The immune checkpoints storm in COVID‐19: Role as severity markers at emergency department admission

Avendaño-Ortíz, José; Lozano-Rodríguez, Roberto; Martín-Quirós, Alejandro; Terrón, Verónica; Eid, Charbel Maroun; Montalbán-Hernández, Karla; Valentín-Quiroga, Jaime; García-Garrido, Miguel Ángel; Val, Elena Muñoz del; Balzo-Castillo, Álvaro del; Peinado, María Antonia Meseguer; Gómez, Laura; Herrero-Benito, Carmen; Rubio, Carolina; Casalvilla-Dueñas, José Carlos; Gómez-Campelo, Paloma; Pascual-Iglesias, Alejandro; Fresno, Carlos del; Aguirre, Luis A.; López-Collazo, Eduardo

doi:10.1002/ctm2.573

Cited by 16 publications

(21 citation statements)

References 12 publications

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“…Few studies have been conducted in the emergency unit regarding the study of early routine biomarkers for the prediction of morbidity and mortality of COVID-19 disease [ 28 , 29 , 32 , 33 ]. D-dimer is a product of fibrinolysis widely used as a marker of activation of the coagulation and fibrinolytic systems and for the diagnosis of thromboembolism [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Early Routine Biomarkers of SARS-CoV-2 Morbidity and Mortality: Outcomes from an Emergency Section

et al. 2022

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Background. COVID-19 is a severe acute respiratory disease caused by SARS-CoV-2, a virus belonging to the Coronaviridae family. This disease has spread rapidly around the world and soon became an international public health emergency leading to an unpredicted pressure on the hospital emergency units. Early routine blood biomarkers could be key predicting factors of COVID-19 morbidity and mortality as suggested for C-reactive protein (CRP), IL-6, prothrombin and D-dimer. This study aims to identify other early routine blood biomarkers for COVID-19 severity prediction disclosed directly into the emergency section. Methods. Our research was conducted on 156 COVID-19 patients hospitalized at the Sapienza University Hospital “Policlinico Umberto I” of Rome, Italy, between March 2020 and April 2020 during the paroxysm’s initial phase of the pandemic. In this retrospective study, patients were divided into three groups according to their outcome: (1) emergency group (patients who entered the emergency room and were discharged shortly after because they did not show severe symptoms); (2) intensive care unit (ICU) group (patients who attended the ICU after admission to the emergency unit); (3) the deceased group (patients with a fatal outcome who attended the emergency and, afterward, the ICU units). Routine laboratory tests from medical records were collected when patients were admitted to the emergency unit. We focused on Aspartate transaminase (AST), Alanine transaminase (ALT), Lactate dehydrogenase (LDH), Creatine kinase (CK), Myoglobin (MGB), Ferritin, CRP, and D-dimer. Results. As expected, ANOVA data show an age morbidity increase in both ICU and deceased groups compared with the emergency group. A main effect of morbidity was revealed by ANOVA for all the analyzed parameters with an elevation between the emergency group and the deceased group. Furthermore, a significant increase in LDH, Ferritin, CRP, and D-dimer was also observed between the ICU group and the emergency group and between the deceased group and ICU group. Receiver operating characteristic (ROC) analyses confirmed and extended these findings. Conclusions. This study suggests that the contemporaneous presence of high levels of LDH, Ferritin, and as expected, CRP, and D-dimer could be considered as potential predictors of COVID-19 severity and death.

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Section: Discussionmentioning

confidence: 99%

Early Routine Biomarkers of SARS-CoV-2 Morbidity and Mortality: Outcomes from an Emergency Section

et al. 2022

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“…As described above, there are eight FDA-approved ICP blocking antibodies against CTLA-4 (Ipilimumab), PD-1 (Nivolumab, Pembrolizumab, Cemiplimab, and Dostarlimab), or PD-L1 (Avelumab, Durvalumab, and Atezolizumab) for cancer immunotherapy (5,(13)(14)(15)(16). These ICP blocking antibodies are also being explored as vital components of the complex therapeutic strategies for treating cancer patients with COVID-19 or HIV infection (16,22,81,(151)(152)(153)(154), and appear to be generally tolerable (16,155). Further studies are needed to investigate the potential risks and benefits of ICP blockade Data are represented as median (interquartile range).…”

Section: Current Progress and Future Perspectives Of Icp Blockade In ...mentioning

confidence: 99%

“…Two recent studies, reported by Kong Y et al ( 80 ) and Avendano-Ortiz J et al ( 81 ), have demonstrated that a “storm” of sICPs occurs in COVID-19 patients and is associated with the severity of COVID-19 ( 80 , 81 ). The Kong study quantified 14 sICPs including sBTLA, sCTLA-4, sGITR, sHVEM, sIDO, sLAG-3, sPD-1, sPD-L1, sPD-L2, sTIM-3, sCD27, sCD28, sCD80, and s4-1BB in the serum samples from patients with asymptomatic, mild/moderate, and severe/critical COVID-19 using the ProcartaPlex Human ImmunoOncology Checkpoint Panel (Invitrogen, Carlsbad, CA) ( 80 ), while the Avendano-Ortiz study quantified 9 sICPs including sCD25, sCD86, sCTLA-4, Galectin-9, sLAG-3, sPD-1, sPD-L1, sTim-3, and s4-1BB using the LEGENDplex HU Immune Checkpoint Panel 1 (BioLegend, San Diego, CA) ( 81 ).…”

Section: Soluble Immune Checkpoints In Patients With Covid-19mentioning

confidence: 99%

Section: Soluble Immune Checkpoints In Patients With Covid-19mentioning

confidence: 99%

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Soluble Immune Checkpoints Are Dysregulated in COVID-19 and Heavy Alcohol Users With HIV Infection

Syed

et al. 2022

Front. Immunol.

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Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world’s most serious public health challenges. A “storm” of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol misuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol misuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.

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“…A possible explanation to the "explosive" clinical course observed could be that concomitant breakdown of the PD-1/PD-L1 interaction (an event reminiscent of IC treatment) and SARS-CoV-2 infection might have negatively synergized. This event has probably induced a hyper-activation of effector immune cells, promoting the so-called "cytokine-storm", considered responsible for the severe acute respiratory distress syndrome in COVID-19 and in IC toxicity (12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Peculiar Case of Inflammatory Colitis After SARS-CoV-2 Infection

et al. 2022

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We report a case of inflammatory colitis after SARS-CoV-2 infection in a patient with no additional co-morbidity who died within three weeks of hospitalization. As it is becoming increasingly clear that SARS-CoV-2 infection can cause immunological alterations, we investigated the expression of the inhibitory checkpoint PD-1 and its ligand PD-L1 to explore the potential role of this axis in the break of self-tolerance. The presence of the SARS-CoV-2 virus in colon tissue was demonstrated by qRT-PCR and immunohistochemical localization of the nucleocapsid protein. Expression of lymphocyte markers, PD-1, and PD-L1 in colon tissue was investigated by IHC. SARS-CoV-2-immunoreactive cells were detected both in the ulcerated and non-ulcerated mucosal areas. Compared to healthy tissue, where PD-1 is weakly expressed and PD-L1 is absent, PD-1 and PD-L1 expression appears in the inflamed mucosal tissue, as expected, but was mainly confined to non-ulcerative areas. At the same time, these markers were virtually undetectable in areas of mucosal ulceration. Our data show an alteration of the PD-1/PD-L1 axis and suggest a link between SARS-CoV-2 infection and an aberrant autoinflammatory response due to concomitant breakdown of the PD-1/PD-L1 interaction leading to early death of the patient.

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The immune checkpoints storm in COVID‐19: Role as severity markers at emergency department admission

Cited by 16 publications

References 12 publications

Early Routine Biomarkers of SARS-CoV-2 Morbidity and Mortality: Outcomes from an Emergency Section

Early Routine Biomarkers of SARS-CoV-2 Morbidity and Mortality: Outcomes from an Emergency Section

Soluble Immune Checkpoints Are Dysregulated in COVID-19 and Heavy Alcohol Users With HIV Infection

Case Report: A Peculiar Case of Inflammatory Colitis After SARS-CoV-2 Infection

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