Photodynamic therapy and Photobiomodulation as adjuvant treatment of oral and facial manifestations in patients with COVID-19 hospitalized in the intensive care unit: series

Orofacial injuries resulting from Coronavirus-19 (COVID-19) are reported in the current literature. The etiology of these manifestations is still unknown, but them seem to have an association between the prone position and patient’ s immunosuppression. Clinical features range from nonspecific ulcers to vesicles that may mimic viral infections. The search for a clinical protocol for the cure of these lesions is necessary. Thus, some studies about photobiomodulation, a low-level light therapy with regenerative tissue action, associated with antimicrobial photodynamic therapy, as a promising adjuvant treatment. Therefore, the present study aims to report a series of cases where photobiomodulation and photodynamic therapy were used in patients positive for COVID-19 and presented orofacial lesions during the time of hospitalization in the intensive care unit. In all cases, tissue regeneration was complete, demonstrating the effectiveness of photobiomodulation and photodynamic therapy as adjuvant therapy associated with the use of medicines. y Las características clínicas infecciones fotobiomodulación, asociada terapia fotodinámica antimicrobiana, serie de casos utiliza fotobiomodulación y terapia fotodinámica pacientes positivos COVID-19 y hospitalización intensivos. En todos los casos la regeneración tisular fue complete, demostrándose la eficacia de la fotobiomolación y la terapia fotodinámica como terapia adyuvante asociada al uso de fármacos.

effectiveness of photobiomodulation and photodynamic therapy as adjuvant therapy associated with the use of medicines. Keywords: Coronavirus; Low-Level light therapy; Methylene blue; Prone position, Hospitalization.

Introduction
Coronavirus disease 2019 (COVID-19) is an infectious disorder responsible for the severe acute respiratory syndrome (SARS) and, may cause a long period of hospitalization, increase of risk of death and significant decrease of quality of life (Ahmed et al., 2020;Jacobs et al., 2020). Not least, some oral manifestations such as taste disturbances, nonspecific oral ulcerations, desquamative gingivitis, petechiae and opportunistic infections may be present and collaborate to general clinical status of the patient (Brandão et al., 2021). To assist in the healing process, photobiomodulation (PBMT) and/or antimicrobial photodynamic therapy (aPDT) have been implemented as adjuvant treatment in orofacial cases probably caused by COVID-19(Amorim dos Santos et al., 2020;Bhujel et al., 2021;Brandão et al., 2021;Ramires et al., 2021;El Kady et al., 2021;Perrillat et al., 2020;Ramalho et al., 2021;Solek et al., 2020).
PBMT is the therapeutic action of light absorbed by endogenous chromophores that trigger painless biological reactions which promote physiological changes in favor of tissue homeostasis (Dompe et al., 2020). Especially in situations of tissue aggression, PBMT promotes significant benefits, such as inflammatory reduction, acceleration of tissue regeneration, prevention of fibrosis, reduction of pain and edema (Meneguzzo et al., 2013).
In aPDT, photosensitizers as methylene or toluidine blue, with concentrations of 0.01% or 0.005% are used in resonance with red laser light, generating reactive oxygen species highly toxic to microorganisms (Christina et al., 2020;La Selva et al., 2020;Ramalho et al., 2021).

Methodology
It is a clinical case series with a descriptive and qualitative approach (Estrela, 2018). In this article, four clinic cases of patients who had extensive lesions in facial and oral cavity possibly caused by COVID-19, submitted to application of PBMT and aPDT with a variable number of points dependents of the lesion size are described.
This study was submitted and approved by São Leopoldo Mandic College Ethical committee and received the approval number 53872221.8.0000.5374.

Case 1
A 38-year-old female patient with COVID-19 was admitted to the intensive care unit (ICU) with 50% of pulmonary involvement. Orotracheal intubation (OTI) was performed in association with 32 hours prone position.
A pre-radiation of 0.01% methylene blue (Chimiolux, DMC, São Carlos, SP, BR) for 5 minutes was carried out covering the entire lesion after vesicular rupture with a sterile needle (40x12) (Fig 1B/C). During aPDT treatment, the formation of crusted areas was noted. After the 17 th session, PBMT with 600 and 808 nm, on contact mode, point by point, with 100mW, 17.8 J/cm 2, 1 J, and 10 s for irradiation per point was performed around the crust, on consecutive days, in 3 sessions with the same equipment, until the complete remission of the lesion (Fig 1D).

Case 2
A 40-year-old female patient, diagnosed with COVID-19, was admitted to the ICU with 75% of pulmonary involvement. OTI with pronation was performed for 5 alternative days, with a total of 18 hours each day. In the lower third of the face, an ulcerative lesion with multiple vesicles surrounded by an erythematous area associated with a pressure lesion was noted ( Fig. 1E/F). Acyclovir IV (250 mg) and Dexamethasone IV (10 mg) were administered, and 10 aPDT sessions were performed on consecutive days following the same protocol described in case 1. After improvement of the ulcerated lesion, 2 sessions of PBMT were made using the same protocol in case 1 as well (Fig. 1G/H).

Case 3
A 34-year-old male patient with a 75% of pulmonary involvement underwent to OTI because of signs and symptoms of COVID-19. He developed 2 ulcerated lesions with hemorrhagic central areas surrounded by crusts and vesicles extending from skin of lateral nose wing to zygomatic area similar to prone position or viral infection ( Fig. 2A). Acyclovir IV (250 mg) was prescribed, and Methylprednisolone IV (40 mg) was already being used. In sequence, the same adjuvant therapy protocol of the previous cases was started (Fig. 2B). 5 sessions of aPDT were performed and, after that, 3 sessions of PBMT, with an important healing was observed (Fig. 2C).

Case 4
A 62-year-old male patient was admitted to the ICU and underwent to OTI due pulmonary complications of COVID-19. The prone position was implemented during 16 hours over a period of 5 alternative days. The intraoral physical examination revealed the presence of crusted and bleeding lesions in the palate, bilateral buccal mucosa, bilateral labial commissure, and upper and lower lips. The same pattern was observed in the region of the right and left face, chin and nose ( Fig. 2D/E/F). Besides, Acyclovir IV (250 mg) and Methylprednisolone IV (125 mg) were prescribed. Additionally, the same protocol of aPDT and PBMT used in the previous cases was performed, observing total remission of the condition (Fig. 2G).

Discussion
Orofacial manifestations associated with COVID-19 have been described in the literature (Amorim dos Santos et al., 2020;Berlingieri et al., 2022;Bhujel et al., 2020;Brandão et al., 2021;El Kady et al., 2021;Perrillat et al., 2020). The exacerbation of these lesions is probably related to time and non-movement during the prone position because it is important to increase respiratory volume and, consequently, to improve the condition of patients with SARS undergoing OTI (Moore et al., 2020;Perrillat et al., 2020).
The chronic use of medications such as corticosteroids improve the clinical condition of SARS, but may suppress the immune system and facilitate the emergence of infections, mainly herpes simplex virus, cytomegalovirus and candidiasis (Brandão et al., 2021;Ochani et al., 2021;Raman et al., 2021;Solek et al., 2020;Lotfi et al., 2020). All patients treated in this article were under corticosteroids treatment for a considerable time and developed lesions clinically compatible with viral infections that may be intensified with the presence of COVID-19. Despite the ulcerated lesions have not been tested for the presence of virus, aPDT is known to be an important adjunct therapy against virus, bacteria, and fungus infections (Berlingieri et al., 2022).
To date, few articles have shown results obtained using aPDT and/or PBMT in cases of orofacial lesions associated with COVID-19 (Brandão et al., 2021;Garcez et al., 2021;Teixeir et al., 2021) . The protocol recommended for PBMT followed that carried out in two other case reports based on consolidated studies about antimicrobial, antifungal and antiviral action (Christina et al., 2020;Teixeira et al., 2021).
Additionally, aPDT and PBMT are non-invasive techniques that may be used safely in patients with a wide range of underlying diseases and comorbidities because of their high decontamination capacity (Pacheco et al., 2022). Furthemore, it is important to emphasize the use of medications and other types of treatment associated with this adjunct therapy in orofacial ulcerated lesions in hospitalized patients, as example, Acyclovir (Teixeira et al., 2021). In these current cases, no side effects with aPDT and PBMT were observed, and positive effects were noted in a short period of time.

Conclusion
The association of PBMT and aPDT proved to be an adjuvant effective treatment and may be implemented by health services, because the healing of these lesions improves the quality of life of hospitalized patients. Thus, it's important to have more studies about the laser efficiency in this kind of lesions related to COVID-19.