Immunometabolic rewiring in long COVID patients with chronic headache

Foo, Suan-Sin; Chen, Weiqiang; Jung, Kyle L.; Azamor, Tamiris; Choi, Un Yung; Zhang, Pengfei; Comhair, Suzy; Erzurum, Serpil C.; Jehi, Lara; Jung, Jae U.

doi:10.1101/2023.03.06.531302

Cited by 4 publications

(5 citation statements)

References 65 publications

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“…Our study confirmed and extended prior reports of metabolic dysregulation in Long Covid (6, 14, 15, 17, 18, 20, 22, 29). We also observed decreased activity of the telomere maintenance pathways and DNA damage recognition pathways in the LC group compated with the CC group, which may signal impaired tissue regeneration in patients with Long Covid (31, 32).…”

Section: Discussionsupporting

confidence: 92%

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Persistent Activation of Chronic Inflammatory Pathways in Long Covid

Aid,

McMahan,

Hachmann

et al. 2024

Preprint

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Long Covid, or Post-Acute Sequelae of COVID-19 (PASC), involves a spectrum of chronic symptoms following resolution of acute SARS-CoV-2 infection. Current hypotheses for the pathogenesis of Long Covid include persistent SARS-CoV-2, activation of other viruses, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction, and complement activation. We evaluated 142 participants, including uninfected controls (N=35), acutely infected individuals (N=54), convalescent controls (N=25), and Long Covid patients (N=28), by comprehensive immunologic, virologic, transcriptomic, and proteomic analyses. Long Covid was characterized by persistent inflammatory pathways compared with convalescent controls and uninfected controls, including upregulation of IL-6 and JAK-STAT pathways as well as activation of coagulation, complement, metabolism, and T cell exhaustion pathways. Moreover, robust activation of these pathways during acute COVID-19 infection correlated with the subsequent development of Long Covid. In an independent validation cohort (N=47), Long Covid patients had higher levels of plasma IL-6R compared with convalescent controls and uninfected controls. These data demonstrate that Long Covid is characterized by persistent activation of chronic inflammatory pathways, suggesting novel therapeutic targets and biomarkers of disease.

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Section: Discussionsupporting

confidence: 92%

“…Clinical symptoms in the Long Covid (LC) cohort included persistent fatigue, shortness of breath, exercise intolerance, brain fog, and abnormal smell and taste (Fig. 1b), similar to prior reports (3,5,(21)(22)(23)(24).…”

Section: Study Participantssupporting

confidence: 82%

Persistent Activation of Chronic Inflammatory Pathways in Long Covid

Aid,

McMahan,

Hachmann

et al. 2024

Preprint

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“…Frequency of chronic headache range widely from ~8–40% among long COVID cases ( 46 , 63–65 ). Individuals mildly affected by SARS-CoV-2 infections seemed more prone to post-COVID headaches ( 64 , 66 ), which were exacerbated with a prior history of migraines ( 63 , 64 ). Our MR analysis showed a strong positive causal association between COVID-19 and chronic headache in long COVID patients.…”

Section: Discussionmentioning

confidence: 99%

“…Our MR analysis showed a strong positive causal association between COVID-19 and chronic headache in long COVID patients. Recent evidence suggests that long COVID headaches appear to be triggered by hyperinflammation and are sustained by chronic inflammatory activation, and dysregulation of neurotransmitters and metabolic inflammation ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

The impact of COVID-19 on pulmonary, neurological, and cardiac outcomes: evidence from a Mendelian randomization study

Shenoy,

Udupa,

et al. 2023

Front. Public Health

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BackgroundLong COVID is a clinical entity characterized by persistent health problems or development of new diseases, without an alternative diagnosis, following SARS-CoV-2 infection that affects a significant proportion of individuals globally. It can manifest with a wide range of symptoms due to dysfunction of multiple organ systems including but not limited to cardiovascular, hematologic, neurological, gastrointestinal, and renal organs, revealed by observational studies. However, a causal association between the genetic predisposition to COVID-19 and many post-infective abnormalities in long COVID remain unclear.MethodsHere we employed Mendelian randomization (MR), a robust genetic epidemiological approach, to investigate the potential causal associations between genetic predisposition to COVID-19 and long COVID symptoms, namely pulmonary (pneumonia and airway infections including bronchitis, emphysema, asthma, and rhinitis), neurological (headache, depression, and Parkinson’s disease), cardiac (heart failure and chest pain) diseases, and chronic fatigue. Using two-sample MR, we leveraged genetic data from a large COVID-19 genome-wide association study and various disorder-specific datasets.ResultsThis analysis revealed that a genetic predisposition to COVID-19 was significantly causally linked to an increased risk of developing pneumonia, airway infections, headache, and heart failure. It also showed a strong positive correlation with chronic fatigue, a frequently observed symptom in long COVID patients. However, our findings on Parkinson’s disease, depression, and chest pain were inconclusive.ConclusionOverall, these findings provide valuable insights into the genetic underpinnings of long COVID and its diverse range of symptoms. Understanding these causal associations may aid in better management and treatment of long COVID patients, thereby alleviating the substantial burden it poses on global health and socioeconomic systems.

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“…The ICDH-3 provides guidance on how to choose the most-likely diagnosis. Headache is one of the most common neurologic symptoms reported in long COVID [39,40]. The World Health Organization de nes the post-COVID-19 condition or long COVID as new symptoms or the presence of symptoms for over two months, within three months following initial SARS-CoV-2 infection that cannot be explained by any other reason [41].…”

Section: Discussionmentioning

confidence: 99%

New daily persistent headache after SARS-CoV-2 infection in Latin America: a cross- sectional study

Carrión-Nessi,

Ascanio,

Pineda-Arapé

et al. 2023

Preprint

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Background Persistent headache is a frequent symptom after coronavirus disease 2019 (COVID-19) and there is currently limited knowledge about its clinical spectrum and predisposing factors. A subset of patients may be experiencing new daily persistent headache (NDPH) after COVID-19, which is among the most treatment-refractory primary headache syndromes.Methods We conducted a cross-sectional study in Latin America to characterize individuals with persistent headache after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and identify risk factors associated with NDPH. Participants over 18 years old who tested positive for SARS-CoV-2 infection and reported persistent headache among their symptoms completed an online survey that included demographics, past medical history, persistent headache clinical characteristics, and COVID-19 vaccination status. Based on participants’ responses, NDPH diagnostic criteria were used to group participants into NDPH and non-NDPH groups.Results Four hundred and twenty-one participants from 11 Latin American countries met the inclusion criteria. One in four participants met the diagnostic criteria for NDPH. The mean age was 40 years, with most participants being female (82%). Over 90% of the participants reported having had mild/moderate COVID-19. Most participants had a history of headache before developing COVID-19 (58%), mainly migraine type (32%). The most predominant clinical characteristics in the NDPH group were occipital location, severe/unbearable intensity, burning character, and radiating pain (p < 0.05). A higher proportion of anxiety symptoms, sleep problems, myalgia, mental fog, paresthesia, nausea, sweating of the face or forehead, and ageusia or hypogeusia as concomitant symptoms were reported in participants with NDPH (p < 0.05). Palpebral edema as a concomitant symptom during the acute phase of COVID-19, occipital location, and burning character of the headache were risk factors associated with NDPH.Conclusion This is the first study in Latin America that explored the clinical spectrum of NDPH after SARS-CoV-2 infection and its risk factors. Clinical evaluation of COVID-19 patients presenting with persistent headache should take into consideration NDPH.

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Immunometabolic rewiring in long COVID patients with chronic headache

Cited by 4 publications

References 65 publications

Persistent Activation of Chronic Inflammatory Pathways in Long Covid

Persistent Activation of Chronic Inflammatory Pathways in Long Covid

The impact of COVID-19 on pulmonary, neurological, and cardiac outcomes: evidence from a Mendelian randomization study

New daily persistent headache after SARS-CoV-2 infection in Latin America: a cross- sectional study

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