Perfil de citocinas pulmonares e sistêmicas em pacientes com Covid-19 grave internados em Unidade de Terapia Intensiva

Abstract

Introduction: The evolution of COVID-19 into a critical and fatal state has been associated with altered patterns of cytokines and chemokines. Recent reports have pointed to distinct inflammatory processes in systemic and pulmonary sites. However, studies comparing the profile of these molecules in these two sites are still scarce. Objective: To study the profile of pulmonary and systemic cytokines and chemokines in critically ill COVID-19 patients. Methods: Prospective observational study conducted in the intensive care unit of the Hospital das Clínicas of the Federal University of Minas Gerais, from May 2020 to April 2021. Adult patients, (≥ 18 years) with confirmed COVID-19 by RT-PCR, who were on invasive mechanical ventilation were included. Patients were followed until outcome (death or hospital discharge) and divided into two groups (survivors and non-survivors) for comparative analyses. The concentration of 18 cytokines and chemokines was measured in peripheral blood samples and pulmonary secretion (mini-bronchoalveolar lavage (mini-BAL)) collected at two-time points after orotracheal intubation: days 1 or 2 (D1-2) and days 5 to 8 (D5-8). Results: Thirty-four patients with critical COVID-19 were included, 16 survivors and 18 non-survivors, with a median age of 58 (41-70) years, and male gender being the most frequent (62%). The main comorbidities were systemic arterial hypertension (16%), diabetes mellitus (12%), and cardiovascular diseases (9%), but there was no significant difference between survivors and non-survivors. The groups were similar at admission regarding severity evaluate by SOFA (p=0.66) and APACHE II (p=0.23) scores. In the mini-BAL, higher levels of CCL4 (p=0.01) were observed in the survivors’ group on D1-2, and higher levels of IFN-γ (p=0.01), IL-2 (p=0.01), IL-4 (p=0.03), G-CSF (p=0.01), and IL-10 (p=0.02) on D5-8 when compared to nonsurvivors. On the other hand, the non-survivors group presented higher plasma levels of CXCL10 (p=0.02) and IL-6 (p=0.02) at the D1-2 point and of CCL2 (p=0.007), CCL4 (p=0.03), CXCL8 (p=0.04), and IL-6 (p=0.04) on D5-8, compared to survivors. At D1-2, higher levels of TNF (p=0.02) and CXCL8 (p=0.04) in the lung were associated with PaO2/FiO2 ≥ 150 mmHg, while PaO2/FiO2 < 150 mmHg was associated with higher plasma levels of IFN-γ (p=0,004) and IL-5 (p=0,01). There was a strong correlation between cytokines and chemokines tested when analyzed separately in the pulmonary and plasma compartments on D1-2 and D5-8, but the levels of these molecules did not correlate when plasma and lungs were compared. Conclusion: Our results suggest that the inflammatory processes occurring in the pulmonary and peripheral territories are regulated differently in patients with critical COVID-19. Higher levels of pulmonary cytokines were associated with lower mortality and better lung oxygen exchange capacity, while higher plasma levels of cytokines were associated with death and worse lung exchange function (PaO2/FiO2 ratio) in the early phase of the critical infection.