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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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“High levels of a subset of these pro-inflammatory chemokines and cytokines, especially IL-6, correlate directly with disease severity and could be responsible for at least some of the disease’s pathological features (42).”
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“More data show that IL-6 rather than IL-1 b is responsible for immunological dysregulation in severe patients with respiratory failure (28).”
COVID-19: systemic pathology and its implications for therapy
Shen, Q., Li, J., Zhang, Z., Guo, S., Wang, Q., An, X., & Chang, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.65911 · Cited by 51
“887 Current studies revealed the role of IL-6 in the pathogenesis of COVID-19, and the 888 development of drugs targeting the IL-6 pathway is promising for relieving 889 inflammation in COVID-19 patients [40].”
BackgroundInfluentialCOVID-19 signalome: Pathways for SARS-CoV-2 infection and impact on COVID-19 associated comorbidity
Lundstrom, K. H., Hromić‐Jahjefendić, A., Bilajac, E., Aljabali, A. A. A., Baralić, K., Sabri, N. A., Shehata, E. M., Raslan, M., Ferreira, A. C. B. H., Orlandi, L., et al. (2022) · Cellular Signalling · doi:10.1016/j.cellsig.2022.110495 · Cited by 46
Sweeney, T. E., Liesenfeld, O., Wacker, J. W., He, Y. D., Rawling, D., Remmel, M., Coyle, S., Midic, U., Kotsaki, A., Kanavou, A., et al. (2020) · Critical Care Medicine · doi:10.1097/ccm.0000000000004786 · Cited by 46
“As reported elsewhere (11), blood was sampled from patients with community-acquired lower respiratory tract infection by polymerase chain reaction (PCR)confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within the first 24 hours of hospital admission, including hospital transfers.”
BackgroundSelf-citationA digital protein microarray for COVID-19 cytokine storm monitoring
Song, Y., Ye, Y., Su, S., Stephens, A., Cai, T., Chung, M. T., Han, M. K., Newstead, M. W., Yessayan, L., Frame, D. G., et al. (2020) · Lab on a Chip · doi:10.1039/d0lc00678e · Cited by 44
Prognostic bioindicators in severe COVID-19 patients
Bergantini, L., Bargagli, E., d’Alessandro, M., Refini, R. M., Cameli, P., Galasso, L., Scapellato, C., Montagnani, F., Scolletta, S., Franchi, F., et al. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155455 · Cited by 44
Delshad, M., Tavakolinia, N., Pourbagheri‐Sigaroodi, A., Safaroghli‐Azar, A., Bagheri, N., & Bashash, D. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107586 · Cited by 49
“It seems that NK cells are one of the targets of SARS-CoV-2, as several pieces of evidence clearly showed their reduction in COVID-19 patients, especially those who are classified as critically ill [8,45,49].”
Dyavar, S. R., Singh, R., Emani, R., Pawar, G. P., Chaudhari, V. D., Podany, A. T., Avedissian, S. N., Fletcher, C. V., & Salunke, D. B. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111794 · Cited by 45
Dhawan, M. K., Rabaan, A. A., Fawarah, M. M., Almuthree, S. A., Alsubki, R. A., Alfaraj, A. H., Mashraqi, M. M., Alshamrani, S., Abduljabbar, W. A., Alwashmi, A. S. S., et al. (2023) · Vaccines · doi:10.3390/vaccines11010101 · Cited by 45
Dysregulation of the immune response affects the outcome of critical COVID‐19 patients
Wei, L., Wang, W., Chen, D., & Xu, B. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26181 · Cited by 44
“Thus, clarifying the pathogenesis of critical COVID-19 to facilitate improvement in treatment is important[16,17].”
BackgroundOpportunistic Fungal Infection Associated With COVID-19
Cafardi, J. M., Haas, D., Lamarre, T., & Feinberg, J. (2021) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofab016 · Cited by 45
Elevated circulating monocytes and monocyte activation in COVID-19 convalescent individuals
Park, J., Dean, L. S., Jiyarom, B., Gangcuangco, L. M. A., Shah, P., Awamura, T., Ching, L. L., Nerurkar, V. R., Chow, D. C., Igno, F., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1151780 · Cited by 46
“Studies have shown that COVID-19 patients display high systemic levels of cytokines and profound immune cell dysregulation that correlates with disease severity (6, 7).”
BackgroundEfficacy of tocilizumab treatment in severely ill COVID-19 patients
Zhao, J., Cui, W., & Tian, B. (2020) · Critical Care · doi:10.1186/s13054-020-03224-7 · Cited by 44
Transcriptomic Signature Differences Between SARS-CoV-2 and Influenza Virus Infected Patients
Bibert, S., Guex, N., Lourenço, J., Brahier, T., Papadimitriou‐Olivgeris, M., Damonti, L., Manuel, O., Liechti, R., Götz, L., Tschopp, J., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.666163 · Cited by 43
“Increasing evidences suggest that SARS-CoV-2 induces specific response mechanisms, probably distinct from those triggered by other viruses, that can lead to major immune dysregulation (12).”
BackgroundNeutrophils and lymphopenia, an unknown axis in severe COVID-19 disease
Peñaloza, H. F., Lee, J. S., & Ray, P. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009850 · Cited by 44
Johnson, B. S., & Laloraya, M. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2020.06.014 · Cited by 42
“Moreover, an increased lymphocyte count was observed in patients SARS CoV2 infection when treated with tocilizumab, the IL-6 receptor antagonist [67,68].”
The PIKfyve Inhibitor Apilimod: A Double-Edged Sword against COVID-19
Baranov, M. V., Bianchi, F., & van den Bogaart, G. (2020) · Cells · doi:10.3390/cells10010030 · Cited by 45
“A recent profiling of immune cells from blood of COVID-19 patients revealed a reduced expression of MHC class II and lower production of proinflammatory cytokines compared to healthy controls (Figure 1B) [16,20].”
BackgroundLee, E. E., Song, K., Hwang, W., Ham, S. Y., Jeong, H., Kim, J. H., Oh, H. S., Kang, Y. M., Lee, E. B., Kim, N. J., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-87668-z · Cited by 45
Estupiñán‐Moreno, E., Ortiz‐Fernández, L., Li, T., Hernández‐Rodríguez, J., Ciudad, L., Andrés‐León, E., Terron-Camero, L. C., Prieto‐González, S., Espígol‐Frigolé, G., Cid, M. C., et al. (2022) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2022-222156 · Cited by 43
SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D
Lee, M. J., Leong, M. W., Rustagi, A., Beck, A., Zeng, L., Holmes, S., Qi, L., & Blish, C. (2022) · bioRxiv · doi:10.1016/j.celrep.2022.111892 · Cited by 31
“…immune response in COVID-19 have noted that NK cells are less abundant in the peripheral blood of severe COVID-19 patients than in healthy donors 5–13 ; a concurrent increase in NK cell frequency in the lungs of critically ill patients suggests that peripheral depletion of NK cells may be due…”
Asashima, H., Mohanty, S., Comi, M., Ruff, W. E., Hoehn, K. B., Wong, P., Klein, J., Lucas, C. G. D. O., Cohen, I., Coffey, S., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2022.111895 · Cited by 41
SARS-CoV-2 Infection and the Liver
Morgan, K., Samuel, K., Vandeputte, M., Hayes, P. C., & Plevris, J. N. (2020) · Pathogens · doi:10.3390/pathogens9060430 · Cited by 43
Yang, M., Chen, X., & Xu, Y. (2020) · Medical Science Monitor · doi:10.12659/msm.926393 · Cited by 43
“As aforementioned, CRP is directly induced by the action of IL-6 in the acute phase of inflammation [22].”
BackgroundViral Glycoproteins Induce NLRP3 Inflammasome Activation and Pyroptosis in Macrophages
Eisfeld, H. S., Simonis, A., Winter, S., Chhen, J., Stroh, L. J., Krey, T., Koch, M., Theobald, S. J., & Rybniker, J. (2021) · Viruses · doi:10.3390/v13102076 · Cited by 44
“As some patients fail to control viral infection, SARS-CoV-2 can cause severe viral pneumonia leading to respiratory failure [4].”
BackgroundMillán, I. F. A., Salvatierra, J., Torres-Parejo, Ú., Faro‐Míguez, N., Callejas-Rubio, J. L., Ceballos-Torres, Á., Cruces-Moreno, M. T., Gómez-Jiménez, F. J., Hernández‐Quero, J., Anguita-Santos, F., et al. (2021) · Internal and Emergency Medicine · doi:10.1007/s11739-020-02600-z · Cited by 44
“Patients with severe respiratory failure associated with SARS-CoV-2 infection present CD4 depletion, so it is likely that IL-1 blockade contributes to an increase in circulating CD4 and thus helps to restore immune balance, with a better prognosis [39].”
BackgroundAdli, A., Rahimi, M., Khodaie, R., Hashemzaei, N., & Hosseini, S. M. (2022) · Journal of Medical Virology · doi:10.1002/jmv.27615 · Cited by 46
“Increased generation of pro‐inflammatory cytokines through lymphocyte and monocytes dysfunction with CD4 lymphopenia are two critical characteristics of this immune dysregulation.(176)”
BackgroundPopescu, I., Snyder, M. E., Iasella, C. J., Hannan, S. J., Koshy, R., Burke, R., Das, A., Brown, M. J., Lyons, E. J., Lieber, S. C., et al. (2022) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202111-2493oc · Cited by 46
Functional reprogramming of monocytes in patients with acute and convalescent severe COVID-19
Brauns, E., Azouz, A., Grimaldi, D., Xiao, H., Thomas, S., Nguyen, M., Olislagers, V., Duc, I. V., Cano, C. O., del Mármol, V., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.154183 · Cited by 42
“Here, in the light on the complex immune dysregulation that occurs during acute infection (6, 13), we hypothesized that COVID-19 could have long-term impact on immune functions, as it is observed in patients who experienced bacterial sepsis (14).”
BackgroundRoutine laboratory testing to determine if a patient has COVID-19
Stegeman, I., Ochodo, E. A., Guleid, F., Holtman, G. A., Yang, B., Davenport, C., Deeks, J. J., Dinnes, J., Dittrich, S., Emperador, D., et al. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013787 · Cited by 76
Cui, Z., Merritt, Z., Assa, A., Mustehsan, H., Chung, E., Liu, S., Kumthekar, A. A., Ayesha, B., McCort, M., Palaiodimos, L., et al. (2021) · Journal of Hospital Medicine · doi:10.12788/jhm.3560 · Cited by 42
Type I Interferons in COVID-19 Pathogenesis
Palermo, E., Carlo, D. D., Sgarbanti, M., & Hiscott, J. B. (2021) · Biology · doi:10.3390/biology10090829 · Cited by 42
Sex-Related Differences in Innate and Adaptive Immune Responses to SARS-CoV-2
Agrawal, S., Salazar, J. V., Tran, T. M., & Agrawal, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.739757 · Cited by 42
Maher, A. K., Burnham, K. L., Jones, E. M., Tan, M. M., Saputil, R. C., Baillon, L., Selck, C., Giang, N., Argüello, R. J., Pillay, C., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-35638-y · Cited by 46
Mitchel, J., Gordon, M. G., Perez, R. K., Biederstedt, E., Bueno, R., Ye, C., & Kharchenko, P. V. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02411-z · Cited by 48
“39,40).”
Deciphering SARS-CoV-2 Virologic and Immunologic Features
Lebeau, G., Vagner, D., Frumence, É., Ah-Pine, F., Guillot, X., Nobécourt, E., Raffray, L., & Gasque, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165932 · Cited by 54
“A study trying to classify COVID-19 patients into three immune states found during sepsis (MAS-like, dysregulation with immunoparalysis or functional) showed that all severe cases had an immune dysfunction with the majority of patients harboring dysregulated immunity while the rest presented MAS-like profile [146].”
InfluentialHasenkrug, K. J., Feldmann, F., Myers, L. M., Santiago, M. L., Guo, K., Barrett, B. S., Mickens, K. L., Carmody, A., Okumura, A., Rao, D., et al. (2021) · mBio · doi:10.1128/mbio.01503-21 · Cited by 40
Multiomics: unraveling the panoramic landscapes of SARS-CoV-2 infection
Wang, X., Xu, G., Liu, X., Liu, Y., Zhang, S., & Zhang, Z. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00754-0 · Cited by 42
Tom, J. A., Bao, M., Tsai, L. W., Qamra, A., Summers, D. M., Carrasco‐Triguero, M., McBride, J., Rosenberger, C. M., Lin, C. J. F., Stubbings, W. J., et al. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000005229 · Cited by 41
Clinical spectrum of COVID-19 and risk factors associated with severity in Spanish children
Tagarro, A., Cobos‐Carrascosa, E., Villaverde, S., Sanz-Santaeufemia, F. J., Grasa, C. D., Soriano‐Arandes, A., Hernánz, A., Navarro, M. L., Pino, R., Epalza, C., et al. (2021) · European Journal of Pediatrics · doi:10.1007/s00431-021-04306-6 · Cited by 42
Peculiarities of the T Cell Immune Response in COVID-19
Kudlay, D. A., Кофиади, И. А., & Khaitov, M. R. (2022) · Vaccines · doi:10.3390/vaccines10020242 · Cited by 43
“In a study by Giamarellos-Bourboulis et al. (2020), it was found that the blood plasma of COVID-19 patients could block HLA-DR expression on CD14 + monocytes, which recovered upon IL-6 inhibition [39].”
BackgroundHamed, M. G. M., & Hagag, R. S. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110140 · Cited by 42
Update in COVID-19 in the intensive care unit from the 2020 HELLENIC Athens International symposium
Rello, J., Belliato, M., Dimopoulos, M. A., Giamarellos‐Bourboulis, E. J., Jaksic, V., Martín‐Loeches, I., Mporas, I., Pelosi, P. P., Poulakou, G., Pournaras, S., et al. (2020) · Anaesthesia Critical Care & Pain Medicine · doi:10.1016/j.accpm.2020.10.008 · Cited by 41
“In parallel, monocytes maintain their potential for the over-production of pro-inflammatory cytokines [4].”
InfluentialSelf-citationBrüssow, H. (2020) · Environmental Microbiology · doi:10.1111/1462-2920.15302 · Cited by 54
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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