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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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“In particular, monocytes from COVID-19 patients have sustained expression of the cytokines tumor necrosis factor (TNF) and interleukin-6 (IL6) [23].”
Beeraka, N. M., Tulimilli, S. V., Karnik, M., Sadhu, S. P., Pragada, R. R., Aliev, G., & Madhunapantula, S. V. (2021) · BioMed Research International · doi:10.1155/2021/8160860 · Cited by 25
“In addition to vascular permeability, the IL-6 can foster endothelial dysfunction; hence, IL-6 is an attractive drug target for mitigating the complications of COVID-19 [110, 111] (Figure 2).”
BackgroundCOVID-19 Vaccines: Current Conditions and Future Prospects
Zieneldien, T., Kim, J., Cao, J. A., & Cao, C. (2021) · Biology · doi:10.3390/biology10100960 · Cited by 24
“Older COVID-19 patients have also exhibited graver cases of lymphopenia, which affects CD4+ T cells, CD8+ T cells, natural killer cells (NKCs), and B cells [54,55].”
BackgroundDifferential dynamics of peripheral immune responses to acute SARS-CoV-2 infection in older adults
Lewis, S. A., Sureshchandra, S., Zulu, M. Z., Doratt, B. M., Jankeel, A., Ibraim, I. C., Pinski, A. N., Rhoades, N. S., Curtis, M., Jiang, X., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00127-2 · Cited by 23
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“5) Sex, n (%) Female 11 (79) 12 (52) 5 (26) 11 (78) Male 3 (21) 11 (48) 14 (74) 3 (22) BMI, mean (SD) 24.”
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Self-citationBlood transcriptome responses in patients correlate with severity of COVID-19 disease
Wang, Y., Schughart, K., Pelaia, T. M., Chew, T., Kim, K., Karvunidis, T., Knippenberg, B., Teoh, S., Phu, A. L., Short, K. R., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1043219 · Cited by 27
Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics
Pavan, M., & Moro, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054401 · Cited by 25
“A group of antiarthritis drugs represents another successful example of drug repurposing to their ability to modulate the immune response [42] and cytokine storm [43] caused by severe SARS-CoV-2 infection.”
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MBOAT7 in liver and extrahepatic diseases
Caddeo, A. M., Spagnuolo, R., & Maurotti, S. (2023) · Liver International · doi:10.1111/liv.15706 · Cited by 26
“105 MBOAT7 is a negative regulator of TLR signalling and its deficiency alters membrane phospholipid composition in macrophages as observed in individuals with COVID-19.”
BackgroundTsiakos, K., Tsakiris, A., Tsibris, G., Voutsinas, P.-M., Panagopoulos, P., Kosmidou, M. S., Petrakis, V., Gravvani, A., Gkavogianni, T., Klouras, E., et al. (2021) · Infectious Diseases and Therapy · doi:10.1007/s40121-021-00505-8 · Cited by 24
Self-citationYou, J., Li, H., Fan, P., Yang, X., Wei, Y., Zheng, L., Li, Z. S., & Cheng, Y. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.853496 · Cited by 23
Ocular manifestations of COVID-19
Ng, H., Scott, D. A. R., Danesh-Meyer, H. V., Smith, J. R., McGhee, C. N. J., & Niederer, R. L. (2024) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2024.101285 · Cited by 25
Lambadiari, V., Kousathana, F., Raptis, A. E., Katogiannis, K., Kokkinos, A. D., & Ikonomidis, I. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.557235 · Cited by 23
Septyaningtrias, D. E., & Susilowati, R. (2021) · Reviews in the Neurosciences · doi:10.1515/revneuro-2020-0092 · Cited by 23
“However, uncontrolled inflammatory innate responses and impaired adaptive immune responses upon virus infection may lead to harmful tissuedamage, both locally and systemically (Cui et al. 2020; Giamarellos-Bourboulis et al. 2020; Xu et al. 2020).”
BackgroundYang, J., Zhong, M., Hong, K., Yang, Q., Zhang, E., Zhou, D., Xia, J., Chen, Y., Sun, M., Zhao, B., et al. (2021) · Clinical & Translational Immunology · doi:10.1002/cti2.1259 · Cited by 24
A novel anti-human IL-1R7 antibody reduces IL-18-mediated inflammatory signaling
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“Indeed, MAS was found to present in some COVID-19 patients and a significantly higher serum IL-18 level was observed in the patients with MAS than patients without MAS (28,43).”
InfluentialTherapeutic approaches for SARS-CoV-2 infection
Gupta, A., Pradhan, A., Maurya, V. K., Kumar, S., Theengh, A., Puri, B., & Saxena, S. K. (2021) · Methods · doi:10.1016/j.ymeth.2021.04.026 · Cited by 23
“Further, elevated IL-1β is also central to macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) [178,179].”
SARS-CoV-2 infection paralyzes cytotoxic and metabolic functions of the immune cells
Singh, Y., Trautwein, C., Fendel, R., Krickeberg, N., Berezhnoy, G., Bissinger, R., Ossowski, S., Salker, M. S., Casadei, N., Rieß, O., et al. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e07147 · Cited by 24
Critical COVID‐19 is associated with distinct leukocyte phenotypes and transcriptome patterns
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Immunosuppression as a Hallmark of Critical COVID-19: Prospective Study
Kalicińska, E., Szymczak, D., Zińczuk, A., Adamik, B., Śmiechowicz, J., Skalec, T., Nowicka‐Suszko, D., Biernat, M., Bogucka‐Fedorczuk, A., Rybka, J., et al. (2021) · Cells · doi:10.3390/cells10061293 · Cited by 24
Myeloid phenotypes in severe COVID-19 predict secondary infection and mortality: a pilot study
Marais, C., Claude, C., Semaan, N., Charbel, R., Barreault, S., Travert, B., Piloquet, J., Demailly, Z., Morin, L., Merchaoui, Z., et al. (2021) · Annals of Intensive Care · doi:10.1186/s13613-021-00896-4 · Cited by 25
SARS-CoV-2 infection and disease outcomes in non-human primate models: advances and implications
Yuan, L., Tang, Q., Zhu, H., Guan, Y., Cheng, T., & Xia, N. (2021) · Emerging Microbes & Infections · doi:10.1080/22221751.2021.1976598 · Cited by 20
“Clinically, the host immune responses to SARS-CoV-2 infection are imbalanced, complicated, and varied over time [6,24,25].”
BackgroundButurović, L. J., Zheng, H., Tang, B. M. P., Lai, K., Kuan, W. S., Gillett, M., Santram, R., Shojaei, M., Almansa, R., Nieto, J. Á., et al. (2022) · Scientific Reports · doi:10.1038/s41598-021-04509-9 · Cited by 26
Self-citationSARS-CoV-2 Dysregulates Neutrophil Degranulation and Reduces Lymphocyte Counts
Muralidharan, A., Wyatt, T. A., & Reid, S. P. (2022) · Biomedicines · doi:10.3390/biomedicines10020382 · Cited by 23
“This, combined with lymphopenia, leading to elevated neutrophil-tolymphocyte ratio (NLR), has been observed as a hallmark of severe COVID-19 suggestive of poor recovery rates [7,14,15].”
BackgroundThe Importance of Nutraceuticals in COVID-19: What’s the Role of Resveratrol?
Domi, E., Hoxha, M., Kolovani, E., Tricarico, D., & Zappacosta, B. (2022) · Molecules · doi:10.3390/molecules27082376 · Cited by 22
“This condition protracted over several days leads to organ injury, followed by organ failure and increased risk of mortality [5].”
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Self-citationZhang, W., Qin, C., Fei, Y., Shen, M. Y., Zhou, Y., Zhang, Y., Zeng, X., & Zhang, S. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109022 · Cited by 23
Tryptophan Metabolism and COVID-19-Induced Skeletal Muscle Damage: Is ACE2 a Key Regulator?
Takeshita, H., & Yamamoto, K. I. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.868845 · Cited by 22
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“plethora of IL1B has been observed in bronchoalveolar lavage fluid of COVID-19 patients.(28) Giamarellos-Bourboulis et al.”
BackgroundTveita, A. A., Murphy, S. L., Holter, J. C., Kildal, A. B., Michelsen, A. E., Lerum, T. V., Kaarbø, M., Heggelund, L., Holten, A. R., Finbråten, A., et al. (2022) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiac313 · Cited by 29
The immune response as a double‐edged sword: The lesson learnt during the COVID ‐19 pandemic
Agrati, C., Carsetti, R., Bordoni, V., Sacchi, A., Quintarelli, C., Locatelli, F., Ippolito, G., & Capobianchi, M. R. (2022) · Immunology · doi:10.1111/imm.13564 · Cited by 22
“SARS-CoV-2 infection has been characterized by increased neutrophil number, which is associated with disease severity and clinical prognosis [69, 70].”
BackgroundSharma, S. B., Melvin, W. J., Audu, C. O., Bame, M., Rhoads, N. M., Wu, W.-S., Kanthi, Y. M., Knight, J. S., Adili, R., Holinstat, M. A., et al. (2022) · Blood · doi:10.1182/blood.2022015917 · Cited by 23
Cardelli, M., Pierpaoli, E., Marchegiani, F., Marcheselli, F., Piacenza, F., Giacconi, R., Recchioni, R., Casoli, T., Stripoli, P., Provinciali, M., et al. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00315-7 · Cited by 22
“An exacerbate inflammatory response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with the overproduction of many inflammatory cytokines, known as “cytokine storm” and often displaying the features of macrophage activation syndrome (MAS), is thought to be a major cause of disease severity and death i…”
BackgroundNK cells in COVID-19—from disease to vaccination
Hammer, Q., Cuapio, A., Bister, J., Björkström, N. K., & Ljunggren, H. (2023) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiad031 · Cited by 25
Sharbatdar, Y., Mousaviyan, R., Varnosfaderani, S. M. N., Aziziyan, F., Liaghat, M., Baziyar, P., Rad, A. Y., Tavakol, C., Moeini, A. M., Nabi‐Afjadi, M., et al. (2023) · Inflammopharmacology · doi:10.1007/s10787-023-01215-y · Cited by 24
Organokines in COVID-19: A Systematic Review
Barbalho, S. M., Minniti, G., Miola, V. F. B., Haber, J. F. D. S., Bueno, P. C. D. S., Haber, L. S. D. A., Gírio, R. J. S., Detregiachi, C. R. P., Dall’Antonia, C., Rodrigues, V. D., et al. (2023) · Cells · doi:10.3390/cells12101349 · Cited by 24
Role of Maternal Immune Factors in Neuroimmunology of Brain Development
Mohebalizadeh, M., Babapour, G., Aghdam, M. M., Mohammadi, T., Jafari, R., & Shafiei‐Irannejad, V. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03749-2 · Cited by 28
“Elevated levels of IL-6 in COVID-19 patients suggest anti-IL-6 antibodies as therapeutic targets [95, 96].”
Liu, T., Guo, Y., Zhao, J., He, S., Bai, Y., Wang, N., Lin, Y., Liu, Q., & Xu, X. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.584057 · Cited by 23
“However, studies involving severe and critically ill COVID-19 patients demonstrated a substantial decrease in circulating monocytes and a sudden decrease in their expression of antigen (HLA)-DR (Giamarellos-Bourboulis et al., 2020; Sanchez-Cerrillo et al., 2020).”
BackgroundA race to determine what drives COVID-19 severity
Koutsakos, M., & Kedzierska, K. (2020) · Nature · doi:10.1038/d41586-020-01915-3 · Cited by 22
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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