The DOI matches its Crossref record; 14 of the 16 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30183-5 · Cited by 48,884 · cited 1×
“This is mostly because severe COVID-19 is associated with hyper-cytokinemia (Guan et al., 2020; Huang et al., 2020).”
Clinical characteristics of coronavirus disease 2019 in China
Guan, W.-J., Ni, Z.-Y., Hu, Y., Liang, W.-H., Ou, C.-Q., He, J.-X., Liu, L., Shan, H., Lei, C.-L., Hui, D. S. C., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2002032 · Cited by 30,246 · cited 1×
“This is mostly because severe COVID-19 is associated with hyper-cytokinemia (Guan et al., 2020; Huang et al., 2020) .”
The third international consensus definitions for sepsis and septic shock (Sepsis-3).
Singer, M., Deutschman, C. S., Seymour, C. W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G. R., Chiche, J.-D., Coopersmith, C. M., et al. (2016) · JAMA · doi:10.1001/jama.2016.0287 · Cited by 28,250
Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China
Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Tao, Y., Xie, C., Ma, K., Shang, K., Wang, W., et al. (2020) · Clinical Infectious Diseases · doi:10.1093/cid/ciaa248 · Cited by 4,775
Fardet, L., Galicier, L., Lambotte, O., Marzac, C., Aumont, C., Chahwan, D., Coppo, P., & Hejblum, G. (2014) · Arthritis & Rheumatology · doi:10.1002/art.38690 · Cited by 1,508 · cited 1×
“HScore is proposed as a classification tool for secondary MAS, and values more than 169 are highly diagnostic (Fardet et al., 2014).”
Thevarajan, I., Nguyen, T. H. O., Koutsakos, M., Druce, J. D., Caly, L., van de Sandt, C. E., Jia, X., Nicholson, S. R., Catton, M. C., Cowie, B., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0819-2 · Cited by 993 · cited 1×
“Statistical comparisons are indicated by the arrows; ns: non-significant; *p < 0.05; **p < 0.01. of one case of COVID-19 of moderate severity (Thevarajan et al., 2020).”
BackgroundInfluentialDysregulation of Immune Response in Patients with COVID-19 in Wuhan, ChinaPreprint
Qin, C., Zhou, L., Hu, Z., Zhang, S., Yang, S., Yu, T., Xie, C., Ma, K., Shang, K., Wang, W., et al. (2020) · SSRN Electronic Journal · doi:10.2139/ssrn.3541136 · Cited by 898
COVID-19: a novel coronavirus and a novel challenge for critical care
Arabi, Y. M., Murthy, S., & Webb, S. A. R. (2020) · Intensive Care Medicine · doi:10.1007/s00134-020-05955-1 · Cited by 313 · cited 1×
“The risk of death of these patients is high, reaching even 60% (Arabi et al., 2020).”
Lukaszewicz, A., Grienay, M., Resche‐Rigon, M., Pirracchio, R., Faivre, V., Boval, B., & Payen, D. M. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181ab858a · Cited by 288
on behalf of the Hellenic Sepsis Study Group, Kyriazopoulou, E., Leventogiannis, K., Norrby‐Teglund, A., Dimopoulos, G., Pantazi, A., Orfanos, S. E., Rovina, N., Tsangaris, I., Gkavogianni, T., et al. (2017) · BMC Medicine · doi:10.1186/s12916-017-0930-5 · Cited by 212 · cited 1×
“Immune responses of critically ill patients with sepsis can be classified into three patterns: macrophage-activation syndrome (MAS) (Kyriazopoulou et al., 2017) , sepsis-induced immunoparalysis characterized by low expression of the human leukocyte antigen D related (HLA-DR) on CD14 monocytes (Lukaszewicz et al., 2009…”
Self-citation
Cited by
Sorted by citations
Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.015 · Cited by 3,595
“Critical (ICU) and fatal COVID-19 (and SARS) outcomes are associated with elevated levels of inflammatory cytokines and chemokines, including interleukin-6 (IL-6) (Giamarellos-Bourboulis et al., 2020; Wong et al., 2004; Zhou et al., 2020) Vaccine development against acute viral infections classically focuses on vaccin…”
Coronavirus biology and replication: implications for SARS-CoV-2
V’kovski, P., Kratzel, A., Steiner, S., Stalder, H., & Thiel, V. (2020) · Nature Reviews Microbiology · doi:10.1038/s41579-020-00468-6 · Cited by 3,371
Longitudinal analyses reveal immunological misfiring in severe COVID-19
Lucas, C., Wong, P., Klein, J., Castro, T. B. R., Silva, J., Sundaram, M., Ellingson, M. K., Mao, T., Oh, J. E., Israelow, B., et al. (2020) · Nature · doi:10.1038/s41586-020-2588-y · Cited by 2,074
Rydyznski Moderbacher, C., Ramirez, S. I., Dan, J. M., Grifoni, A., Hastie, K. M., Weiskopf, D., Belanger, S., Abbott, R. K., Kim, C., Choi, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.038 · Cited by 1,790
A single-cell atlas of the peripheral immune response in patients with severe COVID-19
Wilk, A. J., Rustagi, A., Zhao, N. Q., Roque, J., Martínez-Colón, G. J., McKechnie, J. L., Ivison, G. T., Ranganath, T., Vergara, R., Hollis, T., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0944-y · Cited by 1,493
Immunology of COVID-19: Current State of the Science
Vabret, N., Britton, G. J., Gruber, C., Hegde, S., Kim, J., Kuksin, M., Levantovsky, R., Malle, L., Moreira, A., Park, M. D., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.05.002 · Cited by 1,623
Mathew, D., Giles, J. R., Baxter, A. E., Oldridge, D. A., Greenplate, A. R., Wu, J. E., Alanio, C., Kuri-Cervantes, L., Pampena, M. B., D’Andrea, K., et al. (2020) · Science · doi:10.1126/science.abc8511 · Cited by 1,509
“Together, these data indicate that T cell activation in COVID-19 patients is similar to what has been observed in other acute infections or vaccinations (37, 39, 40) and identify patients with high, low, or essentially no T cell response on the basis of KI67 or CD38HLA-DR expression compared with control individuals.”
ResultSevere COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment
Schulte-Schrepping, J., Reusch, N., Paclik, D., Baßler, K., Schlickeiser, S., Zhang, B., Krämer, B., Krammer, T., Brumhard, S., Bonaguro, L., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.001 · Cited by 1,461
“Patients with severe COVID-19 have high systemic levels of inflammatory cytokines, particularly interleukin (IL)-6 and IL-1b (Chen et al., 2020; Giamarellos-Bourboulis et al., 2020; Lucas et al., 2020;Onget al., 2020),whereas interferon (IFN) responses appear blunted, as shown by whole blood transcriptomics (Hadjadj e…”
InfluentialRisk factors for severe and critically ill COVID‐19 patients: A review
Gao, Y., Ding, M., Dong, X., Zhang, J., Azkur, A. K., Azkur, D., Gan, H. K., Sun, Y., Fu, W., Li, W., et al. (2020) · Allergy · doi:10.1111/all.14657 · Cited by 1,453
Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia
Salama, C., Han, J., Yau, L., Reiss, W. G., Krämer, B., Neidhart, J. D., Criner, G. J., Kaplan‐Lewis, E., Baden, R. P., Pandit, L. M., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2030340 · Cited by 1,306
Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans
Arunachalam, P. S., Wimmers, F., Mok, C. K. P., Perera, R. A. P. M., Scott, M., Hagan, T., Sigal, N., Feng, Y., Bristow, L., Tak-Yin Tsang, O., et al. (2020) · Science · doi:10.1126/science.abc6261 · Cited by 1,186
Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection
Dinnes, J., Deeks, J. J., Adriano, A., Berhane, S., Davenport, C. F., Dittrich, S., Emperador, D., Takwoingi, Y., Cunningham, J. A., Beese, S. E., et al. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013705 · Cited by 1,182
Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia
Rosas, I. O., Bräu, N., Waters, M., Go, R. C., Hunter, B. D., Bhagani, S., Skiest, D. J., Aziz, M. S., Cooper, N., Douglas, I. S., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2028700 · Cited by 1,141
Lamers, M. M., & Haagmans, B. L. (2022) · Nature Reviews Microbiology · doi:10.1038/s41579-022-00713-0 · Cited by 1,066
A dynamic COVID-19 immune signature includes associations with poor prognosis
Laing, A. G., Lorenc, A., del Molino del Barrio, I., Das, A., Fish, M., Monin, L., Muñoz-Ruiz, M., McKenzie, D. R., Hayday, T. S., Francos-Quijorna, I., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-1038-6 · Cited by 946
Considering how biological sex impacts immune responses and COVID-19 outcomes
Scully, E. P., Haverfield, J., Ursin, R. L., Tannenbaum, C., & Klein, S. L. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0348-8 · Cited by 954
SARS-CoV-2 viral load is associated with increased disease severity and mortality
Fajnzylber, J. M., Regan, J., Coxen, K., Corry, H., Wong, C., Rosenthal, A., Worrall, D. P., Giguel, F. F., Trocha, A. K., Atyeo, C. G., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19057-5 · Cited by 903
Winkler, E. S., Bailey, A. L., Kafai, N. M., Nair, S., McCune, B. T., Yu, J., Fox, J. M., Chen, R. E., Earnest, J. T., Keeler, S. P., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0778-2 · Cited by 901
Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19
Silvin, A., Chapuis, N., Dunsmore, G., Goubet, A.-G., Dubuisson, A., Derosa, L., Almire, C., Hénon, C., Kosmider, O., Droin, N., et al. (2020) · Cell · doi:10.1016/j.cell.2020.08.002 · Cited by 834
“, 2009), expression of HLA-DR on CD14High circulating monocytes is low in severe COVID-19, which correlates with, and could be mediated by, IL-6 overproduction (Giamarellos-Bourboulis et al., 2020).”
Lee, J. S., Park, S.-W., Jeong, H. W., Ahn, J. Y., Choi, S. J., Lee, H., Choi, B., Nam, S. K., Sa, M., Kwon, J., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.abd1554 · Cited by 817
COVID-19 and the human innate immune system
Schultze, J. L., & Aschenbrenner, A. C. (2021) · Cell · doi:10.1016/j.cell.2021.02.029 · Cited by 714
T cell responses in patients with COVID-19
Chen, Z., & John Wherry, E. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0402-6 · Cited by 797
Hottz, E. D., de Azevedo-Quintanilha, I. G., Palhinha, L., Teixeira, L., Barreto, E. A., Pão, C. R. R., Righy, C., Franco, S. D. G., Souza, T. M. L., Kurtz, P., et al. (2020) · Blood · doi:10.1182/blood.2020007252 · Cited by 767
Comprehensive mapping of immune perturbations associated with severe COVID-19
Kuri-Cervantes, L., Pampena, M. B., Meng, W., Rosenfeld, A. M., Ittner, C. A. G., Weisman, A. R., Agyekum, R. S., Mathew, D., Baxter, A. E., Vella, L. A., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.abd7114 · Cited by 723
The hypercoagulable state in COVID-19: Incidence, pathophysiology, and management
Abou-Ismail, M. Y., Diamond, A., Kapoor, S., Arafah, Y., & Nayak, L. (2020) · Thrombosis Research · doi:10.1016/j.thromres.2020.06.029 · Cited by 694
“In another study, circulating monocytes were shown to have a sustained production of TNF-α and IL-6, a pattern that differs from bacterial or influenza sepsis [66].”
How COVID-19 induces cytokine storm with high mortality
Hojyo, S., Uchida, M., Tanaka, K., Hasebe, R., Tanaka, Y., Murakami, M., & Hirano, T. (2020) · Inflammation and Regeneration · doi:10.1186/s41232-020-00146-3 · Cited by 663
“As mentioned above, excessive IL-6 levels are highly correlated with the lethal complications of COVID-19 patients [16, 64, 65].”
BackgroundAntibody tests for identification of current and past infection with SARS‐CoV‐2
Geppert, J., Scandrett, K., Bigio, J., Sulis, G., Hettiarachchi, D., Mathangasinghe, Y., Weeratunga, P., Wickramasinghe, D., Bergman, H., Buckley, S. B., et al. (2022) · LSTM Online Archive (Liverpool School of Tropical Medicine) · Cited by 837
Jamilloux, Y., Henry, T., Bélot, A., Viel, S., Fauter, M., Jammal, T. E., Walzer, T., François, B., & Sève, P. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102567 · Cited by 663
“have come to the conclusion that two patterns of immune dysfunction exist in worsening COVID-19: (i) one pattern highly suggestive of macrophage activation syndrome (hyperferritinemia and elevated H score : 25% of patients), which is driven by IL-1β; and (ii) one pattern with immune dysregulation driven by IL-6 [71].”
Antibody tests for identification of current and past infection with SARS-CoV-2
Deeks, J. J., Dinnes, J., Takwoingi, Y., Davenport, C., Spijker, R., Taylor-Phillips, S., Adriano, A., Beese, S., Dretzke, J., di Ruffano, L. F., et al. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013652 · Cited by 649
Multi-Omics Resolves a Sharp Disease-State Shift between Mild and Moderate COVID-19
Su, Y., Chen, D., Yuan, D., Lausted, C. G., Choi, J., Dai, C. L., Voillet, V., Duvvuri, V. R. S. K., Scherler, K., Troisch, P., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.037 · Cited by 605
“Figure S4E is investigating if TNF-a, another marker for monocyte immunoparalysis (Giamarellos-Bourboulis et al., 2020) is also downregulated with increasing disease severity, which we found to be such.”
The signal pathways and treatment of cytokine storm in COVID-19
Yang, L., Xie, X., Tu, Z., Fu, J., Xu, D., & Zhou, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00679-0 · Cited by 618
Immunity, endothelial injury and complement-induced coagulopathy in COVID-19
Perico, L., Benigni, A., Casiraghi, F., Ng, L. F. P., Rénia, L., & Remuzzi, G. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-00357-4 · Cited by 616
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications
McFadyen, J. D., Stevens, H., & Peter, K. (2020) · Circulation Research · doi:10.1161/circresaha.120.317447 · Cited by 600
Rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection
Dinnes, J., Deeks, J. J., Berhane, S., Taylor, M., Adriano, A., Davenport, C., Dittrich, S., Emperador, D., Takwoingi, Y., Cunningham, J., et al. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013705.pub2 · Cited by 591
Kyriazopoulou, E., Poulakou, G., Milionis, H. J., Metallidis, S., Adamis, G., Tsiakos, K., Fragkou, A., Rapti, A., Damoulari, C., Fantoni, M., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01499-z · Cited by 560
Self-citationImmunopathology of Hyperinflammation in COVID-19
Gustine, J. N., & Jones, D. (2021) · The American Journal of Pathology · doi:10.1016/j.ajpath.2020.08.009 · Cited by 516
“Serum cytokine levels are inversely correlated with CD4þ and CD8þ T-cell counts, and improved cytokine levels have been associated with the reversal of lymphopenia in the convalescent period of recovered patients.(4,8,12,61,63) In decedents who had lymphopenia, autopsy evaluations have revealed the extensive cell deat…”
The molecular virology of coronaviruses
Hartenian, E., Nandakumar, D., Lari, A., Ly, M., Tucker, J. M., & Glaunsinger, B. A. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.013930 · Cited by 544
“COVID-19 patients also exhibit a similar pattern of immune dysregulation, with elevated levels of IL-6 in particular, which correlates with severe disease pathology and mortality (221, 246).”
Targeting IL-6 trans-signalling: past, present and future prospects
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M., & Scheller, J. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00856-y · Cited by 524
“Dysregulated IL-6 signalling is a hallmark of infections, including SARS-CoV-2, that are characterized by hyperinflammation 137–145 , with high IL-6 levels in patients with COVID-19 being implicated in the depletion of CD4 + T cells, CD8 + T cells and natural killer cells 146 .”
CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer
Bange, E. M., Han, N. A., Wileyto, P., Kim, J. Y., Gouma, S., Robinson, J., Greenplate, A. R., Hwee, M. A., Porterfield, F., Owoyemi, O., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01386-7 · Cited by 519
The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity
Osuchowski, M. F., Winkler, M. S., Skirecki, T., Cajander, S., Shankar‐Hari, M., Lachmann, G., Monneret, G., Venet, F., Bauer, M. W., Brunkhorst, F. M., et al. (2021) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(21)00218-6 · Cited by 528
Self-citationNakra, N. A., Blumberg, D. A., Herrera-Guerra, A., & Lakshminrusimha, S. (2020) · Children · doi:10.3390/children7070069 · Cited by 523
COVID-19-associated fungal infections
Hoenigl, M., Seidel, D., Sprute, R., Cunha, C., Oliverio, M., Goldman, G. H., Ibrahim, A. S., & Carvalho, A. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01172-2 · Cited by 482
A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies
Hassan, A. O., Case, J. B., Winkler, E. S., Thackray, L. B., Kafai, N. M., Bailey, A. L., McCune, B. T., Fox, J. M., Chen, R. E., Alsoussi, W. B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.011 · Cited by 482
Natural killer cell immunotypes related to COVID-19 disease severity
Maucourant, C., Filipovic, I., Ponzetta, A., Aleman, S., Cornillet, M., Hertwig, L., Strunz, B., Lentini, A., Reinius, B., Brownlie, D., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.abd6832 · Cited by 493
Overview of Immune Response During SARS-CoV-2 Infection: Lessons From the Past
Shah, V. K., Firmal, P., Alam, A., Ganguly, D., & Chattopadhyay, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01949 · Cited by 476
“is due to the buildup of hyper-inflammatory conditions (78).”
BackgroundTrained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection
Netea, M. G., Giamarellos‐Bourboulis, E. J., Domínguez‐Andrés, J., Curtis, N. C., van Crevel, R., van de Veerdonk, F. L., & Bonten, M. J. M. (2020) · Cell · doi:10.1016/j.cell.2020.04.042 · Cited by 467
“Consistent with this, a recent study shows hyperinflammation of the immune response in COVID-19 patients, characterized by high cytokine production capacity of circulating monocytes despite the severity of the disease (which is different frombacterial sepsis) and high systemic concentrations of proinflammatory cytokin…”
Self-citationShakoor, H., Feehan, J., Al Dhaheri, A. S., Ali, H. I., Platat, C., Ismail, L. C., Apostolopoulos, V., & Stojanovska, L. (2021) · Maturitas · doi:10.1016/j.maturitas.2020.08.003 · Cited by 465
Drugging the efferocytosis process: concepts and opportunities
Mehrotra, P., & Ravichandran, K. S. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00470-y · Cited by 459
COVID-19 Associated Pulmonary Aspergillosis (CAPA)—From Immunology to Treatment
Arastehfar, A. A., Carvalho, A., van de Veerdonk, F. L., Jenks, J. D., Koehler, P. A., Krause, R., Cornely, O. A., Perlin, D. S., Lass‐Flörl, C., & Hoenigl, M. (2020) · Journal of Fungi · doi:10.3390/jof6020091 · Cited by 429
“This suggests that while sustained innate immune function leads to hyperinflammation [37], lymphocyte numbers decline, and their function may be defective.”
BackgroundTargeting the NLRP3 Inflammasome in Severe COVID-19
Freeman, T. L., & Swartz, T. H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01518 · Cited by 413
de Almeida-Pititto, B., Dualib, P. M., Zajdenverg, L., Dantas, J. R., de Souza, F. D., Rodacki, M., Bertoluci, M. C., & Brazilian Diabetes Society Study Group (SBD) (2020) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-020-00586-4 · Cited by 391
Winkler, E. S., Gilchuk, P., Yu, J., Bailey, A. L., Chen, R. E., Chong, Z., Zost, S. J., Jang, H., Huang, Y., Allen, J. D., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.026 · Cited by 366
Ferritin in the coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis
Cheng, L., Li, H., Li, L., Liu, C., Yan, S., Chen, H., & Li, Y. (2020) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.23618 · Cited by 413
SARS-CoV-2, COVID-19 and the aging immune system
Bartleson, J. M., Radenkovic, D., Covarrubias, A. J., Furman, D., Winer, D. A., & Verdin, E. (2021) · Nature Aging · doi:10.1038/s43587-021-00114-7 · Cited by 359
Bernardes, J. P., Mishra, N., Tran, F., Bahmer, T., Best, L., Blase, J. I., Bordoni, D., Franzenburg, J., Geisen, U. M., Josephs‐Spaulding, J., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.11.017 · Cited by 362
“Critically ill COVID-19 patients show higher blood plasma amounts of numerous cytokines and chemokines (Chen et al., 2020; Giamarellos-Bourboulis et al., 2020; Huang et al., 2020; Ong et al., 2020) than do less severe cases.”
Aboudounya, M. M., & Heads, R. J. (2021) · Mediators of Inflammation · doi:10.1155/2021/8874339 · Cited by 359
“Recent studies have found that the production of IL-1β, IL-18, TNF-α, and IL-6 was high in severe COVID-19 patients especially those with severe respiratory failure and are linked to the cytokine storm [130, 136]; these cytokines are downstream of the TLR4 canonical MyD88dependent pathway.”
An immune-based biomarker signature is associated with mortality in COVID-19 patients
Abers, M. S., Delmonte, O. M., Ricotta, E., Fintzi, J., Fink, D. L., de Jesus, A. A., Zarember, K. A., Alehashemi, S., Oikonomou, V., Desai, J. V., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.144455 · Cited by 345
“However, it is interesting to note that IL-10 inhibits expression of HLA class II molecules by antigen-presenting cells, a phenomenon that has been observed in myeloid cells of patients with severe COVID-19 (16, 40, 90, 91).”
Siddiqi, H. K., Libby, P., & Ridker, P. M. (2020) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2020.10.005 · Cited by 347
“[5] Giamarellos-Bourboulis EJ , Netea MG , Rovina N , Akinosoglou K , Antoniadou A , Antonakos N , et al.”
Meng, F., Xu, R., Wang, S., Xu, Z., Zhang, C., Li, Y., Yang, T., Shi, L., Fu, J., Jiang, T., et al. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00286-5 · Cited by 322
A guide to immunotherapy for COVID-19
van de Veerdonk, F. L., Giamarellos‐Bourboulis, E. J., Pickkers, P., Derde, L. P. G., Leavis, H. L., van Crevel, R., Engel, J. J., Wiersinga, W. J., Vlaar, A. P. J., Shankar‐Hari, M., et al. (2022) · Nature Medicine · doi:10.1038/s41591-021-01643-9 · Cited by 328
Self-citationVojdani, A., Vojdani, E., & Kharrazian, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.617089 · Cited by 322
“org 2 dysregulation in COVID-19 patients with severe respiratory failure (6).”
BackgroundAutoinflammatory and autoimmune conditions at the crossroad of COVID-19
Rodríguez, Y., Novelli, L., Rojas, M., Santis, M. D., Acosta‐Ampudia, Y., Monsalve, D. M., Ramírez-Santana, C., Costanzo, A., Ridgway, W. M., Ansari, A. A., et al. (2020) · Journal of Autoimmunity · doi:10.1016/j.jaut.2020.102506 · Cited by 319
“[133], published an interesting study indicating that patients with COVID-19 and severe respiratory failure may present with a condition similar to MAS, driven by IL-1β, or to an immune dysregulation, driven by IL-6.”
Hanff, T. C., Mohareb, A. M., Giri, J. S., Cohen, J. B., & Chirinos, J. A. (2020) · American Journal of Hematology · doi:10.1002/ajh.25982 · Cited by 323
“lar, are elevated to a degree not typically seen in bacterial sepsis or influenza.(61) Many of these cytokines demonstrate a prothrombotic effect in other settings, alone or in combination, though a causal link”
BackgroundSystemic and organ-specific immune-related manifestations of COVID-19
Ramos‐Casals, M., Brito‐Zerón, P., & Mariette, X. (2021) · Nature Reviews Rheumatology · doi:10.1038/s41584-021-00608-z · Cited by 316
Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19
Luo, W., Li, Y., Jiang, L., Chen, Q., Wang, T., & Ye, D. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.06.007 · Cited by 294
“They further revealed that increased absolute lymphocyte blood count was observed in the six patients treatedwith the anti-IL-6R antibody, tocilizumab, which could partially rescue the immune dysregulation state driven by SARS-CoV-2 [12].”
Early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy
Ciceri, F., Castagna, A., Rovere, P. Q., COBELLI, F. D., Ruggeri, A., Galli, L., Conte, C., LORENZO, R. D., Poli, A., Ambrosio, A. G., et al. (2020) · Clinical Immunology · doi:10.1016/j.clim.2020.108509 · Cited by 294
Moustaqil, M. D., Ollivier, E., Chiu, H.-P., van Tol, S., Rudolffi-Soto, P., Stevens, C. S., Bhumkar, A., Hunter, D. J. B., Freiberg, A. N., Jacques, D. A., et al. (2020) · Emerging Microbes & Infections · doi:10.1080/22221751.2020.1870414 · Cited by 289
“tory response observed at later stages in severe COVID19 cases [32,33].”
BackgroundDisease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients
(DeCOI), G. C.-1. O. I., Aschenbrenner, A. C., Mouktaroudi, M., Krämer, B., Oestreich, M., Antonakos, N., Nuesch-Germano, M., Gkizeli, K., Bonaguro, L., Reusch, N., et al. (2021) · Genome Medicine · doi:10.1186/s13073-020-00823-5 · Cited by 255
“Strikingly, neither disease, disease severity, nor the inclusion of outcome or immune classification [40] sufficiently explained the structure in the data.”
BackgroundSelf-citationHoepel, W., Chen, H., Geyer, C. E., Allahverdiyeva, S., Manz, X. D., de Taeye, S. W., Aman, J., Mes, L., Steenhuis, M., Griffith, G. R., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abf8654 · Cited by 282
Trougakos, I. P., Stamatelopoulos, K. S., Terpos, E., Tsitsilonis, O., Aivalioti, E., Paraskevis, D. N., Kastritis, E., Pavlakis, G. N., & Dimopoulos, M. A. (2021) · Journal of Biomedical Science · doi:10.1186/s12929-020-00703-5 · Cited by 305
“, the uncontrolled systemic inflammatory response that relates to the release of high amounts of pro-inflammatory cytokines along with complement components, coagulation dysfunction and immunological “misfiring” [68, 123–126]; the idea of adjunct immunotherapies which inhibit key pro-inflammatory pathways such as IL-6…”
BackgroundUnique immunological profile in patients with COVID-19
Varchetta, S., Mele, D., Oliviero, B., Mantovani, S., Ludovisi, S., Cerino, A., Bruno, R., Castelli, A., Mosconi, M., Vecchia, M., et al. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00557-9 · Cited by 282
COVID-19: A review of therapeutic strategies and vaccine candidates
Izda, V., Jeffries, M. A., & Sawalha, A. H. (2020) · Clinical Immunology · doi:10.1016/j.clim.2020.108634 · Cited by 292
“Although not yet associated with pathogenesis, an improvement in COVID-19-associated lymphopenia has also been reported following tocilizumab treatment [101].”
Arastehfar, A. A., Carvalho, A., Nguyen, M. H., Hedayati, M. T., Netea, M. G., Perlin, D. S., & Hoenigl, M. (2020) · Journal of Fungi · doi:10.3390/jof6040211 · Cited by 276
“One exception is the decreased expression of human leukocyte antigen DR on the membrane of circulating monocytes [36], which is considered a marker of immune paralysis; however, its relevance in susceptibility to candidemia is unclear.”
BackgroundSelf-citationSARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes
Ferreira, A. C., Soares, V. C., de Azevedo-Quintanilha, I. G., Dias, S. D. S. G., Rodrigues, N. F., Sacramento, C. Q., Mattos, M., de Freitas, C. S., Temerozo, J. R., Teixeira, L., et al. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00428-w · Cited by 283
The immune system and COVID-19: Friend or foe?
Yazdanpanah, F., Hamblin, M. R., & Rezaei, N. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.117900 · Cited by 272
“Moreover, IL-6 decreases the expression of HLA-DR on the membrane and production of IFN-γ by CD4 cells [4].”
Mudd, P. A., Crawford, J. C., Turner, J. S., Souquette, A. H., Reynolds, D., Bender, D. E., Bosanquet, J. P., Anand, N. J., Striker, D. A., Martin, R. S., et al. (2020) · Science Advances · doi:10.1126/sciadv.abe3024 · Cited by 276
“There has been significant interest in modulating the systemic immune response in an effort to prevent or treat respiratory failure in patients with COVID-19 ( 2 , 8 , 16 – 18 ).”
Monocytes and Macrophages in COVID-19
Knoll, R., Schultze, J. L., & Schulte-Schrepping, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.720109 · Cited by 279
Vanderbeke, L., Van Mol, P., Van Herck, Y., De Smet, F., Humblet-Baron, S., Martinod, K., Antoranz, A., Arijs, I., Boeckx, B., Bosisio, F. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24360-w · Cited by 247
Pathogenesis of COVID-19-induced ARDS: implications for an ageing population
Torres Acosta, M. A., & Singer, B. D. (2020) · European Respiratory Journal · doi:10.1183/13993003.02049-2020 · Cited by 247
“In fact, IL-6 inhibition improved the lymphopenia of severe disease in a subset of COVID-19 patients, suggesting a role for elevated serum cytokines in depleting peripheral T-lymphocytes [71].”
Sánchez‐Cerrillo, I., Landete, P., Orzaiz, B. A., Sánchez‐Alonso, S., Sánchez-Azofra, A., Marcos‐Jiménez, A., Ávalos, E., Alcaraz‐Serna, A., Santos, I. D. L., Mateu‐Albero, T., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci140335 · Cited by 250
Reusch, N., Domenico, E. D., Bonaguro, L., Schulte-Schrepping, J., Bassler, K. E., Schultze, J. L., & Aschenbrenner, A. C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.652470 · Cited by 261
Gallo, O., Locatello, L. G., Mazzoni, A., Novelli, L., & Annunziato, F. (2020) · Mucosal Immunology · doi:10.1038/s41385-020-00359-2 · Cited by 253
Li, Y., Renner, D. M., Comar, C. E., Whelan, J. N., Reyes, H. M., Cardenas‐Diaz, F. L., Truitt, R., Tan, L. H., Dong, B., Alysandratos, K., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2022643118 · Cited by 244
Cunha, L. L., Perazzio, S. F., Azzi, J., Cravedi, P., & Riella, L. V. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01748 · Cited by 245
Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19
Mann, E. R., Menon, M., Knight, S., Konkel, J. E., Jagger, C. P., Shaw, T. N., Krishnan, S., Rattray, M., Ustianowski, A., Bakerly, N. D., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.abd6197 · Cited by 237
Krämer, B., Knoll, R., Bonaguro, L., ToVinh, M., Raabe, J., Astaburuaga-García, R., Schulte-Schrepping, J., Kaiser, K. M., Rieke, G. J., Bischoff, J., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.09.002 · Cited by 250
“In line with earlier studies, we found COVID-19 to be associated with a decrease in circulating NK cells (Giamarellos-Bourboulis et al., 2020; Jiang et al., 2020; Wang et al., 2020b; Wilk et al., 2020) and validated expression of NK cell activation markers, especially in severe COVID-19 (Maucourant et al.”
Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome
Chen, L. Y. C., Hoiland, R. L., Stukas, S. K., Wellington, C. L., & Sekhon, M. S. (2020) · European Respiratory Journal · doi:10.1183/13993003.03006-2020 · Cited by 243
“cell CRS) became apparent.[3-5] The proposition that hypercytokinemia is pathological in some patients with COVID-19 catalyzed numerous clinical trials of immunomodulatory and cytokine-inhibitor therapy.”
BackgroundInfluentialEndothelial Damage in Acute Respiratory Distress Syndrome
Vassiliou, A. G., Kotanidou, Α., Dimopoulou, I., & Orfanos, S. E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228793 · Cited by 249
Della‐Torre, E., Campochiaro, C., Cavalli, G., Luca, G. D. D., Napolitano, A., Marca, S. L., Boffini, N., PRAT, V. D., Terlizzi, G. D., Lanzillotta, M., et al. (2020) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2020-218122 · Cited by 236
GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches
Lang, F. M., Lee, M.-C., Teijaro, J. R., Becher, B., & Hamilton, J. A. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0357-7 · Cited by 237
Xu, G., Qi, F., Li, H., Yang, Q., Wang, H., Wang, X., Liu, X., Zhao, J., Liao, X., Liu, Y., et al. (2020) · Cell Discovery · doi:10.1038/s41421-020-00225-2 · Cited by 236
Delayed production of neutralizing antibodies correlates with fatal COVID-19
Lucas, C. G. D. O., Klein, J., Sundaram, M. E., Liu, F., Wong, P., Silva, J. D. S., Mao, T., Oh, J. E., Mohanty, S., Huang, J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01355-0 · Cited by 289
Maternal-fetal immune responses in pregnant women infected with SARS-CoV-2
Garcia‐Flores, V., Romero, R. J., Xu, Y., Theis, K. R., Arenas‐Hernandez, M., Miller, D., Peyvandipour, A., Bhatti, G., Galaz, J., Gershater, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-021-27745-z · Cited by 234
Soin, A. S., Kumar, K., Choudhary, N. S., Sharma, P., Mehta, Y. B., Kataria, S., Govil, D., Deswal, V., Chaudhry, D., Singh, P., et al. (2021) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(21)00081-3 · Cited by 232
Korakas, E., Ikonomidis, I., Kousathana, F., Balampanis, K., Kountouri, A., Raptis, A. E., Palaiodimou, L., Kokkinos, A. D., & Lambadiari, V. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00198.2020 · Cited by 226
“The cumulative effect of these actions is a state of chronic inflammation and hypercytokinemia, which leads to defective innate immunity and creates a conducive ground for the hyperinflammatory response mediated through MAS in severe COVID-19 cases (10).”
BackgroundPatra, T., Meyer, K., Geerling, L., Isbell, T. S., Hoft, D. F., Brien, J. D., Pinto, A. K., Ray, R. B., & Ray, R. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1009128 · Cited by 229
“A recent study suggested that IL-6 is one of the cytokines responsible for immune dysregulation or macrophage activation syndrome in severe COVID-19 patients, and the use of Tocilizumab partially rescued SARS-CoV-2 associated immune dysregulation [51].”
BackgroundVella, L. A., Giles, J. R., Baxter, A. E., Oldridge, D. A., Diorio, C. J., Kuri-Cervantes, L., Alanio, C., Pampena, M. B., Wu, J. E., Chen, Z., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abf7570 · Cited by 225
The Innate Immune System: Fighting on the Front Lines or Fanning the Flames of COVID-19?
McKechnie, J. L., & Blish, C. A. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.05.009 · Cited by 218
SARS‐CoV‐2 sensing by RIG‐I and MDA5 links epithelial infection to macrophage inflammation
Thorne, L., Reuschl, A., Zuliani‐Alvarez, L., Whelan, M. V. X., Turner, J. L. E., Noursadeghi, M., Jolly, C. L., & Towers, G. J. (2021) · The EMBO Journal · doi:10.15252/embj.2021107826 · Cited by 223
“…to explain the association of severe COVID-19 with the presence of pro-inflammatory macrophages in bronchoalveolar lavage and patient lungs (Giamarellos-Bourboulis et al , 2020; Liao et al , 2020; preprint: Szabo et al , 2020) and inflammatory co-morbidities (Mehra et al , 2020; Williamson…”
InfluentialIn vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains
Chen, R. E., Winkler, E. S., Case, J. B., Aziati, I. D., Bricker, T. L., Joshi, A., Darling, T. L., Ying, B., Errico, J. M., Shrihari, S., et al. (2021) · Nature · doi:10.1038/s41586-021-03720-y · Cited by 209
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
