High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19
Authors: Tveita Anders , Murphy Sarah Louise , 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 , Dudman Susanne Gjeruldsen , Henriksen Katerina Nezvalova , Müller Fredrik , Skjønsberg Ole Henning , Trøseid Marius , Barratt-Due Andreas , Dyrhol-Riise Anne Ma , Aukrust Pål , Halvorsen Bente , Dahl Tuva Børresdatter , Ueland Thor ,   NOR-SOLIDARITY Consortium and the Norwegian SARS-CoV-2 Study Group Investigators, Austad Cathrine , Bogen Mette , Hermann Anne , Opsand Hanne , Steinsvik Trude , Woll Bjørn Martin , Christensen Erik Egeland , Eftestøl Kristin , Hesstvedt Liv , Jenum Synne , Jørgensen Marthe Jøntvedt , Landaas Elisabeth Toverud , Nur Sarah , Ormaasen Vidar , Pettersen Frank Olav , Quist-Paulsen Else , Reikvam Dag Henrik , Røstad Kjerstin , Skeie Linda , Steffensen Anne Katrine , Stiksrud Birgitte , Gravrok Berit , Skogen Vegard , Tylden Garth Daryl , Andersen Jan Terje , Kolderup Anette , Kåsine Trine , Lund-Johansen Fridtjof , Olsen Inge Christoffer , Skåra Karoline Hansen , Tran Trung , Fladeby Cathrine , Hesstvedt Liv , Holberg-Petersen Mona , Jenum Synne , Johal Simreen Kaur , Reikvam Dag Henrik , Røstad Kjerstin , Steffensen Anne Katrine , Stiksrud Birgitte , Vaage Eline Brenno , Christensen Erik Egeland , Jørgensen Marthe Jøntvedt , Nur Sarah , Ormaasen Vidar , Pettersen Frank Olav , Aballi Saad , Brynhildsen Jorunn , Ghanima Waleed , Halstensen Anne Marie , Berg Åse , Blomberg Bjørn , Kvåle Reidar , Langeland Nina , Mohn Kristin Greve Isdahl , Dalgard Olav , Eiken Ragnhild , Molvik Richard Alexander , Ystrøm Carl Magnus , Ernst Gernot , Thoresen Lars , Gustad Lise Tuset , Saxhaug Lars Mølgaard , Skei Nina Vibeche , Hannula Raisa , Haugli Mette , Olsen Roy Bjørkholt , Hoel Hedda , Hoff Dag Arne Lihaug , Johannessen Asgeir , Åsheim-Hansen Bjørn , Kittang Bård Reikvam , Le Lan Ai Kieu , Manotheepan Ravinea , Nordberg Lena Bugge , Rasmussen Hans Schmidt , Stenvik Grethe-Elisabeth , Thorkildsen Ruth Foseide , Vinge Leif Erik , Mielnik Pawel , Skogen Vegard , Skudal Hilde , Tholin Birgitte 
Published: July 2022

Abstract

Background
Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients.

Methods
Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms.

Results
A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up.

Conclusions
Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19.

Clinical Trials Registration
NCT04321616 and NCT04381819.