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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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BackgroundA genetic variant in IL-6 lowering its expression is protective for critical patients with COVID-19
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Is there a link between vitamin D status, SARS‐CoV ‐2 infection risk and COVID ‐19 severity?
Ferrari, D., Locatelli, M., Briguglio, M., & Lombardi, G. (2020) · Cell Biochemistry and Function · doi:10.1002/cbf.3597 · Cited by 29
MINERVA: A Facile Strategy for SARS-CoV-2 Whole-Genome Deep Sequencing of Clinical Samples
Chen, C., Li, J., Di, L., Jing, Q., Du, P., Song, C., Li, J., Li, Q., Cao, Y., Xie, X. S., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.11.030 · Cited by 32
Lessons Learned Comparing Immune System Alterations of Bacterial Sepsis and SARS-CoV-2 Sepsis
Dong, X., Wang, C., Liu, X., Gao, W., Bai, X., & Li, Z. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.598404 · Cited by 27
“In such cases, most clinicians use bacterial sepsis as a prototype to understand the pathogenesis of severe COVID19, and some management protocols for critically ill COVID-19 patients are also based on experience with bacterial sepsis (3, 6).”
BackgroundBelaid, B., Mahammed, L. L., Mihi, B., Rahali, S. Y., Djidjeli, A., Larab, Z., Berkani, L., Berkane, I., Sayah, W., Merah, F., et al. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.4cova1020-703r · Cited by 29
Williamson, C. G., Hadaya, J. E., Mandelbaum, A. D., Verma, A., Gandjian, M., Rahimtoola, R., & Benharash, P. (2021) · CHEST Journal · doi:10.1016/j.chest.2021.02.018 · Cited by 29
Mesenchymal stem cell alongside exosomes as a novel cell-based therapy for COVID-19: A review study
Dauletova, M., Hafsan, H., Mahhengam, N., Zekiy, A. O., Ahmadi, M., & Siahmansouri, H. (2021) · Clinical Immunology · doi:10.1016/j.clim.2021.108712 · Cited by 29
Fabre, V., Karaba, S. M., Amoah, J., Robinson, M. L., Jones, G. F., Dzintars, K., Katz, M. J., Landrum, B. M., Qasba, S. S., Gupta, P., et al. (2021) · Infection Control and Hospital Epidemiology · doi:10.1017/ice.2021.175 · Cited by 29
Silva, P. U. J., Paranhos, L. R., Santos, D. M., Blumenberg, C., Macedo, D. R., & Cardoso, S. V. (2021) · Clinics · doi:10.6061/clinics/2021/e2659 · Cited by 29
“KEYWORDS: Chlorhexidine; COVID-19; Tooth Brushing; Ventilator-Associated Pneumonia.”
BackgroundInfluentialCheon, S. Y., & Koo, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157914 · Cited by 34
“Many patients with COVID-19 die of immunomodulatory failure and organ damage due to SARS-CoV-2-induced pneumonia, ARDS, or CRS [1,3,4].”
BackgroundInfluentialCOVID-19 and Obesity: Role of Ectopic Visceral and Epicardial Adipose Tissues in Myocardial Injury
Lasbleiz, A., Gaborit, B., Soghomonian, A., Bartoli, A., Ancel, P., Jacquier, A., & Dutour, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.726967 · Cited by 30
“Studies have shown that serum levels of IL-6, tumor necrosis factor (TNF-a), granulocyte colony-stimulating factor (G-CSF), interferon-g-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), or macrophage inflammatory protein 1-a, among others, are higher in patients with severe conditions (i.e., r…”
BackgroundInfluentialTheoharides, T. C. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11090860 · Cited by 29
Roy, R. K., Sharma, U., Wasson, M. K., Jain, A., Hassan, M. I., & Prakash, H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.763313 · Cited by 30
Goswami, R., Russell, V. S., Tu, J. J., Thomas, C., Hughes, P. F., Kelly, F. L., Langel, S. N., Steppe, J. T., Palmer, S. M., Haystead, T., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103412 · Cited by 28
“…mild upper airway symptoms to severe lower respiratory complications such as pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ system dysfunction (Huang et al., 2020a), leading to respiratory compromise (Giamarellos-Bourboulis et al., 2020) and death (Mehraeen et al., 2020).”
BackgroundPourgholaminejad, A., Pahlavanneshan, S., & Basiri, M. (2021) · Scandinavian Journal of Immunology · doi:10.1111/sji.13131 · Cited by 32
Temerozo, J. R., Sacramento, C. Q., Rodrigues, N. F., Pão, C. R. R., de Freitas, C. S., Dias, S. D. S. G., Ferreira, A. C., Mattos, M., Soares, V. C., Teixeira, L., et al. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.5cova1121-626r · Cited by 30
ABO Blood System and COVID-19 Susceptibility: Anti-A and Anti-B Antibodies Are the Key Points
Tamayo-Velasco, Á., Peñarrubia-Ponce, M. J., Álvarez, F. J., de la Fuente, I., González, S. P., & Andaluz‐Ojeda, D. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.882477 · Cited by 29
“One of these immunophenotypes is characterized by the coexisting alterations in T cells’ numbers, subset composition, cycling, activation, and gene expression (54, 55).”
BackgroundKassianidis, G., Siampanos, A., Poulakou, G., Adamis, G., Rapti, A., Milionis, H. J., Dalekos, G. Ν., Petrakis, V., Sympardi, S., Metallidis, S., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094894 · Cited by 29
Self-citationJónsdóttir, H. R., Siegrist, D., Julien, T., Padey, B., Bouveret, M., Terrier, O., Pizzorno, A., Huang, S., Samby, K., Wells, T. N. C., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113058 · Cited by 31
“2 pattern of upregulation of pro-inflammatory cytokines, including interleukin (IL)− 6, IL-1β, and tumor necrosis factor-α, has been observed [11,12] with the additional secretion of various chemokines, e.”
Innate Immune Response and Inflammasome Activation During SARS-CoV-2 Infection
Islamuddin, M., Mustfa, S. A., Ullah, S. N. M. N., Omer, U., Kato, K., & Parveen, S. (2022) · Inflammation · doi:10.1007/s10753-022-01651-y · Cited by 31
“As discussed early, lymphopenia is identified as an important hallmark of severity of disease which not only includes reduction in B and T cells but also in NK cells [44, 67] Patients with faster recovery are accompanied with decreased inhibition of NF-κB signaling in NK cells along with increased levels of cytotoxici…”
BackgroundXu, J., He, B., Carver, K. A., VanHeyningen, D., Parkin, B. L., Garmire, L. X., Olszewski, M. A., & Deng, J. C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.970287 · Cited by 29
“Upon SARS-CoV-2 infection, altered neutrophil abundance and functionality have been linked with the pathophysiology of severe COVID-19 disease (5, 7, 42, 43).”
BackgroundHortová-Kohoutková, M., Skotáková, M., Onyango, I. G., Slezáková, M., Panovský, R., Opatřil, L., Slanina, P., Zuani, M. D., Mrkva, O., Andrejčinová, I., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1110540 · Cited by 28
COVID‐19 as a trigger of Guillain‐Barré syndrome: A review of the molecular mechanism
Malekpour, M., Khanmohammadi, S., Meybodi, M. J. E., Shekouh, D., Rahmanian, M. R., Kardeh, S., & Azarpira, N. (2023) · Immunity Inflammation and Disease · doi:10.1002/iid3.875 · Cited by 29
“The depletion of the NK cells causes severe lung injury and damage to other tissues, including the nervous system; in contrast, the immunosuppressive ability of NK cells could protect the nervous system from acquired GBS.(87,88) Many studies have indicated the pivotal role of “cytokine storm” in initiating typical GBS.”
BackgroundAssante, G., Williams, R. L., & Youngson, N. A. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.05.051 · Cited by 30
SARS‐CoV‐2 immunogenicity at the crossroads
Karamloo, F., & König, R. (2020) · Allergy · doi:10.1111/all.14360 · Cited by 28
Clonal Hematopoiesis in Hospitalized Elderly Patients With COVID‐19
Hameister, E., Stolz, S. M., Fuhrer, Y., Thienemann, F., Schaer, D. J., Nemeth, J., Schuepbach, R. A., Goede, J. S., Reinhart, S., Schmidt, A. E., et al. (2020) · HemaSphere · doi:10.1097/hs9.0000000000000453 · Cited by 28
“However, the pathogenesis of severe COVID19 has remained enigmatic.(17) An excessive release of inflammatory cytokines (ie, cytokine storm) has been observed in severe COVID-19.”
BackgroundThe Virological, Immunological, and Imaging Approaches for COVID-19 Diagnosis and Research
Tan, A. S., Nerurkar, S. N., Tan, W. C. C., Goh, D. L. M., Lai, C. P. T., & Yeong, J. P.-S. (2020) · SLAS TECHNOLOGY · doi:10.1177/2472630320950248 · Cited by 28
Bhattacharyya, R., Iyer, P., Phua, G. C., & Lee, J. H. (2020) · Pulmonary Therapy · doi:10.1007/s41030-020-00126-5 · Cited by 28
Su, W., Qiu, Z., Zhou, L., Hou, J., Wang, Y., Huang, F., Zhang, Y., Jia, Y., Zhou, J., Liu, D., et al. (2020) · Aging · doi:10.18632/aging.103793 · Cited by 28
“Also, dysregulated immune responses were shown to play an important role in COVID-19 pathogenesis [14, 15], and functional exhaustion of antiviral lymphocytes occurred in severely ill patients with COVID-19 [16].”
BackgroundFouladseresht, H., Doroudchi, M., Rokhtabnak, N., Abdolrahimzadehfard, H., Roudgari, A., Sabetian, G., & Paydar, S. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2020.10.002 · Cited by 29
“Tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, IL-17, IL-18, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ inducible protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory proteins (MIP)-1A, and MIP-1B are parts of a wide array of inflamma…”
InfluentialCalvet, J., Jordi Gratacós, A., Amengual, M. J., Llop-Vilaltella, M., Navarro, M., Moreno, A., Berenguer, A., Serrano-Suárez, A., Orellana, C., & Cervantes, M. (2020) · Viruses · doi:10.3390/v12111277 · Cited by 28
“Most people suffered a mild to moderate self-limiting disease, but several cases experienced a sudden clinical deterioration 7–8 days after symptom onset, suggesting that severe respiratory failure in COVID-19 is driven by a unique pattern of immune dysfunction [3].”
BackgroundIn fatal COVID-19, the immune response can control the virus but kill the patient
Casadevall, A., & Pirofski, L. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021128117 · Cited by 28
A Suggested Role of Human Growth Hormone in Control of the COVID-19 Pandemic
Elkarow, M. H., & Hamdy, A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.569633 · Cited by 30
“Recent data suggests that the IL-6-JAK-STAT3 axis is closely involved in the development of severe COVID-19 disease (28, 29).”
BackgroundCOVID-19: The Emerging Immunopathological Determinants for Recovery or Death
Ahmad, T., Chaudhuri, R., Joshi, M. C., Almatroudi, A., Rahmani, A. H., & Ali, S. M. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.588409 · Cited by 30
Rapid detection of SARS‐CoV‐2‐specific memory T‐cell immunity in recovered COVID‐19 cases
Lineburg, K. E., Srihari, S., Altaf, M., Swaminathan, S., Panikkar, A., Raju, J., Crooks, P., Ambalathingal, G. R., Martins, J. P., Matthews, K. K., et al. (2020) · Clinical & Translational Immunology · doi:10.1002/cti2.1219 · Cited by 27
“Patients with severe symptoms show high expression of checkpoint markers, including PD-1, which suggests poor T-cell priming during the early stages of infection.(21,22) Conversely, patients who resolve infection have recently been shown to generate antigen-specific Tcell responses against proteins encoded by SARSCoV-…”
BackgroundWang, C., Xu, J., Wang, S., Pan, S., Zhang, J., Han, Y., Huang, M., Wu, D., Yang, Q., Yang, X., et al. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.600989 · Cited by 27
Heparin binding protein in severe COVID-19—A prospective observational cohort study
Mellhammar, L., Thelaus, L., Elén, S., Fisher, J., & Linder, A. (2021) · PLoS ONE · doi:10.1371/journal.pone.0249570 · Cited by 28
Coronavirus infection: An immunologists' perspective
Sanctis, J. B. D., García, A. H., Moreno, D., & Hajdúch, M. (2021) · Scandinavian Journal of Immunology · doi:10.1111/sji.13043 · Cited by 27
The immune checkpoints storm in COVID‐19: Role as severity markers at emergency department admission
Ortiz, J. A., Lozano‐Rodríguez, R., Martín‐Quirós, A., Terrón, V., Maroun‐Eid, C., Montalbán-Hernández, K. M., Valentín‐Quiroga, J., García-Garrido, M. Á., del Val, E. M., del Balzo‐Castillo, Á., et al. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.573 · Cited by 27
Barreda, D., Santiago, C. A., Rodríguez, J. R., Rodrígúez, J. F., Casasnovas, J. M., Mérida, I., & Ávila‐Flores, A. (2021) · Cells · doi:10.3390/cells10123279 · Cited by 28
“Other factors that contribute to the fluctuation of the innate immune response are aging and pre-existing diseases [15,16].”
BackgroundNatural resistance against infections: focus on COVID-19
Netea, M. G., Domínguez‐Andrés, J., van de Veerdonk, F. L., van Crevel, R., Pulendran, B., & van der Meer, J. W. M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.12.001 · Cited by 32
“These profiles are defined by the inflammatory responses developed in response to infection, interferon (IFN) release, and antibody production [3].”
Self-citationLiver dysfunction as a cytokine storm manifestation and prognostic factor for severe COVID-19
Taneva, G., Dimitrov, D. S., & Velikova, T. V. (2021) · World Journal of Hepatology · doi:10.4254/wjh.v13.i12.2005 · Cited by 30
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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