Can J Respir Ther. 2020; 56: 25–31.
Published online 2020 Jul 23. doi: 10.29390/cjrt-2020-015
PMCID: PMC7428000
PMID: 32844112
Low level laser therapy as a modality to attenuate cytokine storm at multiple levels, enhance recovery, and reduce the use of ventilators in COVID-19
Soheila Mokmeli, MD Anesthesiologist
1 and Mariana Vetrici, MD, PhD2
Author information Copyright and License information Disclaimer
1Canadian Optic and Laser Center (Training Institute), Victoria, BC, Canada
2Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada
Corresponding author.
Correspondence: Soheila Mokmeli, Canadian Optic and Laser Center (Training Institute), 744A Lindsay Street, Victoria, BC V8Z 3E1, Canada. Tel.: +1 (250) 480-7868, E-mail: moc.oohay@ilemkom.rd Mariana A. Vetrici, Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada, Tel.: +1 (865) 888-3095, E-mail: moc.liamg@icirtevanairam
Copyright notice
This open-access article is distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC) (http://creativecommons.org/licenses/by-nc/4.0/), which permits reuse, distribution and reproduction of the article, provided that the original work is properly cited and the reuse is restricted to noncommercial purposes. For commercial reuse, contact moc.trsc@rotide
Abstract
The global pandemic COVID-19 is a contagious disease and its mortality rates ranging from 1% to 5% are likely due to acute respiratory distress syndrome (ARDS), and cytokine storm. A significant proportion of patients who require intubation succumb to the disease, despite the availability of ventilators and the best treatment practices. Researchers worldwide are in search of anti-inflammatory medicines in the hope of finding a cure for COVID-19. Low-level laser therapy (LLLT) has strong, anti-inflammatory effects confirmed by meta-analyses, and it may be therapeutic to ARDS. LLLT has been used for pain management, wound healing, and other health conditions by physicians, physiotherapists, and nurses worldwide for decades. In addition, it has been used in veterinary medicine for respiratory tract disease such as pneumonia. Laser light with low-power intensity is applied to the surface of the skin to produce local and systemic effects. Based on the clinical experience, peer-reviewed studies, and solid laboratory data in experimental animal models, LLLT attenuates cytokine storm at multiple levels and reduces the major inflammatory metabolites. LLLT is a safe, effective, low-cost modality without any side-effects that may be combined with conventional treatment of ARDS. We summarize the effects of LLLT on pulmonary inflammation and we provide a protocol for augmenting medical treatment in COVID-19 patients. LLLT combined with conventional medical therapy has the potential to prevent the progression of COVID-19, minimize the length of time needed on a ventilator, enhance the healing process, and shorten recovery time.
Keywords: COVID-19, ARDS, cytokine storm, low level laser therapy, anti-inflammatory, ventilator, photobiomodulation
INTRODUCTION
What is low level laser therapy?
Low level laser therapy (LLLT) is also known as cold laser therapy or photobiomodulation therapy. LLLT utilizes visible light and infrared laser beams in the range of 450–1000 nm. Single wavelength or monochromatic light is emitted from a low-intensity laser diode (<500 mW). The light source is placed in contact with the skin, allowing the photon energy to penetrate tissue, where it interacts with various intracellular biomolecules to restore normal cell function and enhance the body’s healing processes [1]. This contrasts with the thermal effects produced by the high-power lasers that are used in cosmetic and surgical procedures to destroy tissue [1], as mentioned in the PubMed Medical Subject Heading (MeSH) subheading for LLLT.
LLLT effects are not due to heat but rather to a photochemical reaction that occurs when a photoacceptor molecule within the cell absorbs a photon of light, becomes activated, and changes the cell’s membrane permeability and metabolism. Presently, cytochrome c oxidase, opsins and their associated calcium channels, and water molecules have been identified as the main mediators of the photochemical mechanisms [2]. This leads to increased mRNA synthesis and cell proliferation. LLLT produces reactive oxygen species (ROS) in normal cells, but ROS levels are lowered when it is used in oxidatively stressed cells, like in animal models of disease. LLLT up-regulates antioxidant defenses and decreases oxidative stress [2].
Low-level lasers are a safe, noninvasive technology approved by both the US Food and Drug Administration and Health Canada for several chronic and degenerative conditions, temporary pain relief, cellulite treatment, body contouring, lymphedema reduction, hair growth, and chronic musculoskeletal injuries. LLLT increases microcirculation, lymphatic drainage, and cellular metabolism, thereby relieving many acute and chronic conditions.
The MeSH database in PubMed contains more than 7000 articles on LLLT. The effects of LLLT have been confirmed through several meta–analysis studies and include anti-inflammatory [3] and analgesic effects [4], tissue healing [5], treating tendinopathy [6], and improving lymphedema [7]. Recent lab and animal studies suggest LLLT is ready for clinical trials over myocardial infarction [5]. In 2010, a meta-analysis concluded that there was strong evidence of an anti-inflammatory effect of LLLT [3].
To date, published reports indicate that LLLT up-regulates antioxidant defenses and decreases ROS in oxidatively stressed cells and animal models of disease. The anti-inflammatory effect of LLLT directly addresses the main pathology of disorders such as musculoskeletal, lungs, wounds, brain, trauma, etc. LLLT reduces NF-kB, a protein complex that controls transcription of DNA, in pathological conditions. Reports have shown reductions in reactive nitrogen species and prostaglandins in various animal models [2].
LLLT has diverse effects [8]:
reduces pain related to inflammation via dose-dependent reduction of prostaglandin E2, prostaglandin-endoperoxide synthase-2, IL-1, IL-6, TNFa, as well as the cellular influx of neutrophils, oxidative stress, edema, and bleeding;
decreases edema and swelling by increasing lymphatic drainage;
increases collagen and protein production, and cell proliferation;
accelerates wound healing and scar formation;
improves quality and tensile strength of tissue;
stimulates nerve function and regeneration;
accelerates bone regeneration and remineralization;
reduces the pain threshold and enhances endorphins;
washes inflammatory debris away from the injured site; and
augments blood flow.
LLLT has been used in respiratory tract diseases since 1978. Empirical practice on over 1000 patients produced data pertaining to chronic pneumonia, acute pneumonia, asthma, and chronic bronchitis in children, adults, and elderly. Common findings include reduced chest pain and heaviness; normalization of respiratory function; improved blood, immunological, and radiological parameters; and shortened recovery times. In community-acquired pneumonia, intravenous LLLT of blood added to conventional treatment significantly promoted the bactericidal activity of neutrophils. In asthma, the addition of LLLT was more effective than medical treatment alone and it shortened the duration of treatment and recovered bronchial sensitivity to sympathomimetics [9–11]. In newborns with pneumonia, LLLT combined with conventional medical regimens optimized the treatment infectious and inflammatory diseases, reduced the incidence of complications, and shortened recovery periods [12].
LLLT is a well-known treatment modality in veterinary medicine. Upper and lower respiratory conditions in dogs and cats are common, and viral and bacterial infections are often highly contagious. Regardless of etiology, inflammation is the major pathology of these conditions. The addition of LLLT to conventional treatment alleviates symptoms and stimulates the healing process in tissues. General guidelines for the use of laser therapy in animals and protocols for specific conditions are published [13].
The pathogenesis of COVID-19 in respiratory tract
Coronaviruses are a large group of viruses that affect animals. In humans, they produce diseases such as the common cold, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome. The disease caused by the novel coronavirus, SARS-CoV-2, has been named COVID-19 and the clinical manifestations range from asymptomatic to severe acute respiratory distress syndrome (ARDS) to death [14].
Respiratory viruses infect either the upper or lower airways. Typical upper-respiratory infections are milder, more contagious, and spread easily, whereas lower-respiratory infections spread much less frequently but are more severe and dangerous. SARS-CoV-2 appears to infect both upper and lower airways. It spreads while still limited to the upper airways, before traveling into the deeper respiratory tract and leading to severe symptoms [15].
SARS-CoV-2 attaches to a protein called angiotensin converting enzyme (ACE2), on the surface of cells in the respiratory tract. As SARS-CoV-2 attacks the cells, dead cells flow down and block the airways with debris while the virus moves deeper into the lungs. Breathing becomes difficult because the lungs become clogged with dead cells and fluid. The immune system attacks the virus causing inflammation and fever. In severe cases, the immune system goes wild, causing more damage to the lungs than the actual virus. Blood vessels dilate to increase blood flow and become more permeable to maximize transport of chemical and cellular mediators the infection site. Inevitably, the lungs get filled with fluid. This exaggerated immune response is called cytokine storm and it leads to ARDS, fever, multiorgan failure, and death [15, 16].
During cytokine storm, the immune system attacks indiscriminately without clearing the specific targets. Cytokine storm also affects other organs, especially if people already have chronic diseases [15]. The severity of cytokine storm determines who is hospitalized and who will be treated in the intensive care unit (ICU). The classification of COVID-19 is summarized in Table 1 [17].
Table 1
The staging and classification of COVID-19 [17]
Class
Symptoms
Imaging
Respiratory criteria
Mild infection
Mild
Negative signs of pneumonia
Normal
Moderate infection
Fever and upper respiratory tract symptoms
Positive signs of pneumonia
Normal
Severe infection
Fever, upper and lower respiratory tract symptoms
>50% lesion progression within 24–48 hours
Respiratory rate ? 30 /min
O2 saturation ? 93% at rest
Arterial partial pressure of O2 (PaO2)/oxygen concentration (FiO2) ? 300 mm Hg
Critical infection
Respiratory failure requiring mechanical ventilator and (or) presence of shock and (or) other organ failure that requires monitoring and (or) treatment in the ICU
> 50% lesion progression within 24–48 hours
Early stage:
Oxygenation index 100.1–149.9 mmHg.
Respiratory system compliance (RSC) ? 30 ml/cmH2O.
No organ failure other than the lungs.
Middle stage:
60 mmHg < O2 index ? l00 mmHg.
30 mL/cmH2O > RSC ? 15 mL/cmH2O.
Maybe complicated by mild or moderate dysfunction of other organs.
Late stage:
O2 index ? 60 mmHg.
RSC < 15 mL/cmH2O.
Diffuse consolidation of both lungs that requires the use of extracorporeal membrane oxygenation or failure of other vital organs.
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Note: A confirmed case is based on the epidemiological history (including cluster transmission), clinical symptoms (fever and respiratory symptoms), lung imaging, and results of SARS-CoV-2 nucleic acid detection and serum-specific antibodies [17].
The morbidity and mortality of COVID-19 are due to excessive inflammatory cytokine production and immune hyperactivity. Alveolar macrophage activation and cytokine storm are the main pathogenesis of severe COVID-19. The pathological features include exudation and hemorrhage, epithelial injuries, infiltration of macrophages into the lungs, and fibrosis of lung tissue. The mucous plug with fibrinous exudate in the alveoli and the activation of alveolar macrophage are characteristic abnormalities [18, 19]. Chemical and genetic studies have shown that the pulmonary endothelium is a key component of the cytokine storm. Therefore, modulation of the involved cellular signaling pathways may have therapeutic effects [20, 21].
COVID-19 begins when SARS-CoV-2 uses ACE2 as the entry receptor for infection [22]. This induces ACE2 downregulation and shedding. Loss of ACE2 from the endothelium causes dysfunction of the renin-angiotensin system, and it enhances inflammation and vascular permeability. Shedding of ACE2 from the endothelium releases enzymatically active soluble ACE2 (sACE2), which is tightly linked to tumor necrosis factor alpha (TNF-?) production in cell culture [23].
Multiple signaling pathways are activated during an immune response and cytokine storm. The P2X purinoceptor 7 (P2X7r) is major factor involved in activation of the cytokine storm and lung pathology in response to viruses [24, 25], infection, inflammation, hypoxia, or trauma [26]. P2X7r is an adenosine triphosphate (ATP) gated, nonselective cation channel, allowing Ca2+ and Na+ influx and K+ efflux. Extracellular ATP plays a central role in apoptotic cell death [27], the induction of inflammation [28], and mitochondrial failure in monocytes [29]. P2X7r mediates ATP-induced cell death in different cells and it promotes assembly and release of proinflammatory interleukins (IL-1? and IL-18) from immune cells after exposure to lipopolysaccharide and ATP [27]. P2X7r is constitutively expressed in many cells, including respiratory epithelial cells and most immune cells like neutrophils, monocytes, macrophages, dendritic, natural killer, B and T lymphocytes [27].
Studies stratified COVID-19 patients as: (i) severe symptoms and ICU admission and (ii) mild and moderate symptoms requiring hospitalization but not ICU [17, 19]. The severe patients have significantly higher levels of plasma pro-inflammatory factors (IL-2, IL-7, IL-10, GSCF, IP-10, MCP-1, MIP1A, TNF-?) [19] and (IL-2, IL-6, IL-10, TNF-?) [18] than non-ICU patients, and they were likely in cytokine storm [17, 19]. These findings justify the use of IL-6 receptor antagonists [18, 19]; however, a therapy to reduce inflammation at multiple levels, such as LLLT, could be more successful in controlling the unbalanced immune response (Figure 1).
FIGURE 1
The effects of SARS-CoV-2 on alveolar cell and cytokine storm.
The effects of LLLT on pulmonary inflammation
LLLT is effective against cytokine storm and ARDS while promoting healing and tissue regeneration. Experimental and animal models of pulmonary disease and infection have revealed multiple cellular and molecular effects, which are both local and systemic. LLLT reduces inflammation without impairing lung function in acute lung injuries and is a promising therapeutic approach for lung inflammatory diseases such as Chronic obstructive pulmonary disease [26].
In murine models of acute inflammation of the airways and lungs, transcutaneous LLLT delivered over the trachea decreases pulmonary microvascular leakage [30, 31], IL-1b levels [26, 30], IL-6 [26, 32], MIP-2 mRNA expression [30], and intracellular ROS production [24]. LLLT produces anti-inflammatory effects on tracheal hyperactivity, and reduces neutrophil influx [26, 30, 32–34] by inhibiting COX-2-derived metabolites [33]. In ARDS, LLLT elevates cyclic adenosine monophosphate [32, 34], a signaling molecule that stimulates IL-10 and G-CSF expression and blocks TNF-a and MIP-1. LLLT also reduces TNF-a levels in bronchoalveolar lavage fluid and alveolar macrophages [26, 31–34]. In hemorrhagic lesions of the lungs, LLLT significantly reduces the hemorrhagic index and myeloperoxidase activity, to levels comparable to Celecoxib [35].
LLLT contributes to the resolution of inflammation by upregulating IL-10 and downregulating P2X7r. LLLT changes the profile of inflammatory cytokines and elevates IL-10 [26, 31, 36], known as human cytokine synthesis inhibitory factor, in the lung and abolishes lung inflammation via a reduction of inflammatory cytokines and mast cell degranulation [31]. LLLT decreases collagen deposition as well as the expression of the P2X7r [26].
LLLT contributes to healing by promoting apoptosis of inflammatory cells while suppressing apoptotic pathways in lung tissue. In a model of acute lung injury, LLLT reduced DNA fragmentation and apoptotic pathways via increased B-cell-lymphoma-2 (Bcl-2), the key regulator of the intrinsic or mitochondrial pathway for apoptosis, in alveolar epithelial cells while promoting DNA fragmentation in inflammatory cells [37]. In pulmonary idiopathic fibrosis, LLLT inhibits pro-inflammatory cytokines and increases expression of proliferating cell nuclear antigen [38], attenuates airway remodeling by balancing pro- and anti-inflammatory cytokines in lung tissue, and inhibiting fibroblast secretion of the pro-fibrotic cytokines [36].
LLLT provides synergy in combination with medical treatment. It has a synergic anti-inflammatory action over alveolar macrophages pretreated with N-acetyl cysteine, an effective oral medicine for coughs and some lung conditions [39]. The synergic effects of LLLT combined with conventional treatments were reported on over 1000 patients in Russian studies [9–11].
Extended time on ventilators causes lung injury but LLLT minimizes this side effect. In experimental models of ventilator-induced lung injury (VILI), LLLT following VILI resulted in lower injury scores, decreased total cell count and neutrophil count in bronchoalveolar lavage, and reduced alveolar neutrophil infiltration. LLLT in an experimental model of VILI in rats demonstrated the anti-inflammatory effect via decreased lung injury scores and lower counts of neutrophils in alveolar, interstitial, and bronchial lavage [39] (Figure 2).
FIGURE 2
The effects of SARS-CoV-2 versus LLLT on cytokine storm and lung tissue.
Evidence from the literature supports the use of LLLT for the treatment of COVID-19.
It has significant anti-inflammatory effects confirmed by meta–analyses. Eleven cell studies, 27 animal studies, and another six animal studies for drug comparisons and LLLT interactions verified that there is strong evidence of an anti-inflammatory effect of LLLT. The scale of the anti-inflammatory effect is not significantly different than non-steroidal anti-inflammatory drugs, but it is slightly less than glucocorticoid steroids [3].
It has diverse applications and effects confirmed through several meta-analysis studies include analgesia [4], tissue healing [5], treating tendinopathy [6], and improved lymphedema [7].
LLLT is approved by the US FDA and Health Canada for several chronic and degenerative conditions, temporary pain relief, cellulite treatment, body contouring, lymphedema reduction, and hair growth. It has been used in veterinary medicine for upper and lower respiratory conditions in dogs and cats [13].
It has been used for human respiratory tract disease. Empirical use on over 1000 patients produced data pertaining to chronic pneumonia, acute pneumonia, asthma, and chronic bronchitis in children, adults, and the elderly [9–12]. Light therapy and LLLT has been mentioned as a potential treatment for pandemic coronavirus infections [40].
The anti-inflammatory effect of LLLT in lung inflammation is confirmed in at least 14 experimental animal studies. LLLT attenuates cytokine storm at multiple levels and reduces the major inflammatory metabolites such as IL-6 and TNF-?. IL-6 antagonists are being investigated for treating COVID-19 but LLLT reduces the production of IL-6, as well as other chemokines and metabolites [26–39, 41].
There are US FDA and Health Canada approved laser machines for pain management, lymphedema after breast cancer surgery, and cellulite treatments that can be used and set to treat lung inflammation.
LLLT is an affordable modality compared with other treatments and medicines like IL-6 antagonists. LLLT is a safe, effective, low-cost modality without any reported side-effects compared with other approaches. A laser machine costs Can$35,000.00–200,000.00, and each machine can fully treat 20,000 patients for COVID-19. In comparison, an IL-6 antagonist costs US$1000.00 per injection, and each patient would need 3–6 injections for complete COVID-19 treatment. Treating 20,000 patients would cost US$ 60,000,000.00–US$ 120,000,000.00.
Based on this information, LLLT will accelerate recovery from COVID-19 and will get patients off ventilator support and out of the ICU more rapidly. This could significantly decompress our severely overburdened health care systems.
Therapeutic technique and dosage of LLLT
Laser dose is the amount of energy delivered per second per cm2. The effect of laser therapy is related to the amount of laser energy per cm2. The Arndt-Schultz Law is considered the standard to describe the dose dependent effects of LLLT [42]. The minimum therapeutic dose for a bio-stimulatory effect for red and infrared laser is 0.01 J/cm2 while for ultraviolet, blue, green laser it is 0.001 J/cm2. LLLT has a noticeable biphasic dose response. The effective stimulation dose is 1 J/cm2 on the target tissue. Doses greater than 10 J/cm2 produces inhibitory effects. The inhibitory effects are used in conditions requiring inhibition and suppression [2].
Therapeutic protocol: early phase of COVID-19: (Figure 3, Table 2)
FIGURE 3
LLLT for COVID-19.
Table 2
Therapeutic protocol: Early phase of COVID-19
Laser system parameters
Wavelengths
Infrared laser (780–900 nm), or red laser (630–660 nm)
Average power
50–100 mW
Dose
4–6 J/cm2
Area
10 cm2
Sessions
3–8 once-daily sessions
Laser probe positions
Intranasal:
1 minute/cm2 (100 mW)
2 minutes/cm2 (50 mW)
Noncontact technique
Over right and left tonsils
1 minute/cm2 (100 mW)
2 minutes/cm2 (50 mW)
Transcutaneous (place laser over the skin)
Over the trachea
1 minute/cm2 (100 mW)
2 minutes/cm2 (50 mW)
Transcutaneous
Over the veins in the cubital areas
8 minute/cm2 (100 mW)
15 minutes/cm2 (50 mW)
Transcutaneous blood laser therapy
Laser parameters:
Laser type: infrared laser (780–900 nm), or red laser (630–660 nm)
Average power: 50–100 mW
Dose: 4–6 J/cm2
Area: 10 cm2
Time: 1–2 minutes/cm2
Sessions: 3–8 once-daily sessions
Laser probe positions:
Intranasal: 2 minutes, noncontact technique
Over right and left tonsils: transcutaneous (place laser over the skin)
Over the trachea: transcutaneous
Over the veins in the cubital areas: transcutaneous blood laser therapy, 10–15 minutes
Therapeutic protocol: medium–severe phase of COVID-19: (Figure 3, Table 3)
Table 3
Therapeutic protocol: medium–severe phase of COVID-19
Laser system parameters
Wavelengths
Infrared laser (780–900 nm), or red laser (630–660 nm)
Average power
50–100 mW
Dose
6–10 J/cm2
Area
10 cm2
Sessions
3–10 once-daily sessions
Laser probes positions
Intranasal:
1 minute/cm2 (100 mW)
2 minutes/cm2 (50 mW)
Noncontact technique
Over right and left tonsils
1 minute/cm2 (100 mW)
2 minutes/cm2 (50 mW)
Transcutaneous (place laser over the skin)
Over the trachea
1 minute/cm2 (100 mW)
2 minutes/cm2 (50 mW)
Transcutaneous
Over the veins in the cubital areas
8 minute/cm2 (100 mW)
15 minutes/cm2 (50 mW)
Transcutaneous blood laser therapy
Over the lungs
1:30–2 minute/cm2 (100 mW)
2–3 minutes/cm2 (50 mW)
Bilaterally over apical, middle, and lower lobes, front and back of thorax; transcutaneous over the intercostal spaces
Over the bronchus
1:30–2 minute/cm2 (100 mW)
2–3 minutes/cm2 (50 mW)
Upper mediastinal area: transcutaneous
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Laser parameters:
Laser type: infrared laser (780–900 nm) or red laser (630–660 nm)
Average power: 50–100 mW
Dose: 6–10 J/cm2
Area: 10 cm2
Time: 2–3 minutes/cm2
Sessions: 3–10 once-daily sessions
Laser Probe Positions:
Over the lungs: bilaterally over apical, middle, and lower lobes and front and back of thorax, transcutaneous over the intercostal spaces
Over the trachea: transcutaneous
Over the bronchus: upper mediastinal area, transcutaneous
Over right and left tonsils: transcutaneous
Over the veins in the cubital areas: transcutaneous blood laser therapy; 10–15 minutes
Contraindications and side effects of LLLT [42]
Although LLLT is safe and noninvasive and there are no reports of mutagenicity, genotoxicity, or carcinogenicity of LLLT after 60 years of its use. However, there are some contraindications:
work over the site of tumors and cancer;
benign tumors with possibility of converting to malignant tumors;
the first 3 months of pregnancy (in the second and third trimesters, avoid work on abdominal and spine area); and
light sensitivity conditions.
Precautions [42]
epiphyseal line in children;
glands: avoid ovaries, testes;
in patients with severe end organ damage: heart, kidney, liver, and lung;
epilepsy: the possibility of nerve discharge is increased in LLLT, especially with low-frequency protocols, 5–10 HZ.
Side effects of LLLT
Optical side effects
Because of the high intensity of lasers and the absorption of its wavelengths by different parts of ocular system, there is a possibility of damage to the eyes. It is important to use protective glasses that can absorb the specific wavelength. Protective glasses for each wavelength are different; therefore, choose the protective goggles specified for each wavelength. Both therapists and clients should wear protective goggles [42].
Early sense of healing
The analgesic effect of laser manifests earlier than its healing effect, and the patients feel better because of this, but the actual tissue damage has not yet healed. Patients feel relaxed and more energetic because the pain is gone. However, they must allow enough time for recovery [42].
Fatigue and tiredness
Fatigue is the most common symptom following LLLT. This is due to hormonal and metabolite changes after laser therapy that increase expression natural pain killers like endorphins and enkephalins. These metabolites induce relaxation and sleepiness [42].
Low blood pressure and dizziness
Very rarely, when the treated area is close to large blood vessels, a patient may experience a temporary drop in the blood pressure and orthostasis. This is due to vasodilatation and increased circulation to the limbs. To avoid dizziness, it is recommended that patients drink fluids before LLLT, and then wait for a few minutes before getting up from the supine position [42].
CONCLUSION
COVID-19 is potentially lethal because of cytokine storm and ARDS. Although most patients who contract COVID-19 may recover at home, a significant proportion require hospitalization and (or) ICU treatment. Many of the patients that are placed on ventilators succumb to the disease despite the best treatment practices. Often, patients are maintained on ventilators for longer than expected, and this may contribute to ventilator induced lung injury while depleting the patient’s convalescent resources. Modulation of inflammatory factors and a boost to healing are necessary to help patients come off the ventilators. LLLT is a safe and noninvasive modality that has been used for decades in pain management, wound healing, and health conditions including diseases of the respiratory tract. LLLT was combined successfully with standard medical care to optimize response to treatments, reduce inflammation, promote healing, and accelerate recovery times. Scientific evidence shows that LLLT attenuates the inflammatory cytokines and chemokines in cytokine storm at multiple levels. In addition, LLLT promotes apoptosis of inflammatory cells and protects alveolar cells from damage. These findings suggest that LLLT is a feasible modality in the treatment of ARDS. LLLT can be added to the conventional treatment in COVID-19 at different stages of the disease. Because of its anti-inflammatory effect, and ability to shorten recovery times, LLLT can reduce the need of ventilators in the healing process. Clinical trials are necessary to objectively evaluate the effect of LLLT on COVID-19 treatment and recovery.
Contributors
Soheila Mokmeli and Mariana Vetrici contributed to the conception and design of the work.
Competing interests
All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval
Informed consent was obtained from all participants.
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Articles from Canadian Journal of Respiratory Therapy: CJRT = Revue Canadienne de la Thérapie Respiratoire : RCTR are provided here courtesy of Canadian Society of Respiratory Therapy
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J Photochem Photobiol B. 2020 Aug 19 : 111999.
doi: 10.1016/j.jphotobiol.2020.111999 [Epub ahead of print]
PMCID: PMC7435279
Light-based technologies for management of COVID-19 pandemic crisis
Caetano P. Sabino,a,b,??,1 Anthony R. Ball,c,1 Mauricio S. Baptista,d,?,1 Tianhong Dai,e,f,1 Michael R. Hamblin,e,g,1 Martha S. Ribeiro,h,1 Ana L. Santos,c,i,j,1 Fábio P. Sellera,k,l,1 George P. Tegos,c,m,1 and Mark Wainwrightn,1
Author information Article notes Copyright and License information Disclaimer
aDepartment of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, SP, Brazil
bBioLambda, Scientific and Commercial LTD, São Paulo, SP, Brazil
cGAMA Therapeutics LLC, Massachusetts Biomedical Initiatives, Worcester, USA
dDepartment of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil.
eWellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
fVaccine and Immunotherapy Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
gLaser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
hCenter for Lasers and Applications, Nuclear, and Energy Research Institute, National Commission for Nuclear Energy, São Paulo, SP, Brazil
iDepartment of Chemistry Rice University, Houston, TX, USA
jIdISBA – Fundación de Investigación Sanitaria de las Islas Baleares, Palma, Spain
kDepartment of Internal Medicine, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, SP, Brazil
lSchool of Veterinary Medicine, Metropolitan University of Santos, Santos, Brazil.
mMicromoria LLC, Marlborough, USA
nSchool of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK
Caetano P. Sabino: moc.adbmaloib@onateac; Mauricio S. Baptista: rb.psu.qi@atsitpab
?Corresponding author. rb.psu.qi@atsitpab
??Corresponding author at: Department of Clinical Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, SP, Brazil. moc.adbmaloib@onateac
1All authors contributed equally to the manuscript
Copyright © 2020 Elsevier B.V. All rights reserved.
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company’s public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre – including this research content – immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
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Abstract
The global dissemination of the novel coronavirus disease (COVID-19) has accelerated the need for the implementation of effective antimicrobial strategies to target the causative agent SARS-CoV-2. Light-based technologies have a demonstrable broad range of activity over standard chemotherapeutic antimicrobials and conventional disinfectants, negligible emergence of resistance, and the capability to modulate the host immune response. This perspective article identifies the benefits, challenges, and pitfalls of repurposing light-based strategies to combat the emergence of COVID-19 pandemic.
Keywords: photoinactivation, ultraviolet, photodynamic, photobiomodulation, germicidal, virucidal, photobiology
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1. Introduction
The pandemic spread of the novel coronavirus disease (COVID-19), caused by the SARS-CoV-2 virus, is a red-alert global health threat [1,2]. In December 2019, COVID-19 expanded from Wuhan throughout China and was then exported throughout the world [[1], [2], [3], [4]]. So far, more than 10 million people have been diagnosed with COVID-19 infection, and many more are expected to be diagnosed within the coming months [5,6]. As the epidemic evolves, national and global organizations are facing an urgent need to coordinate and combat this unprecedented large-scale public health crisis [6].
The epidemiological features of COVID-19 (i.e., severity, full spectrum of disease, transmissibility) have not been fully dissected [7]. The consensus is that the risk for severe acute disease symptoms and death is higher among the elderly and the immunocompromised [[8], [9], [10]]. In severe cases, infected patients need to be transferred to intensive care units for tracheal intubation [11]. This phenomenon is particularly worrisome because it can overwhelm healthcare facilities during the epidemic peak [[10], [11], [12], [13]].
The spread and persistence of SARS-CoV-2 in diverse environments, such as healthcare, community, and residential areas, underlines the urgency for developing effective decontamination approaches as the pandemic crisis evolves [14]. A successful disinfection strategy coupled with additional infection-prevention countermeasures may substantially reduce transmissibility from asymptomatic carriers, a feature that is considered pivotal in the rapid dissemination of SARS-CoV-2. New light-mediated disinfection protocols are currently validated in hospitals and healthcare facilities for surface, air, and water as well as personal protective equipment (PPE), including eyewear, N95 respirators, and masks. Additionally, photobiomodulation, a light-based anti-inflammatory therapy, may have some palliative effects on patients suffering from severe COVID-19. This review examines the potential of light-based technologies to prevent COVID-19 infection and control its dissemination by direct viral inactivation and to treat COVID-19 by modulating the host immune system. The direct antimicrobial actions of solar and UV radiation, photodynamic therapy, antimicrobial blue light, and ultrafast pulsed lasers for disinfection or in vivo use are considered, and the application of photobiomodulation to stimulate the host to mount an anti-viral response is discussed.
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2. SARS-CoV-2 Stability Outside The Human Body
SARS-CoV-2 is highly infectious [15] and transmission occurs through contaminated air, water, and surfaces, which plays a pivotal role in its unbridled dissemination. A recent study by van Doremalen and colleagues investigated the stability of SARS-CoV-2 in aerosols and on inanimate surfaces (e.g., glass, metal, plastic, or cardboard) that can act as important transmission vectors [16]. Their findings suggest that aerosol and fomite transmission of SARS-CoV-2 is likely, indicating that the virus can remain viable and infectious for hours in aerosols and up to days on surfaces. This is in agreement with a recent comparative analysis of 22 studies looking at the persistence of a broader panel of human coronaviruses on inanimate surfaces [17] This study included prominent pathogenic coronavirus species such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and endemic human coronaviruses (HCoV) and concluded that: 1) viruses can remain infectious from 2 h to 9 days; 2) incubation temperature is critical, as some viruses can remain viable at 4 °C for up to 28 days whereas at 30–40 °C viral viability is reduced.
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3. Historical Milestones of Antimicrobial Light
The microbicidal effects of light have been widely known for more than a century. In 1885, Duclaux experimented with several microbial species and concluded that “sunlight is the best, cheapest, and most universally applicable microbicidal agent that we have” [18]. As early as 1877, Downes and Blunt observed that light could effectively kill a series of microorganisms and reported that this effect was dependent on light parameters such as intensity, duration (i.e., light dose) and that the shortest wavelengths (e.g., blue to ultraviolet light) were the most effective [19] The first report on the virucidal effects of UV radiation dates back to 1928 when Rivers and Gates used UV light to inactivate viral particles in suspension and proved the efficacy of the method through subsequent subcutaneous inoculation of rabbits [20].
In 1903, Niels Finsen was awarded the Nobel Prize in Physiology or Medicine for his contribution to the treatment of infectious diseases, especially cutaneous tuberculosis, using visible light [21,22]. Virtually at the same time, Herman Von Tappeiner and Oscar Raab discovered by accident that the use of fluorescent dyes could enhance the microbial killing effect of visible light via photodynamic reactions [22]. By the 1930s, germicidal low-pressure Mercury (Hg) discharge lamps emitting quasi-monochromatic UV-C light (peak emission at 254 nm) had been introduced into the market as highly efficient disinfection equipment [23]. Thus, since the pre-antibiotic era, light-based strategies have been extensively studied and used to treat and prevent infections [24]. However, each photoinactivation strategy has its pros and cons that must be carefully considered when designing a new microbial control strategy.
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4. Natural Ultraviolet Light
Ultraviolet (UV) radiation is naturally and ubiquitously emitted by the sun, representing 10% of its total light output. Only a small portion of the sunlight spectra has direct antimicrobial properties (UV-C). However, since most UV-C light is filtered by the atmospheric ozone layer, in practical terms, the antimicrobial activity associated with sunlight is mostly caused by photochemical reactions induced by UV-A and UV-B photons which are absorbed by endogenous chromophores such as amino acid residues, flavins, and porphyrin derivatives [25]. While UV-A alone does not seem to exert any significant virucidal effects, natural and artificial sunlight, as well as radiation in the UV-B spectrum, have been shown to inactivate bacteriophages and human viruses [26]. A model for the potential of solar UV radiation to inactivate viruses aerosolized in the atmosphere concluded that a full day of sun exposure would on average decrease the infectivity of UV-sensitive viruses by 3 log10 [27].
Besides its virucidal potential, solar UV radiation can also play a protective role against infectious diseases via its modulating effect on vitamin D production [28]. Vitamin D is known to upregulate the production of human cathelicidin, LL-37. This antimicrobial peptide has both antimicrobial and antiendotoxin activities, and also attenuates the production of proinflammatory cytokines which typically accompany respiratory tract infections. Accordingly, it was recently suggested that vitamin D could reduce the incidence, severity, and risk of death due to respiratory tract infections, notably those caused by COVID-19 [29]. However, conclusive evidence for an association between vitamin D supplementation and decreased risk of respiratory tract infections is still lacking.
UV-C is directly absorbed by pyrimidine bases causing their dimerization, which leads to viral inactivation via DNA or RNA damage [30]. Thymine is the main chromophore in DNA while uracil is its counterpart in RNA. Upon UV-C exposure, thymine and uracil form cyclobutane-dimers and pyrimidine-protein cross-links [30]. It must be stressed that UV-C usage must be limited to inanimate objects since it is highly dangerous to human skin. The viral protein coat has been shown to protect nucleic acids from UV-C radiation, by shielding the RNA, quenching the excited states of RNA, and/or by surrounding the bases with a hydrophobic environment and limiting the mobility of the individual bases. This results in a reduction of the overall rate of photoreactions, which allows the formation of non-cyclobutane-type dipyrimidines and uridine hydrates. Viral coating proteins themselves may suffer UV photodamage and become cross-linked to RNA.
The International Ultraviolet Association (IUVA) recently released a fact sheet detailing the efficacy of UV on SARS-CoV-2 [31] in which they reviewed all the appropriate requirements for the safety of UV-C disinfection devices and discussed the corresponding performance standards and validation protocols. Coronaviruses display a wide range of UV-C LD90 (UV-C dose necessary to inactivate 90% of a microbial population) values, from 7 to 241 J/m2 so one might assume that the UV-C susceptibility of the novel SARS-CoV-2 (COVID-19) virus probably lies within this range [32]. Therefore, based on previous studies with SARS-CoV-1 and other RNA-based coronaviruses, UV-C light can be used to effectively inactivate such pathogens present in the air, liquids and over several surfaces [33,34].
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5. Ultraviolet Germicidal Irradiation (UVGI)
UV-C lamps have long been used in hospital and industrial settings for decontamination purposes. In the context of a mitigation approach to infection spreading, UV-C can be particularly helpful in the inactivation of virus-containing aerosols and surfaces.
Air disinfection via upper-room germicidal UV-C light fixtures may be able to reduce viral transmission via the airborne route. Accordingly, an observational study during the 1957 influenza pandemic reported that patients housed in hospital wards with upper-room UV-C had an infection rate of 1.9%, compared to an infection rate of 18.9% among patients housed in wards without UV-C [35]. However, it is important to note that the germicidal effect of UV-C seems to be strongly dependent on the relative humidity of the air, with UV-C effectiveness against influenza virus decreasing with increasing relative humidity [36].
The potential of viral spreading via contaminated surfaces depends on the ability of the virus to maintain infectivity in the environment, which in turn is influenced by several biological, physical, and chemical factors, including the type of virus, temperature, relative humidity, and type of surface [37]. Importantly, single-stranded nucleic acid (ssRNA and ssDNA) viruses were more susceptible to UV inactivation than viruses with double-stranded nucleic acid (dsRNA and dsDNA). Also, the UV dose necessary to achieve the same level of virus inactivation at 85% relative humidity (RH) was higher than that at 55% RH [37].
In a recent study, Fischer et al. showed that UV-C light can inactivate more than 99.9% of SARS-CoV-2 viral particles deposited over the filtering material of N95 masks and stainless steel surface [38]. As expected, inactivation kinetics over stainless steel was much faster (i.e., more than 99.9% for (0.33 J/cm2). However, after sufficient exposure (1.98 J/cm2) UV-C could promote germicidal efficacy levels that were similar to those promoted by ethanol, dry heat or vaporized hydrogen peroxide. Older studies have hypothesized that the necessary dose to inactivate 90% of viruses present in N95 filtering facepiece respirator (FFR) material would be about 30 times higher than over the surface of non-porous materials [39]. This was an interesting estimation, but we should keep in mind that UV-C emission spectrum and irradiance of different UV-C equipment as well as material composition are widely variable [40]. Therefore, such estimatives cannot be used as a robust procedure and experimental demonstrations must always be presented. Indeed, a recent in silico study demonstrated that for effective and fast decontamination one should consider the FFR shape besides the optical properties of the FFR model, which has to be determined at the UV-C specific wavelength [41]. Even though UV does not seem to affect the filtrating capacity of FFRs, it is important to note that high UV-C doses can lead to reduced tensile strength of its materials [42,43].
The combination of multiple light wavelengths has been explored for cosmetic, environmental (water disinfection) and clinical (microbial catheter disinfection) applications. However, the precise photobiological mechanism of action and the experimental workflow to develop a marketable application is still missing [44,45].
It must be remarked that UV-C light at 254 nm is harmful to the eyes and skin and, therefore, it is recommended to use it in setups that avoid direct human exposure. Although, far-UV-C (207–222 nm) has been proposed as a disinfection technology that seems to be safer to human exposure [46]. This has been claimed because far-UV-C range is strongly absorbed by amino acid residues and, therefore, is further blocked by the acellular stratum corneum of the skin and the cornea of the eye, leading to lower levels of UV-C light reaching the cellular layers of eyes and skin. However, as far as our knowledge goes, robust studies showing the actual safety of far-UV-C towards animal tissues in short and long terms have not been strongly established and degradation of proteins can also lead to serious eye and skin damages. Thus, we can only recommend UV-C application to inanimate objects. Additionally, far-UV-C technology is not broadly available in the market yet and the cost is far higher than common LP-Hg lamps. On the other hand, UV-C LED technology is limited to very compact applications. The shortest wavelengths available are around 255 nm, with the price per Watt being up to 1000 times higher than that of LP-Hg lamps, while displaying an energy efficiency (< 1%) far lower than that of LP-Hg lamps (25–40%) at 254 nm.
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6. Photoantimicrobials and Photodynamic Therapy
Visible light can exert antiviral effects via photodynamic mechanisms that are initiated upon absorption of light by exogenous photosensitizer compounds, such as phenothiazinium salts, porphyrins, nanoparticles, and others [[47], [48], [49], [50]]. The inactivation of microorganisms and viruses by visible light is based on the generation of lethal oxidant species via photosensitized oxidation reactions, which usually require three components: the chromophore, termed the photosensitizer (PS), light, and oxygen, even though some PS may also work through alternative reactions in the absence of oxygen [51]. After light absorption, excited oxygen states are quickly formed, initially in the singlet, and subsequently in the triplet states (i.e., considering the photocycle of organic molecules). These species can release the excitation energy in the form of light emission (e.g., fluorescence and phosphorescence) or heat release (non-radiative decay). Since excited states are intrinsically more reactive than ground states, energy and electron transfer reactions can occur. There are two main mechanisms of photosensitized oxidation: Type I reactions depend on the encounter of the excited species with biological substrates. These reactions usually occur through electron or hydrogen abstraction, leading to radical chain reactions; Type II reactions rely on energy transfer reaction from the PS triplet state to molecular oxygen, generating singlet oxygen (1O2) (Fig. 1 ) [52]. Spacially, type I reactions require the PS to be within a subnanometer distance to the virus, whereas type II reactions allow singlet oxygen diffusion to more than 100 nm [51].
Fig. 1
Mechanisms of photosensitized oxidation reactions. The photosensitizer (PS) is a molecule capable of absorbing light depending on its specific absorption spectra. Once excited, the PS is converted from the ground state 1PS to its singlet excited 1PS? and triplet excited 3PS? states. Via Type I (contact-dependent) reactions both 1PS? and 3PS? can react directly with O2 or biomolecules, like carbohydrates, lipids, proteins, or nucleic acids, resulting in the formation of radicals capable of initiating redox chain reactions. Otherwise, 3PS? can react with molecular oxygen (3O2), via the Type II (energy transfer) reaction, generating the reactive state of singlet oxygen (1O2).
Light energy is thus converted into oxidation potential that can damage biomolecules. Antimicrobial photodynamic therapy (aPDT) is based on this process and it has been used to treat localized microbial infections caused by viruses, bacteria, fungi, and parasites [53]. Among the many pathogens that can be targeted by aPDT, viruses are perhaps the most vulnerable, as they depend on entering a host cell for survival and replication and can be inactivated by damaging the capsid or envelope molecules (lipids, carbohydrates, proteins) or internal molecules (nucleic acids) (Fig. 1). Thus, many viruses can be treated via aPDT, including papillomavirus (HPV), hepatitis A virus (HAV), and herpes simplex virus (HSV) [[54], [55], [56]]. Additionally, the disinfection of biological fluids (plasma and blood products) by photoantimicrobials has been performed for decades and is a well-regarded technological application of these compounds. For instance, extracorporeal photoinactivation of coronaviruses and other clinically relevant pathogens using methylene blue (MB)-mediated aPDT has been reported [[57], [58], [59], [60], [61], [62]].
It is possible that photosensitized oxidation can neutralize SARS-CoV-2 and, consequently, play a role in mitigating the ongoing pandemic; however, there is no data available on the photodynamic inactivation of this virus. Thus, here we sought to find and discuss scientific literature that could help predict whether COVID-19 is more or less susceptible to oxidant species generated during aPDT.
While all types of viruses can be neutralized by aPDT, the inactivation efficiency depends on both the PS and the virus [63,64]. As a rule of the thumb, RNA-type phages are more easily photoinactivated than their DNA-type counterparts, suggesting that SARS-CoV-2, which is an enveloped RNA-type virus, can be easily neutralized by aPDT [64,65]. Guanine bases are the major targets for oxidation by photosensitizing agents in both RNA and DNA [66]. The formation of RNA-protein crosslinks may also be an important lesion involved in virus inactivation via aPDT [67].
Enveloped viruses are more prone to aPDT neutralization than those without an envelope, due to the role of PS in damaging envelope components [68,69]. Initial studies on viral inactivation by aPDT demonstrated the importance of the PS reaching specific reaction sites, so-called “marked targets”, for efficient viral inactivation [70]. Other reports have confirmed the importance of PS binding on the efficiency of virus inactivation via aPDT, and the PS membrane partition coefficients can be used as a predictor of its virus inactivation efficacy [71,72]. Transmission electron microscopy data has revealed that low PS concentrations degrade envelope surface glycoproteins blocking virus internalization, while higher PS concentrations can destroy lipid membranes [73]. These results can be interpreted in terms of the current mechanistic understanding of photosensitized oxidation, specifically the important role of direct-contact reactions. Irreversible membrane damage occurs with the abstraction of a hydrogen atom from an unsaturated fatty acid by direct reaction with the triplet excited state of the PS. Subsequent formation of peroxyl and alkoxyl radicals leads to the build-up of truncated lipid aldehydes, which are ultimately responsible for opening membrane pores [74]. The fact that irreversible damage occurs due to contact-dependent reactions, indicates that the damage can be confined within the nanometer location site of the PS [75].
In terms of the application of aPDT to treat COVID-19 patients, it is encouraging to note that this technique is already used to treat several respiratory diseases [76]. PDT has been used for decades to treat lung cancers and its successful application in the treatment of laryngeal papillomas has also been reported [77]. Geralde et al. recently demonstrated that acute pneumonia caused by Streptococcus pneumoniae could be treated via inhalation of indocyanine green combined with extracorporeal administration of infrared light [78]. A prophylactic approach proposed by Soares et al. showed that aPDT can also be used to eliminate bacterial biofilms frequently associated with endotracheal tubes and that can lead to more severe stages of acute respiratory syndromes [79]. More recently, Schikora and colleagues reported succesfull use of aPDT to disinfect oral and nasal cavity of patients in early stages of COVID-19 infection This approach can potentially lead to a temporary and moderate reduction of disease progression but cannot be regarded as a potential therapeutic procedure since aPDT is limited to local effects and COVID-19 is a systemic disease [80].
Considering that: 1) SARS-CoV2 is an enveloped RNA virus, 2) aPDT is efficient at neutralizing such viruses, and 3) light is already used to treat lung and airway-related infections, we propose that aPDT is a good candidate for treating COVID-19 or as an adjunct to disinfect biological fluids. Alternatively, photosensitizers could also be used to decontaminate liquids and surfaces or be incorporated into polymeric matrices such as plastics, fabrics, paper, and paints to produce photoantimicrobial materials [53,58,81]. Allotropes of carbon such as fullerenes, carbon nanotubes, and graphene can also show light-activated antimicrobial effects, including the inactivation of viruses [69,82,83].
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7. Antimicrobial Blue Light
Visible blue light exhibits microbicidal effects in the wavelength range of 405–470 nm [25,[84], [85], [86], [87], [88]]. High-intensity narrow-spectrum light at 405 nm has been used for continuous decontamination of inpatient and outpatient burn units and patient-occupied intensive care isolation rooms, as well as the treatment of surgical site infections in an orthopedic operating room [[89], [90], [91]]. Compared to UV-C, in general terms antimicrobial blue light (aBL) requires a much higher radiant exposure (or longer exposure times) to reach similar levels of microbial inactivation if irradiance of the light sources is similar. Even though aBL displays decreased deleterious effects on mammalian cells, one should avoid direct eye exposure because eye lens focuses visible light and overexposure can promote either flash blindness or retinal lesions.
The exact mechanisms underlying the antimicrobial effects of blue light are not yet completely understood but appear to involve the formation of short-lived reactive oxygen species (ROS) [92]. The most widely accepted view of the process posits that the photochemical mechanisms of aBL are based on light energy excitation of endogenous microbial intracellular light receptors (chromophores), such as porphyrins and flavins. Once excited, these receptors undergo energy transfer processes that lead to the generation of cytotoxic ROS which react with intracellular components resulting in photodamage and cell death by oxidative stress [93]. Since endogenous photoreceptors appear to be absent in viruses, the mechanisms by which aBL affects these pathogens remains unclear. However, it is currently known that: 1) the use of exogenous photosensitizers improves the efficiency of inactivation by blue light, and 2) the inactivation is more pronounced when viral particles are present in body fluids, e.g., saliva, feces, and blood plasma, which contain photosensitive substances [94,95].
Accordingly, antimicrobial blue light has been explored in the treatment of infectious diseases and as a disinfection adjuvant in healthcare settings. Clinical trials have revealed the efficiency of aBL in the treatment of acne, Helicobacter pylori gastrointestinal infections, and dental infections [87,[96], [97], [98]]. aBL was recently shown to rescue mice from methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa wound infections [99,100]. Oral anaerobic periodontopathogenic bacteria (Porphyromonas gingivalis, Prevotella intermedia, and P. nigrescens) were also inhibited or completely eradicated under blue light irradiation [101,102].
In a recent bioinformatics study, SARS-CoV-2 infection was reported to be dependent on porphyrin, which it captures from human hemoglobin, resulting in altered heme metabolism [103]. However, the in silico methods used to obtain such results have been questioned by a commentary publication, putting into doubt wheter SARS-CoV-2 actually interacts with heme metabolism and accumulates porphyrins [103]. If this thesis is experimentally proven to be correct, aBL might be able to kill SARS-CoV-2 by photoexcitation of its acquired porphyrins. Thus, experimental studies are required to verify the potential of aBL to prevent and control COVID-19.
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8. Photobiomodulation Therapy
Photobiomodulation (PBM) employs low levels of red or near-infrared (NIR) light to treat and heal wounds and injuries, reduce pain and inflammation, regenerate damaged tissue, and protect tissue at risk of dying [104]. Instead of directly targeting viruses, PBM mainly acts on the host cells, which absorb light in the red and near-infrared spectral region [104]. Literature indicates that photons are absorbed by multiple cellular chromophores, including mitochondrial enzymes, to trigger the biological effects of PBM [[104], [105], [106]]. Cytochrome c oxidase (i.e., unit IV in the mitochondrial respiratory chain) appears to play a main role in this process [104]. Other molecular chromophores include light and heat-sensitive ion channels (transient receptor potential) that, upon light activation, lead to changes in calcium concentrations. Nanostructured water (interfacial water) is also likely to act as a chromophore. Upon irradiation, the mitochondrial membrane potential is raised and oxygen consumption and ATP generation are increased. Subsequent activation of signaling pathways and transcription factors leads to fairly long-lasting effects even after relatively brief exposure of the tissue to light [107].
In the early 1900s, Finsen reported that patients exposed to red light exhibited significantly better recovery from smallpox infections than unexposed counterparts [21]. Since then, PBM has been used in the treatment of acute lung injury, pulmonary inflammation, and models of acute respiratory distress syndrome (ARDS), due to its ability to substantially reduce systemic inflammation while preserving lung function. [[108], [109], [110]]. There are currently 90 published papers on PBM concerning “acute lung injury” [110] OR “pulmonary inflammation” [111] OR “lung inflammation” [109] OR “ARDS” [112] OR “lung oxidative stress” [113] OR “asthma” [114] many involving small animal models where it can be argued that light penetrates more easily than in humans. Because COVID-19 involves a “cytokine storm”, PBM delivered to the torso (chest and back) might not only allow some light to reach the lungs but might also reduce the systemic inflammation responsible for COVID-19 sepsis-like syndrome [115] and disseminated intravascular coagulation [116] that can be deadly [117]. Moreover, PBM is more effective on hypoxic cells [118], suggesting it could be effective for COVID-19 infection, which seems to be characterized by severe hypoxia [119]. Nevertheless, so far there are no experimental data supporting the influence of PBM on COVID-19. Therefore, clinical studies have to be performed to understand whether PBM therapy may actually reduce the cytokine storm impacts for COVID-19 patients.
Hospitalized patients receiving mechanical ventilation or under high-oxygen continuous positive airway pressure (CPAP) treatment could be placed on an LED pad. These do not generate unacceptable levels of heat, so the high fever experienced by these patients should not be a problem. LED-based PBM devices similar to these have been approved by the FDA for general health and wellness applications, and there are no reported adverse effects [120]. However, PBM is not recommended to be used over cancerous lesions since the effects on tumor cells are not fully understood yet [121].
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9. Ultrafast Laser Irradiation
Ultrashort pulse lasers (USPLs) emitting visible to near-infrared light have been used to inactivate a broad spectrum of viruses (human immunodeficiency virus, human papillomavirus, encephalomyocarditis virus, M13 bacteriophage, tobacco mosaic virus, and murine cytomegalovirus) with no damage to human or murine cells [[122], [123], [124], [125], [126]]. Regardless of wavelength, ultrafast laser irradiation at low mean irradiance levels (? 1 W/cm2) does not promote ionization effects that could impair host cells. This irradiation does not appear to destroy either bovine serum albumin or single-stranded DNA, nor cause adverse effects like those produced by toxic or carcinogenic chemicals. Previous works suggest that the antimicrobial effect of USPLs at low mean irradiance is exerted via impulsive stimulated Raman scattering, whereby high-frequency resonance vibrations provoke vibrations of sufficient strength to disintegrate the capsid into subunits through the breaking of weak links (e.g., hydrogen bonds and hydrophobic contacts) in non-enveloped viruses [126]. For enveloped virus, USPLs promote vibrations on the proteins of the capsid. These excitations break the hydrogen bonds and hydrophobic contacts causing partial unfolding of the proteins. Since the concentration of confined proteins is very high within the capsid of a virus, they can assemble with other neighboring proteins, leading to the aggregation of proteins [125]. In contrast, an intense laser pulse could generate shock wave-like vibrations upon impact with the virus to promote viral inactivation [126].
However, laser pulsing may not be necessary for its antimicrobial action. Recently, Kingsley et al. applied a tunable mode-locked Ti-Sapphire laser emitting femtosecond pulses at wavelengths of 400, 408, 425, 450, 465, and 510 nm to verify inactivation of murine norovirus (MNV) [92]. Using an average power of 150 mW, authors observed that femtosecond-pulsed light emitting at 408, 425 and 450 nm promoted more than 99.9% of virus inactivation after 3 h of illumination, indicating that the inactivation mechanism is not wavelength-specific. In addition, they reported that a continuous wave 408 nm laser at similar power also promoted reduction of plaque-forming units, although the addition of exogenous photosensitizers has increased MNV inactivation. These data suggest that virus inactivation does not require pulsing and can be improved in the presence of singlet oxygen enhancers, as previously reported for aBL (see section 7).
Potential use of USPLs encompasses the inactivation of pathogens in pharmaceuticals, blood products and uncooked foods as well as chemical-free whole inactivated virus vaccine preparation [127,128]. Laser treatment resulted in 1-log, 2-log, and 3-log reductions in hepatitis A, human immunodeficiency, and murine cytomegalovirus, respectively, in human plasma with no changes in the structure of fibrinogen [127]. Further, in mice USPL-induced inactivation of H1N1 influenza virus was more effective than formalin and did not cause damage to viral surface proteins or resulted in the production of carbonyl groups in proteins [128].
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Concluding remarks
As we presented in this review, light-based technologies have unique features that could be useful to face the COVID-19 pandemic, but could also present pitfalls that deserve to be highlighted. Thus, we compiled at Table 1 their advantages and disadvantages.
Table 1
Light-based strategies available to combat the emergence of COVID-19 pandemic. FFR: filtering facepiece respirator.
Light-based Platform
Potential Applications
Advantages
Disavantages
Natural Ultraviolet Light
Synthesis of vitamin D
Sunburn following overexposure
Microbicidal activity
Long-term aging and cancer risk
Ultraviolet Germicidal Irradiation
Surface, FFR reuse, air and water disinfection
Low exposure time to reach high levels of pathogen inactivation (< 1 min) depending on irradiance of light source
Risk of tissue damage and cancer
Potential long-term degradation of materials
Photoantimicrobials and Photodynamic Therapy
Environmental and surface disinfection, therapeutics, virus inactivation in biological products
Efficient and selective pathogen inactivation following short period of illumination if photosensitizer is resonant to light source wavelength
Photosensitizer could promote material and/or tissue staining
Systemic PS administration may cause photosensitivity
Succesfull results depend on light parameters, type of microorganism, PS concentration and pre-irradiation time
Non-invasive approach
Succesfull results in humans with artificial light sources
Antimicrobial Blue Light
Environmental and surface disinfection, therapeutics, virus inactivation in biological materials
Can be used in inhabited places and to treat infections in humans
Long exposure time (above 30 min)
No notable detrimental effect in materials following long periods of illumination
Effect is more pronounced in the presence of exogenous photoabsorbers
Photobiomodulation Therapy
Therapeutics
Non-invasive technique
Succesfull results depend on light parameters, patient characteristics and disease aetiology
Succesfull results in humans with artificial light sources
Adjuvant to conventional therapies
Ultrafast Laser Irradiation at low irradiance
Selective virus inactivation in blood products, pharmaceuticals, food and vaccine development
Selective pathogen inactivation
Long exposure time (~3 h)
Chemical-free vaccine preparation
Expensive light sources
Open in a separate window
In summary, we have described how light-based strategies can be used to reduce SARS-CoV-2 transmission through air, water, and surfaces as well as potential therapeutic applications that can reduce COVID-19 morbidity and mortality. From our perspective, light provides several practical answers to the new logistical and therapeutic challenges brought by COVID-19. Therefore, we suggest that the death toll and quarantine extent can be significantly mitigated if at least part of these strategies are encouraged and implemented by health systems. Given the urgent demand raised by the current uncontrolled pandemic we must be ready to use all the available armamentarium to fight COVID-19.
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Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
We attest no conflict of interest in the manuscript we are submitting entitled “Antimicrobial light-based technologies for management of COVID-19 pandemic crisis”.
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Acknowledgements
CPS was supported by the São Paulo Research Foundation (FAPESP, grant 2017/22406-0) and by the Brazilian National Council for Scientific and Technological Development (CNPq, scholarship 141901/2016-0). FPS is supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES Finance code 001). ALS is supported by a Marie-Curie Global Fellowship mentored by GPT (EU project 843116 – REBELLION). TD is supported by USA National Institutes of Health (NIH, grant R01AI123312) and by the Department of Defense (DoD, grant FA9550-17-1-0277). MRH is supported by USA National Institutes of Health (NIH, grants R01AI050875 and R21AI121700). MSR thanks Photonics Institute (INCT/CNPq, grant 465763/2014-6) for financial support. MSB acknowledges FAPESP for the CEPID Redoxoma grant 2013/07937-8.
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