Abstract

Background: The effects of immunomodulators in patients with Coronavirus Disease 2019 (COVID-19) pneumonia are still unknown. We investigated the cellular inflammatory and molecular changes in response to standard-of-care + pidotimod (PDT) and explored the possible association with blood biomarkers of disease severity. Methods: Clinical characteristics and outcomes, neutrophil-to-lymphocyte ratio (NLR), plasma and cell supernatant chemokines, and gene expression patterns after SARS-CoV-2 and influenza (FLU) virus in vitro stimulation were assessed in 16 patients with mild-moderate COVID-19 pneumonia, treated with standard of care and PDT 800 mg twice daily (PDT group), and measured at admission, 7 (T1), and 12 (T2) days after therapy initiation. Clinical outcomes and NLR were compared with age-matched historical controls not exposed to PDT. Results: Hospital stay, in-hospital mortality, and intubation rate did not differ between groups. At T1, NLR was 2.9 (1.7–4.6) in the PDT group and 5.5 (3.4–7.1) in controls (p = 0.037). In the PDT group, eotaxin and IL-4 plasma concentrations progressively increased (p < 0.05). Upon SARS-CoV-2 and FLU-specific stimulation, IFN-γ was upregulated (p < 0.05), while at genetic transcription level, Pathogen Recognition Receptors (TRLs) were upregulated, especially in FLU-stimulated conditions. Conclusions: Immunomodulation exerted by PDT and systemic corticosteroids may foster a restoration in the innate response to the viral infection. These results should be confirmed in larger RCTs.

Highlights

  • Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the pathogen that causes the Coronavirus Disease 2019 (COVID-19), a pandemic pathology currently affecting almost 200 million patients worldwide

  • The clinical manifestations of COVID-19 are very heterogeneous, ranging from mild forms with uncomplicated illness to critical cases associated with significant in-hospital mortality, characterized by severe bilateral pneumonia leading to acute respiratory distress syndrome (ARDS) and the need for mechanical ventilation [1,2,3,4]

  • The observation that pro-inflammatory cytokines and chemokines, including Interleukin-6 (IL-6), Interferon-γ (IFNγ), Monocyte Chemoattractant Protein-1 (MCP-1), and Interferon gamma-induced protein 10 (IP-10), are massively produced in severe COVID-19 indicate the presence of a T helper 1 (TH1) cell-polarized response, resulting in the homing of monocytes and T lymphocytes, but not neutrophils, into infected sites [5]

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Summary

Introduction

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is the pathogen that causes the Coronavirus Disease 2019 (COVID-19), a pandemic pathology currently affecting almost 200 million patients worldwide. (MCP-1), and Interferon gamma-induced protein 10 (IP-10), are massively produced in severe COVID-19 indicate the presence of a T helper 1 (TH1) cell-polarized response, resulting in the homing of monocytes and T lymphocytes, but not neutrophils, into infected sites [5]. In these patients, absolute counts and percentages of lymphocytes including. We investigated in patients with COVID-19 pneumonia and mild to moderate respiratory failure whether the immunomodulatory activity of PDT could beneficially modulate immune responses and if this could be associated with changes in serum inflammatory biomarkers and improved clinical outcomes

Study Design
Patients’ Characteristics
In-Hospital Treatment
Pidotimod and Historical Control Group
PBMC Isolation and Stimulation
Multiplex Cytokine Analyses
Quantigene Plex Gene Expression Assay
Neutrophil to Lymphocyte Ratio
Study Outcomes
2.10. Statistical Analysis
Patients’ Clinical Characteristics
Clinical Outcomes
Cytokine and Chemokine Plasma Levels
SARS-CoV-2 Specific Immune Profile
Discussion
Study Limitations
Conclusions
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