that would offer more than coincidence. References offered are speculative rather than confirming, largely from one group and even include some clearly unproven claims "...primary causation by externally derived viral variants (from space via cometary dust). " (Qu 2018 - one of the authors of the paper you cited). do you share that perspective of alien origin? Further, the article ignores criticism of the concept (e.g. https://www.nature.com/articles/344010b0.pdf?origin=ppub ).
Phil - It is difficult to provide a proof of the conjecture establishing the link between solar activity and viral mutations. The system to be considered includes forcings linked to solar activity and to the stress of an ecosystem in the area responsible for an epidemic. One of the main factors generally excluded from most studies is the state of the atmosphere. Local winds, stratification, clouds and magnetic fields influence the chances of mutations in addition to the solar factors. For this reason, the correlations proposed in the paper attached to my comment are not always obvious for all pandemics.
Ideally, the mutation model is a multi-layered system comprising virology, ecology, meteorology, geophysics and astronomy as well as many human factors. In our age of highly specialized research, it is not easy to obtain such a description. I am convinced, however, that the current situation will help to see the problem of pandemics in a broader perspective, breaking down the barriers of specialization.
Prediction of the epidemic diseases will be made in the near future and I think we have many tools to start working on this difficult problem.
UV index is an important factor in vitamin D synthesis, which in turn, is a key component in the regulation of the immune system.
Mast cells, Th17 cells, Vitamin D and Vitamin D receptors
When considering the T cell response to COVID 19 infection and the T-cell differentiation, other pathways must be considered in addition to Th1 and Th2 driven responses. Mast cell derived cytokines are implicated in Th17 cells activity while Th17 cells promote mast cell proliferation.
In the case of HIV infection Th17 cells can be reservoirs of the virus in patients taking antiretroviral therapy contributing to the latency of HIV infection.
1,25-Dihydroxyvitamin D3(1,25(OH)2D3), the active form of vitamin D, has emerged as a direct regulator of immune system function in humans. Important mechanisms involving the human immune system are mediated through the nuclear receptor, vitamin D receptor (VDR) via the non-canonical processes of vitamin D binding to the receptor. This receptor is expressed by macrophages, dendritic cells and activated T cells. Vitamin D is able to prevent autoimmune inflammatory diseases, particularly by supressing Th17 cells as accumulating reports demonstrated that 1,25(OH)2D3 possessed anti-inflammatory activity on Th17 cells to maintain immunologic homeostasis. Indeed, the active form of Vitamin D directly inhibits Th17 differentiation. VDR is elevated in Th17 cells.
Human memory Th17 Cell populations change Into anti-inflammatory cells with regulatory capacity upon exposure to active Vitamin D metabolite (1,25(OH)2D3).
Th17 cells are a subset of CD4+ T helper cells that produce IL-17. Th17 has an important role in the human immune system by in the host defence against infection but also considered key in the development of autoimmune inflammatory disorders. Loss of h17 can result in chronic infections. They have immunosuppressive properties that decrease the antiviral response to infections, such as HIV and the loss of Th17 can result in a loss of balance between Th17 and Treg cells. IL21 encourages Th17 differentiation and proliferation. IL-17A expression is up regulated by Th17 cells, at sites of inflammation in several autoimmune diseases. IL-17 is a pleiotropic cytokine, where the one gene exhibits two or more phenotypic traits.
Vitamin D is considered to supress IL-17A production in T cells in some conditions (RA, MS, colitis). IL-6 and IL-22 expression may also be down regulated from naive and memory CD4+T cells. Confusingly, Th17 cells are not always pathogenic unless exposed to IL-23.
A high number of CCR6+ Th17 cells were observed in a severely affected COVID 19 patient supporting the hypothesis that Th17 cells are important factors in the cytokine storm in the disease. Elevated Th17 cells and enhanced IL-17 pathways were a factor in patients with MERS-CoV and SRS-CoV. In H1N1 infection in mice acute lung injury was a factor induced by IL-17 expression.
There are some anti Th17 and IL17 blockades in antibody form currently being trialled.
IL-17 is increased in patients infected with COVID 19, in intensive care, as opposed to those not in intensive care. An anti IL-17 drug is currently being trialled in China, ixekizumab a drup developed for the treatment of psoriasis.
In the case of HIV neutralisation of IL-17 eliminates virus infected cells thus enhancing, viral clearance and boosting the ability of cytotoxic T cells to lyse infected cells. Th1 cytokines (IFNϒ) driving a Th1 response have a powerful antiviral function that inhibits Th17 differentiation. Could this be a similar scenario with COVID 19?
Zhang, H., Shih, D. Q., & Zhang, X. (2013). Mechanisms underlying effects of 1,25-Dihydroxyvitamin D3 on the Th17 cells. European journal of microbiology & immunology, 3(4), 237–240. https://doi.org/10.1556/EuJMI.3.2013.4.1
Josset, L., Menachery, V. D., Gralinski, L. E., Agnihothram, S., Sova, P., Carter, V. S., Yount, B. L., Graham, R. L., Baric, R. S., & Katze, M. G. (2013). Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. mBio, 4(3), e00165-13. https://doi.org/10.1128/mBio.00165-13Hamzaoui, Agnes; Berraïes, Anissa; Hamdi,
Besma; Kaabachi, Wajih; Ammar, Jamel; Hamzaoui, Kamel (November 2014). "Vitamin D reduces the differentiation and expansion of Th17 cells in young asthmatic children". Immunobiology. 219 (11): 873–879.doi:10.1016/j.imbio.2014.07.009. ISSN 0171-2985.PMID 25128460.
Janusz - predictions re. epidemics and their dynamics have been, are and will be constant, divergent and abundant . Those from the public health community, esp. WHO, are typically poor. That we have tools merely offers more "experts" myopically leveraging their tool to speculate (and promote their career) as in influenza causing sunspots.
Phil, thank you for your comments. Since the numerous alpha- and betacoronaviruses have been identified in bats populating the abandoned mineshaft in Yunan, the chance of a pandemic has been seriously contemplated by experts in virology and epidemic diseases. Please kindly consult the attached paper on this subject.
Do we need the controversial theories on the boundary of astrophysics and biology to explain some discrepancies in the genetic makeup? It is certainly an open question.
As far as the models are concerned, I agree with you that the scientific quality varies from system to system, but I can’t imagine how we can handle the current epidemic of this serious disease without them. There is certainly a challenge in bringing together the interdisciplinary group of scientists from various fields to finally build solid models. For my part, I am trying to develop mathematical equations to describe the spread of pathogens, even in this area there are many knowledge gaps.
For now, we must observe the sound regulations concerning the face mask and general cleanliness.
It is also interesting to look at the problem from a historical point of view; we can still learn something from this study.