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Light as a Cure in COVID-19: History
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Contributor: Laura Marinela Ailioaie , Constantin Ailioaie , Gerhard Litscher
The history of the use of light in modern medicine dates to the early 1900s, when Finsen reported significant recoveries of smallpox patients exposed to red light compared to unexposed controls. Finsen was awarded the Nobel Prize in 1903 “in recognition of his contribution to the treatment of diseases, especially lupus vulgaris, with concentrated light radiation, whereby he has opened a new avenue for medical science". The exceptional demonstrations of N.R. Finsen have inaugurated a new stage in contemporary medicine regarding the effectiveness of light therapies, followed by implementing new laser technologies after Endre Mester incidentally detected the positive effect of a ruby laser beam on hair growth and wound healing in mice. Originally called Low Level Light/Laser Therapy (LLLT), nowadays, photobiomodulation (PBM) is a modality that consists of projecting light to influence the activity of living cells, tissues, and even the entire organism to stimulate the immune system, promote tissue repair, advance healing, decrease inflammation, and control pain.
  • antimicrobial
  • cytokine storm
  • hyperinflammation
  • immunomodulation
  • photobiomodulation

1. Photobiomodulation (PBM) Applied in Pulmonary Inflammation Caused by COVID-19

The first case report of a 57-year-old African American male with severe COVID-19, to whom photobiomodulation therapy (PBMT) was applied as adjunctive or supportive therapy to treat lung infection and prevent the cytokine storm, was published by Sigman et al. in August 2020. It is relied on the pre-pandemic findings of scientific studies on human subjects but also on experimental models of respiratory diseases, which had already scientifically proven that PBMT is an adjuvant safe therapy with important anti-inflammatory and regenerative effects in lung disorders. PBMT was applied with a laser in scanner mode (with near-infrared wavelengths of 808 nm in pulses, and 905 nm in super-pulses), 28 min at each session, i.e., 14 min each lung, for four consecutive days, with the patient in the prone position. Both laser diodes operated synchronously and simultaneously with coincident propagation axes, as follows: (1) GaAlAs diode (808 nm), peak power: 3 W, pulse duration: 333 μs, dose: 7.2 J/cm2; (2) GaAs diode (905 nm), peak power: 75 W × 3, pulse duration: 100 ns, dose: 113.4 mJ/cm2. For both laser diodes, the modulation frequency was equal to 1500 Hz, the total scanned area was 25 × 10 = 250 cm2, and the total energy delivered was 3600 J per session. An energy density of 7.2 J/cm2 over the skin penetrated the chest wall (1.6 to 6 cm) to provide the lung with just over 0.01 J/cm2 of laser energy, which proved to be sufficient for biostimulation. The patient tolerated all four daily sessions well and had an important amelioration in breathing right after each therapy. The subject was assessed previously and post-therapy by blood tests, radiographic assessment of lung edema (RALE), indices of pulmonary severity, oxygen demands, and a set of questions. PBMT results were good, as follows: oxygen saturation increased from 93–94% to 97–100%, oxygen demand decreased from 2–4 L/min to 1 L/min, RALE improved from 8 to 5, and the pneumonia severity index ameliorated from 142 (Class V) to 67 (Class II). Other additional pulmonary indices both declined from 4 to 0. C-reactive protein (CRP), initially equal to 15.1 mg/dL returned to normal (1.23 mg/dL), and the subject reported a substantial improvement in the perception of pneumonia in a couple of days, without necessity for artificial ventilation. Herein, PBMT modulated the immune system, reduced inflammation and edema, and stimulated healing processes, being non-invasive, cost-effective, and without known side effects. It is agreed on the request for further controlled clinical trials to investigate in depth the results of PBMT on the outcome of severe cases of COVID-19 [1].
Another case published by Sigman et al. refers to a 32-year-old Asian patient with morbid obesity and severe COVID-19 who received four consecutive sessions of once-daily PBMT via a dual-wavelength pulsed 808 nm laser scanner (diode GaAlAs, 3 W, frequency 1500 Hz, 330 microseconds pulse duration) and 905 nm (GaAs diode, 75 W × 3, super-pulsed 1500 Hz, 100 nanoseconds pulse duration) administered over the posterior thorax for 28 min. Each lung was scanned at a distance of 20 cm above the skin for 14 min from apex to base over a 250 cm2 area of the posterior thorax with a dose of 7.2 J/cm2 and a total delivered energy equal to 3600 J. Initially, the SpO2 measured by pulse oximetry was 88–93% at 5–6 L of oxygen received, and after PBMT, SpO2 increased to 97–99% at 1–3 L of oxygen required. At the same time, there was a decrease in the RALE score from 8 to 3, and the Brescia-COVID indices decreased from 4 to 0, and the SMART-COP decreased from 5 to 0. The level of interleukin 6 (IL-6) decreased from 45.89 to 11.7 pg/mL, ferritin from 359 to 175 ng/mL, and CRP from 3.04 to 1.43 mg/dL. At the end of treatment, the patient felt a marked improvement in breathing. The case presented by the authors motivates the use of PBMT as an adjuvant method in the conventional treatment of patients with severe COVID-19 and morbid obesity [2].
Reproducing the case reports mentioned above, but on a larger scale, Vetrici et al. evaluated the supporting role of PBMT for COVID-19, investigating clinical outcome and pulmonary severity indices in a small-scale study with 10 patients randomized to standard care, or the same therapy plus adjuvant PBMT, i.e., two groups that were not statistically different in terms of demographic characteristics at the beginning of the trial. The laser lot received PBMT using a near-infrared Multiwave Locked System (MLS) scanner-equipped laser (approved by the US Food and Drug Administration as a nonsignificant risk device) as daily sessions for four consecutive days to target pulmonary tissue. The laser system included two different laser arrays: (1) three GaAlAs laser diodes (808 nm), 1 W (peak power) and 500 mW (average power) for each diode, 75 mW/cm2 power density, 330 µs each pulse; and (2) three superpulsed GaAs laser diodes (905 nm), 75 W (peak power) and 203 mW (average power) for each diode, 31 mW/cm2 power density, 100 ns pulse duration; both arrays with the same frequency of 1500 Hz (train pulses 90 kHz modulated at 1 Hz ÷ 2 kHz), the same spot size of 19.6 cm2 and a total energy delivered of 3590 J per session. The mobile laser scanner was 20 cm above each subject, who was lying in a prone position. The patient’s clinical condition was investigated using blood tests, chest X-rays, pulse oximetry, and other standard instruments prescribed for evaluating pneumonia. Patients with PBMT were considered for ICU and intubation, but all recovered without mechanical ventilation, and all manifested a rise in oxygenation just 10 min from the onset of PBMT during each session. Three control patients had fulminant results and were intubated until day 2 due to the very fast decrease in oxygen saturation, and two of them died. At a 5-month follow-up, two of the three live control patients (one recovered spontaneously, and the other was placed on mechanical ventilation) still had severe lung-related signs. All patients with PBMT recovered without side effects or mechanical ventilation and were discharged within one week of enrollment in the study, all of whom were asymptomatic at 5 months of follow-up. Adjuvant PBMT led to an important amelioration in all investigated pulmonary indices, proving a rapid recovery, lack of hospitalization in ICU, no need for mechanical ventilation, and no long-term sequelae after 5 months after initiation of the therapy. Due to the fact that 60% of the control group were transferred to the ICU for mechanical ventilation and had an overall mortality of 40%, and another 40% suffered long-term sequelae at 5-month follow-up, compared to the good results in the PBMT group, the authors concluded that PBMT is a reliable, effective, and feasible therapy for lung inflammation in COVID-19, favorably modulating the clinical condition, avoiding the necessity for mechanical ventilation, long-term sequelae, or mortality of patients with COVID-19. The authors acknowledged that the small number of patients herein is an important limitation for this research, and that future academic and university clinical trials with larger groups are needed to substantiate the effect of PBMT in COVID-19 [3].
Pelletier-Aouizerate et al. used red light photobiomodulation therapy (RL-PBMT) in two severe cases of COVID-19 concurrently with conventional drugs. The patients benefited from RL-PBMT through an LED device that simultaneously emitted wavelengths of 630 nm and 660 nm, respectively, applied transcutaneously, 3 sessions of 15 min each per week, at a power density of 55 mW/cm2 with a fluence of 50 J/cm2, on the presternal region 7 cm above the skin. Patients continued RL-PBMT for an additional 9 months post-illness to aid their recovery, particularly fatigue on exertion. RL-PBMT triggered an improvement in blood oxygenation, modulated the patients’ inflammatory response, and did not induce complications during treatment. It is recommend the use of RL-PBMT from the early stages of inflammation and respiratory pathology; this effective treatment method has a low cost and the advantage that it can be used in the clinic or at the patient’s home [4].
Pereira et al. estimated the efficacy of PBMT on immunomodulatory markers and physiological parameters in COVID-19 patients at a moderate to high risk of death. 20 patients with severe COVID-19 were non-blind randomized into two groups. The laser group received six days of therapy in five areas: the lung area, face, tonsillar fossae, trachea, and bronchi. The results showed a reduction in CRP levels, a return to normal platelet counts, and a consistent improvement in partial arterial oxygen pressure (PaO2) compared to the control group. It is proved that PBMT may be a viable option in patients diagnosed with COVID-19 who develop severe forms of the disease, including acute hypoxemic respiratory failure or ARDS, acute renal failure, and thromboembolic events, and who require hospitalization in the ICU [5].
Marashian et al. aimed to evaluate the level of pro-inflammatory cytokines to find a therapeutic strategy based on PBMT to inhibit their uncontrolled release in some patients with COVID-19, thus avoiding ICU admission or damage to vital organs. The study included 52 hospitalized patients with mild to moderate COVID-19 who were randomized into two groups (PBMT and placebo). In the group of 24 patients treated with PBMT, light was provided by 8 LEDs with wavelengths between 620–635 nm with an energy density of 45.40 J/cm2 and a power density of 0.12 W/cm2, twice a day, for three days, along with conventional drugs. The serum levels of the cytokines IL-6, IL-8, IL-10, and TNF-alpha were determined for both groups during the research. The results demonstrated a significant decrease in serum levels of IL-6, IL-8, and TNF-α; and the IL-6/IL-10 ratio was notably reduced in the PBMT group compared to the placebo group. In conclusion, It is claimed that the level of major cytokines (IL-6, IL-8, and TNF-α) in COVID-19 patients undergoing PBMT significantly decreased, thus paving the way for managing the cytokine storm within days [6].
Williams et al. published a non-randomized study on 50 positive COVID-19 patients using transdermal dynamic photobiomodulation of deep tissues throughout the body. PBMT was applied by algorithmically alternating red (650 nm) and near-infrared (NIR; 850 nm) LEDs with an average power density of 11 mW/cm2, dynamically sequenced at multiple pulse frequencies, each session of 84 min, with 20 kJ for the sinuses and 15 kJ for each lung at skin temperatures below 42 °C. The results show a significant reduction in the duration and severity of disease symptoms (fever, pain, respiratory distress with paroxysmal cough; pulmonary congestion, dyspnea, hypoxia, sinus congestion, acute ocular inflammation, and extreme malaise), which disappeared in 41/50 patients within 4 days of starting treatment, and then in 50/50 patients in the following 3 weeks, without the need for additional oxygen. SpO2 concentrations improved by up to 9 points in all patients [7].

2. PBMT in Combination with Static Magnetic Field in COVID-19

PBMT as a single method or in combination with a static magnetic field (PBMT-sMF) has been confirmed in terms of beneficial effects in tissue regeneration, modulation of inflammatory processes, and improvement of pulmonary functional capacity. However, the PBMT-sMF combination as a therapeutic modality has been applied less to the respiratory tract in patients with COVID-19. Tomazoni et al. used PBMT-sMF in a case of low peripheral oxygen saturation with massive lung injury and fibrosis after COVID-19. PBMT-sMF was administered once daily for 45 days by irradiating six sites of the lower thorax and upper abdominal cavity, and two sites in the neck area. Each area was treated for 60 s, a total of 480 s per sMF session. For PBMT, 4 lasers were used that emitted at a wavelength of 905 nm, at a frequency of 250 Hz, with an output power of 50 W, and power density of 3.91 mW/cm2—each, a dose of 0.075 J each; and 8 red LEDs (633 nm), at a frequency of 2 Hz, with a dose of 1.50 J each; as well as 8 other LEDs (850 nm), frequency of 250 Hz and output power of 40 mW. After the first 10 days of PBMT, the patient’s SpO2 increased from/to 89% to 2 L/min oxygen, and at 45 days, the patient was off supplemental oxygen, and pulmonary and radiological severity scores improved. Finally, after 4 months, the patient reached 98% SpO2, with normal parameters of respiratory mechanics and a complete recovery [8].
De Marchi et al. conducted a prospective triple-blind randomized placebo-controlled trial in a group of 30 patients admitted to an ICU with COVID-19, who required invasive treatment, including mechanical ventilation. Patients were randomly assigned equally to two groups to receive either PBMT-sMF or a daily placebo throughout their ICU stay. PBMT was delivered via a 20-diode cluster probe that included 4 infrared diodes (905 nm, peak power: 50 W, average optical output: 1.25 mW, power density: 3.91 mW/cm2, spot size: 0.32 cm2, superpulsed operation mode); 8 red diodes (633 nm, average optical output: 25 mW, power density: 29.41 mW/cm2, spot size: 0.85 cm2 and pulsed operation mode); and another 8 infrared diodes (850 nm, average output power: 40 mW, power density: 71.23 mW/cm2, spot size: 0.56 cm2 and pulsed operation mode). PBMT-sMF was applied in six sites (33 cm2 each site) in the lower thoracic/upper abdominal region, and two sites (33 cm2 each site) in the neck area (the sternocleidomastoid muscle). The exposure time was 60 s on site, with a total treatment time of 480 s (8 min). The energy delivered to the site was 31.50 J, resulting in a total energy input of 189 J and 63 J to the lower chest and neck regions, respectively. The total irradiated surface was 264 cm2, with a dose of 0.95 J/cm2. The effects of PBMT-sMF in preserving respiratory muscles and modulating inflammatory processes were quantified during ICU stay, survival rate, diaphragm muscle function, ventilatory, and blood parameters, including arterial blood gas concentration. The results confirmed that the PBMT-sMF group had a shorter ICU hospital stay, no significant decrease in diaphragm thickness, improved ventilatory parameters and lymphocyte counts, and significantly lower C-reactive protein levels than the control group. There was no significant difference in ICU length of stay between the PBMT-sMF and placebo groups for severe cases of COVID-19 requiring invasive mechanical ventilation. However, PBMT-sMF is associated with increased diaphragm thickness, PaO2/FiO2 ratio, and lymphocyte count and decreased FiO2, CRP levels, and hemoglobin count [9].

3. PBMT Applied in Olfactory and Taste Dysfunctions Caused by COVID-19

Intranasal irradiation could provide neuroprotection through anti-inflammatory and antioxidant pathways due to abundant blood capillaries but with relatively slow blood flow; other possible mechanisms of action include activation of neural stem cells in the olfactory nerve, bulb, and endothelium, as well as the autonomic nervous and lymphatic systems, as Salehpour et al., argues [10].
Persistent olfactory dysfunction is often observed in many viral infections that initially affect the lining of the respiratory tract, and in SARS-CoV-2 infection, this impairment has been very common, but the pathophysiological mechanisms are not yet fully understood.
Soares et al. treated 14 cases of COVID-19 who lost their smell. PBMT was applied topically intranasally for 3 min with a laser device (660 nm, output power 100 mW, energy 18 J). The patients were divided into three groups, as follows: group 1 (5 patients received 10 laser sessions, twice a week, with a break of 48 h); group 2 (6 patients, 5 laser sessions, twice a week, with a break of 48 h); group 3 (3 patients were given 10 PBMT daily), 3 min of irradiation per nostril for each group. Finally, there was an improvement in olfactory function in all patients, regardless of PBMT protocol, but with different degrees. However, the number of cases was very small and without a control group, so It is postulated that PBMT would be beneficial for smell recovery by modulating local inflammatory processes and improving tissue vascularity [11].
Brandão et al. presented and analyzed a series of eight cases of SARS-CoV-2 infection with necrotic mouth ulcers and aphthous-like ulcers with a loss of taste and smell. The most severe and widespread oral lesions were in the elderly, with severe forms of COVID-19. It is hypothesize a novel etiopathogenic process between ACE-2 receptors (very present on the epithelial cells of the tongue and salivary glands) and SARS-CoV-2 in the oral cavity but admit the demand for additional studies to confirm their hypothesis and elucidate exactly the etiopathogenesis, which is still unknown. It is applied the PBMT protocol used for patients with OM associated with cancer therapy. PBMT device (660 nm, 40 mW output power, 0.04 cm2 beam area, 1 W/cm2 irradiance, 0.4 J energy, and 10 J/cm2 fluence) was positioned perpendicular to the surface of each lesion, for 10 s per site, daily for 10 consecutive days. Patients reported relief of symptoms after 2–4 days and fully recovered after all PBMT sessions. It is acknowledged that the necessity for future scientific investigations to elucidate whether SARS-CoV-2 directly infects and replicates in oral keratinocytes and fibroblasts, and generates painful oral ulcers, or whether these lesions are developing along with COVID-19. It is also concluded that dysgeusia and early anosmia should be considered potential markers of SARS-CoV-2 infection, especially by dental staff who are highly exposed to the infection, in which case patients with such symptoms should be scheduled for consultations by telemedicine, be guided for further investigations, be immediately isolated, and have adequate medical management [12].
One of the most common symptoms reported in patients with COVID-19 was, in addition to impaired smell, the loss of taste. The pathophysiology by which viral infection disrupts tongue epithelial cells and taste receptors is not yet known. As good results have been obtained in the pathology of orofacial lesions and smell disorders, PBMT has been proposed as an easy means of restoring taste in patients with COVID-19. Campos et al. treated 10 patients with impaired taste (partial or complete) after SARS-CoV-2 infection using PBMT with a laser device emitting at 660 nm, with an output power of 100 mW and 2 J per point; a total of 7 points on the dorsal face and 3 points on each lateral edge of the tongue were treated. The results showed improvements in taste recovery for all patients [13].
Inflammation produced by SARS-CoV-2 infection is the main cause of smell and taste dysfunction in many patients. Knowing the anti-inflammatory and antioxidant effects of PBMT, de Souza et al. applied 10 sessions in the case of anosmia and ageusia related to COVID-19. The patient was treated for anosmia in the intranasal cavity with a laser device for 5 min (808 nm, output power 100 mW, beam area 3.0 mm2, fluence 1000 J/cm2, power density 3.33 W/cm2 and the total energy delivered in each nostril 30 J). For the pathological loss of the sense of taste, the patient was treated with a vacuum laser without the use of the suction cup, with 6 laser beams (3 red with a wavelength of 680 nm, and 3 IR with a wavelength of 808 nm). The laser protocol parameters were as follows: power of each beam 100 mW, beam area 1.76 mm2 (each), fluence equal to 682 J/cm2, irradiance equal to 5.6 W/cm2, application time 2 min on the back of the tongue and the sides of the tongue, and the inner mucosa of the cheeks, with total energy delivered to each area of 72 J, with a break of at least 48 h between sessions, over 25 days. In conclusion, It is showed that the patient regained his olfactory and gustatory functions and considered PBMT a promising therapeutic modality, especially for sequelae related to COVID-19 [14].

This entry is adapted from the peer-reviewed paper 10.3390/photonics9100686

References

  1. Sigman, S.A.; Mokmeli, S.; Monici, M.; Vetrici, M.A. A 57-Year-Old African American Man with Severe COVID-19 Pneumonia Who Responded to Supportive Photobiomodulation Therapy (PBMT): First Use of PBMT in COVID-19. Am. J. Case Rep. 2020, 21, e926779.
  2. Sigman, S.A.; Mokmeli, S.; Vetrici, M.A. Adjunct low level laser therapy (LLLT) in a morbidly obese patient with severe COVID-19 pneumonia: A case report. Can. J. Respir. Ther. 2020, 56, 52–56.
  3. Vetrici, M.A.; Mokmeli, S.; Bohm, A.R.; Monici, M.; Sigman, S.A. Evaluation of Adjunctive Photobiomodulation (PBMT) for COVID-19 Pneumonia via Clinical Status and Pulmonary Severity Indices in a Preliminary Trial. J. Inflamm. Res. 2021, 14, 965–979.
  4. Pelletier-Aouizerate, M.; Zivic, Y. Early cases of acute infectious respiratory syndrome treated with photobiomodulation, diagnosis and intervention: Two case reports. Clin. Case Rep. 2021, 9, 2429–2437.
  5. Pereira, F.L.C.; Luchi, E.; Corassa, J.M.; Rossi, F.M.; da Silva Mendes, P.; de Castro Roque, E.A.; Caliari, J.S.; Pedrazas, V.S.; Pereira, V.S.; Fonseca, R.M.C.; et al. Use of photobiomodulation therapy for the evolution of immunomodulatory markers and physiological parameters in patients with Covid-19. IJDR 2021, 11, 47152–47157.
  6. Marashian, S.M.; Hashemian, M.; Pourabdollah, M.; Nasseri, M.; Mahmoudian, S.; Reinhart, F.; Eslaminejad, A. Photobiomodulation Improves Serum Cytokine Response in Mild to Moderate COVID-19: The First Randomized, Double-Blind, Placebo Controlled, Pilot Study. Front. Immunol. 2022, 13, 929837.
  7. Williams, R.K.; Raimondo, J.; Cahn, D.; Williams, A.; Schell, D. Whole-organ transdermal photobiomodulation (PBM) of COVID-19: A 50-patient case study. J. Biophotonics 2022, 15, e202100194, Erratum in J. Biophotonics 2022, 15, e202190015.
  8. Tomazoni, S.S.; Johnson, D.S.; Leal-Junior, E.C.P. Multi-Wavelength Photobiomodulation Therapy Combined with Static Magnetic Field on Long-Term Pulmonary Complication after COVID-19: A Case Report. Life 2021, 11, 1124.
  9. De Marchi, T.; Frâncio, F.; Ferlito, J.V.; Weigert, R.; de Oliveira, C.; Merlo, A.P.; Pandini, D.L.; Pasqual-Júnior, B.A.; Giovanella, D.; Tomazoni, S.S.; et al. Effects of Photobiomodulation Therapy Combined with Static Magnetic Field in Severe COVID-19 Patients Requiring Intubation: A Pragmatic Randomized Placebo-Controlled Trial. J. Inflamm. Res. 2021, 14, 3569–3585.
  10. Salehpour, F.; Gholipour-Khalili, S.; Farajdokht, F.; Kamari, F.; Walski, T.; Hamblin, M.R.; DiDuro, J.O.; Cassano, P. Therapeutic potential of intranasal photobiomodulation therapy for neurological and neuropsychiatric disorders: A narrative review. Rev. Neurosci. 2020, 31, 269–286.
  11. Soares, L.; Guirado, M.; Berlingieri, G.; Ramires, M.; Lyra, L.; Teixeira, I.S.; Oliveira, P.C.; Tateno, R.Y.; Palma, L.F.; Campos, L. Intranasal photobiomodulation therapy for COVID-19-related olfactory dysfunction: A Brazilian multicenter case series. Photodiagnosis Photodyn. Ther. 2021, 36, 102574.
  12. Brandão, T.B.; Gueiros, L.A.; Melo, T.S.; Prado-Ribeiro, A.C.; Nesrallah, A.; Prado, G.; Santos-Silva, A.R.; Migliorati, C.A. Oral lesions in patients with SARS-CoV-2 infection: Could the oral cavity be a target organ? Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2021, 131, e45–e51.
  13. Campos, L.; Soares, L.; Berlingieri, G.; Ramires, M.; Guirado, M.; Lyra, L.; Teixeira, I.S.; Oliveira, P.C.; Alvares, C.; Palma, L.F. A Brazilian multicenter pilot case series on the efficacy of photobiomodulation therapy for COVID-19-related taste dysfunction. Photodiagnosis Photodyn. Ther. 2022, 37, 102643.
  14. de Souza, V.B.; Ferreira, L.T.; Sene-Fiorese, M.; Garcia, V.; Rodrigues, T.Z.; Junior, A.E.A.; Bagnato, V.S.; Panhoca, V.H. Photobiomodulation therapy for treatment olfactory and taste dysfunction COVID-19-related: A case report. J. Biophotonics 2022, 15, e202200058.
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