过度炎症引发长新冠头痛

 

概要

 

新冠患者可能会出现如嗅觉味觉丧失、疲倦等一系列新冠后遗症。在这些症状中，神经系统类如慢性头痛是最常见的一种。而众所周知，SARS-CoV-2还会诱发炎症。有研究显示炎症与长新冠之间存在着一定的联系，但与长新冠导致的头痛等神经受损症状相关的免疫学、生物代谢学之间的联系研究还不够充分。

在最近发布到bioRxiv*预印本服务器的一项研究中，研究人员探索了长新冠急性后遗症和康复期期间慢性头痛发作所涉及的免疫和代谢改变之间的联系。

研究发现过度以及持续的炎症可能会导致持续的长新冠头痛的发生。在长新冠头痛患者中，免疫代谢的重新编程可能是导致脂质和精氨酸代谢物积累的原因，多种神经递质的代谢失调可能是长新冠相关的慢性头痛的标志。

而受试者的羟色胺水平在头痛发作前后的所有时间点都明显较高。在头痛发生之前，多巴胺代谢物、γ-氨基丁酸（GABA）和谷氨酸的水平则明显下降。这意味着神经递质的代谢失调可能也参与了长新冠患者慢性头痛的诱导过程。

研究结果表明，无论是轻症还是重症，慢性的全身性炎症都会诱发头痛。而长新冠头痛患者中，研究人员还观察到头痛发病前葡萄糖代谢和炎症增强的现象，这导致了高炎症状态。而且即便新冠愈后病毒已经被清除，长新冠患者体内的炎症仍然在持续。

总的来说，该研究结果突出了有慢性头痛症状的长新冠患者的免疫代谢组学情况，为潜在的治疗干预提供了启示。

 

Hyperinflammation triggers long COVID headaches

 

In a recent study posted to the bioRxiv* preprint server, researchers characterize the immunological and metabolic alterations involved in chronic headache onset during the acute and convalescent periods of post-acute sequelae of the coronavirus disease 2019 (COVID-19) (PASC).

 

Study: Immunometabolic rewiring in long COVID patients with chronic headache. Image Credit: goodluz / Shutterstock.com

 

Background

 

COVID-19 patients may experience persistent symptoms, which is often referred to as post-COVID-19 condition (PCC), PASC, or long COVID. Among the long-term neurological symptoms, chronic headache is most commonly reported.

 

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for COVID-19, induces inflammation. However, immunological, biological, and metabolomic and factors associated with long COVID headaches are not well-characterized.

 

About the study

 

In the present study, researchers evaluate the immuno-metabolomic changes among long COVID patients experiencing chronic headaches.

 

Blood samples were obtained between May 2020 to October 2021 from adults with long COVID [(+)LC]-associated chronic headaches and without long COVID [(-)LC] in the post-acute COVID-19 period. The time points for blood collection following headache onset were -8 days, -7 to seven days, eight to 30 days, one to three months, and over three months. Study participants were registered with the Cleveland Clinic COVID registry and Cleveland Clinic BioRepository (CC-BioR).

 

The diagnosis of COVID-19 was confirmed using a quantitative reverse-transcription polymerase chain reaction (RT-qPCR) assay. Blood samples were subjected to complete blood count (CBC) analysis, and multi-omics analyses, including bulk ribonucleic acid (RNA) sequencing (RNAseq) transcriptomics, metabolomics, and proteomics, were also performed. In addition, bulk RNAseq analysis was performed on isolated white blood cells to assess immunological responses triggering the onset of PCC headaches.

 

Enrichment analysis was performed to evaluate canonical signaling pathway alterations in long COVID groups between -8 days and over three months after COVID-19 onset. In addition, ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) was performed for plasma metabolomic profiling, and nitric oxide (NO) levels were detected in plasma using nitrite assays.

 

Results

 

Hyperinflammation was involved in triggering the onset of PCC-associated headache symptoms, with sustained inflammation potentially contributing to the development of persistent long COVID headaches. Immuno-metabolic reprogramming among PCC-headache patients may be responsible for the accumulation of lipid and arginine metabolites that contribute to long-term inflammation. The dysregulated metabolism of multiple neurotransmitters could be the hallmark of PCC-associated chronic headaches.

 

Dehydration was reported among (+)LC patients, thus indicating a probable estimator of PCC headaches. In the analysis, (+)LC individuals exhibited modest elevations in erythrocyte counts, hematocrit, and hemoglobin levels in the early COVID-19 convalescence period with a notable increase in leukocyte and platelet counts in the late COVID-19 convalescence period as compared to the (-)LC group.

 

Among (+)LC patients, upregulation of interferon (IFN)-related factors such as signal transducer and activator of transcription-1 (STAT-1), IFN-stimulated gene 15 (ISG-15), and IFN-induced protein with tetratricopeptide repeats-3 (IFIT-3), chemokines such as C-X-C motif chemokine ligand (CXCL)-1,-2,-3, and -10, and chemokine ligand-5 (CCL-5), as well as pro-inflammatory cytokine molecules including IFN-γ, 6, 7, 20, and 31, was observed.

 

The study findings indicate that chronic generalized inflammation drives COVID headaches, irrespective of COVID-19 severity. Enhanced glucose metabolism and inflammation were also observed among PCC headache patients before headache onset, which likely served as an energy source that subsequently led to a hyper-inflammatory state.

 

Despite SARS-CoV-2 clearance, PCC patients sustained inflammation, as reflected by persistently elevated levels of cytokines such as IFN-gamma and IFN-6, and chemokine molecules such as CCL-7, CCL-8, and CXCL-10 for over three months after the onset of chronic headaches. Increased expression of several fat metabolism products such as plasmalogen, sphingomyelins, sphingolipids, cholesterol, and phospholipids in the plasma of PCC individuals was observed throughout chronic headache progression.

 

These findings highlight the implications of dysfunctional lipid metabolism, which provides evidence of meta-inflammatory conditions that are likely present in long COVID patients with chronic headaches.

 

In addition to M1 macrophage-skewing and lipidomic-type profiles among PCC-headache patients, increased arginine and oxo-arginine were observed, with lower expression of nitric oxide synthase (NOS) inhibitors, asymmetric and symmetric dimethylarginine (ADMA and SDMA), and urea. These observations emphasize the essential roles of M1-type macrophage-mediated persistent inflammation among long COVID headache patients.

 

NO expression was increased among PCC patients, which likely contributed to their chronic headache symptoms. Therefore, anti-NOS drugs that reduce NO production could offer a new therapeutic approach to reduce long-term headaches and inflammation among PCC patients.

 

Serotonin levels were significantly higher at all time points, even prior to the onset of headaches, whereas the levels of dopamine metabolites, gamma-aminobutyric acid (GABA), and glutamate were significantly decreased. Thus, the dysregulated metabolism of neurotransmitters may also be involved in the progression of chronic headaches among PCC patients.

 

Overall, the study findings highlight the immuno-metabolomic landscape of long COVID patients with chronic headaches, which may provide insights into potential therapeutic interventions.

 

Source:

News-Medical

Published on Mar 13 2023

 

 

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