Dexamethasone treatment for COVID-19 is related to increased mortality in hematologic malignancy patients: results from the EPICOVIDEHA Registry.

Not available.

Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia.

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2/3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting.

Immunoglobulin heavy chain variable ( IGHV ) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p < 0.0001), and shorter OS (112 vs. 246 months, p < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

COVID-19 Outcomes in Patients with Hematologic Malignancies in the Era of COVID-19 Vaccination and the Omicron Variant.

A greater understanding of clinical trends in COVID-19 outcomes among patients with hematologic malignancies (HM) over the course of the pandemic, particularly the Omicron era, is needed. This ongoing, observational, and registry-based study with prospective data collection evaluated COVID-19 clinical severity and mortality in 1818 adult HM patients diagnosed with COVID-19 between 27 February 2020 and 1 October 2022, at 31 centers in the Madrid region of Spain. Of these, 1281 (70.5%) and 537 (29.5%) were reported in the pre-Omicron and Omicron periods, respectively. Overall, patients aged ≥70 years (odds ratio 2.16, 95% CI 1.64-2.87), with >1 comorbidity (2.44, 1.85-3.21), or with an underlying HM of chronic lymphocytic leukemia (1.64, 1.19-2.27), had greater odds of severe/critical COVID-19; odds were lower during the Omicron BA.1/BA.2 (0.28, 0.2-0.37) or BA.4/BA.5 (0.13, 0.08-0.19) periods and among patients vaccinated with one or two (0.51, 0.34-0.75) or three or four (0.22, 0.16-0.29) doses. The hospitalization rate (75.3% [963/1279], 35.7% [191/535]), rate of intensive care admission (30.0% [289/963], 14.7% [28/191]), and mortality rate overall (31.9% [409/1281], 9.9% [53/536]) and in hospitalized patients (41.3% [398/963], 22.0% [42/191]) decreased from the pre-Omicron to Omicron period. Age ≥70 years was the only factor associated with higher mortality risk in both the pre-Omicron (hazard ratio 2.57, 95% CI 2.03-3.25) and Omicron (3.19, 95% CI 1.59-6.42) periods. Receipt of prior stem cell transplantation, COVID-19 vaccination(s), and treatment with nirmatrelvir/ritonavir or remdesivir were associated with greater survival rates. In conclusion, COVID-19 mortality in HM patients has decreased considerably in the Omicron period; however, mortality in hospitalized HM patients remains high. Specific studies should be undertaken to test new treatments and preventive interventions in HM patients.

Correction: Rivas et al. Tendon-Derived Mesenchymal Stem Cells (TDSCs) as an In Vitro Model for Virological Studies in Wild Birds. Viruses 2023, 15, 1455.

In the original publication [...].

Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY.

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.

Remdesivir or Nirmatrelvir/Ritonavir Therapy for Omicron SARS-CoV-2 Infection in Hematological Patients and Cell Therapy Recipients.

BACKGROUND: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. METHODS: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. RESULTS: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. CONCLUSIONS: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.

Functional Characterization of Four Olive Squalene Synthases with Respect to the Squalene Content of the Virgin Olive Oil.

The release of new olive cultivars with an increased squalene content in their virgin olive oil is considered an important target in olive breeding programs. In this work, the variability of the squalene content in a core collection of 36 olive cultivars was first studied, revealing two olive cultivars, 'Dokkar' and 'Klon-14', with extremely low and high squalene contents in their oils, respectively. Next, four cDNA sequences encoding squalene synthases (SQS) were cloned from olive. Sequence analysis and functional expression in bacteria confirmed that they encode squalene synthases. Transcriptional analysis in distinct olive tissues and cultivars indicated that expression levels of these four SQS genes are spatially and temporally regulated in a cultivar-dependent manner and pointed to OeSQS2 as the gene mainly involved in squalene biosynthesis in olive mesocarp and, therefore, in the olive oil. In addition, the biosynthesis of squalene appears to be transcriptionally regulated in water-stressed olive mesocarp.

The Five "Ws" of Frailty Assessment and Chronic Lymphocytic Leukemia: Who, What, Where, Why, and When.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, but chronological age does not accurately discriminate frailty status at the inter-individual level. Frailty describes a person's overall resilience. Since CLL is a stressful situation, it is relevant to assess the patient´s degree of frailty, especially before starting antineoplastic treatment. We are in the era of targeted therapies, which have helped to control the disease more effectively and avoid the toxicity of chemo (immuno) therapy. However, these drugs are not free of side effects and other aspects arise that should not be neglected, such as interactions, previous comorbidities, or adherence to treatment, since most of these medications are taken continuously. The challenge we face is to balance the risk of toxicity and efficacy in a personalized way and without forgetting that the most frequent cause of death in CLL is related to the disease. For this purpose, comprehensive geriatric assessment (GA) provides us with the opportunity to evaluate multiple domains that may affect tolerance to treatment and that could be improved with appropriate interventions. In this review, we will analyze the state of the art of GA in CLL through the five Ws.

Magnetic separation and concentration of Aß 1-42 molecules dispersed at the threshold concentration for Alzheimer's disease diagnosis in clinically-relevant volumes of sample.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia and loss of autonomy in the elderly, implying a progressive cognitive decline and limitation of social activities. The progressive aging of the population is expected to exacerbate this problem in the next decades. Therefore, there is an urgent need to develop quantitative diagnostic methodologies to assess the onset the disease and its progression especially in the initial phases. RESULTS: Here we describe a novel technology to extract one of the most important molecular biomarkers of AD (Aß1-42) from a clinically-relevant volume - 100 µl - therein dispersed in a range of concentrations critical for AD early diagnosis. We demonstrate that it is possible to immunocapture Aß1-42 on 20 nm wide magnetic nanoparticles functionalized with hyperbranced KVLFF aptamers. Then, it is possible to transport them through microfluidic environments to a detection system where virtually all (~ 90%) the Aß1-42 molecules are concentrated in a dense plug of ca.50 nl. The technology is based on magnetic actuation by permanent magnets, specifically designed to generate high gradient magnetic fields. These fields, applied through submillimeter-wide channels, can concentrate, and confine magnetic nanoparticles (MNPs) into a droplet with an optimized shape that maximizes the probability of capturing highly diluted molecular biomarkers. These advancements are expected to provide efficient protocols for the concentration and manipulation of molecular biomarkers from clinical samples, enhancing the accuracy and the sensitivity of diagnostic technologies. CONCLUSIONS: This easy to automate technology allows an efficient separation of AD molecular biomarkers from volumes of biological solutions complying with the current clinical protocols and, ultimately, leads to accurate measurements of biomarkers. The technology paves a new way for a quantitative AD diagnosis at the earliest stage and it is also adaptable for the biomarker analysis of other pathologies.

The evolving landscape of COVID-19 and post-COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.

Molnupiravir compared to nirmatrelvir/ritonavir for COVID-19 in high-risk patients with haematological malignancy in Europe. A matched-paired analysis from the EPICOVIDEHA registry.

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

Real-World Evidence on the Clinical Characteristics and Management of Patients with Chronic Lymphocytic Leukemia in Spain Using Natural Language Processing: The SRealCLL Study.

The SRealCLL study aimed to obtain real-world evidence on the clinical characteristics and treatment patterns of patients with chronic lymphocytic leukemia (CLL) using natural language processing (NLP). Electronic health records (EHRs) from seven Spanish hospitals (January 2016-December 2018) were analyzed using EHRead® technology, based on NLP and machine learning. A total of 534 CLL patients were assessed. No treatment was detected in 270 (50.6%) patients (watch-and-wait, W&W). First-line (1L) treatment was identified in 230 (43.1%) patients and relapsed/refractory (2L) treatment was identified in 58 (10.9%). The median age ranged from 71 to 75 years, with a uniform male predominance (54.8-63.8%). The main comorbidities included hypertension (W&W: 35.6%; 1L: 38.3%; 2L: 39.7%), diabetes mellitus (W&W: 24.4%; 1L: 24.3%; 2L: 31%), cardiac arrhythmia (W&W: 16.7%; 1L: 17.8%; 2L: 17.2%), heart failure (W&W 16.3%, 1L 17.4%, 2L 17.2%), and dyslipidemia (W&W: 13.7%; 1L: 18.7%; 2L: 19.0%). The most common antineoplastic treatment was ibrutinib in 1L (64.8%) and 2L (62.1%), followed by bendamustine + rituximab (12.6%), obinutuzumab + chlorambucil (5.2%), rituximab + chlorambucil (4.8%), and idelalisib + rituximab (3.9%) in 1L and venetoclax (15.5%), idelalisib + rituximab (6.9%), bendamustine + rituximab (3.5%), and venetoclax + rituximab (3.5%) in 2L. This study expands the information available on patients with CLL in Spain, describing the diversity in patient characteristics and therapeutic approaches in clinical practice.

Examining the Effects of Homochirality for Electron Transfer in Protein Assemblies.

Protein voltammetry studies of cytochrome c, immobilized on chiral tripeptide monolayer films, reveal the importance of the electron spin and the film's homochirality on electron transfer kinetics. Magnetic film electrodes are used to examine how an asymmetry in the standard heterogeneous electron transfer rate constant arises from changes in the electron spin direction and the enantiomer composition of the tripeptide monolayer; rate constant asymmetries as large as 60% are observed. These findings are rationalized in terms of the chiral induced spin selectivity effect and spin-dependent changes in electronic coupling. Lastly, marked differences in the average rate constant are shown between homochiral ensembles, in which the peptide and protein possess the same enantiomeric form, compared to heterochiral ensembles, where the handedness of the peptide layer is opposite to that of the protein or itself comprises heterochiral building blocks. These data demonstrate a compelling rationale for why nature is homochiral; namely, spin alignment in homochiral systems enables more efficient energy transduction.

Tendon-Derived Mesenchymal Stem Cells (TDSCs) as an In Vitro Model for Virological Studies in Wild Birds.

The use of wild animals in research is complicated due to the capture and housing conditions, as well as to legal aspects, making it difficult to develop in vivo and in vitro models for the study of pathologies that affect these species. Here we validate an in vitro model of tendon-derived mesenchymal cells (TDSC) from Eurasian blackbird (Turdus merula) cadaveric samples. Through the expression of surface markers and the ability to differentiate into multiple lineages, the nature of the cells was confirmed. We then evaluated Mesenchymal Stem Cells (MSCs) as an infection model for the Usutu Flavivirus. To this aim, blackbird TDSCs were compared to Vero E6 cells, commonly used in Flavivirus studies. Both cells showed permissiveness to USUV infection as confirmed by immunocytochemistry. Moreover, TDSCs exhibited replication kinetics similar to, although slightly lower than, Vero E6, confirming these cells as a pertinent study model for the study of the pathogenesis of USUV. In this work, we isolated and characterized tendon-derived mesenchymal stem cells, which represent an interesting and convenient in vitro model for the study of wildlife species in laboratories.

Organotypic Hippocampal Slice Cultures from Adult Tauopathy Mice and Theragnostic Evaluation of Nanomaterial Phospho-TAU Antibody-Conjugates.

Organotypic slice culture models surpass conventional in vitro methods in many aspects. They retain all tissue-resident cell types and tissue hierarchy. For studying multifactorial neurodegenerative diseases such as tauopathies, it is crucial to maintain cellular crosstalk in an accessible model system. Organotypic slice cultures from postnatal tissue are an established research tool, but adult tissue-originating systems are missing, yet necessary, as young tissue-originating systems cannot fully model adult or senescent brains. To establish an adult-originating slice culture system for tauopathy studies, we made hippocampal slice cultures from transgenic 5-month-old hTau.P301S mice. In addition to the comprehensive characterization, we set out to test a novel antibody for hyperphosphorylated TAU (pTAU, B6), with and without a nanomaterial conjugate. Adult hippocampal slices retained intact hippocampal layers, astrocytes, and functional microglia during culturing. The P301S-slice neurons expressed pTAU throughout the granular cell layer and secreted pTAU to the culture medium, whereas the wildtype slices did not. Additionally, cytotoxicity and inflammation-related determinants were increased in the P301S slices. Using fluorescence microscopy, we showed target engagement of the B6 antibody to pTAU-expressing neurons and a subtle but consistent decrease in intracellular pTAU with the B6 treatment. Collectively, this tauopathy slice culture model enables measuring the extracellular and intracellular effects of different mechanistic or therapeutic manipulations on TAU pathology in adult tissue without the hindrance of the blood-brain barrier.

Ruminococcus gnavus bacteremia: Literature review and a case report associated with acute flare of ulcerative colitis in an immunocompromised patient.

We present a case of bacteremia caused by Ruminococcus gnavus in an immunocompromised patient. R. gnavus is a Gram-positive strict anaerobe bacterium that forms chains. The bacteremia has been associated with an acute flare of ulcerative colitis. Anaerobic bacteremia is becoming increasingly frequent in patients with compromised gastrointestinal barrier. The role of the human microbiota and its alterations in the pathogenesis of immune-related diseases is an expanding area of interest. R. gnavus has been identified as a microorganism that may be responsible for the development of these diseases. The contribution of anaerobic bacteria to the pathogenesis of inflammatory bowel disease (IBD) is discussed, and cases reported up until 2023 were reviewed.

Lung ultrasound score severity cut-off points in COVID-19 pneumonia. A systematic review and validating cohort.

Objectives: Our purpose was to establish different cut-off points based on the lung ultrasound score (LUS) to classify COVID-19 pneumonia severity. Methods: Initially, we conducted a systematic review among previously proposed LUS cut-off points. Then, these results were validated by a single-centre prospective cohort study of adult patients with confirmed SARS-CoV-2 infection. Studied variables were poor outcome (ventilation support, intensive care unit admission or 28-days mortality) and 28-days mortality. Results: From 510 articles, 11 articles were included. Among the cut-off points proposed in the articles included, only the LUS > 15 cut-off point could be validated for its original endpoint, demonstrating also the strongest relation with poor outcome (odds ratio [OR] = 3.636, confidence interval [CI] 1.411-9.374). Regarding our cohort, 127 patients were admitted. In these patients, LUS was statistically associated with poor outcome (OR = 1.303, CI 1.137-1.493), and with 28-days mortality (OR = 1.024, CI 1.006-1.042). LUS > 15 showed the best diagnostic performance when choosing a single cut-off point in our cohort (area under the curve 0.650). LUS ≤ 7 showed high sensitivity to rule out poor outcome (0.89, CI 0.695-0.955), while LUS > 20 revealed high specificity to predict poor outcome (0.86, CI 0.776-0.917). Conclusions: LUS is a good predictor of poor outcome and 28-days mortality in COVID-19. LUS ≤ 7 cut-off point is associated with mild pneumonia, LUS 8-20 with moderate pneumonia and ≥20 with severe pneumonia. If a single cut-off point were used, LUS > 15 would be the point which better discriminates mild from severe disease.

Objetivos: Establecer diferentes puntos de corte basados en el Lung Ultrasound Score (LUS) para clasificar la gravedad de la neumonía COVID-19. Métodos: Inicialmente, realizamos una revisión sistemática entre los puntos de corte LUS propuestos previamente. Estos resultados fueron validados por una cohorte prospectiva unicéntrica de pacientes adultos con infección confirmada por SARS-CoV-2. Las variables analizadas fueron la mala evolución y la mortalidad a los 28 días. Resultados: De 510 artículos, se incluyeron 11. Entre los puntos de corte propuestos en los artículos incluidos, solo LUS > 15 pudo ser validado para su objetivo original, demostrando también la relación más fuerte con mala evolución (odds ratio [OR] = 3,636, intervalo de confianza [IC] 1,411-9,374). Respecto a nuestra cohorte, se incluyeron 127 pacientes. En estos pacientes, el LUS se asoció estadísticamente con mala evolución (OR = 1,303, IC 1,137-1,493) y con mortalidad a los 28 días (OR = 1,024, IC 1,006-1,042). LUS > 15 mostró el mejor rendimiento diagnóstico al elegir un único punto de corte en nuestra cohorte (área bajo la curva 0,650). LUS ≤ 7 mostró una alta sensibilidad para descartar mal resultado (0,89, IC 0,695-0,955), mientras que LUS > 20 reveló gran especificidad para predecir mala evolución (0,86, IC 0,776-0,917). Conclusiones: LUS es un buen predictor de mala evolución y mortalidad a 28 días en COVID-19. LUS ≤ 7 se asocia con neumonía leve, LUS 8-20 con neumonía moderada y ≥ 20 con neumonía grave. Si se utilizara un único punto de corte, LUS > 15 sería el que mejor discriminaría la enfermedad leve de la grave.

Lung ultrasound score severity cut-off points in COVID-19 pneumonia. A systematic review and validating cohort / Puntos de corte de gravedad del Lung Ultrasound Score en la neumonía COVID-19. Revisión sistemática de la literatura y cohorte de validación

Objectives Our purpose was to establish different cut-off points based on the lung ultrasound score (LUS) to classify COVID-19 pneumonia severity. Methods Initially, we conducted a systematic review among previously proposed LUS cut-off points. Then, these results were validated by a single-centre prospective cohort study of adult patients with confirmed SARS-CoV-2 infection. Studied variables were poor outcome (ventilation support, intensive care unit admission or 28-days mortality) and 28-days mortality. Results From 510 articles, 11 articles were included. Among the cut-off points proposed in the articles included, only the LUS>15 cut-off point could be validated for its original endpoint, demonstrating also the strongest relation with poor outcome (odds ratio [OR]=3.636, confidence interval [CI] 1.411–9.374). Regarding our cohort, 127 patients were admitted. In these patients, LUS was statistically associated with poor outcome (OR=1.303, CI 1.137–1.493), and with 28-days mortality (OR=1.024, CI 1.006–1.042). LUS>15 showed the best diagnostic performance when choosing a single cut-off point in our cohort (area under the curve 0.650). LUS≤7 showed high sensitivity to rule out poor outcome (0.89, CI 0.695–0.955), while LUS>20 revealed high specificity to predict poor outcome (0.86, CI 0.776–0.917). Conclusions LUS is a good predictor of poor outcome and 28-days mortality in COVID-19. LUS≤7 cut-off point is associated with mild pneumonia, LUS 8–20 with moderate pneumonia and ≥20 with severe pneumonia. If a single cut-off point were used, LUS>15 would be the point which better discriminates mild from severe disease (AU)

Objetivos Establecer diferentes puntos de corte basados en el Lung Ultrasound Score (LUS) para clasificar la gravedad de la neumonía COVID-19. Métodos Inicialmente, realizamos una revisión sistemática entre los puntos de corte LUS propuestos previamente. Estos resultados fueron validados por una cohorte prospectiva unicéntrica de pacientes adultos con infección confirmada por SARS-CoV-2. Las variables analizadas fueron la mala evolución y la mortalidad a los 28 días. Resultados De 510 artículos, se incluyeron 11. Entre los puntos de corte propuestos en los artículos incluidos, solo LUS>15 pudo ser validado para su objetivo original, demostrando también la relación más fuerte con mala evolución (odds ratio [OR]=3,636, intervalo de confianza [IC] 1,411-9,374). Respecto a nuestra cohorte, se incluyeron 127 pacientes. En estos pacientes, el LUS se asoció estadísticamente con mala evolución (OR=1,303, IC 1,137-1,493) y con mortalidad a los 28 días (OR=1,024, IC 1,006-1,042). LUS>15 mostró el mejor rendimiento diagnóstico al elegir un único punto de corte en nuestra cohorte (área bajo la curva 0,650). LUS≤7 mostró una alta sensibilidad para descartar mal resultado (0,89, IC 0,695-0,955), mientras que LUS>20 reveló gran especificidad para predecir mala evolución (0,86, IC 0,776-0,917). Conclusiones LUS es un buen predictor de mala evolución y mortalidad a 28 días en COVID-19. LUS≤7 se asocia con neumonía leve, LUS 8-20 con neumonía moderada y ≥20 con neumonía grave. Si se utilizara un único punto de corte, LUS>15 sería el que mejor discriminaría la enfermedad leve de la grave (AU)