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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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ResultSelf-citationCAR-NK cell therapy: a potential antiviral platform.
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ResultAn Impaired Inflammatory and Innate Immune Response in COVID-19
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Self-citationCD8 + T Cells Exhibit an Exhausted Phenotype in Hemophagocytic Lymphohistiocytosis
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“Along with this, a considerable reduction of B and NK cells is observed in HLH as described previously in severe inflammatory disorders [18, 19].”
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BackgroundPathogenesis of Vascular Retinal Manifestations in COVID-19 Patients: A Review
D’Alessandro, E., Kawasaki, A., & Eandi, C. M. (2022) · Biomedicines · doi:10.3390/biomedicines10112710 · Cited by 20
“Moreover, retinal findings might indicate a predominantly hypercoagulable state, which requires anticoagulant drugs, rather than an inflammatory response requiring steroids and inhibitors of interleukines such as IL-6 according to the phase of the disease.”
BackgroundInfluentialAge-dependent NK cell dysfunctions in severe COVID-19 patients
Fionda, C., Ruggeri, S., Sciumè, G., Laffranchi, M., Quinti, I., Milito, C., Palange, P., Menichini, I., Sozzani, S., Frati, L., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1039120 · Cited by 20
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BackgroundMechanistic understanding of innate and adaptive immune responses in SARS-CoV-2 infection
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“COVID-19 patients who present with acute respiratory distress syndrome (ARDS) have been shown to respond to anti-IL-6R blockade with tocilizumab (Yao et al., 2020; Giamarellos-Bourboulis et al., 2020).”
BackgroundSARS- CoV-2 infection and oxidative stress in early-onset preeclampsia
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COVID-19: Imbalanced Immune Responses and Potential Immunotherapies
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“monocytes were detected in COVID-19 patients inversely correlating with a high circulating level of IL-6 (56), suggesting a sepsis-induced immunoparalysis.”
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BackgroundMast cells: Therapeutic targets for COVID ‐19 and beyond
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“IL-6 blocker can partially elevate HLA-DR expression, leading to decrease levels of M-MDSC in severe COVID-19 patients [99].”
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The deciphering of the immune cells and marker signature in COVID‐19 pathogenesis: An update
Jasim, S. A., Mahdi, R. S., Bokov, D. O., Najm, M. A. A., Sobirova, G. N., Bafoeva, Z. O., Taifi, A., Alkadir, O. K. A., Mustafa, Y. F., Mirzaei, R., et al. (2022) · Journal of Medical Virology · doi:10.1002/jmv.28000 · Cited by 21
“Aside from that, human leukocyte antigen‐DR isotype (HLA‐DR) expressed on monocyte is significantly reduced in patients with severe COVID‐19, whereas its expression could be partly reversed by an IL‐6 antagonist.(86) MHC II”
BackgroundIL-6 drives T cell death to participate in lymphopenia in COVID-19
Zhou, X., Ye, G., Lv, Y., Guo, Y., Pan, X., Li, Y., Shen, G., He, Y., & Lei, P. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109132 · Cited by 20
“2 unique pattern of immune dysregulation, associated with sustained cytokine production and hyper-inflammation [19].”
Damme, K. F. A. V., Hoste, L., Declercq, J., Leeuw, E. D., Maes, B., Martens, L., Colman, R., Browaeys, R., Bosteels, C., Verwaerde, S., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0252 · Cited by 20
Shi, J., Pei, X., Peng, J., Wu, C., Lv, Y., Wang, X., Zhou, Y., Yuan, X., Dong, X., Zhou, S., et al. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70226 · Cited by 19
Dysregulation of the mevalonate pathway during SARS‐CoV‐2 infection: An in silico study
Marti, J. L. G., Wells, A. H., & Brufsky, A. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26743 · Cited by 18
“Inactivation of HMGB1 during the latent phase could remain an important cause for the immune‐deficient environment seen in COVID‐19.”
BackgroundInfluentialRencilin, C. F., Rosy, J. C., Mohan, M., Coico, R., & Sundar, K. (2021) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2021.104712 · Cited by 19
Peddapalli, A., Gehani, M., Kalle, A. M., Peddapalli, S. R., Peter, A. E., & Sharad, S. (2021) · Viruses · doi:10.3390/v13030378 · Cited by 19
“Mazzoni, A.; Salvati, L.; Maggi, L.; Capone, M.; Vanni, A.; Spinicci, M.; Mencarini, J.; Caporale, R.; Peruzzi, B.; Antonelli, A.; et al. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent.”
BackgroundInfluentialSeddiki, N., & French, M. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.649567 · Cited by 20
Innate immunity to SARS-CoV-2 infection: a review
Silva, M. J. A., Rodrigues, Y. C., Lima, K. V. B., & Lima, L. N. G. C. (2022) · Epidemiology and Infection · doi:10.1017/s095026882200125x · Cited by 22
Beyond dexamethasone, emerging immuno‐thrombotic therapies for COVID‐19
Jensen, M. P., George, M., Gilroy, D., & Sofat, R. (2021) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14540 · Cited by 17
“defects in lymphoid function driven by IL-6-mediated decrease in human leukocyte antigen-D related expression, resulting in CD4 Tcell lymphopenia followed by B-cell lymphopenia, distinct from bacterial sepsis and influenza.(63) Accordingly severe and fatal COVID-19 is associated with older age which is in turn associa…”
BackgroundKaravanaki, K., Rodolaki, K., Soldatou, A., Karanasios, S., & Kakleas, K. (2022) · Endocrine · doi:10.1007/s12020-022-03266-7 · Cited by 20
COVID-19, what could sepsis, severe acute pancreatitis, gender differences, and aging teach us?
Gallo, C. G., Fiorino, S., Posabella, G., Antonacci, D., Tropeano, A., Pausini, E., Pausini, C., Guarniero, T., Hong, W., Giampieri, E., et al. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155628 · Cited by 17
Phenotypes of severe COVID-19 ARDS receiving extracorporeal membrane oxygenation
Zhang, J., Whebell, S. F., Sanderson, B., Retter, A., Daly, K., Paul, R., Barrett, N. A., Agarwal, S., Lams, B., Meadows, C. I. S., et al. (2020) · British Journal of Anaesthesia · doi:10.1016/j.bja.2020.12.023 · Cited by 18
Zhou, X., Liu, J., Yu, M., Xing, W., Li, S., Ding, G., Chen, L., Zhang, J., Liu, T., Tong, W., et al. (2020) · Risk Management and Healthcare Policy · doi:10.2139/ssrn.3695178 · Cited by 18
Ouyang, W., Xie, T., Fang, H., Gao, C., Stantchev, T. S., Clouse, K. A., yuan, K., Ju, T., & Frucht, D. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147540 · Cited by 18
“A delayed IFN response, together with high load of virus and proinflammatory cytokines causes an unbalanced immune state, promoting the progression of COVID-19 disease (24-32).”
BackgroundAlshammary, A. F., & Alsulaiman, A. M. (2021) · Virulence · doi:10.1080/21505594.2021.1929800 · Cited by 18
Zulu, M. Z., Sureshchandra, S., Pinski, A. N., Doratt, B. M., Shen, W., & Messaoudi, I. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.760288 · Cited by 17
Uranga-Murillo, I., Morte-Romea, E., Hidalgo, S., Pesini, C., García‐Mulero, S., Sierra-Monzón, J. L., Santiago, L., Arias, M. A., de Miguel, D., Encabo-Berzosa, M. D. M., et al. (2021) · Theranostics · doi:10.7150/thno.63463 · Cited by 20
“Indeed, similar to other studies we also found elevated serum cytokines in plasma from moderate/severe COVID19 (11, 12, 15, 29).”
BackgroundResultMicrofluidic Systems to Study Neutrophil Forward and Reverse Migration
Babatunde, K. A., Ayuso, J. M., Kerr, S. C., Huttenlocher, A., & Beebe, D. J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.781535 · Cited by 16
Chastain, D. B., Henao‐Martínez, A. F., Dykes, A., Steele, G. M., Stoudenmire, L. L., Thomas, G. M., Kung, V. M., & Franco‐Paredes, C. (2022) · Therapeutic Advances in Infectious Disease · doi:10.1177/20499361211066363 · Cited by 18
Ke, C., Yu, C., Yue, D., Zeng, X., Hu, Z., & Yang, C. (2020) · Medicina Clínica · doi:10.1016/j.medcli.2020.06.055 · Cited by 18
The mechanistic basis linking cytokine storm to thrombosis in COVID-19
Wolf, A. J., Khimani, F., Yoon, B., Gerhart, C. R. B., Endsley, D., Ray, A., Yango, A. F., Flynn, S. D., Lip, G. Y. H., Gonzalez, S. A., et al. (2022) · Thrombosis Update · doi:10.1016/j.tru.2022.100110 · Cited by 18
“Studies have reported that patients with a more severe presentation of SARS-CoV-2 infection exhibit significantly lower levels of HLA-DR as well as lower CD4 and CD8 T-cell counts despite an elevated white blood cell count [12].”
Skin capillary alterations in patients with acute SarsCoV2 infection
Rosei, C. A., Gaggero, A., Famà, F., Malerba, P., Chiarini, G., Nardin, M., Brami, V., Rossini, C., Coschignano, M. A., Porteri, E., et al. (2022) · Journal of Hypertension · doi:10.1097/hjh.0000000000003271 · Cited by 18
Abbaspour‐Aghdam, S., Hazrati, A., Abdolmohammadi‐Vahid, S., Tahmasebi, S., Mohseni, J. H., Valizadeh, H., Nadiri, M., Mikaeili, H., Sadeghi, A., Yousefi, M., et al. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175267 · Cited by 18
“Nonetheless, we believe that a decent understanding of COVID-19 immunopathology is pivotal for better managing the ongoing pandemic (Giamarellos-Bourboulis et al., 2020).”
Tapela, K., Oyawoye, F. O., Olwal, C. O., Opurum, P. C., Amponsah, J. A., Segbedzi, K. A. L., Tetteh, B. E., Kumi-Ansah, F., Mutungi, J. K., Obodai, E., et al. (2022) · BMC Medicine · doi:10.1186/s12916-022-02571-2 · Cited by 18
Emerging roles of SARS-CoV-2 Spike-ACE2 in immune evasion and pathogenesis
Baldari, C. T., Onnis, A., Andreano, E., Giudice, G. D., & Rappuoli, R. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.04.001 · Cited by 18
“High neutrophil number promotes excessive formation of neutrophil extracellular traps resulting in autoantibodies and cytokine production, and possible activation of prothrombotic pathways [12,66,72,73].”
BackgroundLee, G., Schauner, R., Burke, J., Borocz, J., Vasana, S., Sobieraj, L., Giraudo, M. F., Jackson, Z., Ansari, M. Q., Navas, M. E., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1022890 · Cited by 18
“Not reported 4 2 (8) 0 (0) 2 (4) 1 (6)”
BackgroundKyriazopoulou, E., Hasin-Brumshtein, Y., Midic, U., Poulakou, G., Milionis, H. J., Metallidis, S., Astriti, M., Fragkou, A., Rapti, A., Taddei, E., et al. (2024) · Critical Care · doi:10.1186/s13054-024-04852-z · Cited by 18
Self-citationHyperpyrexia in patients with COVID‐19
Suwanwongse, K., & Shabarek, N. (2020) · Journal of Medical Virology · doi:10.1002/jmv.26154 · Cited by 18
“SARS‐CoV‐2 leads to a unique pattern of immune dysfunction characterized by a defective antigen presentation and lymphoid cells, but preserved monocytes function to secrete tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6).(16) Patients with severe COVID‐19 have substantially higher serum levels of proinflammat…”
BackgroundThe role of the allergist/immunologist in the COVID-19 pandemic: A Janus-faced presentation
Bellanti, J. A. (2020) · Allergy and Asthma Proceedings · doi:10.2500/aap.2020.41.200072 · Cited by 18
Systems Biology Approaches for Therapeutics Development Against COVID-19
Jaiswal, S., Kumar, M., Mandeep, SUNITA, S., Singh, Y. P., & Shukla, P. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.560240 · Cited by 17
de Campos‐Mata, L., Vaquero, S. T., Tachó‐Piñot, R., Piñero, J., Grasset, E. K., Arrieta‐Aldea, I., Melero, N. R., Carolis, C., Horcajada, J. P., Cerutti, A., et al. (2021) · Clinical & Translational Immunology · doi:10.1002/cti2.1339 · Cited by 17
“Indeed, such decrease in HLA-DR expression has been recently associated with defective antigen presentation driven by an excessive release of IL-6.(5) Finally, we found persistent changes in the circulating NK cell pool of patients infected with SARS-CoV-2.”
InfluentialOn Deep Landscape Exploration of COVID-19 Patients Cells and Severity Markers
Vázquez-Jiménez, A., de León, U. A.-P., Matadamas-Guzman, M. L., Muciño-Olmos, E. A., Martínez-López, Y. E., Escobedo-Tapia, T., & Reséndis-Antonio, O. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.705646 · Cited by 18
Immune Profiling of COVID-19 in Correlation with SARS and MERS
Khalil, B. A., Shakartalla, S. B., Goel, S., Mdkhana, B., Halwani, R., Maghazachi, A. A., AlSafar, H. S., Al‐Omari, B., & Bataineh, M. T. A. (2022) · Viruses · doi:10.3390/v14010164 · Cited by 18
SARS-CoV-2 Infection: A Possible Risk Factor for Incidence and Recurrence of Cancers
Jafarzadeh, A., Gosain, R., Mortazavi, S. M. J., Nemati, M., Jafarzadeh, S., & Ghaderi, A. A. (2022) · International Journal of Hematology-Oncology and Stem Cell Research · doi:10.18502/ijhoscr.v16i2.9205 · Cited by 19
Therapeutic Effects of Cannabinoids and Their Applications in COVID-19 Treatment
Pérez, R., Glaser, T., Villegas, C., Burgos, V., Ulrich, H., & Paz, C. (2022) · Life · doi:10.3390/life12122117 · Cited by 20
COVID-19 Outcomes in 4712 consecutively confirmed SARS-CoV2 cases in the city of MadridPreprint
Heili-Frades, S. B., Mínguez, P., Mahíllo, I., Prieto-Rumeau, T., Herrero, A., de la Fuente, L., Rodríguez‐Nieto, M. J., Romero, G. P.-B., Peces-Barba, M., de Miguel, M. D. P. C., et al. (2020) · medRxiv · doi:10.1101/2020.05.22.20109850 · Cited by 18
Neutralizing antibodies mediate virus-immune pathology of COVID-19
Jacobs, J. J. L. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.109884 · Cited by 17
“However it is unclear why and how suddenly a severe systemic immune activation would be triggered [4].”
BackgroundImmunological features of coronavirus disease 2019 in patients with cancer
Thibaudin, M., Fumet, J.-D., Bon, M., Hampe, L., Limagne, E., & Ghiringhelli, F. (2020) · European Journal of Cancer · doi:10.1016/j.ejca.2020.08.013 · Cited by 17
Tempering Macrophage Plasticity for Controlling SARS-CoV-2 Infection for Managing COVID-19 Disease
Toor, D., Jain, A., Kalhan, S., Manocha, H., Sharma, V. K., Jain, P., Tripathi, V., & Prakash, H. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.570698 · Cited by 17
“Both ARDS and MAS contribute to the significant depletion of CD8+ CTLs which are associated with disease severity (Luo et al., 2020) in COVID-19 patients.”
InfluentialStervbo, U., Rahmann, S., Roch, T., Westhoff, T. H., & Babel, N. (2020) · Scientific Reports · doi:10.1038/s41598-020-75972-z · Cited by 26
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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