High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19
Anders Tveita, Sarah Louise Murphy, Jan Cato Holter, Anders Benjamin Kildal, Annika E. Michelsen, Tøri Vigeland Lerum, Mari Kaarbø, Lars Heggelund, Aleksander Rygh Holten, Ane-Kristine Finbråten, Karl Erik Müller, Alexander Mathiessen, Simen Bøe, Børre Fevang, Beathe Kiland Granerud, Kristian Tonby, Andreas Lind, Susanne Dudman, Kateřina Nezvalová‐Henriksen, Fredrik Müller, Ole Henning Skjønsberg, Marius Trøseid, Andreas Barratt‐Due, Anne Ma Dyrhol‐Riise, Pål Aukrust, Bente Halvorsen, Tuva B. Dahl, Thor Ueland, Cathrine Austad, Mette Bogen, Anne Pernille Hermann, Hanne Opsand, Trude Steinsvik, Bjørn Martin Woll, Erik Egeland Christensen, Kristin Eftestøl, Liv Hesstvedt, Synne Jenum, Marthe Jøntvedt Jørgensen, Elisabeth Toverud Landaas, Sarah Nur, Vidar Ormaasen, Frank Olav Pettersen, Else Quist‐Paulsen, Dag Henrik Reikvam, Kjerstin Røstad, Linda Gail Skeie, Anne Katrine Steffensen, Birgitte Stiksrud, Berit Gravrok, Vegard Skogen, Garth D. Tylden, Jan Terje Andersen, Anette Kolderup, Trine Kåsine, Fridtjof Lund‐Johansen, Inge Christoffer Olsen, Karoline H. Skåra, Trung Tran, Cathrine Fladeby, Liv Hesstvedt, Mona Holberg‐Petersen, Synne Jenum, Simreen Kaur Johal, Dag Henrik Reikvam, Kjerstin Røstad, Anne Katrine Steffensen, Birgitte Stiksrud, Eline Brenno Vaage, Erik Egeland Christensen, Marthe Jøntvedt Jørgensen, Sarah Nur, Vidar Ormaasen, Frank Olav Pettersen, Saad Aballi, Jorunn Brynhildsen, Waleed Ghanima, Anne Marie Halstensen, Åse Berg, Bjørn Blomberg, Reidar Kvåle, Nina Langeland, Kristin Greve Isdahl Mohn, Olav Dalgård, Ragnhild Eiken, Richard Alexander Molvik, Carl Magnus Ystrøm, Gernot Ernst, Lars Thoresen, Lise Tuset Gustad, Lars Mølgaard Saxhaug, Nina Vibeche Skei, Raisa Hannula, Mette Haugli, Roy Bjørkholt Olsen, Hedda Hoel, Dag Arne Lihaug Hoff, Asgeir Johannessen, Bjørn Åsheim-Hansen, Bård Reikvam Kittang
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.