HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: a window to the infection-related headache mechanism

Hayrunnisa Bolay,Özlem Gülbahar,Ömer Karadas,Riza Sonkaya,Tuba D S Bulut,Betül Baykan,Bahar Tasdelen,Bilgin Oztürk,Aynur Özge

doi:10.1186/s10194-021-01306-7

Abstract

Background and aimPathogenesis of COVID-19 -related headache is unknown, though the induction of the trigeminal neurons through inflammation is proposed. We aimed to investigate key systemic circulating inflammatory molecules and their clinical relations in COVID-19 patients with headache.MethodsThis cross-sectional study enrolled 88 COVID-19 patients, hospitalized on a regular ward during the second wave of the pandemic. Clinical characteristics of COVID-19 patients were recorded, and laboratory tests were studied.ResultsThe mean ages of 48 COVID-19 patients with headache (47.71 ± 10.8) and 40 COVID-19 patients without headache (45.70 ± 12.72) were comparable. COVID-19 patients suffered from headache had significantly higher serum levels of HMGB1, NLRP3, ACE2, and IL-6 than COVID-19 patients without headache, whereas CGRP and IL-10 levels were similar in the groups. Angiotensin II level was significantly decreased in the headache group. COVID-19 patients with headache showed an increased frequency of pulmonary involvement and increased D- dimer levels. Furthermore, COVID-19 was more frequently associated with weight loss, nausea, and diarrhea in patients with headache. Serum NLRP3 levels were correlated with headache duration and hospital stay, while headache response to paracetamol was negatively correlated with HMGB1 and positively associated with IL-10 levels.ConclusionStronger inflammatory response is associated with headache in hospitalized COVID-19 patients with moderate disease severity. Increased levels of the circulating inflammatory and/or nociceptive molecules like HMGB1, NLRP3, and IL-6 may play a role in the potential induction of the trigeminal system and manifestation of headache secondary to SARS-CoV-2 infection.

Highlights

COVID-19 is characterized by robust systemic inflammation and the release of inflammatory molecules and pro-inflammatory cytokines [1, 2]
In a prospective clinical study, we demonstrated that COVID-19 headache was associated with inflammation and the headache phenotypes were determined by several factors including elevated circulating IL-6 levels [5]
The present study aimed to investigate whether serum levels of NLRP3, high mobility group box-1 (HMGB1), IL-6, IL-10, angiotensin II and angiotensin converting enzyme 2 (ACE2) were different in COVID-19 patients with headache

Summary

Introduction

COVID-19 is characterized by robust systemic inflammation and the release of inflammatory molecules and pro-inflammatory cytokines [1, 2]. Headache is one of the presenting and frequent symptoms of COVID-19 [3,4,5,6,7]. Headache frequency is reported to be 12% in a metaanalysis [3] and 29% in hospitalized COVID 19 patients with moderate disease severity [5]. It is hypothesized that dysregulated angiotensin system and NLRP3 inflammasome play a key role in trigeminal induction and headache symptom in COVID-19 [2, 9]. Pathogenesis of COVID-19 -related headache is unknown, though the induction of the trigeminal neurons through inflammation is proposed. We aimed to investigate key systemic circulating inflammatory molecules and their clinical relations in COVID-19 patients with headache

Objectives

Methods

Results

Discussion

Conclusion