endotracheal application of ultraviolet a light in critically ill severe acute respiratory CORD-Papers-2022-06-02 (Version 1)

Title: Endotracheal application of ultraviolet A light in critically ill severe acute respiratory syndrome coronavirus-2 patients: A first-in-human study
Abstract: Background: Promising preclinical experiments show that under specific and monitored conditions ultraviolet-A (UVA) exposure reduces certain bacteria fungi and viruses including coronavirus-229E without harming mammalian columnar epithelial cells. We aimed to evaluate the safety and effects of UVA therapy administered by a novel device via endotracheal tube in critically ill subjects with SARS-CoV-2 infection. Methods: Five newly intubated mechanically ventilated adults with SARS-CoV-2 infection with an endotracheal tube size 7.5mm or greater were treated with UVA for 20 minutes daily for 5 days and followed for 30 days. Results: Five subjects were enrolled (mean age 56.6yrs 3 male). At baseline all subjects scored 9/10 on the WHO clinical severity scale (10=death) with predicted mortality ranging from 21 to 95%. Average log changes in endotracheal viral load from baseline to day 5 and day 6 were -2.41 (range -1.16 to -4.54; Friedman P=0.002) and -3.20 (range -1.20 to -6.77; Friedman P<0.001) respectively. There were no treatment-emergent adverse events. One subject died 17 days after enrollment due to intracranial hemorrhagic complications of anticoagulation while receiving extracorporeal membrane oxygenation. The remaining subjects clinically improved and scored 2 4 5 and 7 on the WHO scale at day 30. In these subjects the slope of viral load reduction during UVA treatment correlated with the slope of improvement in clinical WHO severity score over time (Spearman rho=1 P<0.001). Conclusion: In this first-in-human study endotracheal UVA therapy under specific and monitored settings was safe with a significant reduction in respiratory SARS-CoV-2 viral burden over the treatment period.
Published: 2021-03-08
DOI: 10.1101/2021.03.05.21252997
DOI_URL: http://doi.org/10.1101/2021.03.05.21252997
Author Name: Rezaie A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/rezaie_a
Author Name: Melmed G Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/melmed_g_y
Author Name: Leite G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/leite_g
Author Name: Mathur R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mathur_r
Author Name: Takakura W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/takakura_w
Author Name: Pedraza I
Author link: https://covid19-data.nist.gov/pid/rest/local/author/pedraza_i
Author Name: Lewis M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lewis_m
Author Name: Murthy R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/murthy_r
Author Name: Chaux G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chaux_g
Author Name: Pimentel M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/pimentel_m
sha: eb1d9cb434aa8af9f5cf0d7b203704ca91a0f252
license: medrxiv
source_x: MedRxiv; WHO
source_x_url: https://www.who.int/
url: https://doi.org/10.1101/2021.03.05.21252997 http://medrxiv.org/cgi/content/short/2021.03.05.21252997v1?rss=1
has_full_text: TRUE
Keywords Extracted from Text Content: UVA NCT04572399 columnar epithelial cells coronavirus-229E endotracheal tube endotracheal viral SARS-CoV-2 intracranial rho=1 9/10 ultraviolet-A membrane endotracheal UVA mitochondrial columnar epithelial cells coronavirus-229E medRxiv exhaled human tracheal cells p=047 MAVS ETT multi-LED UVA coronavirus disease 2019 patients endotracheal aspirate COVID-19.[1-3 SARS- UVA ultraviolet-A ( NCT04572399 ECMO Figure 1 endotracheal viral sheath coxsackievirus endotracheal UVA endotracheal SARS-CoV-2 Oxygen intracranial hemorrhage umbilical cells women tracheal cells -258.9 ± 621.4 upper airway human human cells Aytu Biosciences COVID-19 coronavirus-2 endotracheal aspirates ferritin COVID-19 patients VAP interleukin-6 murine C-reactive endotracheal tube tracheae SARS-CoV-2 tissue GA SARS-CoV-2-infected tracheal cells endotracheal medRxiv preprint 12 medRxiv preprint ≥ tube nasal swab cell endotracheal UVA light medRxiv medRxiv preprint permission.(which
Extracted Text Content in Record: First 5000 Characters:Promising preclinical experiments show that, under specific and monitored conditions, ultraviolet-A (UVA) exposure reduces certain bacteria, fungi, and viruses including coronavirus-229E without harming mammalian columnar epithelial cells. We aimed to evaluate the safety and effects of UVA therapy administered by a novel device via endotracheal tube in critically ill subjects with SARS-CoV-2 infection. with an endotracheal tube size 7.5mm or greater, were treated with UVA for 20 minutes daily for 5 days, and followed for 30 days. Results: Five subjects were enrolled (mean age 56.6yrs, 3 male). At baseline, all subjects scored 9/10 on the WHO clinical severity scale (10=death) with predicted mortality ranging from 21 to 95%. Average log changes in endotracheal viral load from baseline to day 5 and day 6 were -2.41 (range -1.16 to -4.54; Friedman P=0.002) and -3.20 (range -1.20 to -6.77; Friedman P<0.001), respectively. There were no treatment-emergent adverse events. One subject died 17 days after enrollment due to intracranial hemorrhagic complications of anticoagulation while receiving extracorporeal membrane oxygenation. The remaining subjects clinically improved and scored 2, 4, 5, and 7 on the WHO scale at day 30. In these subjects, the slope of viral load reduction during UVA treatment correlated with the slope of improvement in clinical WHO severity score over time (Spearman rho=1, P<0.001). In this first-in-human study, endotracheal UVA therapy under specific and monitored settings, was safe with a significant reduction in respiratory SARS-CoV-2 viral burden over the treatment period. Trial Registration: ClinicalTrials.gov #NCT04572399. Since the first report of severe acute respiratory syndrome coronavirus-2 (SARS- infection in December 2019, the global quest to find a highly effective modality to treat severe coronavirus disease 2019 (COVID-19) has been disappointing. Direct cytotoxic effects of SARS-CoV-2 along with dysregulated inflammatory responses and secondary respiratory infections continue to inflict substantial morbidity and mortality in severe and critical cases of COVID-19.[1-3] One mechanism to explain SARS-CoV-2 virulence may be through impairment of the mitochondrial antiviral signaling (MAVS) protein, responsible for innate antiviral responses. [4] Externally applied ultraviolet light therapy is an approved treatment for several atopic, inflammatory and dysplastic dermatologic disorders. [5] In preclinical experiments, ultraviolet-A (UVA) exposure under monitored conditions (i.e. specific intensity, peak wavelength, exposure time and distance to target tissue), reduces bacteria, fungi, and viruses including coronavirus-229E but does not harm human (in vitro) or murine (in vivo) columnar epithelial cells. [6] Moreover, UVA exposure of coronavirus-229E transfected human primary tracheal cells led to activation of the MAVS protein, reduction in spike protein, and resumption of cell proliferation similar to uninfected cells, suggesting that UVA may induce a beneficial antiviral state in infected human cells. [6] Using these newly discovered principles, we aimed to investigate the safety and treatment effects of a novel device inserted into the endotracheal tube to deliver UVA and reduce the viral burden of respiratory SARS-CoV-2 in critically ill subjects. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In this first-in-human study, we aimed to recruit and treat 5 subjects. The trial protocol (ClinicalTrials.gov number NCT04572399) was approved by the institutional review board of Cedars-Sinai, Los Angeles and was overseen by an independent data and safety monitoring board (DSMB). Subjects' legally authorized representatives provided written informed consent. Inclusion criteria included age over 18 years, positive PCR test result for SARS-CoV-2 on nasal swab, and mechanical ventilation with an endotracheal tube (ETT) inner diameter of ≥ 7.5 mm. Pregnant women were excluded. Subjects received all standard supportive care; concomitant use of any other COVID-19 treatments was permitted. The UVA therapy device (Aytu Biosciences, Englewood, CO) consisted of a 5.4 mm diameter sterile sealed multi-LED UVA light catheter within a protective sheath and endotracheal adaptor, umbilical, and control unit (Fig. S1 ). The UVA catheter adaptor was connected to the ETT using a double-swivel multi-access port (Halyard Health, GA) to maintain a closed-loop system and prevent ambient exposure to exhaled air upon introduction of the catheter into the ETT. Within 24 hours of enrollment, subjects underwent 20 minutes of endotracheal UVA therapy, which was repeated once daily for a total of 5 consecutive days. All subjects received 100% FiO 2 for 30 minutes prior to the procedure (see Supplemental Materials and Methods for protocol). The UVA catheter was inserted to
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