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
Items 901–1,000 of 1,002
Monitoring immunomodulation in patients with sepsis
Kyriazopoulou, E., & Giamarellos‐Bourboulis, E. J. (2020) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2020.1851199 · Cited by 17
Self-citationFundus evaluation in COVID-19 positives with non-severe disease
Bypareddy, R., Rathod, B. L. S., D, S. Y., R, H. H., Nagaraj, K. B., Hemalatha, B., Basumatary, J., Bekal, D., Niranjan, R., & Anusha, P. (2021) · Indian Journal of Ophthalmology · doi:10.4103/ijo.ijo_3227_20 · Cited by 17
Ciccocioppo, R., Gibellini, D., Astori, G., Bernardi, M., Bozza, A., Chieregato, K., Elice, F., Ugel, S., Caligola, S., Sanctis, F. D., et al. (2021) · Stem Cell Research & Therapy · doi:10.1186/s13287-021-02376-9 · Cited by 17
“flurry of active molecules which gives rise to the socalled “cytokine storm” [3], largely dominated by interleukin (IL)-6 and tumor necrosis factor (TNF)-α [4].”
BackgroundLung-Centric Inflammation of COVID-19: Potential Modulation by Vitamin D
Fakhoury, H. M. A., Kvietys, P. R., Shakir, I. M., Shams, H., Grant, W. B., & AlKattan, K. M. (2021) · Nutrients · doi:10.3390/nu13072216 · Cited by 17
Hypotheses and facts for genetic factors related to severe COVID-19
Kotsev, S. V., Miteva, D., Krayselska, S., Shopova, M., Pishmisheva, M., Stanilova, S. A., & Velikova, T. V. (2021) · World Journal of Virology · doi:10.5501/wjv.v10.i4.137 · Cited by 18
Stoian, A., Bajkó, Z., Maier, S., Cioflinc, R. A., Grigorescu, B. L., Moțățăianu, A., Bărcuţean, L., Bălașa, R., & Stoian, M. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10616 · Cited by 18
Udovičić, I., Stanojević, I., Djordjevic, D., Zeba, S., Rondović, G., Abazovic, T., Lazic, S., Vojvodić, D., To, K., Abazović, D., et al. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10245815 · Cited by 19
Kumar, A., Sharma, A., Tirpude, N. V., Sharma, S., Padwad, Y. S., & Kumar, S. (2022) · Inflammopharmacology · doi:10.1007/s10787-021-00903-x · Cited by 18
Naveed, Z., Sarwar, M., Ali, Z., Saeed, D., Choudhry, K., Sarfraz, A., Sarfraz, Z., Félix, M., & Chérrez-Ojeda, I. (2022) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.24434 · Cited by 17
Ustiuzhanina, M. O., Vavilova, J. D., Boyko, A. A., Streltsova, M. A., Kust, S. A., Kanevskiy, L. M., Sapozhnikov, A. M., Iskhakov, R. N., Gubernatorova, E. O., Drutskaya, M. S., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031996 · Cited by 20
Multivariate indicators of disease severity in COVID-19
Bean, J., Kuri-Cervantes, L., Pennella, M., Betts, M. R., Meyer, N. J., & Hassan, W. M. (2023) · Scientific Reports · doi:10.1038/s41598-023-31683-9 · Cited by 17
Wolszczak-Biedrzycka, B., Dorf, J., Wojewódzka‐Żeleźniakowicz, M., Żendzian‐Piotrowska, M., Dymicka-Piekarska, V., Matowicka-Karna, J., & Maciejczyk, M. (2023) · Journal of Inflammation Research · doi:10.2147/jir.s439217 · Cited by 17
Zivanovic, N., Öner, D., Abraham, Y., McGinley, J., Drysdale, S. B., Wildenbeest, J., Crabbe, M., Vanhoof, G., Thys, K., Thwaites, R. S., et al. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1507 · Cited by 19
“60 Proliferative (Ki67 High ) blood monocytes have also been reported in coronavirus disease 2019 (COVID-19)-infected patients, 61,62 suggesting that the observed immune profile is not specific or solely limited to severe RSV disease.”
BackgroundSex differences in immune responses to SARS-CoV-2 in patients with COVID-19
Guo-lian, Z., Xu, Y., Li, J., Cui, X., Tan, X., Zhang, H., & Dang, L. (2020) · Bioscience Reports · doi:10.1042/bsr20202074 · Cited by 17
SARS-CoV-2: Outline, Prevention, and Decontamination
Janik, E., Bartos, M., Niemcewicz, M., Gorniak, L., & Bijak, M. (2021) · Pathogens · doi:10.3390/pathogens10020114 · Cited by 21
T Cell Phenotyping in Individuals Hospitalized with COVID-19
Rupp, J., Dreo, B., Gütl, K., Fessler, J., Moser, A. M., Haditsch, B., Schilcher, G., Matzkies, L.-M., Steinmetz, I., Greinix, H., et al. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2001034 · Cited by 16
“CRS is thought to be caused by betacoronavirus infection of macrophages, leading to their activation and secretion of proinflammatory cytokines (4).”
BackgroundInfluentialNajm, A., Alunno, A., Mariette, X., Terrier, B., Marco, G. D., Emmel, J., Mason, L., McGonagle, D., & Machado, P. (2021) · RMD Open · doi:10.1136/rmdopen-2020-001549 · Cited by 17
Indoor Air Quality Monitoring Systems and COVID-19
Saini, J., Dutta, M., & Marques, G. (2021) · Studies in systems, decision and control · doi:10.1007/978-3-030-67716-9_9 · Cited by 17
“reported that patients with immune dysregulation are more likely to experience severe respiratory failure by COVID-19 [52].”
BackgroundCOVID-19 does not impact HLA antibody profile in a series of waitlisted renal transplant candidates
Roll, G. R., Lunow-Luke, T., Braun, H. J., Buenaventura, O., Mallari, M., Stock, P. G., & Rajalingam, R. (2021) · Human Immunology · doi:10.1016/j.humimm.2021.04.002 · Cited by 17
Complexity of immune responses in COVID-19
Mather, M. W., Jardine, L., Talks, B. J., Gardner, L. C. S., & Haniffa, M. A. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101545 · Cited by 19
“Elevated IL-6 is seen in macrophage activation syndromes and immunotherapy-associated cytokine release syndromes, and IL-6 in vitro reduces HLA-DR expression on monocytes, a key feature of COVID immunoparesis discussed below [27].”
Driving force of COVID-19 among people living with HIV in Wuhan, China
Guo, W., Ming, F., Dong, Y., Zhang, Q., Liu, L., Gao, M., Zhang, X., Mo, P., Feng, Y., Tang, W., et al. (2022) · AIDS Care · doi:10.1080/09540121.2022.2052259 · Cited by 17
“Such lengthy terms of immune de fi ciency could make a ff ected individuals more vulnerable to SARS-CoV-2 infection (Giamarellos-Bourboulis et al., 2020; Ong et al., 2020).”
BackgroundRetinal microvascular impairment in COVID‐19 patients: A meta‐analysis
Wang, S., Wang, J., Hu, J., & Wang, N. (2022) · Immunity Inflammation and Disease · doi:10.1002/iid3.619 · Cited by 17
“COVID‐19 is a highly contagious disease that causes severe respiratory, immune, and other organ systems dysfunction, leading to severe morbidity and mortality.(2) Studies have shown that COVID‐19 patients manifest as cardiovascular, neurological, hematological, cutaneous, and taste, gastrointestinal symptoms in additi…”
BackgroundMultiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection TrajectoriesPreprint
Su, Y., Chen, D., Lausted, C. G., Yuan, D., Choi, J., Dai, C. L., Voillet, V., Scherler, K., Troisch, P., Duvvuri, V. R. S. K., et al. (2020) · SSRN Electronic Journal · doi:10.1101/2020.07.27.224063 · Cited by 17
“This is reminiscent of monocyte “immunoparalysis” reported in sepsis where, under conditions of high inflammation, the monocytes become dysfunctional (Giamarellos-Bourboulis et al., 2020).”
BackgroundBCG's role in strengthening immune responses: Implications for tuberculosis and comorbid diseases
Naqvi, N., Ahuja, Y., Zarin, S., Alam, A., Ali, W., Shariq, M., Hasnain, S. E., & Ehtesham, N. Z. (2024) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2024.105703 · Cited by 16
Vrettou, A., Parissis, J., & Ikonomidis, I. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00129 · Cited by 16
“As has been recently shown in mechanically ventilated patients with COVID-19 infection (75), excessive IL-6 production is associated with lymphopenia and immunoparesis as assessed by low expression of the humanleukocyte antigen (HLA)-DR on CD14-monocytes, and this effect is reversed by tocilizumab.”
BackgroundIntegrative Transcriptome Analyses Empower the Anti-COVID-19 Drug Arsenal
El-Hachem, N., Eid, E. S., Nemer, G. M., Dbaibo, G. S., Abbas, O. M., Rubeiz, N., Zeineldine, S. M., Matar, G. M., Bikorimana, J., Shammaa, R., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101697 · Cited by 16
Moon, C. Y., Schilder, B. M., Raj, T., & Huang, K. (2021) · iScience · doi:10.1016/j.isci.2021.102550 · Cited by 16
Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum
Rovina, N., Koukaki, E., Romanou, V., Ampelioti, S., Loverdos, K., Chantziara, V., Koutsoukou, A., & Dimοpoulos, G. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11072017 · Cited by 17
Self-citationVillemonteix, J., Cohen, L., Guihot, A., Guérin, V., Moulin, C., Caséris, M., Carol, A., Bonacorsi, S., & Carcelain, G. (2022) · Immunity Inflammation and Disease · doi:10.1002/iid3.617 · Cited by 15
Borouchaki, A., de Roquetaillade, C., Barthélémy, R., Mebazaa, A., & Chousterman, B. G. (2022) · Journal of Critical Care · doi:10.1016/j.jcrc.2022.154137 · Cited by 16
Genetics of COVID ‐19 and myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review
Tziastoudi, M., Cholevas, C., Stefanidis, I., & Theoharides, T. C. (2022) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51631 · Cited by 19
Yang, Y., Li, W., Liu, K., Xue, H., Yu, R., Zhang, M., Bao, Y., Lai, X., Fan, J., Huang, Y., et al. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.05.011 · Cited by 16
“In the SARS-CoV-2-induced hyperin fl ammatory reaction, several reports have shown that the IL-1 e IL-6 axis is the most biologically relevant signal [49].”
Immunosenescence and Inflammaging in COVID-19
Asghari, F., Asghary, A., Zolbanin, N. M., Faraji, F., & Jafari, R. (2023) · Viral Immunology · doi:10.1089/vim.2023.0045 · Cited by 17
“…of T cells and NK cells, cellular exhaustion, inhibition of IFN-c production, dysfunction of CD8 + T cells, immune dysregulation, suppression of antiviral immune responses, and tissue damage (Brasier, 2010; Giamarellos-Bourboulis et al., 2020; Velazquez-Salinas et al., 2019; Xiong et al., 2011).”
Cytokine storm and translating IL-6 biology into effective treatments for COVID-19
Li, T., Wang, D., Wei, H., & Xu, X. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-1044-4 · Cited by 16
Liu, H., Guo, N., Zheng, Q., Zhang, Q., Chen, J., Cai, Y., Luo, Q., Xu, Q., Chen, X., Yang, S., et al. (2024) · BMC Infectious Diseases · doi:10.1186/s12879-024-09205-3 · Cited by 16
“Elevated ferritin levels due to cytokine storm and secondary hemophagocytic lymphohistiocytosis (sHLH) have also been previously reported in patients with critical COVID-19 [34].”
BackgroundHolloman, B. L., Wilson, K. M., Cannon, A. S., Nagarkatti, M., & Nagarkatti, P. S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1330373 · Cited by 17
RNA Viruses, Toll-Like Receptors, and Cytokines: The Perfect Storm?
Stegeman, S. K., Kourko, O., Amsden, H., Pellizzari-Delano, I. E., Mamatis, J. E., Roth, M., Colpitts, C. C., & Gee, K. (2025) · Journal of Innate Immunity · doi:10.1159/000543608 · Cited by 17
Perspectives and Challenges in the Fight Against COVID-19: The Role of Genetic Variability
Guilger‐Casagrande, M., de Barros, C. T., Antunes, V. A. N., de Araújo, D. R., & de Lima, R. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.598875 · Cited by 17
“As a result, there may be a failure in antigen presentation preventing the action of the immune system against the virus, followed by hyperinflammation due to the high production of pro-inflammatory cytokines (Giamarellos-Bourboulis et al., 2020).”
BackgroundDalekos, G. Ν., Stefos, A., Georgiadou, S. P., Lygoura, V., Michail, A., Ntaios, G., Samakidou, A., Giannoulis, G., Gabeta, S., Vlychou, M., et al. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.03.026 · Cited by 15
“Severe coronavirus disease-2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and characterized by complex dysregulation of the immune system resulting in hyperinflammation and full-blown viral pneumonia, which in turn, can lead to severe respiratory failure, multiorgan…”
BackgroundSelf-citationde Roquetaillade, C., Mansouri, S., Brumpt, C., Neuwirth, M., Voicu, S., Dorze, M. L., Fontaine, C., Barthélémy, R., Gayat, É., Mégarbane, B., et al. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000005088 · Cited by 16
“Recent reports have highlighted marked lymphopenia and elevated neutrophil count as well as reduced human leukocyte antigen D receptor (HLA-DR) expression on CD14+ monocytes (mHLA-DR) (5, 6), such modifications could evoke immune suppression similar to this observed in sepsis (7); however, correlation with severity an…”
BackgroundPetzer, V., Schwendinger, S., Haschka, D., Vogi, V., Tymoszuk, P., Burkert, F. R., Sahanic, S., Sonnweber, T., Bellmann‐Weiler, R., Löffler‐Ragg, J., et al. (2021) · American Journal of Hematology · doi:10.1002/ajh.26251 · Cited by 16
“To characterize the interplay between CH, inflammation and Covid-19 course, we divided our patient cohort into “severe Covid-19” and “non-severe Covide-19” based on the following criteria: Patients, requiring ≥2 L/min of supplemental oxygen support at any given time point were classified as “severe Covid-19.””
BackgroundInfluentialThe Many Faces of Innate Immunity in SARS-CoV-2 Infection
Hanan, N., Doud, R. L., Park, I.-W., Jones, H. P., & Mathew, S. O. (2021) · Vaccines · doi:10.3390/vaccines9060596 · Cited by 17
“Low HLA-DR is caused by monocyte hyperactivation, high levels of circulating IL-6, and lymphopenia [61].”
BackgroundInfluentialNanotechnology-based Approaches and Investigational Therapeutics against COVID-19
Rahman, M. M., Ahmed, M., Islam, M. T., Khan, M. R., Sultana, S., Maeesa, S. K., Hasan, S., Hossain, M. A., Ferdous, K. S., Mathew, B., et al. (2021) · Current Pharmaceutical Design · doi:10.2174/1381612827666210701150315 · Cited by 17
Saleh, K. B., Hafiz, A., Sulaiman, K. A. A., Aljuhani, O. A., Alharbi, S., Alharbi, A. A., Vishwakarma, R. K., Albekairy, A. M., Alkathiri, A., Alanazi, F., et al. (2021) · American Heart Journal Plus Cardiology Research and Practice · doi:10.1016/j.ahjo.2021.100033 · Cited by 16
“The inflammatory response, which occurs in COVID-19 as an elevated immune response, might explain the increase in mortality in patients with COVID-19 accompanied by HF [10].”
Codd, A. S., Hanna, S. J., Compeer, E. B., Richter, F. C., Pring, E. J., Gea-Mallorquí, E., Borsa, M., Moon, O. R., Scourfield, D. O., Ahern, D., et al. (2021) · Oxford Open Immunology · doi:10.1093/oxfimm/iqab016 · Cited by 16
Биличенко, Т. Н. (2021) · Russian Medical Inquiry · doi:10.32364/2587-6821-2021-5-5-237-244 · Cited by 18
“Правильное ведение больных COVID-19 требует лучшего понимания патогенеза заболевания [20].”
Masiá, M., Padilla, S., García, J. A., García‐Abellán, J., Navarro‐Ruiz, A., Guillén, L., Telenti, G., Mascarell, P., Botella, Á., & Gutiérrez, F. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.749657 · Cited by 17
“IL-6 has been shown to play a central role in the immune dysregulation that characterizes COVID19 pneumonia, in which the levels of this cytokine have been associated with disease severity (18).”
BackgroundPirabe, A., Heber, S., Schrottmaier, W. C., Schmuckenschlager, A., Treiber, S. M., Pereyra, D., Santol, J., Pawelka, E., Traugott, M. T., Schoergenhofer, C., et al. (2021) · Cells · doi:10.3390/cells10123373 · Cited by 17
“A previous study found that the MHC-2 expression on monocytes and lymphocytes were strongly inhibited by plasma from COVID-19 patients with high IL-6 levels, supporting the notion that an overproduction of IL-6 contributes to disease progression [30].”
BackgroundImmune Signature of COVID-19: In-Depth Reasons and Consequences of the Cytokine Storm
Niedźwiedzka‐Rystwej, P., Majchrzak, A., Kurkowska, S., Małkowska, P., Sierawska, O., Hrynkiewicz, R., & Parczewski, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094545 · Cited by 19
“Studies from 2020 showed that the IL-6-JAK-STAT3 pathway is strongly associated with the severity of COVID-19 symptoms [80,81].”
BackgroundFoletto, V. S., da Rosa, T. F., Serafin, M. B., & Hörner, R. (2022) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-022-03372-5 · Cited by 16
“A study conducted on coronavirus patients reported that the severity of cases occurs due to malfunction or deficiency of the immune system [30].”
BackgroundRubina, K. A., Shmakova, A., Курбанович, Ш. А., Andreev, Y., Боровкова, Н. В., Кулабухов, В. В., Evseev, A. K., Попугаев, К. А., Petrikov, S. S., & Semina, E. V. (2022) · PLoS ONE · doi:10.1371/journal.pone.0264072 · Cited by 16
COVID-19 and earlier pandemics, sepsis, and vaccines: A historical perspective
Cavaillon, J.-M., & Osuchowski, M. F. (2021) · Journal of Intensive Medicine · doi:10.1016/j.jointm.2021.04.003 · Cited by 17
“[38] Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al.”
Ma, K., Sivalingam, A., & Haller, J. A. (2020) · Ophthalmology Retina · doi:10.1016/j.oret.2020.05.011 · Cited by 15
Post-COVID fungal infections of maxillofacial region: a systematic review
Jain, A., & Taneja, S. (2021) · Oral and Maxillofacial Surgery · doi:10.1007/s10006-021-01010-5 · Cited by 18
Development of Single-Cell Transcriptomics and Its Application in COVID-19
Wang, C., Huyan, T., Zhou, X., Zhang, X., Duan, S., Gao, S., Jiang, S., & Li, Q. (2022) · Viruses · doi:10.3390/v14102271 · Cited by 15
“Moreover, COVID-19 patients with severe expiratory dyspnea exhibit a complicated immune system dysfunction [3].”
BackgroundJeong, H., Lee, J. S., Ko, J., Hong, S., Oh, S. T., Choi, S., Peck, K. R., Yang, J. H., Chung, S. H., Kim, S., et al. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-00964-8 · Cited by 17
Pathological Effects of SARS-CoV-2 Associated with Hematological Abnormalities
Shama, S., Mahmood, A., Mehmood, S., & Zhang, W. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45090453 · Cited by 18
Immune landscape and redox imbalance during neurological disorders in COVID-19
Thakur, A., Sharma, V., Averbek, S., Liang, L., Pandya, N., Kumar, G., Cili, A., & Zhang, K. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06102-6 · Cited by 15
Adaptive immune cells are necessary for SARS-CoV-2–induced pathology
Imbiakha, B., Sahler, J., Buchholz, D. W., Ezzatpour, S., Jager, M. C., Choi, A., Monreal, I. A., Byun, H., Adeleke, R. A., Leach, J. R., et al. (2024) · Science Advances · doi:10.1126/sciadv.adg5461 · Cited by 14
“The dysregulation of the innate and adaptive immune systems following SARS- CoV-2 infection has been reported to contribute to immuno-pathology ( 29 , 30 ).”
BackgroundProgress in SARS-CoV-2, diagnostic and clinical treatment of COVID-19
Li, Y., Lu, S.-M., Wang, J.-L., Yao, H., & Liang, L. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e33179 · Cited by 15
“In addition, the results showed that guanosine derivatives (IDX-184), Setrobuvir, and YAK are the first choice for antiviral therapy, with potential against SARS-CoV-2 strains [86,87].”
ResultMURCH, S. H. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110168 · Cited by 15
“CD14 HLA-DR cells have been identified at high frequency in cases of severe Covid-19 infection with immune dysregulation [30].”
Weichmann, F., & Rohdewald, P. J. (2020) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2020.106191 · Cited by 15
Understanding the immunopathogenesis of COVID-19: Its implication for therapeutic strategy
Shimizu, Y. (2020) · World Journal of Clinical Cases · doi:10.12998/wjcc.v8.i23.5835 · Cited by 16
Ullah, M. A., Rittchen, S., Li, J., Hasnain, S. Z., & Phipps, S. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00405-7 · Cited by 16
Anti‐COVID‐19 measurements for hidradenitis suppurativa patients
Giamarellos‐Bourboulis, E. J., Bettoli, V., Jemec, G. B. E., del Mármol, V., Marzano, A. V., Prens, E. P., Tzellos, T., & Zouboulis, C. C. (2021) · Experimental Dermatology · doi:10.1111/exd.14339 · Cited by 15
Self-citationRETRACTED: SBracing NK cell based therapy to relegate pulmonary inflammation in COVID-19
Jeyaraman, M., Muthu, S., Bapat, A., Jain, R., Sushmitha, E. S., Gulati, A., Anudeep, T. C., Dilip, S. J., Jha, N. K., Kumar, D., et al. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e07635 · Cited by 16
“The decrease in the CD8 þ cell count and the drop in the number of NK cells are marked as the distinctive feature of disease by SARS-CoV-2 [30].”
InfluentialRetractedCOVID‐19 in lung transplant recipients: an overview of the Swedish national experience
Magnusson, J. M., Larsson, H., Alsaleh, A., Ekelund, J., Karason, K., Schult, A., Friman, V., Felldin, M., Søfteland, J. M., Dellgren, G., et al. (2021) · Transplant International · doi:10.1111/tri.14148 · Cited by 16
“significant reduction in immunosuppression, possibly because of the virus-induced immunosuppression and the lymphopenia seen in COVID-19 patients [5,25,26].”
BackgroundBrake, S. J., Eapen, M. S., McAlinden, K. D., Markos, J., Haug, G., Larby, J., Chia, C., Hardikar, A., Singhera, G. K., Hackett, T. L., et al. (2022) · International Journal of COPD · doi:10.2147/copd.s329783 · Cited by 15
“One study found that patients with COVID-19 related severe respiratory failure displayed features of macrophage activation syndrome.(56) It has been suggested that alveolar macrophages play the role of the trojan horse in COVID-19, providing a mobile viral anchoring point specifically within the alveolar spaces and pu…”
BackgroundEfficacy of Combination Therapy with the JAK Inhibitor Baricitinib in the Treatment of COVID-19
Thoms, B. L., Gosselin, J., Libman, B. S., Littenberg, B., & Budd, R. C. (2022) · SN Comprehensive Clinical Medicine · doi:10.1007/s42399-022-01121-4 · Cited by 15
“These include tocilizumab, an IL-6 receptor(R) inhibitor [8, 16]; anakinra, an IL-1R antagonist [17]; and inhibitors of the Janus kinase (JAK) pathways [18–22].”
BackgroundWhere do T cell subsets stand in SARS-CoV-2 infection: an update
Tarique, M., Suhail, M., Naz, H., Muhammad, N., Tabrez, S. S. M., Zughaibi, T. A., Abuzenadah, A. M., Hashem, A. M., Shankar, H., Saini, C., et al. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.964265 · Cited by 16
“It was found that tocilizumab, an IL-6 receptor antagonist, increases circulating lymphocytes in support of this hypothesis (Giamarellos-Bourboulis et al., 2020).”
BackgroundFeng, Z., Bao, Y., Yang, Y., Zheng, Y., & Shen, K. (2020) · Pediatric Investigation · doi:10.1002/ped4.12225 · Cited by 14
“Immune response to SARS-CoV-2 involves both cell-mediated immunity and antibody production.(19) During SARSCoV-2 infection, cytotoxic T cells (i.”
BackgroundResultPerrotta, F., & Perrini, M. P. (2021) · Medicina · doi:10.3390/medicina57050424 · Cited by 15
“SARS-CoV-2 has linked impaired antigen presentation or acquired immunosuppression with concomitant lymphopenia [16,17], and the macro- and microcirculation alterations associated to the SARS-CoV-2 hypercoagulability [18] can likely increase the risk of bacterial translocation [19], the classic example being the intest…”
BackgroundHou, C., Hu, Y., Yang, H., Chen, W., Zeng, Y., Ying, Z., Hu, Y., Sun, Y., Qu, Y., Gottfreðsson, M., et al. (2021) · BMC Medicine · doi:10.1186/s12916-021-02177-0 · Cited by 15
“This hypothesis is supported by a recent finding suggesting a profound impact of SARS-CoV-2 on immune systems [6], which seemed sustained even among individuals who have recovered from the primary infection [7, 8].”
ResultImmunopathology, host-virus genome interactions, and effective vaccine development in SARS-CoV-2
Singh, D. D., Han, I., Choi, E. H., & Yadav, D. K. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.11.011 · Cited by 14
“Individuals recovred from SARS-CoV-2 have shown an early expression of interferons IFN-a , IFN-c , CXCL-10, and CCL2 [29].”
Leemans, S., Maillart, E., Noten, H. V., dos Santos, L. O., Leahu, L. M., Kamgang, P., Gallerani, A., & Clevenbergh, P. A. (2020) · Clinical Case Reports · doi:10.1002/ccr3.3600 · Cited by 13
Cai, Y., Zhang, X., Zeng, H., Wei, X., Zhang, Z.-Y., Chen, L.-D., Wang, M.-H., Wen-zhen, Y., Huang, Q.-F., & Ye, Z.-Q. (2021) · Aging · doi:10.18632/aging.203501 · Cited by 16
“Immune dysfunction plays an important role in the severity of COVID-19 [8].”
BackgroundZhong, Y., Ashley, C. L., Steain, M. C., & Ataide, S. F. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.975322 · Cited by 15
“Neutrophilia, is also observed in distal parts of the lung and blood of severely affected patients (Giamarellos-Bourboulis et al., 2020; Liao et al., 2020).”
BackgroundNew Insights into SARS-CoV-2 and Cancer Cross-Talk: Does a Novel Oncogenesis Driver Emerge?
Rapti, V., Τσαγανός, Θ., Vathiotis, I. A., Syrigos, N. K., Li, P., & Poulakou, G. (2022) · Vaccines · doi:10.3390/vaccines10101607 · Cited by 16
“Indeed, cytokine storms correlate with the severity and progression of COVID-19 and can result in serious complications such as acute respiratory distress syndrome (ARDS) and multiple organ failure, which are the leading causes of death from the disease [115,116].”
BackgroundNeutrophil Activation and Immune Thrombosis Profiles Persist in Convalescent COVID-19
Hocini, H., Wiedemann, A., Blengio, F., Lefebvre, C., Cervantes-Gonzalez, M., Foucat, E., Tisserand, P., Surénaud, M., Coléon, S., Prague, M., et al. (2023) · Journal of Clinical Immunology · doi:10.1007/s10875-023-01459-x · Cited by 15
“Concomitantly, severe COVID-19 has also been shown to be associated with altered hematopoiesis, as shown by lymphopenia and an increase in myelopoiesis [10, 11].”
BackgroundSarhan, N. M., Warda, A. E. A., Ghareeb, H. S., Schaalan, M. F., & Fathy, S. (2023) · Scientific Reports · doi:10.1038/s41598-023-33484-6 · Cited by 14
Carelli, S., Dell’Anna, A. M., Montini, L. M., Bernardi, G., Gozza, M., Cutuli, S. L., Natalini, D., Bongiovanni, F., Tanzarella, E. S., Pintaudi, G., et al. (2023) · Heart & Lung · doi:10.1016/j.hrtlng.2023.07.012 · Cited by 14
Association of Vitamin D with Severity and Outcome of COVID-19: Clinical and Experimental Evidence
Renieris, G., Foutadakis, S., Andriopoulou, T., Spanou, V. M., Droggiti, D.-E., Kafousopoulos, D., Gkavogianni, T., Damoraki, G., Vatsellas, G., & Giamarellos‐Bourboulis, E. J. (2023) · Journal of Innate Immunity · doi:10.1159/000535302 · Cited by 14
Self-citationWauters, E., Thevissen, K., Wouters, C. H., Bosisio, F. M., Smet, F. D., Gunst, J., Humblet‐Baron, S., Lambrechts, D., Liston, A., Matthys, P., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01642 · Cited by 14
Bellucci, G., Ballerini, C., Mechelli, R., Bigi, R., Rinaldi, V., Reniè, R., Buscarinu, M. C., Baranzini, S. E., Madireddy, L., Matarese, G., et al. (2020) · F1000Research · doi:10.12688/f1000research.25593.1 · Cited by 12
COVID-19 and the heart: what we have learnt so far.
Shaha, K. B., Manandhar, D. N., Cho, J. R., Adhikari, A., & C, M. B. K. (2021) · PubMed Central · doi:10.1136/postgradmedj-2020-138284 · Cited by 14
Blaess, M. F., Kaiser, L., Sommerfeld, O., Csük, R., & Deigner, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041797 · Cited by 14
“ARDS/severe COVID‐19 pneumonia is often accompanied by the macrophage activation syndrome (MAS) or an IL‐6‐mediated very low human leu‐ kocyte antigen D related (HLA‐DR) expression; a profound depletion (lymphopenia) of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells; and hyper‐inflamma‐ tion [19].”
BackgroundHasbal, N. B., Turgut, D., Oğuz, E. G., Sena Memnune, U. L. U., & Güngör, Ö. (2021) · Annals of Transplantation · doi:10.12659/aot.929279 · Cited by 14
“Bourboulis et al evaluated immune responses of COVID-19 patients (n=54) with macrophage activation syndrome and found that CD4+ T lymphocytes, CD19+ B lymphocytes, and NK cells, and their human leucocyte antigen (HLA)-DR expression were significantly decreased [29].”
BackgroundTocilizumab: From Rheumatic Diseases to COVID-19
Raiteri, A., Piscaglia, F., Granito, A., & Tovoli, F. (2021) · Current Pharmaceutical Design · doi:10.2174/1381612827666210311141512 · Cited by 14
Cytomegalovirus proctitis as a complication of COVID-19 with immunosuppressive treatments
Maillet, F., Pourbaix, A., Pluart, D. L., Sirmai, L., Postolache, A., Couvelard, A., Houhou‐Fidouh, N., Males, L., Deconinck, L., & Lescure, F.-X. (2021) · IDCases · doi:10.1016/j.idcr.2021.e01111 · Cited by 14
“There is also a specific decrease in CD4+ T-cells, especially in memory and regulatory CD4+ T-cells subsets [6].”
Effects of Simulated COVID-19 Cytokine Storm on Stent Thrombogenicity
Cornelissen, A., Kutyna, M. D., Cheng, Q., Sato, Y., Kawakami, R., Sakamoto, A., Kawai, K., Mori, M., Fernandez, R., Guo, L., et al. (2021) · Cardiovascular revascularization medicine · doi:10.1016/j.carrev.2021.03.023 · Cited by 14
“Another study reported serum IL-6 levels up to nearly 2000 pg/mL in 54 patients with COVID-19 infection and macrophage activation syndrome or immune dysregulation, while TNFα levels ranged between 8 and 37 pg/mL even in patients with only intermediate functional state of the immune system [9].”
Role of the Immune Microenvironment in SARS-CoV-2 Infection
Ye, C.-H., Hsu, W., Peng, G.-R., Yu, W.-C., Lin, W., Hu, S., & Yu, S. (2021) · Cell Transplantation · doi:10.1177/09636897211010632 · Cited by 15
Monocytes and macrophages in severe COVID‐19 – friend, foe or both?
Dress, R. J., & Ginhoux, F. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12464 · Cited by 14
“This dramatic shift between a high expression of HLA-DR in the airways but downregulation of HLA-DR on blood monocytes is in line with other recent publications, suggesting an immature or dysregulated phenotype of monocytes and macrophages as a driver for pathogenesis during SARS-CoV-2 infection.(3,4,7) In general, fe…”
ResultRubik, B., & Brown, R. S. (2021) · Journal of Clinical and Translational Research · doi:10.18053/jctres.07.202105.007 · Cited by 14
Epidemiological and clinical risk factors related to severe COVID-19 in Iran: a multi-center study
Hashemi‐Shahri, S. M., Tabatabaei, S. M. N., Ansari‐Moghaddam, A., Mohammadi, M., Okati‐Aliabad, H., Tabatabaei, S. M., Ansari, H., Abbasi, M., Sheikhzadeh, K., Baygi, M. Z., et al. (2022) · BMC Infectious Diseases · doi:10.1186/s12879-022-07165-0 · Cited by 14
Gatselis, N., Lygoura, V., Lyberopoulou, A., Giannoulis, G., Samakidou, A., Vaiou, A., Vatidis, G., Antoniou, K. M., Stefos, A., Georgiadou, S. P., et al. (2022) · Viruses · doi:10.3390/v14040787 · Cited by 16
“Several theories have been proposed to explain the mechanisms of lymphopenia in COVID-19 patients [2,37], such as extensive lymphocytes infiltration in affected organs [38], infection of lymphocytes caused by viral attachment to their ACE2 receptor, resulting in lymphocyte death [39], and induction of lymphocyte apopt…”
BackgroundDysregulation of the leukocyte signaling landscape during acute COVID-19
Turnbull, I. R., Fuchs, A. G., Remy, K. E., Kelly, M. P., Frazier, E. P., Ghosh, S., Chang, S.-W., Mazer, M. B., Hess, A., Leonard, J. M., et al. (2022) · PLoS ONE · doi:10.1371/journal.pone.0264979 · Cited by 13
“This hypothesis is consistent with studies demonstrating defects in dendritic cell response during COVID-19 [23, 45], and other data demonstrating a strong negative correlation between plasma IL-6 levels and monocytes HLA-DR expression [46].”
Cytokine Storm and its Implication in Coronavirus disease 2019 (COVID-19)
Datta, C., & Bhattacharjee, A. (2020) · Journal of Immunological Sciences · doi:10.29245/2578-3009/2020/2.1190 · Cited by 14
Latifi-Pupovci, H. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113368 · Cited by 16
“pattern of immune dysregulation in extreme COVID-19 was characterized by low HLA-DR expression regulated by IL-6 and lymphopenia, combined with prolonged development of cytokines and hyper-inflammation [139].”
RNF213-associated urticarial lesions with hypercytokinemia
Louvrier, C., Awad, F., Cosnes, A., Khouri, E. E., Assrawi, E., Daskalopoulou, A., Copin, B., Bocquet, H., Chantot‐Bastaraud, S., Garcia, A. A., et al. (2022) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2022.06.016 · Cited by 14
Valenzuela-Méndez, B., Valenzuela-Sánchez, F., Gutiérrez, J. F. R., Bohollo-de-Austria, R. Á., Estella, Á., Martínez-García, P., González-García, M. Á., WATERER, G. W., & Rello, J. (2022) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2022.07.010 · Cited by 14
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
