Long-COVID is a new emerging syndrome worldwide that is characterized by the persistence of unresolved signs and symptoms of COVID-19 more than 4 weeks after the infection and even after more than 12 weeks. The underlying mechanisms for Long-COVID are still undefined, but a sustained inflammatory response caused by the persistence of SARS-CoV-2 in organ and tissue sanctuaries or resemblance with an autoimmune disease are within the most considered hypotheses. In this study, we analyzed the usefulness of several demographic, clinical, and immunological parameters as diagnostic biomarkers of Long-COVID in one cohort of Spanish individuals who presented signs and symptoms of this syndrome after 49 weeks post-infection, in comparison with individuals who recovered completely in the first 12 weeks after the infection. We determined that individuals with Long-COVID showed significantly increased levels of functional memory cells with high antiviral cytotoxic activity such as CD8+ TEMRA cells, CD8±TCRγδ+ cells, and NK cells with CD56+CD57+NKG2C+ phenotype. The persistence of these long-lasting cytotoxic populations was supported by enhanced levels of CD4+ Tregs and the expression of the exhaustion marker PD-1 on the surface of CD3+ T lymphocytes. With the use of these immune parameters and significant clinical features such as lethargy, pleuritic chest pain, and dermatological injuries, as well as demographic factors such as female gender and O+ blood type, a Random Forest algorithm predicted the assignment of the participants in the Long-COVID group with 100% accuracy. The definition of the most accurate diagnostic biomarkers could be helpful to detect the development of Long-COVID and to improve the clinical management of these patients.

Infection by novel coronavirus SARS-CoV-2 causes different presentations of COVID-19 and some patients may progress to a critical, fatal form of the disease that requires their admission to ICU and invasive mechanical ventilation. In order to predict in advance which patients could be more susceptible to develop a critical form of COVID-19, it is essential to define the most adequate biomarkers. In this study, we analyzed several parameters related to the cellular immune response in blood samples from 109 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centers in Madrid, Spain, during the first pandemic peak between April and June 2020. Hospitalized patients with the most severe forms of COVID-19 showed a potent inflammatory response that was not translated into an efficient immune response. Despite the high levels of effector cytotoxic cell populations such as NK, NKT and CD8+ T cells, they displayed immune exhaustion markers and poor cytotoxic functionality against target cells infected with pseudotyped SARS-CoV-2 or cells lacking MHC class I molecules. Moreover, patients with critical COVID-19 showed low levels of the highly cytotoxic TCRγδ+ CD8+ T cell subpopulation. Conversely, CD4 count was greatly reduced in association to high levels of Tregs, low plasma IL-2 and impaired Th1 differentiation. The relative importance of these immunological parameters to predict COVID-19 severity was analyzed by Random Forest algorithm and we concluded that the most important features were related to an efficient cytotoxic response. Therefore, efforts to fight against SARS-CoV-2 infection should be focused not only to decrease the disproportionate inflammatory response, but also to elicit an efficient cytotoxic response against the infected cells and to reduce viral replication.

BCR-ABL is an aberrant tyrosine kinase responsible for chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKIs) induce a potent antileukemic response mostly based on the inhibition of BCR-ABL, but they also increase the activity of Natural Killer (NK) and CD8+ T cells. After several years, patients may interrupt treatment due to sustained, deep molecular response. By unknown reasons, half of the patients relapse during treatment interruption, whereas others maintain a potent control of the residual leukemic cells for several years. In this study, several immunological parameters related to sustained antileukemic control were analyzed. According to our results, the features more related to poor antileukemic control were as follows: low levels of cytotoxic cells such as NK, (Natural Killer T) NKT and CD8±TCRγβ+ T cells; low expression of activating receptors on the surface of NK and NKT cells; impaired synthesis of proinflammatory cytokines or proteases from NK cells; and HLA-E*0103 homozygosis and KIR haplotype BX. A Random Forest algorithm predicted 90% of the accuracy for the classification of CML patients in groups of relapse or non-relapse according to these parameters. Consequently, these features may be useful as biomarkers predictive of CML relapse in patients that are candidates to initiate treatment discontinuation.

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The aortic annulus measurements obtained by TTE, TEE, and angiography correlated well, while tomography correlated poorly with other techniques. The imaging techniques that showed the best agreement between estimated aortic annulus size and implanted aortic valve size were TTE and TEE.

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Background/Introduction Cardiovascular (CV) disease represents the leading cause of death and disability in developed countries with elevated LDL-C among the main risk factors for CV events. Purpose We conducted a study to describe the clinical profile of patients initiating evolocumab in real-world clinical practice, specifically hospital cardiology units in Spain. Methods Retrospective, observational, serial chart review of consecutive hyperlipidemic patients (≥18 years) who initiated evolocumab in 31 Spanish hospital cardiology units from February-2016 to May-2017. Relevant patients characteristics and clinical data were collected from medical records at 12 weeks pre- and 12±4 weeks post-evolocumab initiation. Baseline values correspond to data collected up to 12 weeks prior to initiation of evolocumab. Results 186 patients were enrolled: 72.0% men, mean (SD) age 60.3 (9.8) years, mean (SD) body mass index 28.5 (4.3) kg/m2. CV history and CV risk factors at evolocumab initiation are summarised below (Figure). Half of all patients were statin intolerant and almost all (94.1%) were secondary prevention. At baseline, half (51.1%) of all patients were receiving ezetimibe and 44.1% were receiving high-intensity statins. At baseline, mean (SD) LDL-C was 144.0 (49.0) mg/dL; 38.7% of patients had LDL-C 100-<130 mg/dL, 28.0% had LDL-C 130-<160 mg/dl, 12.4% had LDL-C ≥160 mg/dL, 12.9% had LDL-C ≥190 mg/dL. Mean (SD) baseline HDL-C was 47.7 (13.0) mg/dL. After 12 weeks of evolocumab treatment, mean (SD) LDL-C was reduced by 57.6% (21.6) to 62.2% (44.1) mg/dL (p<0.0001; LDL-C reductions of 57.5% [23.2]/57.6% [21.6] in patients with/without FH and 46.0% [21.5]/58.5% [22.1] in primary/secondary prevention patients, respectively). At week 12, 64.9% patients reached LDL-C levels <70 mg/dL, and 49.1% <50 mg/dL, while statin use remained stable (data not shown). Only 3.2% (n=6) patients discontinued evolocumab (voluntary withdrawal, mostly). Baseline CV history and CV risk factors Conclusions In Spanish Cardiology Units, evolocumab was typically prescribed in patients with FH and/or atherosclerotic cardiovascular disease, aligned with 2016 ESC/EAS guidelines recommendation on PCSK9i usage. Patients tended to have LDL-C levels above the recommended thresholds with LDL- levels markedly reduced after 12 (± 4) weeks of evolocumab treatment. Acknowledgement/Funding This work was supported by Amgen.

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