Circulating levels of calcitonin gene-related peptide (CGRP) are lower in COVID-19 patients

Background: To better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in SARS-CoV-2 positive patients. Methods: Levels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n=24) were measured by ELISA. In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of RAMP1, one of the components of the CGRP receptor, in autopsy lung specimens. Results: CGRP levels greatly decreased in COVID-19 patients (p<0.001) when compared to controls, and there were no significant differences due to disease severity, sex, age, or comorbidities. We found that COVID-19 patients treated with proton pump inhibitors had lower levels of CGRP than other patients not taking this treatment (p=0.001). RAMP1 immunoreactivity was found in smooth muscle cells of large blood vessels and the bronchial tree, and in the airways epithelium. In COVID-19 samples, RAMP1 was also found in proliferating type II pneumocytes, a common finding in these patients. Conclusions: The lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.