Long‐term disruption of cytokine signalling networks is evident in patients who required hospitalization for SARS‐CoV‐2 infection

Ahearn-Ford, Sinead; Lunjani, Nonhlanhla; McSharry, Brian P.; MacSharry, John; Fanning, Liam J.; Murphy, Gérard F.; Everard, C.; Barry, Aoife; McGreal, Aimee; Lawati, Sultan Mohamed Al; Lapthorne, Susan; Sherlock, Colin; McKeogh, Anna; Jackson, Arthur; Faller, Eamonn; Horgan, Mary; Sadlier, Corinna; O’Mahony, Liam

doi:10.1111/all.14953

Cited by 26 publications

(25 citation statements)

References 6 publications

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“…Persistent endothelial dysfunction may be responsible for the wide variation in symptoms reported [11][12][13]. There is also some evidence suggesting that altered inflammatory cytokine pathways may persist during convalescence [14].…”

Section: Introductionmentioning

confidence: 99%

Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection

et al. 2021

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The emergence of persistent symptoms following SARS-CoV-2 infection, known as long COVID, is providing a new challenge to healthcare systems. The cardinal features are fatigue and reduced exercise tolerance. Vitamin D is known to have pleotropic effects far beyond bone health and is associated with immune modulation and autoimmunity. We hypothesize that vitamin D levels are associated with persistent symptoms following COVID-19. Herein, we investigate the relationship between vitamin D and fatigue and reduced exercise tolerance, assessed by the Chalder Fatigue Score, six-minute walk test and modified Borg scale. Multivariable linear and logistic regression models were used to evaluate the relationships. A total of 149 patients were recruited at a median of 79 days after COVID-19 illness. The median vitamin D level was 62 nmol/L, with n = 36 (24%) having levels 30–49 nmol/L and n = 14 (9%) with levels <30 nmol/L. Fatigue was common, with n = 86 (58%) meeting the case definition. The median Borg score was 3, while the median distance covered for the walk test was 450 m. No relationship between vitamin D and the measures of ongoing ill-health assessed in the study was found following multivariable regression analysis. These results suggest that persistent fatigue and reduced exercise tolerance following COVID-19 are independent of vitamin D.

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Section: Introductionmentioning

confidence: 99%

Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection

et al. 2021

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“…6–8 Acute illness is associated with substantial immune activation 9–11 and central nervous system (CNS) dysfunction. 11–16 A handful of studies have measured serum glial fibrillary acidic protein (GFAP), an intermediate filament protein found in the cytoskeleton of CNS astrocytes, 17 and neurofilament light chain (NfL), a cytoskeletal protein expressed in the axons of neurons 18 during acute COVID-19. 19–28 In some cases, higher levels of these markers were identified in patients with neurologic symptoms during acute infection; 21–25 other studies have not identified such relationships.…”

Section: Introductionmentioning

confidence: 99%

Plasma markers of neurologic injury and systemic inflammation in individuals with self-reported neurologic post-acute sequelae of SARS-CoV-2 infection (PASC)

Peluso

Sans

Forman

et al. 2021

Preprint

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BackgroundThe biologic mechanisms underlying neurologic post-acute-sequelae of SARS-CoV-2 infection (PASC) are incompletely understood.MethodsWe measured markers of neuronal injury (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and soluble markers of inflammation among a cohort of people with prior confirmed SARS-CoV-2 infection at early and late recovery following the initial illness (defined as less than and greater than 90 days, respectively). The primary clinical outcome was the presence of self-reported central nervous system (CNS) PASC symptoms during the late recovery timepoint. We compared fold-changes in marker values between those with and without CNS PASC symptoms using linear mixed effects models and examined relationships between neurologic and immunologic markers using rank linear correlations.ResultsOf 121 individuals, 52 reported CNS PASC symptoms. During early recovery, those who went on to report CNS PASC symptoms had elevations in GFAP (1.3-fold higher mean ratio, 95% CI 1.04-1.63, p=0.02), but not NfL (1.06-fold higher mean ratio, 95% CI 0.89-1.26, p=0.54). During late recovery, neither GFAP nor NfL levels were elevated among those with CNS PASC symptoms. Although absolute levels of NfL did not differ, those who reported CNS PASC symptoms demonstrated a stronger downward trend over time in comparison to those who did not report CNS PASC symptoms (p=0.041). Those who went on to report CNS PASC also exhibited elevations in IL-6 (48% higher during early recovery and 38% higher during late recovery), MCP-1 (19% higher during early recovery), and TNF-alpha (19% higher during early recovery and 13% higher during late recovery). GFAP and NfL correlated with levels of several immune activation markers during early recovery; these correlations were attenuated during late recovery.ConclusionsSelf-reported neurologic symptoms present >90 days following SARS-CoV-2 infection are associated with elevations in markers of neurologic injury and inflammation at early recovery timepoints, suggesting that early injury can result in long-term disease. The correlation of GFAP and NfL with markers of systemic immune activation suggests one possible mechanism that might contribute to these symptoms. Additional work is needed to better characterize these processes and to identify interventions to prevent or treat this condition.Key PointsQuestionDo individuals with and without self-reported neurologic symptoms following SARS-CoV-2 infection have different levels of biomarkers of neurologic injury or immune activationãFindingsIn this cohort study of 121 adults, individuals reporting neurologic symptoms beyond 90 days following SARS-CoV-2 infection had higher levels of glial fibrillary acidic protein but not neurofilament light chain. Levels of several markers of inflammation including interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 were also elevated.MeaningPost-acute neurologic symptoms following SARS-CoV-2 infection are associated with significant differences in levels of certain biomarkers. Further investigation may provide clues to the biologic pathways underlying these symptoms.

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“…Importantly, TSLP levels were previously shown to be elevated in patients with long COVID, suggesting that long-term impacts of SARS-CoV-2 on epithelial cells should be examined in more detail, potentially guiding future therapeutic interventions. 36 While elevated proinflammatory cytokine levels are a common feature also associated with severe responses to other respiratory viruses such as influenza A(H1N1), the pattern of polyfunctional cytokine responses described in the current study seems to be specifically associated with severe COVID-19, potentially due to the broad infective capacity of SARS-CoV-2 to invade tissues and organs outside the respiratory tract. 37 , 38 …”

Section: Discussionmentioning

confidence: 53%

A high-risk gut microbiota configuration associates with fatal hyperinflammatory immune and metabolic responses to SARS-CoV-2

et al. 2022

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Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and associated clinical sequelae requires well-coordinated metabolic and immune responses that limit viral spread and promote recovery of damaged systems. However, the role of the gut microbiota in regulating these responses has not been thoroughly investigated. In order to identify mechanisms underpinning microbiota interactions with host immune and metabolic systems that influence coronavirus disease 2019 (COVID-19) outcomes, we performed a multi-omics analysis on hospitalized COVID-19 patients and compared those with the most severe outcome (i.e. death, n = 41) to those with severe non-fatal disease (n = 89), or mild/moderate disease (n = 42), that recovered. A distinct subset of 8 cytokines (e.g. TSLP) and 140 metabolites (e.g. quinolinate) in sera identified those with a fatal outcome to infection. In addition, elevated levels of multiple pathobionts and lower levels of protective or anti-inflammatory microbes were observed in the fecal microbiome of those with the poorest clinical outcomes. Weighted gene correlation network analysis (WGCNA) identified modules that associated severity-associated cytokines with tryptophan metabolism, coagulation-linked fibrinopeptides, and bile acids with multiple pathobionts, such as Enterococcus . In contrast, less severe clinical outcomes are associated with clusters of anti-inflammatory microbes such as Bifidobacterium or Ruminococcus , short chain fatty acids (SCFAs) and IL-17A. Our study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection. These features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to SARS-CoV-2 and other infectious agents.

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Long‐term disruption of cytokine signalling networks is evident in patients who required hospitalization for SARS‐CoV‐2 infection

Cited by 26 publications

References 6 publications

Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection

Investigating the Relationship between Vitamin D and Persistent Symptoms Following SARS-CoV-2 Infection

Plasma markers of neurologic injury and systemic inflammation in individuals with self-reported neurologic post-acute sequelae of SARS-CoV-2 infection (PASC)

A high-risk gut microbiota configuration associates with fatal hyperinflammatory immune and metabolic responses to SARS-CoV-2

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