Latent class cluster analysis identified hidden headache phenotypes in COVID-19: impact of pulmonary infiltration and IL-6

Abstract

Background and objective Clinical studies on COVID-19 headache are limited. This prospective study aimed to define headache characteristics, associated clinical and laboratory factors, and treatment response in COVID-19. Methods Cross-sectional study enrolled 287 patients diagnosed with COVID-19 and hospitalized on a regular ward during the pandemic. All patients were examined face to face and followed by a neurologist during their stay in the hospital. The characteristics, concomitant symptoms, treatment responses, and laboratory findings of COVID-19-associated headaches were recorded. Results Eighty-three COVID-19 patients reported headache (28.9%), in which 85.5% had no prior headaches. Mean age was 48.40 ± 15.90 and 58% was men. Compared to COVID-19 patients without headache ( n = 204), patients with headache showed significantly higher frequency of pulmonary involvement (76%) and increased D-dimer levels. Fifty-nine percent of headaches responded iv paracetamol 1000 mg, and 85% of the paracetamol unresponsive headaches were relieved by greater occipital nerve (GON) blocks. Latent class cluster analysis identified 2 distinct class of bilateral, frontal, throbbing headaches: severe (VAS > 84), longer (> 14 h), frequent (> 7 headache days), paracetamol unresponsive-GON responsive headaches (85%), with pulmonary involvement (100%), and higher IL-6 levels (> 90 pg/mL) were classified in cluster 1. Cluster 2 included moderately affected patients (VAS > 54, > 6 h, > 4 days, 60% pulmonary involvement, > 20 pg/mL IL-6) and paracetamol responsive headaches (96%). VAS scores showed positive linear correlation with IL-6 levels ( p < 0.001; r = 0.567). Conclusion The intensity, duration, frequency, bilateral frontal location, and treatment response of COVID-19 headache was related to pulmonary involvement and IL-6 levels, which indicated a role of inflammation in determining the headache manifestations in moderately affected hospitalized patients. ROC curve cutoff values pointed that VAS > 70 severity, > 9 h duration, > 5 headache days, and IL-6 > 43 pg/mL levels can be diagnostic for COVID-19 headache. GON blocks can effectively abort headache when patients are unresponsive to paracetamol, and other NSAIDs are avoided during the SARS-CoV-2 infection.

HMGB1, NLRP3, IL-6 and ACE2 Levels Are Elevated in COVID-19 with Headache: A Window to the Infection-Related Headache Mechanism

“…Likewise, hospitalization days were less in COVID-19 patients without pulmonary in ltration compared to that of with pulmonary involvement (7.8 ± 2.4 vs 6.8 ± 2.08 p = 0.03). Headache was bilateral, severe, pulsating/pressing quality and unrelenting in COVID-19 patients that was consistent with our previous reports in other series (4,5,8). COVID-19 related headache was unresponsive to paracetamol in 75% of the patients and its duration was 5.1 ± 1.2 days (median:5, range 4-8 days).…”

“…Exclusion criteria were patients transferred to ICU, headache attributed to other secondary causes, patients who had severe hearing or speech impairment to interfere with communication and patients who refused further laboratory investigations. COVID-19 patients with mild-moderate headaches, displaying VAS ≤ 7 (visual analog scale) were excluded, to create reliably differentiating groups with versus without headache based on a previous report (5). Consequently, among 107 patients diagnosed with COVID-19 illness; 88 patients were enrolled in the study.…”

“…COVID-19 is characterized by robust systemic in ammation and the release of in ammatory molecules and pro-in ammatory cytokines (1,2). Headache is one of the presenting and frequent symptoms of COVID-19 (3)(4)(5)(6)(7). It is intriguing to note that headache is not seen in all COVID-19 patients or not only prevalent in those primary headache sufferers, such as migraine.…”

“…It is intriguing to note that headache is not seen in all COVID-19 patients or not only prevalent in those primary headache sufferers, such as migraine. Headache frequency was reported to be 12% in a meta-analysis (3) and 29% in hospitalized COVID 19 patients with moderate disease severity (5). New-onset, unrelenting, moderate to severe, frontally located, pulsating or pressing headaches, associated with the anosmia/ageusia and gastrointestinal complaints, especially when seen in men, were more frequently associated with COVID-19 (4)(5)(6)(7)(8).…”

“…Activation of in ammasome complex by a direct SARS-CoV-2 protein induction and/or angiotensin II-mediated pathway was hypothesized to take a key role in the necessary neuroin ammation in the trigeminal system (2,9). A recent prospective study demonstrated the involvement of in ammation in COVID-19 headache and disclosed two classes of headache phenotypes determined by several factors, including elevated circulating IL-6 levels (5). It has been reported that SARS-CoV-2 can directly activate NLRP3 (Nod-like receptor pyrin domain-containing 3), and different responses of COVID-19 patients could be attributed to differences in properly downregulation of NLRP3 in ammasome activation (10).…”