The DOI matches its Crossref record; 14 of the 16 references it cites were found in a registry or an index.
Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure
Open accessAbstract
Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation.
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“the IL-6 receptor antagonist, tocilizumab, increased the number of circulating lymphocytes in COVID-19 patients122.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [122]
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Cites
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30183-5 · Cited by 48,884 · cited 1×
“This is mostly because severe COVID-19 is associated with hyper-cytokinemia (Guan et al., 2020; Huang et al., 2020).”
Clinical characteristics of coronavirus disease 2019 in China
Guan, W.-J., Ni, Z.-Y., Hu, Y., Liang, W.-H., Ou, C.-Q., He, J.-X., Liu, L., Shan, H., Lei, C.-L., Hui, D. S. C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2002032 · Cited by 30,246 · cited 1×
“This is mostly because severe COVID-19 is associated with hyper-cytokinemia (Guan et al., 2020; Huang et al., 2020) .”
The third international consensus definitions for sepsis and septic shock (Sepsis-3).
Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G. R., Chiche, J.-D., Coopersmith, C. M., et al. (2016) · JAMA · doi:10.1001/jama.2016.0287 · Cited by 28,250
Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., Xie, C., Ma, K., Shang, K., Wang, W., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa248 · Cited by 4,775
Fardet, L., Galicier, L., Lambotte, O., Marzac, C., Aumont, C., Chahwan, D., Coppo, P., & Hejblum, G. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38690 · Cited by 1,508 · cited 1×
“HScore is proposed as a classification tool for secondary MAS, and values more than 169 are highly diagnostic (Fardet et al., 2014).”
Thevarajan, I., Nguyen, T. H. O., Koutsakos, M., Druce, J. D., Caly, L., van de Sandt, C. E., Jia, X., Nicholson, S. R., Catton, M. C., Cowie, B., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0819-2 · Cited by 993 · cited 1×
“Statistical comparisons are indicated by the arrows; ns: non-significant; *p < 0.05; **p < 0.01. of one case of COVID-19 of moderate severity (Thevarajan et al., 2020).”
BackgroundInfluentialDysregulation of Immune Response in Patients with COVID-19 in Wuhan, ChinaPreprint
Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Yu, T., Xie, C., Ma, K., Shang, K., Wang, W., et al. (2020) · SSRN Electronic Journal · doi:10.2139/ssrn.3541136 · Cited by 898
COVID-19: a novel coronavirus and a novel challenge for critical care
Arabi, Y. M., Murthy, S., & Webb, S. A. R. (2020) · Intensive Care Medicine · doi:10.1007/s00134-020-05955-1 · Cited by 313 · cited 1×
“The risk of death of these patients is high, reaching even 60% (Arabi et al., 2020).”
Lukaszewicz, A., Grienay, M., Resche‐Rigon, M., Pirracchio, R., Faivre, V., Boval, B., & Payen, D. M. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181ab858a · Cited by 288
on behalf of the Hellenic Sepsis Study Group, Kyriazopoulou, E., Leventogiannis, K., Norrby‐Teglund, A., Dimopoulos, G., Pantazi, A., Orfanos, S. E., Rovina, N., Tsangaris, I., Gkavogianni, T., et al. (2017) · BMC Medicine · doi:10.1186/s12916-017-0930-5 · Cited by 212 · cited 1×
“Immune responses of critically ill patients with sepsis can be classified into three patterns: macrophage-activation syndrome (MAS) (Kyriazopoulou et al., 2017) , sepsis-induced immunoparalysis characterized by low expression of the human leukocyte antigen D related (HLA-DR) on CD14 monocytes (Lukaszewicz et al., 2009…”
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Predisposition of COVID-19 patients to secondary infections: set in stone or subject to change?
Sopirala, M. M. (2021) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000736 · Cited by 8
“SARS-CoV-2 infection leads to sustained production of tumour necrosis factor- a (TNF- a) and inter-leukin-6 (IL-6) resulting in hyper-inflammation [11].”
BackgroundSARS-CoV-2 INFECTED PATIENTS: FROM A HEMATOLOGIST PERSPECTIVE: COVID-19 and Hematology
Kreidieh, F., & Temraz, S. (2020) · Mediterranean Journal of Hematology and Infectious Diseases · doi:10.4084/mjhid.2020.078 · Cited by 7
Metadata
- Authors
- Giamarellos-Bourboulis, E. J., Netea, M. G., Rovina, N., Akinosoglou, K., Antoniadou, A., Antonakos, N., Damoraki, G., Gkavogianni, T., Adami, M.-E., Katsaounou, P., Ntaganou, M., Kyriakopoulou, M., Dimopoulos, G., Koutsodimitropoulos, I., Velissaris, D., Koufargyris, P., Karageorgos, A., Katrini, K., Lekakis, V., Lupse, M., Kotsaki, A., Renieris, G., Theodoulou, D., Panou, V., Koukaki, E., Koulouris, N., Gogos, C., & Koutsoukou, A.
- Affiliations
- University of Bonn (DE)
- National and Kapodistrian University of Athens (GR)
- University of Patras (GR)
- ORCID
- Netea, Mihai G.
- Rovina, Nikoletta
- Akinosoglou, Karolina
- Antoniadou, Anastasia
- Antonakos, Nikolaos
- Damoraki, Georgia
- Gkavogianni, Theologia
- Katsaounou, Paraskevi
- Kyriakopoulou, Magdalini
- Koutsodimitropoulos, Ioannis
- Velissaris, Dimitrios
- Koufargyris, Panagiotis
- Lekakis, Vasileios
- Kotsaki, Antigone
- Koukaki, Evangelia
- Koulouris, Nikolaos
- Koutsoukou, Antonia
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2020-06
- Volume
- 27
- Issue
- 6
- Pages
- 992-1000.e3
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC7172841
- OpenAlex
- W3016288338
- Cited by
- 2,045
- References
- 16
- Citations by year
- 2026: 39 · 2025: 73 · 2024: 141 · 2023: 228 · 2022: 412 · 2021: 640 · 2020: 508
- FWCI
- 58.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- European Research Council (833247)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Pfizer
- National and Kapodistrian University of Athens
- Astellas Pharma US
- Horizon 2020 (847422)
- Meso Scale Diagnostics
- Gilead Sciences
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- COVID-19 pandemic, severe respiratory failure, immune dysregulation, macrophage activation syndrome, HLA-DR expression, lymphopenia, CD4 depletion, natural killer cells, monocyte cytokine production, interleukin-6, TNF-α, tocilizumab, hyperinflammation, cytokine storm
- MeSH terms
- COVID-19, Aged, Female, HLA-DR Antigens, Humans, Inflammation, Killer Cells, Natural, Lymphopenia, Macrophage Activation, Male, Monocytes, Pneumonia, Viral, Respiratory Insufficiency, Interleukin-6, Coronavirus Infections, Pandemics, Antibodies, Monoclonal, Humanized
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