Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae
Authors: Thompson Ryan C. , Simons Nicole W. , Wilkins Lillian , Cheng Esther , Del Valle Diane Marie , Hoffman Gabriel E. , Cervia Carlo , Fennessy Brian , Mouskas Konstantinos , Francoeur Nancy J. , Johnson Jessica S. , Lepow Lauren , Le Berichel Jessica , Chang Christie , Beckmann Aviva G. , Wang Ying-chih , Nie Kai , Zaki Nicholas , Tuballes Kevin , Barcessat Vanessa , Cedillo Mario A. , Yuan Dan , Huckins Laura , Roussos Panos , Marron Thomas U. ,   The Mount Sinai COVID-19 Biobank Team, Agashe Charuta , Agrawal Priyal , Akyatan Alara , Alesso-Carra Kasey , Alibo Eziwoma , Alvarez Kelvin , Amabile Angelo , Argmann Carmen , Argueta Kimberly , Ascolillo Steven , Bailey Rasheed , Batchelor Craig , Beckmann Noam D. , Begani Priya , Bogunovic Dusan , Bose Swaroop , Cimen Bozkus Cansu , Bravo Paloma , Brown Stacey-Ann , Buckup Mark , Burka Larissa , Calorossi Sharlene , Cambron Lena , Carbonell Guillermo , Carrara Gina , Cedillo Mario A. , Chang Christie , Chang Serena , Chen Steven T. , Chien Jonathan , Chowdhury Mashkura , Chung Jonathan , Comella Phillip H. , Cosgrove Dana , Cossarini Francesca , Cotter Liam , Dave Arpit , Dawson Travis , Dayal Bheesham , Dhainaut Maxime , Dornfeld Rebecca , Dul Katie , Eaton Melody , Eber Nissan , Elaiho Cordelia , Ellis Ethan , Fabris Frank , Faith Jeremiah , Falci Dominique , Feng Susie , Fernandes Marie , Fishman Nataly , Francoeur Nancy J. , Gangadharan Sandeep , Geanon Daniel , Gelb Bruce D. , Glicksberg Benjamin S. , Gnjatic Sacha , Gonzalez-Kozlova Edgar , Grabowska Joanna , Gyimesi Gavin , Hamdani Maha , Handler Diana , Harris Jocelyn , Hartnett Matthew , Hatem Sandra , Herbinet Manon , Herrera Elva , Hochman Arielle , Hoffman Gabriel E. , Hook Jaime , Horta Laila , Humblin Etienne , Jaladanki Suraj , Jamal Hajra , Jordan Daniel , Kang Gurpawan , Karekar Neha , Karim Subha , Kelly Geoffrey , Kim Jong , Kim-Schulze Seunghee , Kumar Arvind , Lacunza Jose , Lansky Alona , Lebovitch Dannielle , Lee Brian , Lee Grace , Lee Gyu Ho , Lee Jacky , Leech John , Leventhal Michael B. , Liharska Lora E. , Lindblad Katherine , Livanos Alexandra , Machado Rosalie , Madrid Kent , Mahmood Zafar , Mar Kelcey , Marron Thomas U. , Martin Glenn , Marvin Robert , Maskey Shrisha , Matthews Paul , Meckel Katherine , Mehandru Saurabh , Merad Miriam , Mercedes Cynthia , Merzier Elyze , Meyer Dara , Mollaoglu Gurkan , Morris Sarah , Mouskas Konstantinos , Moya Emily , Nadkarni Girish , Nie Kai , Nisenholtz Marjorie , Ofori-Amanfo George , Onel Kenan , Ounadjela Merouane , Patel Manishkumar , Patel Vishwendra , Pruitt Cassandra , Rahman Adeeb , Rathi Shivani , Redes Jamie , Reyes-Torres Ivan , Rodrigues Alcina , Rodriguez Alfonso , Roudko Vladimir , Roussos Panos , Ruiz Evelyn , Scalzo Pearl , Schadt Eric E. , Scott Ieisha , Sebra Robert , Serrano Sandra , Shah Hardik , Shervey Mark , Silva Pedro , Sloofman Laura , Smith Melissa , Soares Schanoski Alessandra , Soto Juan , Sridhar Shwetha Hara , Stefanos Hiyab , Straw Meghan , Sweeney Robert , Tabachnikova Alexandra , Teague Collin , Tin Manying , Tuballes Kevin , Tyler Scott R. , Upadhyaya Bhaskar , Vaid Akhil , Van Der Heide Verena , Vaninov Natalie , Vlachos Konstantinos , Wacker Daniel , Walker Laura , Walsh Hadley , Wang Bo , Wang Wenhui , Wang Ying-chih , Wilk C. Matthias , Wilson Jessica , Wilson Karen M. , Xie Hui , Xue Li , Yeboah Naa-akomaah , Yi Nancy , Yishak Mahlet , Young Sabina , Yu Alex , Zaki Nicholas , Zaks Nina , Zha Renyuan , Glicksberg Benjamin S. , Nadkarni Girish , Heath James R. , Gonzalez-Kozlova Edgar , Boyman Onur , Kim-Schulze Seunghee , Sebra Robert , Merad Miriam , Gnjatic Sacha , Schadt Eric E. , Charney Alexander W. , Beckmann Noam D. 
Published: December 2022

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were followed clinically into the post-acute period. Distinct gene expression signatures of post-acute sequelae were already present in whole blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell-associated gene expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in individuals with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.