Intranasal dexamethasone: a new clinical trial for the control of inflammation and neuroinflammation in COVID-19 patients

Graciela Cárdenas, María Chávez-Canales, Ana María Espinosa, Antonio Jordán-Ríos, Daniel Anica Malagon, Manlio Fabio Márquez Murillo, Laura Victoria Torres Araujo, Ricardo Leopoldo Barajas Campos, Rosa María Wong-Chew, Luis Esteban Ramirez González, Karent Ibet Cresencio, Enrique García Velázquez, Mariana Rodriguez de la Cerda, Yoana Leyva, Joselin Hernández-Ruiz, María Luisa Hernández-Medel, Mireya León-Hernández, Karen Medina Quero, Anahí Sánchez Monciváis, Sergio Hernández Díaz, Ignacia Rosalia Zeron Martínez, Adriana Martínez-Cuazitl, Iván Noé Martínez Salazar, Eduardo Beltrán Sarmiento, Aldo Figueroa Peña, Patricia Saraí Hernández, Rafel Ignacio Aguilar Reynoso, Daniela Murillo Reyes, Luis Rodrigo Del Río Ambriz, Rogelio Antonio Alfaro Bonilla, Jocelyn Cruz, Leonor Huerta, Nora Alma Fierro, Marisela Hernández, Mayra Pérez-Tapia, Gabriela Meneses, Erick Espíndola-Arriaga, Gabriela Rosas, Alberto Chinney, Sergio Rosales Mendoza, Juan Alberto Hernández-Aceves, Jaquelynne Cervantes-Torres, Anai Fuentes Rodríguez, Roxana Olguin Alor, Sandra Ortega Francisco, Evelyn Alvarez Salazar, Hugo Besedovsky, Marta C Romano, Raúl J Bobes, Helgi Jung, Gloria Soldevila, Juan López-Alvarenga, Gladis Fragoso, Juan Pedro Laclette, Edda Sciutto, Graciela Cárdenas, María Chávez-Canales, Ana María Espinosa, Antonio Jordán-Ríos, Daniel Anica Malagon, Manlio Fabio Márquez Murillo, Laura Victoria Torres Araujo, Ricardo Leopoldo Barajas Campos, Rosa María Wong-Chew, Luis Esteban Ramirez González, Karent Ibet Cresencio, Enrique García Velázquez, Mariana Rodriguez de la Cerda, Yoana Leyva, Joselin Hernández-Ruiz, María Luisa Hernández-Medel, Mireya León-Hernández, Karen Medina Quero, Anahí Sánchez Monciváis, Sergio Hernández Díaz, Ignacia Rosalia Zeron Martínez, Adriana Martínez-Cuazitl, Iván Noé Martínez Salazar, Eduardo Beltrán Sarmiento, Aldo Figueroa Peña, Patricia Saraí Hernández, Rafel Ignacio Aguilar Reynoso, Daniela Murillo Reyes, Luis Rodrigo Del Río Ambriz, Rogelio Antonio Alfaro Bonilla, Jocelyn Cruz, Leonor Huerta, Nora Alma Fierro, Marisela Hernández, Mayra Pérez-Tapia, Gabriela Meneses, Erick Espíndola-Arriaga, Gabriela Rosas, Alberto Chinney, Sergio Rosales Mendoza, Juan Alberto Hernández-Aceves, Jaquelynne Cervantes-Torres, Anai Fuentes Rodríguez, Roxana Olguin Alor, Sandra Ortega Francisco, Evelyn Alvarez Salazar, Hugo Besedovsky, Marta C Romano, Raúl J Bobes, Helgi Jung, Gloria Soldevila, Juan López-Alvarenga, Gladis Fragoso, Juan Pedro Laclette, Edda Sciutto

Abstract

Background: By end December of 2021, COVID-19 has infected around 276 million individuals and caused over 5 million deaths worldwide. Infection results in dysregulated systemic inflammation, multi-organ dysfunction, and critical illness. Cells of the central nervous system are also affected, triggering an uncontrolled neuroinflammatory response. Low doses of glucocorticoids, administered orally or intravenously, reduce mortality among moderate and severe COVID-19 patients. However, low doses administered by these routes do not reach therapeutic levels in the CNS. In contrast, intranasally administered dexamethasone can result in therapeutic doses in the CNS even at low doses.

Methods: This is an approved open-label, multicenter, randomized controlled trial to compare the effectiveness of intranasal versus intravenous dexamethasone administered in low doses to moderate and severe COVID-19 adult patients. The protocol is conducted in five health institutions in Mexico City. A total of 120 patients will be randomized into two groups (intravenous vs. intranasal) at a 1:1 ratio. Both groups will be treated with the corresponding dexamethasone scheme for 10 days. The primary outcome of the study will be clinical improvement, defined as a statistically significant reduction in the NEWS-2 score of patients with intranasal versus intravenous dexamethasone administration. The secondary outcome will be the reduction in mortality during hospitalization.

Conclusions: This protocol is currently in progress to improve the efficacy of the standard therapeutic dexamethasone regimen for moderate and severe COVID-19 patients.

Trial registration: ClinicalTrials.gov NCT04513184 . Registered November 12, 2020. Approved by La Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS) with identification number DI/20/407/04/36. People are currently being recruited.

Keywords: COVID-19; Dexamethasone; Inflammation; Intranasal administration; Neuroinflammation.

Conflict of interest statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Inflammatory phenomena associated with SARS-CoV-2 infection and its neurological and respiratory manifestations. The SARS-CoV-2 virus mainly enters the respiratory tract and reaches the lungs through direct ventilation and the CNS through the olfactory and trigeminal nerves. The entry of the virus is facilitated by NRP-1, ACE2 receptors, and protein S activation by TMPRSS2. In the CNS, the virus infects neurons, glial cells, and endothelial cells, increasing the permeability of the BBB. This may cause cerebral edema, intracranial hypertension, and neuroinflammation. If the viral infection continues, the damage spreads throughout the body, causing heart and systemic failure. This damage is associated with increased neuroinflammation directed by microglia and oligodendrocytes, causing damage to the brain stem and dysfunction of the heart and lungs. The exacerbated inflammation and intravascular coagulation induce respiratory arrest, possibly leading to the patient’s death. The inflammation is triggered by viral components (PAMPS) that activate TLR3, 7, and 8 receptors on the cell surface. Consequently, there is an increased production of pro-inflammatory cytokines (TNFα and IL 1β) and ROS, which can modify the P2X7 receptor in the brain and activate the inflammasome by the decrease of K+. The activation of the inflammasome increases the production of IL-6 and pyroptosis. This diagram is based on the knowledge at the time of writing the manuscript
Fig. 2
Fig. 2
Outline of the REVIVAL trial clinical protocol. Initially, patients will be informed about the clinical trial; if they accept and sign the consent, they will be randomized using the Sealed envelope® software. Group A will receive intranasal DXM; Group B will receive intravenous DXM. Both groups will be sampled on days 0, 3, 6, and 10 post-treatment to collect sera and nasopharyngeal swabs. Patients will be monitored throughout the study. The results will be tested for statistical differences between groups

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