Immune Alterations in a Patient with SARS-CoV-2-Related Acute Respiratory Distress Syndrome
Lila Bouadma, Aurélie Wiedemann, Juliette Patrier, Mathieu Surénaud, Paul-Henri Wicky, Emile Foucat, Jean-Luc Diehl, Boris P Hejblum, Fabrice Sinnah, Etienne de Montmollin, Christine Lacabaratz, Rodolphe Thiébaut, J F Timsit, Yves Lévy, Lila Bouadma, Aurélie Wiedemann, Juliette Patrier, Mathieu Surénaud, Paul-Henri Wicky, Emile Foucat, Jean-Luc Diehl, Boris P Hejblum, Fabrice Sinnah, Etienne de Montmollin, Christine Lacabaratz, Rodolphe Thiébaut, J F Timsit, Yves Lévy
Abstract
We report a longitudinal analysis of the immune response associated with a fatal case of COVID-19 in Europe. This patient exhibited a rapid evolution towards multiorgan failure. SARS-CoV-2 was detected in multiple nasopharyngeal, blood, and pleural samples, despite antiviral and immunomodulator treatment. Clinical evolution in the blood was marked by an increase (2-3-fold) in differentiated effector T cells expressing exhaustion (PD-1) and senescence (CD57) markers, an expansion of antibody-secreting cells, a 15-fold increase in γδ T cell and proliferating NK-cell populations, and the total disappearance of monocytes, suggesting lung trafficking. In the serum, waves of a pro-inflammatory cytokine storm, Th1 and Th2 activation, and markers of T cell exhaustion, apoptosis, cell cytotoxicity, and endothelial activation were observed until the fatal outcome. This case underscores the need for well-designed studies to investigate complementary approaches to control viral replication, the source of the hyperinflammatory status, and immunomodulation to target the pathophysiological response. The investigation was conducted as part of an overall French clinical cohort assessing patients with COVID-19 and registered in clinicaltrials.gov under the following number: NCT04262921.
Keywords: COVID-19; T cells; cytokines; immune dysfunction.
Conflict of interest statement
The authors declare that they have no conflict of interest.
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References
- Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, et al. 2020. 10.1101/2020.02.07.937862.
- Phelan AL, Katz R, Gostin LO. The novel coronavirus originating in Wuhan, China: challenges for global health governance. JAMA. 2020;323:709. doi: 10.1001/jama.2020.1097.
- Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan. China Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5.
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–1034. doi: 10.1016/s0140-6736(20)30628-0.
- Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–2629. doi: 10.1172/JCI137244.
- Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, Sanvito F, Ponzoni M, Doglioni C, Cristofori P, Traversari C, Bordignon C, Ciceri F, Ostuni R, Bonini C, Casucci M, Bondanza A. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24(6):739–748. doi: 10.1038/s41591-018-0036-4.
- Hui DSC, Zumla A. Severe acute respiratory syndrome: historical, epidemiologic, and clinical features. Infect Dis Clin N Am. 2019;33(4):869–889. doi: 10.1016/j.idc.2019.07.001.
- Rockx B, Baas T, Zornetzer GA, Haagmans B, Sheahan T, Frieman M, Dyer MD, Teal TH, Proll S, van den Brand J, Baric R, Katze MG. Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. J Virol. 2009;83(14):7062–7074. doi: 10.1128/JVI.00127-09.
- Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13(1):3–10. doi: 10.1038/cmi.2015.74.
- Lescure F-X, Bouadma L, Nguyen D, Parisey M, Wicky P-H, Behillil S, Gaymard A, Bouscambert-Duchamp M, Donati F, le Hingrat Q, Enouf V, Houhou-Fidouh N, Valette M, Mailles A, Lucet JC, Mentre F, Duval X, Descamps D, Malvy D, Timsit JF, Lina B, van-der-Werf S, Yazdanpanah Y. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis. 2020;20:697–706. doi: 10.1016/s1473-3099(20)30200-0.
- Ward JH. Hierarchical grouping to optimize an objective function. J Am Stat Assoc. 1963;58(301):236–244. doi: 10.1080/01621459.1963.10500845.
- Arabi YM, Murthy S, Webb S. Correction to: COVID-19: a novel coronavirus and a novel challenge for critical care. Intensive Care Med. 2020;46:1087–1088. doi: 10.1007/s00134-020-06009-2.
- Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med. 2020;46(4):579–582. doi: 10.1007/s00134-020-05967-x.
- Liu Y, Yan L-M, Wan L, Xiang T-X, Le A, Liu J-M, et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020;20:656–657. doi: 10.1016/s1473-3099(20)30232-2.
- Cunha CB, Opal SM. Middle East respiratory syndrome (MERS): a new zoonotic viral pneumonia. Virulence. 2014;5(6):650–654. doi: 10.4161/viru.32077.
- Adrie C, Lugosi M, Sonneville R, Souweine B, Ruckly S, Cartier JC, et al. Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission. Ann Intensive Care. 2017;7(1):30. doi: 10.1186/s13613-017-0242-0.
- Thevarajan I, Nguyen THO, Koutsakos M, Druce J, Caly L, van de Sandt CE, Jia X, Nicholson S, Catton M, Cowie B, Tong SYC, Lewin SR, Kedzierska K. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med. 2020;26(4):453–455. doi: 10.1038/s41591-020-0819-2.
- Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H et al. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019;4(4). 10.1172/jci.insight.123158.
- Augustin A, Kubo RT, Sim GK. Resident pulmonary lymphocytes expressing the gamma/delta T-cell receptor. Nature. 1989;340(6230):239–241. doi: 10.1038/340239a0.
- Cheng M, Hu S. Lung-resident gammadelta T cells and their roles in lung diseases. Immunology. 2017;151(4):375–384. doi: 10.1111/imm.12764.
- Poccia F, Agrati C, Castilletti C, Bordi L, Gioia C, Horejsh D, Ippolito G, Chan PKS, Hui DSC, Sung JJY, Capobianchi MR, Malkovsky M. Anti-severe acute respiratory syndrome coronavirus immune responses: the role played by V gamma 9V delta 2 T cells. J Infect Dis. 2006;193(9):1244–1249. doi: 10.1086/502975.
- Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, et al. 2020. 10.1101/2020.02.23.20026690.
- Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B, Puel A, Biswas SK, Moshous D, Picard C, Jais JP, D’Cruz D, Casanova JL, Trouillet C, Geissmann F. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity. 2010;33(3):375–386. doi: 10.1016/j.immuni.2010.08.012.
- Wei H, Xu X, Tian Z, Sun R, Qi Y, Zhao C, et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev. 2020. 10.1093/nsr/nwaa041.
- Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420–422. doi: 10.1016/s2213-2600(20)30076-x.
- Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, et al. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis. 2020. 10.1093/cid/ciaa449.
- Yang Y, Shen C, Li J, Yuan J, Yang M, Wang F, et al. 2020. 10.1101/2020.03.02.20029975.
- Arabi YM, Balkhy HH, Hayden FG, Bouchama A, Luke T, Baillie JK, al-Omari A, Hajeer AH, Senga M, Denison MR, Nguyen-van-Tam JS, Shindo N, Bermingham A, Chappell JD, van Kerkhove MD, Fowler RA. Middle East respiratory syndrome. N Engl J Med. 2017;376(6):584–594. doi: 10.1056/NEJMsr1408795.
- Faure E, Poissy J, Goffard A, Fournier C, Kipnis E, Titecat M, Bortolotti P, Martinez L, Dubucquoi S, Dessein R, Gosset P, Mathieu D, Guery B. Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? PLoS One. 2014;9(2):e88716. doi: 10.1371/journal.pone.0088716.
- Sheahan TP, Sims AC, Leist SR, Schafer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222. doi: 10.1038/s41467-019-13940-6.
- Zumla A, Hui DS, Azhar EI, Memish ZA, Maeurer M. Reducing mortality from 2019-nCoV: host-directed therapies should be an option. Lancet. 2020;395(10224):e35–ee6. doi: 10.1016/s0140-6736(20)30305-6.
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