High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19

Tveita, Anders Aune; Murphy, Sarah; Holter, Jan Cato; Kildal, Anders Benjamin; Michelsen, Annika E.; Lerum, Tøri Vigeland; Kaarbø, Mari; Heggelund, Lars; Holten, Aleksander Rygh; Finbråten, Ane Kristine; Müller, Karl Erik; Mathiessen, Alexander; Bøe, Simen; Fevang, Børre; Granerud, Beathe Kiland; Tonby, Kristian; Lind, Andreas; Nezvalová-Henriksen, Kateřina; Müller, Fredrik; Skjønsberg, Ole Henning; Trøseid, Marius; Barratt‐Due, Andreas; Dyrhol‐Riise, Anne Ma; Aukrust, Pål; Halvorsen, Bente; Dahl, Tuva B.; Ueland, Thor

doi:10.1093/infdis/jiac313

Cited by 12 publications

(5 citation statements)

References 46 publications

(50 reference statements)

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“…Moreover, CCL21 was associated with all-cause and cardiovascular mortality [18], which was similar with our study. The same trend was seen in studies related to lung disease, where excessive levels of both chemicals were associated with poorer outcomes [32]. Lung diseases, such as pulmonary edema, are also present in heart failure patients, which also confirms the association between elevated levels of CCL21 and poor outcomes in heart failure patients.…”

Section: Discussionsupporting

confidence: 76%

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Predictive value of Serum CCL21 and CCL19 levels in heart failure patients : A prospective study

Zeng,

Li,

Wang

et al. 2023

Preprint

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Background: Chemokine C-C motif ligand (CCL)21 and CCL19 are well-recognized to associate with adverse events of cardiovascular disease, especially long-term prognosis. However, few studies have reported its correlation with heart failure. Purpose: To investigate and compare the predictive value of CCL21 and CCL19 serum levels in patients with heart failure. Methods: In this prospective, observational, single-center study, 221 patients with heart failure and 55 healthy controls were included. ROC curves were generated to analyze and compare the serum levels of CCL21 and CCL19 in predicting all-cause mortality and composite events. Cox regression and Kaplan-Meier survival analyses were performed to identify independent risk factors for prognosis. Pearson correlation was used to measure the correlation between creatinine and CCL21 / CCL19 levels. Results: The study observed 108 events (30 deaths and 78 occurred composite endpoints) over a median follow-up of 494.5(231.5,950.0) days. CCL21 showed strong predictive value for both all-cause mortality (P=0.001) and composite endpoints (P <0.001). while the combination of CCL21 and NT-proBNP further improved the predictive power, respectively (both P<0.001). K-M survival analysis revealed that patients with increased CCL21 and CCL19 exhibited higher all-cause mortality (both P<0.05). Meanwhile, higher incidence of composite endpoint events was also observed in patients with elevated CCL21 (P<0.05). Importantly, multivariate COX regression analysis demonstrated that smoking, higher level of CCL21 and ischemic heart disease were independent risk factors for all-cause mortality (P<0.001). Furthermore, diabetes and elevation of CCL21 were associated with an increased risk of composite endpoints (P<0.001). On the other hand, changes in CCL19 levels showed a graded association with worse renal function, resulting in a slight increasing trend in G3 and G4/5, (overall interaction P<0.05), with higher concentrations in G3 and G4/5(overall interaction P<0.05). Conclusions: Serum concentrations of CCL21 and CCL19 were significantly elevated in heart failure patients. High level of CCL21 is an independent risk factor for the adverse events in heart failure and may complement the prediction of those events which are less affected by renal function.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionsupporting

confidence: 60%

Predictive value of Serum CCL21 and CCL19 levels in heart failure patients : A prospective study

Zeng,

Li,

Wang

et al. 2023

Preprint

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“…3c). High levels of CCL21 were found to be associated with persisting pulmonary impairment for at least 3 months after hospital admission with COVID-19 42 . CCR7, the receptor for CCL21, is expressed by IPF fibroblasts in contrast to normal lung fibroblasts, and CCR7 + IPFderived fibroblasts respond to CCL21 with activation, migration, survival, and proliferation 43,44 .…”

Section: Discussionmentioning

confidence: 95%

Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19

Mothes

Pascual-Reguant

Koehler³

et al. 2023

Nat Commun

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Prolonged lung pathology has been associated with COVID-19, yet the cellular and molecular mechanisms behind this chronic inflammatory disease are poorly understood. In this study, we combine advanced imaging and spatial transcriptomics to shed light on the local immune response in severe COVID-19. We show that activated adventitial niches are crucial microenvironments contributing to the orchestration of prolonged lung immunopathology. Up-regulation of the chemokines CCL21 and CCL18 associates to endothelial-to-mesenchymal transition and tissue fibrosis within these niches. CCL21 over-expression additionally links to the local accumulation of T cells expressing the cognate receptor CCR7. These T cells are imprinted with an exhausted phenotype and form lymphoid aggregates that can organize in ectopic lymphoid structures. Our work proposes immune-stromal interaction mechanisms promoting a self-sustained and non-resolving local immune response that extends beyond active viral infection and perpetuates tissue remodeling.

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“…In the present study, data from two prospective cohort studies were pooled as previously described [23]. Briefly, Cohort 1 was the NOR Solidarity trial (NCT04321616), a multicentre, open‐label, adaptive, randomised controlled trial evaluating the effect of SoC alone or in combination with hydroxychloroquine (HCQ) or remdesivir in COVID‐19 patients admitted to 23 Norwegian hospitals, as part of the WHO solidarity trial [24].…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, data from two prospective cohort studies were pooled as previously described [23]. [26].…”

Section: Study Design and Participantsmentioning

confidence: 99%

Circulating markers of extracellular matrix remodelling in severe COVID‐19 patients

Murphy,

Halvorsen,

Holter

et al. 2023

J Intern Med

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BackgroundAbnormal remodelling of the extracellular matrix (ECM) has generally been linked to pulmonary inflammation and fibrosis and may also play a role in the pathogenesis of severe COVID‐19. To further elucidate the role of ECM remodelling and excessive fibrogenesis in severe COVID‐19, we examined circulating levels of mediators involved in various aspects of these processes in COVID‐19 patients.MethodsSerial blood samples were obtained from two cohorts of hospitalized COVID‐19 patients (n = 414). Circulating levels of ECM remodelling mediators were quantified by enzyme immunoassays in samples collected during hospitalization and at 3‐month follow‐up. Samples were related to disease severity (respiratory failure and/or treatment at the intensive care unit), 60‐day total mortality, and pulmonary pathology after three months. We also evaluated the direct effect of inactivated SARS‐CoV‐2 on the release of the different ECM mediators in relevant cell lines.ResultsSeveral of the measured markers were associated with adverse outcome, notably osteopontin, S100 calcium‐binding protein A12 and YKL‐40 were associated with disease severity and mortality. High levels of ECM mediators during hospitalisation were associated CT thorax pathology after three months. Some markers (i.e., growth differential factor 15, galectin 3 and matrix metalloproteinase 9) were released from various relevant cell lines (i.e., macrophages and lung cell lines) in vitro after exposure to inactivated SARS‐CoV‐2 suggesting a direct link between these mediators and the causal agent of COVID‐19.ConclusionOur findings highlight changes to ECM remodelling and particularly a possible role of osteopontin, S100A12 and YKL‐40 in the pathogenesis of severe COVID‐19.This article is protected by copyright. All rights reserved

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High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19

Cited by 12 publications

References 46 publications

Predictive value of Serum CCL21 and CCL19 levels in heart failure patients : A prospective study

Predictive value of Serum CCL21 and CCL19 levels in heart failure patients : A prospective study

Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19

Circulating markers of extracellular matrix remodelling in severe COVID‐19 patients

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