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Review
. 2023 Sep 11:14:1232472.
doi: 10.3389/fimmu.2023.1232472. eCollection 2023.

Rationale for combined therapies in severe-to-critical COVID-19 patients

Aitor Gonzaga  1   2 , Etelvina Andreu  1   3 , Luis M Hernández-Blasco  1 , Rut Meseguer  1   4 , Karima Al-Akioui-Sanz  1   5 , Bárbara Soria-Juan  6 , Jose Carlos Sanjuan-Gimenez  1 , Cristina Ferreras  5 , Juan R Tejedo  7   8 , Guillermo Lopez-Lluch  9 , Rosa Goterris  4 , Loreto Maciá  10 , Jose M Sempere-Ortells  1   11 , Abdelkrim Hmadcha  7   12 , Alberto Borobia  13 , Jose L Vicario  14 , Ana Bonora  15 , Cristobal Aguilar-Gallardo  15 , Jose L Poveda  15 , Cristina Arbona  16 , Cristina Alenda  1 , Fabian Tarín  1 , Francisco M Marco  1   17 , Esperanza Merino  1   18   19 , Francisco Jaime  1 , José Ferreres  20 , Juan Carlos Figueira  21 , Carlos Cañada-Illana  22 , Sergio Querol  23 , Manuel Guerreiro  24 , Cristina Eguizabal  25   26 , Alejandro Martín-Quirós  22 , Ángel Robles-Marhuenda  27 , Antonio Pérez-Martínez  5   28 , Carlos Solano  29 , Bernat Soria  1   2   8
Affiliations
Review

Rationale for combined therapies in severe-to-critical COVID-19 patients

Aitor Gonzaga et al. Front Immunol. .

Abstract

An unprecedented global social and economic impact as well as a significant number of fatalities have been brought on by the coronavirus disease 2019 (COVID-19), produced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute SARS-CoV-2 infection can, in certain situations, cause immunological abnormalities, leading to an anomalous innate and adaptive immune response. While most patients only experience mild symptoms and recover without the need for mechanical ventilation, a substantial percentage of those who are affected develop severe respiratory illness, which can be fatal. The absence of effective therapies when disease progresses to a very severe condition coupled with the incomplete understanding of COVID-19's pathogenesis triggers the need to develop innovative therapeutic approaches for patients at high risk of mortality. As a result, we investigate the potential contribution of promising combinatorial cell therapy to prevent death in critical patients.

Keywords: COVID-19; SARS-CoV-2; advanced therapies; cytokine storm; immunomodulation; mesenchymal stromal cells.

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Conflict of interest statement

AP-M, CF and BS filed patents on this topic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flow Chart of clinical outcome and epidemiology distribution of COVID-19 patients. Percentages are dependent on variants, country, age and other morbidities.
Figure 2
Figure 2
Overview of the Immune System Response. NET: Neutrophile Extracellular Traps. APC: Antigen Presenting Cell. NK: Natural Killer. TCR: T-cell Receptor. HLA-I/HLA-II: Human Leukocyte Antigen I and II. Th1: T Helper 1 Lymphocyte. Tfc: Follicular T Helper Cell. CD8+ CTL: Cytotoxic T Lymphocyte. (A) Course for a normal immune response engulfing innate and adaptive immunity. (B) Memory T-cells (modified from Ferreras et al, 2021). CD45RA-: CD45RA isoform depleted cells. CM: Central Memory T-cells. EM: Effector Memory T-cells.
Figure 3
Figure 3
Dysfunctional SARS-Cov-2 induced immune response. NET: Neutrophile Extracellular Traps. APC: Antigen Presenting Cell. MAS: Macrophage Activation Syndrome. NK: Natural Killer. (A) SARS-Cov-2 blocks normal immune response. (B) Pathogenic mechanism of the dysregulated immune response.
Figure 4
Figure 4
Time-course and clinical outcomes for COVID-19. Conservative treatment is being used for the first infection phase, which lasts up to 3–5 days and progresses with mild symptomatology and increased viral load, whereas in a small proportion of patients the second phase, 7 day onwards, yields extensive inflammatory response and an anti-inflammatory approach is recommended. Therapeutic proposal: Use SARS-Cov-2 memory CD45RA-CD3+CD4+ during the first phase (viral) and safe and HLA-compliant mesenchymal stromal cells for the second phase (complications).
Figure 5
Figure 5
Clinical outcomes after CD45RA- (A) and MSC (B) treated patients. (A) T-cell memory based therapy (CD45RA depleted infused). Time-course and clinical outcome. (B) Cell-based therapy. Mesenchymal Stromal-stem Cell (MSC) infusions and timing are represented in arrows. In the X axis, days from the first MSC infusion are specified. Type of ventilation support is graded in colors through each row. MSC: Mesenchymal Stromal-stem Cells; ICU: Intensive Care Unit; ECMO: Extra Corporeal Membrane Oxygenation.
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