Transcriptomic clustering of critically ill COVID-19 patients.

BACKGROUND: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit. METHODS: In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings. RESULTS: We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results. CONCLUSIONS: These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies.

SARS-CoV-2 Breakthrough Infections: Incidence and Risk Factors in a Large European Multicentric Cohort of Health Workers.

BACKGROUND: The research aimed to investigate the incidence of SARS-CoV-2 breakthrough infections and their determinants in a large European cohort of more than 60,000 health workers. METHODS: A multicentric retrospective cohort study, involving 12 European centers, was carried out within the ORCHESTRA project, collecting data up to 18 November 2021 on fully vaccinated health workers. The cumulative incidence of SARS-CoV-2 breakthrough infections was investigated with its association with occupational and social-demographic characteristics (age, sex, job title, previous SARS-CoV-2 infection, antibody titer levels, and time from the vaccination course completion). RESULTS: Among 64,172 health workers from 12 European health centers, 797 breakthrough infections were observed (cumulative incidence of 1.2%). The primary analysis using individual data on 8 out of 12 centers showed that age and previous infection significantly modified breakthrough infection rates. In the meta-analysis of aggregated data from all centers, previous SARS-CoV-2 infection and the standardized antibody titer were inversely related to the risk of breakthrough infection (p = 0.008 and p = 0.007, respectively). CONCLUSION: The inverse correlation of antibody titer with the risk of breakthrough infection supports the evidence that vaccination plays a primary role in infection prevention, especially in health workers. Cellular immunity, previous clinical conditions, and vaccination timing should be further investigated.

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

Patients with severe COVID-19 often need mechanical ventilation to help them breathe and other types of intensive care. The outcome for many of these patients depends on how their immune system reacts to the infection. If the inflammatory response triggered by the immune system is too strong, this can cause further harm to the patient. One gene that plays an important role in inflammation is IFIH1 which encodes a protein that helps the body to recognize viruses. There are multiple versions of this gene which each produce a slightly different protein. It is possible that this variation impacts how the immune system responds to the virus that causes COVID-19. To investigate, Amado-Rodríguez, Salgado del Riego et al. analyzed the IFIH1 gene in 227 patients admitted to an intensive care unit in Spain for severe COVID-19 between March and December 2020. They found that patients with a specific version of the gene called TT experienced less inflammation and were more likely to survive the infection. Physicians typically treat patients with moderate to severe COVID-19 with corticosteroid drugs that reduce the inflammatory response. However, Amado-Rodríguez, Salgado del Riego et al. found that patients with the TT version of the IFIH1 gene were at greater risk of dying if they received corticosteroids. The team then applied the distribution of IFIH1 variants among different ethnic ancestries to data from a previous clinical trial, and simulated the effects of corticosteroid treatment. This 'mock' clinical trial supported their findings from the patient-derived data, which were also validated by laboratory experiments on immune cells from individuals with the TT gene. The work by Amado-Rodríguez, Salgado del Riego et al. suggests that while corticosteroids benefit some patients, they may cause harm to others. However, a real-world clinical trial is needed to determine whether patients with the TT version of the IFIH1 gene would do better without steroids.

Beers versus STOPP criteria in polyharmacy community-dwelling older patients / Criterios de Beers versus STOPP en pacientes mayores, polimedicados y residentes en la comunidad

Objective: To assess potentially inappropriate prescribing (PIP) using Beers (2012 version) and STOPP (2008 version) criteria in polypharmacy, community-dwelling, older patients. Methods: From the information collected in the invoicing data of the prescriptions and the electronic medical records, a sample was selected of 223 greater than or equal to 65-year-old patients who were taking simultaneously 10 or more drugs per day. Beers and STOPP criteria were separately applied, and the results obtained with the two methods were compared. Results: A total of 141 (63.2%) patients presented at least one Beers criterion. The two most frequently observed Beers criteria independent of diagnosis were the use of benzodiazepines and the use of non-COX-2-selective non-steroidal anti-inflammatory drugs. With regard to Beers criteria considering diagnosis, the most frequent were the use of anticholinergic drugs in patients with lower urinary tract symptoms or benign prostatic hyperplasia, and the use of benzodiazepines, antipsychotics, zolpidem or H2 -antihistamines, in patients with dementia or cognitive impairment. A total of 165 (73.9%) patients had at least one PIP according to the STOPP criteria. Duplicate drug classes and long-term use of long-acting benzodiazepines were the two most frequent STOPP criteria. Discussion: Our study identified a high frequency of PIP in polymedicated community-dwelling older patients. Simultaneous application of Beers and STOPP criteria represents a useful tool to improve prescribing in this population group (AU))

Objetivo: Evaluar la prescripción potencialmente inapropiada (PPI) mediante la aplicación de los criterios Beers (versión 2012) y STOPP (versión 2008) en pacientes mayores, polimedicados y residentes en la comunidad. Métodos: A partir de la información recogida en los datos de facturación de recetas y de las historias clínicas electrónicas se seleccionó una muestra de 223 pacientes de 65 o más años, que tomaban simultáneamente 10 o más medicamentos/día. Se aplicaron separadamente los criterios de Beers y STOPP y se compararon los resultados obtenidos con ambos métodos. Resultados: Un total de 141 pacientes (63,2%) presentaban al menos un criterio de Beers. Los dos criterios de Beers independientes del diagnóstico observados con más frecuencia fueron el uso de benzodiazepinas y el uso de antiinflamatorios no esteroideos no selectivos de ciclooxigenasa-2. Con respecto a los criterios de Beers considerando el diagnóstico, los más frecuentes fueron el uso de anticolinérgicos en pacientes con síntomas del tracto urinario inferior o con hiperplasia benigna de próstata y el uso de benzodiazepinas, antipsicóticos, zolpidem o antihistamí- nicos H2 , en pacientes con demencia o deterioro cognitivo. Un total de 165 (73,9%) pacientes tenían al menos una PPI según los criterios STOPP. La duplicidad terapéutica y el uso prolongado de benzodiazepinas de vida media larga fueron los dos criterios STOPP más comunes. Discusión: Nuestro estudio identificó una alta frecuencia de PPI en pacientes mayores, polimedicados y residentes en la comunidad. La aplicación simultánea de los criterios de Beers y STOPP constituye una herramienta útil para mejorar la prescripción en este grupo de población (AU)

Beers versus STOPP criteria in polyharmacy community-dwelling older patients.

OBJECTIVE: To assess potentially inappropriate prescribing (PIP) using Beers (2012 version) and STOPP (2008 version) criteria in polypharmacy, community-dwelling, older patients. METHODS: From the information collected in the invoicing data of the prescriptions and the electronic medical records, a sample was selected of 223 ≥ 65-year-old patients who were taking simultaneously 10 or more drugs per day. Beers and STOPP criteria were separately applied, and the results obtained with the two methods were compared. RESULTS: A total of 141 (63.2%) patients presented at least one Beers criterion. The two most frequently observed Beers criteria independent of diagnosis were the use of benzodiazepines and the use of non-COX-2-selective non-steroidal anti-inflammatory drugs. With regard to Beers criteria considering diagnosis, the most frequent were the use of anticholinergic drugs in patients with lower urinary tract symptoms or benign prostatic hyperplasia, and the use of benzodiazepines, antipsychotics, zolpidem or H2-antihistamines, in patients with dementia or cognitive impairment. A total of 165 (73.9%) patients had at least one PIP according to the STOPP criteria. Duplicate drug classes and long-term use of long-acting benzodiazepines were the two most frequent STOPP criteria. DISCUSSION: Our study identified a high frequency of PIP in polymedicated community-dwelling older patients. Simultaneous application of Beers and STOPP criteria represents a useful tool to improve prescribing in this population group.

Objetivo: Evaluar la prescripcion potencialmente inapropiada (PPI) mediante la aplicacion de los criterios Beers (version 2012) y STOPP (version 2008) en pacientes mayores, polimedicados y residentes en la comunidad. Metodos: A partir de la informacion recogida en los datos de facturacion de recetas y de las historias clinicas electronicas se selecciono una muestra de 223 pacientes de 65 o mas anos, que tomaban simultaneamente 10 o mas medicamentos/dia. Se aplicaron separadamente los criterios de Beers y STOPP y se compararon los resultados obtenidos con ambos metodos. Resultados: Un total de 141 pacientes (63,2%) presentaban al menos un criterio de Beers. Los dos criterios de Beers independientes del diagnostico observados con mas frecuencia fueron el uso de benzodiazepinas y el uso de antiinflamatorios no esteroideos no selectivos de ciclooxigenasa-2. Con respecto a los criterios de Beers considerando el diagnostico, los mas frecuentes fueron el uso de anticolinergicos en pacientes con sintomas del tracto urinario inferior o con hiperplasia benigna de prostata y el uso de benzodiazepinas, antipsicoticos, zolpidem o antihistaminicos H2, en pacientes con demencia o deterioro cognitivo. Un total de 165 (73,9%) pacientes tenian al menos una PPI segun los criterios STOPP. La duplicidad terapeutica y el uso prolongado de benzodiazepinas de vida media larga fueron los dos criterios STOPP mas comunes. Discusion: Nuestro estudio identifico una alta frecuencia de PPI en pacientes mayores, polimedicados y residentes en la comunidad. La aplicacion simultanea de los criterios de Beers y STOPP constituye una herramienta util para mejorar la prescripcion en este grupo de poblacion.

Optimización de la información sobre la medicación de personas polimedicadas en atención primaria / Optimization of information on the medication of polypharmacy patients in primary care

Dentro del protocolo de pacientes polimedicados/as elaborado por el Servicio de Salud del Principado de Asturias, los/las médicos/as de atención primaria reciben periódicamente los listados de los tratamientos de pacientes de cualquier edad que consumen 10 o más medicamentos/día durante un período de 6 meses. Actualmente, el Servicio de Salud del Principado de Asturias está desarrollando un proyecto orientado a evaluar las medicaciones de pacientes polimedicados/as, con el fin de identificar: 1) el consumo de medicamentos de utilidad terapéutica baja, 2) el consumo de fármacos potencialmente nefrotóxicos en pacientes con filtrado glomerular disminuido, y 3) la posible prescripción inadecuada en pacientes mayores de 65 años. El proyecto se inició con una primera fase llevada a cabo en el Área Sanitaria II y actualmente se pretende extenderlo a las áreas sanitarias restantes. Consideramos que su automatización y aplicación generalizada podrían ser útiles para optimizar la prescripción de medicamentos (AU)

As part of the protocol of the Health Service of the Principality of Asturias (Spain), primary care physicians periodically receive listings of the treatments of patients of any age taking 10 or more drugs/day for 6 months. Currently, the Health Service of the Principality of Asturias is developing a project that aims to assess the medications of polypharmacy patients. The aim is to identify: 1) the consumption of medicines of low therapeutic usefulness, 2) the consumption of potentially nephrotoxic drugs in patients with a low glomerular filtration rate, and 3) potentially inappropriate prescribing in patients aged 65 years or older. The project was started in Health Area II and the aim is to extend it to the remaining health areas. In our opinion, its automation and general implementation could be useful to optimize drug prescription (AU)

Inappropriate prescribing in polypharmacy elderly outpatients taking multiple medications. Are the STOPP criteria useful?

OBJECTIVE: To assess potentially inappropriate medications (PIMs) in elderly outpatients taking multiple medications. METHODS: Invoicing data of the prescriptions and electronic medical records were used to apply the STOPP (screening tool of older people's prescriptions) criteria. RESULTS: Three out of 4 patients included in the study received PIMs. The most common criteria found were: duplicate drug class prescriptions (n = 58 (17.4%)), long-term long-acting benzodiazepines (n = 54 (16.2%)), and acetylsalicylic acid with no history of coronary, cerebral, or peripheral vascular symptoms or occlusive event (n = 32 (9.6%)). CONCLUSION: Our results highlight the relevance of the systematic review of the pharmacological treatments in these patients.

[Optimization of information on the medication of polypharmacy patients in primary care]. / Optimización de la información sobre la medicación de personas polimedicadas en atención primaria.

As part of the protocol of the Health Service of the Principality of Asturias (Spain), primary care physicians periodically receive listings of the treatments of patients of any age taking 10 or more drugs/day for 6 months. Currently, the Health Service of the Principality of Asturias is developing a project that aims to assess the medications of polypharmacy patients. The aim is to identify: 1) the consumption of medicines of low therapeutic usefulness, 2) the consumption of potentially nephrotoxic drugs in patients with a low glomerular filtration rate, and 3) potentially inappropriate prescribing in patients aged 65 years or older. The project was started in Health Area II and the aim is to extend it to the remaining health areas. In our opinion, its automation and general implementation could be useful to optimize drug prescription.

Seguridad de los agonistas beta-2-adrenérgicos inhalados: ¿qué aporta la notificación espontánea? / Safety of inhaled beta-2-adrenergics: spontaneous notification data

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