CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients

Abstract

SARS-CoV-2 is the etiological agent of COVID-19, an extremely heterogenous disease that can cause severe respiratory failure and critical illness. To date, reliable biomarkers allowing for early patient stratification according to disease severity are still lacking. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in lung pathophysiology and immune modulation and is poorly investigated in the COVID-19 context. In this observational, prospective cohort study, we investigated the correlation between CGRP and clinical disease evolution in hospitalized moderate to severe COVID-19 patients. Between January and May 2021 (Italian third pandemic wave), 135 consecutive SARS-CoV-2 patients were diagnosed as being eligible for the study. Plasma CGRP level evaluation and routine laboratory tests were performed on blood samples collected at baseline and after 7 days of hospitalization. At baseline, the majority our patients had a moderate to severe clinical presentation, and higher plasma CGRP levels predicted a higher risk of in-hospital negative evolution (odds-ratio OR 2.84 [IQR 1.07–7.51]) and were correlated with pulmonary intravascular coagulopathy (OR 2.92 [IQR 1.19–7.17]). Finally, plasma CGRP levels were also correlated with plasma IP10 levels. Our data support a possible crosstalk between the lung and the neuroimmune axis, highlighting a crucial role for plasma CGRP in sustaining COVID-19-related hyperinflammation.

Calcitonin Gene–Related Peptide Monoclonal Antibodies and Risk of SARS-CoV-2 Infection and Severe COVID-19 Outcomes Among Veterans With Migraine Disorder

“…[23][24][25] Yet, there is no study, to our knowledge, that directly observed the efficacy of CGRP antagonists for patients with COVID-19, and results from animal or observational studies are controversal. 13,14,26,27 In our study, although we found that patients with migraine who were treated with CGRP mAbs had better inflammatory profiles (lower ferritin and procalcitonin levels), which could have been associated with better outcomes, 28 their clinical courses were no better than controls in terms of hospitalization, requiring supplemental oxygen or mechanical ventilation, and death. However, those results should be interpreted with caution due to the small number of events in addition to the fact that CGRP induces inotropy, suppresses elevated pulmonary arterial pressure, and attenuates cardiac remodeling, 29,30 which may be beneficial to patients with severe COVID-19 who develop acute respiratory distress and septic shock.…”

“…13 On the contrary, another prospective cohort study observed that higher plasma CGRP levels were associated with a higher risk of hospitalization and pulmonary intravascular coagulopathy, highlighting a role for plasma CGRP in sustaining COVID-19-related hyperinflammation. 14 Furthermore, a multicenter study did not find significant differences in COVID-19 prevalence or disease course among 300 patients with migraine who received or did not receive CGRP mAbs. 15 To address this knowledge gap, we used data from the Veterans Health Administration (VHA), the largest integrated health system in the US, and emulated a target trial to examine the association of CGRP mAbs with risk of SARS-CoV-2 infection and developing severe clinical outcomes among US veterans who were diagnosed with migraine disorder between January 20, 2020, and May 19, 2022.…”

“…A cross-sectional study reported that CGRP levels were decreased in 57 patients with COVID-19 and suggested that restoration of normal CGRP circulatory levels can be therapeutic . On the contrary, another prospective cohort study observed that higher plasma CGRP levels were associated with a higher risk of hospitalization and pulmonary intravascular coagulopathy, highlighting a role for plasma CGRP in sustaining COVID-19–related hyperinflammation . Furthermore, a multicenter study did not find significant differences in COVID-19 prevalence or disease course among 300 patients with migraine who received or did not receive CGRP mAbs .…”

COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters

“…The available evidence regarding CGRP’s role as a predictive biomarker for COVID-19 evolution is still scarce, which at present, prevents us from drawing any conclusion, but fosters new studies on the topic. As reported by Rizzi and coworkers [ 196 ], this peptide appears to be promising not only for patient stratification at admission, but also for early detection of those patients who have already experienced and/or are experiencing pulmonary and vascular events. This study was monocentric and limited only to non-ICU hospitalized COVID-19 patients with moderate or severe symptoms, thus precluding the generalizability of the obtained conclusions without dedicated studies.…”

“…Unfortunately, so far, only a few studies have focused on this topic, with conflicting results [ 194 , 196 , 197 ]. While the most recent one [ 196 ] reported a direct correlation between circulating CGRP levels and disease severity, the previous ones [ 194 , 197 ] obtained different results: in particular, one found low serum CGRP levels in COVID-19 patients along with a high RAMP1 (receptor activity-modifying protein 1) lung expression [ 194 ], while the other [ 197 ] failed to find a direct correlation between this peptide and headache in moderate COVID-19 patients. The observed heterogeneity of the results of these studies can mainly be explained by the different compositions of clinical cohorts, as well as by the different therapeutic regimens adopted.…”