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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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Khosroshahi, L. M., Rokni, M., Mokhtari, T., & Noorbakhsh, F. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2020.107364 · Cited by 90
“Treatment with IL6 blocker Tocilizumab leads to an increase in the numbers of circulating lymphocytes, pointing to the role of IL-6 signaling in COVID-19-associated lymphopenia [85,120].”
InfluentialInterleukin-6 Perpetrator of the COVID-19 Cytokine Storm
Shekhawat, J. K., Gauba, K., Gupta, S., Purohit, P., Mitra, P., Garg, M. K., Misra, S., Sharma, P., & Banerjee, M. (2021) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-021-00989-8 · Cited by 90
Temgoua, M. N., Endomba, F. T., Nkeck, J. R., Kenfack, G. U., Tochie, J. N., & Essouma, M. (2020) · SN Comprehensive Clinical Medicine · doi:10.1007/s42399-020-00417-7 · Cited by 88
Haljasmägi, L., Salumets, A., Rumm, A. P., Jürgenson, M., Krassohhina, E., Remm, A., Sein, H., Kareinen, L., Vapalahti, O., Sironen, T. A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-77525-w · Cited by 86
Systemic inflammation as fuel for acute liver injury in COVID-19
Effenberger, M., Grander, C., Grabherr, F., Griesmacher, A., Ploner, T., Hartig, F., Bellmann‐Weiler, R., Joannidis, M., Zoller, H., Weiß, G., et al. (2020) · Digestive and Liver Disease · doi:10.1016/j.dld.2020.08.004 · Cited by 88
“[15] Giamarellos-Bourboulis EJ , Netea MG , Rovina N , et al.”
Won, T., Wood, M. K., Hughes, D. M., Talor, M. V., Ma, Z., Schneider, J., SKINNER, J. T., Asady, B., Goerlich, E., Halushka, M. K., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103812 · Cited by 89
Urwyler, P., Moser, S., Charitos, P., Heijnen, I., Rudin, M., Sommer, G., Giannetti, B., Bassetti, S., Sendi, P., Trendelenburg, M., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.02072 · Cited by 84
Nidadavolu, L. S., & Walston, J. D. (2020) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaa209 · Cited by 86
Haemophagocytic syndrome and COVID-19
Retamozo, S., Brito‐Zerón, P., Sisó‐Almirall, A., Flores-Chávez, A., Cárdenas, M. J. S., & Ramos‐Casals, M. (2021) · Clinical Rheumatology · doi:10.1007/s10067-020-05569-4 · Cited by 88
Javed, H., Meeran, M. F. N., Jha, N. K., & Ojha, S. K. (2021) · Frontiers in Plant Science · doi:10.3389/fpls.2020.601335 · Cited by 89
COVID-19 Impairs Immune Response to Candida albicans
Moser, D., Biere, K., Han, B., Hoerl, M., Schelling, G., Choukèr, A., & Woehrle, T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.640644 · Cited by 85
“However, the immune response of COVID-19 patients with ARDS can be categorized into three different groups: i) immune dysregulation with low HLA-DR expression and features of sepsis-induced immune paralysis, ii) monocyte activation syndrome with high inflammatory responses, mildly affected HLA-DR levels and sustained…”
BackgroundCOVID-19 disease and immune dysregulation
Davitt, E., Davitt, C., Mazer, M. B., Areti, S. S., Hotchkiss, R. S., & Remy, K. E. (2022) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2022.101401 · Cited by 84
“Among the patients with severe respiratory failure, one-fourth were characterized as having macrophage-activation syndrome [17].”
InfluentialImpact of aging on immunity in the context of COVID-19, HIV, and tuberculosis
Grifoni, A., Alonzi, T., Alter, G., Noonan, D. M., LANDAY, A. L., Albini, A., & Goletti, D. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1146704 · Cited by 90
He, B., Liu, S., Wang, Y., Xu, M., Cai, W., Liu, J., Bai, W., Ye, S., Ma, Y., Hu, H., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00610-7 · Cited by 78
Hultcrantz, M. L., Richter, J. R., Rosenbaum, C. A., Patel, D., Smith, E. L., Korde, N., Lu, S. X., Mailankody, S., Shah, U. A., Lesokhin, A. M., et al. (2020) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-20-0102 · Cited by 91
Canziani, L. M., Trovati, S., Brunetta, E., Testa, A., Santis, M. D., Bombardieri, E., Guidelli, G. M., Albano, G., Folci, M., Squadroni, M., et al. (2020) · Journal of Autoimmunity · doi:10.1016/j.jaut.2020.102511 · Cited by 83
Selvaraj, K., Ravichandran, S., Krishnan, S., Radhakrishnan, R. K., Manickam, N., & Kandasamy, M. (2021) · Reproductive Sciences · doi:10.1007/s43032-020-00441-x · Cited by 87
Tang, J., Ravichandran, S., Lee, Y., Grubbs, G., Coyle, E. M., Klenow, L., Genser, H., Golding, H., & Khurana, S. (2021) · Nature Communications · doi:10.1038/s41467-021-21463-2 · Cited by 81
Diabetes and COVID-19; A Bidirectional Interplay
Kazakou, P., Lambadiari, V., Ikonomidis, I., Kountouri, A., Panagopoulos, G. N., Athanasopoulos, S., Korompoki, E., Kalomenidis, I., Dimopoulos, M. A., & Mitrakou, A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.780663 · Cited by 90
“To further support the role of pro-inflammatory cytokines in COVID-19 pathophysiology, another recent study showed that the inhibition of IL-6 by tocilizumab reverses lymphopenia in critically ill ventilated COVID-19 patients (51).”
Repurposing anticancer drugs for the management of COVID-19
Bairi, K. E., Trapani, D., Petrillo, A., Page, C. L., Zbakh, H., Daniele, B., Belbaraka, R., Curigliano, G., & Afqir, S. (2020) · European Journal of Cancer · doi:10.1016/j.ejca.2020.09.014 · Cited by 82
“Elevated serum levels of pro-inflammatory cytokines (known as cytokine release syndrome or cytokine storm), such as tumour-necrosis factor alpha (TNF-a) and interleukin 6 (IL-6), seem to cause multiple organ failure by damaging tissues, contributing to the poor outcomes in COVID-19 patients [14,24,70,117,159,210,218,2…”
BackgroundHypoferremia is Associated With Increased Hospitalization and Oxygen Demand in COVID‐19 Patients
Hippchen, T., Altamura, S., Muckenthaler, M. U., & Merle, U. (2020) · HemaSphere · doi:10.1097/hs9.0000000000000492 · Cited by 81
“This may be explained by immune dysregulation in severe COVID-19 patients that has previously been shown to be only partially normalized by tocilizumab.(26) The fact that in our studies hypoferremia reacts differently than CRP- and IL-6 levels shows that immune dysregulation in COVID-19 is complex and has to be furthe…”
BackgroundColleselli, K., Stierschneider, A., & Wiesner, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512464 · Cited by 93
Rossi, N. D., Scarpazza, C., Filippini, C., Cordioli, C., Rasia, S., Mancinelli, C. R., Rizzoni, D., Romanelli, G., Cossi, S., Vettoretto, N., et al. (2020) · EClinicalMedicine · doi:10.1016/j.eclinm.2020.100459 · Cited by 80
“Indeed, levels of IL-6 have been found to be directly associated with severe lung damage [10,11], and a recent meta-analysis of six studies investigating IL-6 concentration in COVID-19 demonstrated 2.”
ResultThe Enigma of Endothelium in COVID-19
Kaur, S., Tripathi, D. M., & Yadav, A. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00989 · Cited by 78
“COVID-19 patients also show IL-6-mediated low HLADR expression and lymphopenia (Giamarellos-Bourboulis et al., 2020).”
BackgroundChen, C., Lin, Y., Chen, T., Tseng, T.-Y., Wong, H.-L., Kuo, C.-Y., Lin, W.-P., Huang, S.-R., Wang, W., Liao, J.-H., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0242763 · Cited by 80
Immunogenic and reactogenic efficacy of Covaxin and Covishield: a comparative review
Das, S., Kar, S. S., Samanta, S., Banerjee, J., Giri, B., & Dash, S. K. (2022) · Immunologic Research · doi:10.1007/s12026-022-09265-0 · Cited by 82
“In COVID-19 patients, IL-1 and IL-6 from circulating monocytes and macrophages cause macrophage activation syndrome (MAS), which leads to severe respiratory failure [104].”
BackgroundA Longitudinal Study of Immune Cells in Severe COVID-19 Patients
Payen, D. M., Cravat, M., Maadadi, H., Didelot, C., Prosic, L., Dupuis, C., Losser, M.-R., & Bittencourt, M. D. C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.580250 · Cited by 77
Hematopoietic responses to SARS-CoV-2 infection
Elahi, S. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04220-6 · Cited by 79
Temporal landscape of human gut RNA and DNA virome in SARS-CoV-2 infection and severity
Zuo, T., Liu, Q., Zhang, F., Yeoh, Y. K., Wan, Y., Zhan, H., Lui, G. C.-Y., Chen, Z., Li, A. Y. L., Cheung, C. P., et al. (2021) · Microbiome · doi:10.1186/s40168-021-01008-x · Cited by 76
Pontali, E., Volpi, S., Signori, A., Antonucci, G., Castellaneta, M., Buzzi, D., Montale, A., Bustaffa, M., Angelelli, A., Caorsi, R., et al. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2021.01.024 · Cited by 76
Advances and gaps in SARS-CoV-2 infection models
Muñoz‐Fontela, C., Widerspick, L., Albrecht, R. A., Beer, M., Carroll, M. W., de Wit, E., Diamond, M., Dowling, W. E., Funnell, S. G. P., García‐Sastre, A., et al. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010161 · Cited by 76
“This is also consistent with findings in older patients, in which immune senescence, loss of type I IFN responses, decline in antigen presentation, and reduced T cell responses have shown to delay viral clearance [81,82].”
ResultQudus, M. S., Tian, M., Sirajuddin, S., Liu, S., Afaq, U., Wali, M., Liu, J., Pan, P., Luo, Z., Zhang, Q., et al. (2023) · Journal of Medical Virology · doi:10.1002/jmv.28751 · Cited by 84
“associated inflammasome signatures using flow cytometric and single‐cell transcriptomic analysis.(65,140)”
MethodThe role of trained immunity in COVID-19: Lessons for the next pandemic
Netea, M. G., Ziogas, A., Benn, C. S., Giamarellos‐Bourboulis, E. J., Joosten, L. A. B., Arditi, M., Chumakov, K., van Crevel, R., Gallo, R. C., Aaby, P., et al. (2023) · Cell Host & Microbe · doi:10.1016/j.chom.2023.05.004 · Cited by 79
“Initially, most of the attention was centered on the clear hyperinflammatory profile that characterized many of the patients with severe forms of the disease.(1,2) An exaggerated production and release of proinflammatory cytokines, especially interleukin-1 (IL-1) and -6 (IL-6), has been hypothesized to induce systemic…”
Self-citationImmune Mechanisms in Cardiovascular Diseases Associated With Viral Infection
Gopal, R., Marinelli, M. A., & Alcorn, J. F. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.570681 · Cited by 77
Leptin correlates with monocytes activation and severe condition in COVID-19 patients
Wang, J., Xu, Y., Zhang, X., Wang, S., Peng, Z., Guo, J. R., Jiang, H., Liu, J., Xie, Y., Wang, J., et al. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.5hi1020-704r · Cited by 75
Li, Y., Hou, G., Zhou, H., Wang, Y., Tun, H. M., Zhu, A., Zhao, J., Xiao, F., Liu, D., Liu, D., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00508-4 · Cited by 76
“36 Modulating macrophage activation might be a potential therapeutic strategy for severe COVID-19 patients.”
Cellular Immune Response to COVID-19 and Potential Immune Modulators
Zhou, X. K., & Ye, Q. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.646333 · Cited by 77
“In contrast, the interferon response is slower, and immunoglobulin G (IgG) and total antibody levels are increased (24, 30).”
BackgroundHumoral immune mechanisms involved in protective and pathological immunity during COVID-19
Widjaja, G., Jalil, A. T., Rahman, H. S., Abdelbasset, W. K., Bokov, D. O., Suksatan, W., Ghaebi, M., Marofi, F., Navashenaq, J. G., Jadidi‐Niaragh, F., et al. (2021) · Human Immunology · doi:10.1016/j.humimm.2021.06.011 · Cited by 75
Inflammation, Immunity and Immunogenetics in COVID-19: A Narrative Review
Lingeswaran, M., Goyal, T., Ghosh, R., Suri, S., Mitra, P., Misra, S., & Sharma, P. (2020) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-020-00897-3 · Cited by 78
“HLA-DR expression on CD14 monocytes of COVID-19 patients were found to be significantly low among severe cases when compared to mild cases, the levels of which improved on treatment with IL-6 inhibitor (Toclizumab) [53].”
BackgroundInfluentialThe dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome
Blot, M., Bour, J., Quenot, J., Bourredjem, A., Nguyen, M., Guy, J., Monier, S., Georges, M., Large, A., Dargent, A., et al. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02646-9 · Cited by 75
“Factor 1 associated [1] baseline severity and extrarespiratory organ dysfunction (SOFA and PSI scores, lactate, creatinine and NT-ProBNP levels which were higher in non-COVID-19, except for SOFA score), [2] “classical” inflammatory mediators (i.”
Background
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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