Cell-Type-Specific Immune Dysregulation in Severely Ill COVID-19 Patients.

Recent studies have demonstrated immunologic dysfunction in severely ill coronavirus disease 2019 (COVID-19) patients. We use single-cell RNA sequencing (scRNA-seq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) from healthy (n = 3) and COVID-19 patients with moderate disease (n = 5), acute respiratory distress syndrome (ARDS, n = 6), or recovering from ARDS (n = 6). Our data reveal transcriptomic profiles indicative of defective antigen presentation and interferon (IFN) responsiveness in monocytes from ARDS patients, which contrasts with higher responsiveness to IFN signaling in lymphocytes. Furthermore, genes involved in cytotoxic activity are suppressed in both natural killer (NK) and CD8 T lymphocytes, and B cell activation is deficient, which is consistent with delayed viral clearance in severely ill COVID-19 patients. Our study demonstrates that COVID-19 patients with ARDS have a state of immune imbalance in which dysregulation of both innate and adaptive immune responses may be contributing to a more severe disease course.

Cell type-specific immune dysregulation in severely ill COVID-19 patients.

Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease course in COVID-19.

Hemorragias en pacientes tratados con heparinas de bajo peso molecular / Hemorrhages among patients treated with low-molecular-weight heparins

Objetivo. Se han descrito diversos casos de pacientes con hemorragias graves por heparinas de bajo peso molecular (HBPM). El objetivo del estudio fue analizar los factores de riesgo hemorrágico de los pacientes diagnosticados de hemorragia por HBPM. Método. Estudio retrospectivo (1989-1999) de los pacientes diagnosticados de hemorragias por HBPM en un hospital universitario de tercer nivel. Se revisaron: a) las historias clínicas de los archivos hospitalarios y b) las notificaciones de reacciones adversas a medicamentos de un programa de monitorización intensiva de reacciones adversas hospitalarias. Se recogió información de las variables clínicas de los pacientes, del tratamiento, de la localización y de la gravedad de la hemorragia. Resultados. Se identificaron 36 pacientes diagnosticados de hemorragias por HBPM. La edad mediana de los pacientes fue de 76 años (mínimo 39 y máximo 94 años). En 11 (31 por ciento) pacientes la hemorragia se originó durante un tratamiento ambulatorio que motivó ingreso hospitalario. Todos los pacientes presentaban uno o más factores de riesgo hemorrágico: edad 65 años (34; 94 por ciento); comorbilidad de riesgo hemorrágico (28; 78 por ciento); uso de antiagregantes plaquetarios o antiinflamatorios no esteroideos (AINE) (17; 47 por ciento); duración del tratamiento > 7 días (17; 47 por ciento), y uso de dosis anticoagulantes (16; 44 por ciento). Las hemorragias más frecuentes fueron las gastrointestinales y las musculares (24; 67 por ciento). La mayoría de pacientes presentaron hemorragias mayores (26; 72 por ciento), y en 5 casos fueron mortales. En ningún paciente se ajustó la dosis mediante la monitorización de la actividad anti-Xa. Conclusiones. La mayoría de pacientes con hemorragias por HBPM tienen diversos factores de riesgo hemorrágico. Es necesaria una valoración cuidadosa de los factores de riesgo hemorrágico de los pacientes cuando se utilizan HBPM, y en especial en los tratamientos ambulatorios. Se deberían ajustar la dosis de las HBPM en los pacientes con factores de riesgo hemorrágico (AU)

[Hemorrhages among patients treated with low-molecular-weight heparins]. / Hemorragias en pacientes tratados con heparinas de bajo peso molecular.

OBJECTIVE: Several cases have been reported of patients with severe hemorrhages caused by low-molecular-weight heparins (LMWH). The objective of the present report was to analyse risk factors for hemorrhage among patients diagnosed of hemorrhage due to LMWH. METHODS: Retrospective study (1989-1999) of patients diagnosed of LMWH hemorrhages in a third-level teaching hospital. A review was made of: a) clinical records from hospital files; b) reports of adverse drug reactions from a program on intensive surveillance of hospital adverse reactions. Information was collected of clinical perameters of patients, treatment, site, and severity of hemorrhage. RESULTS: A total of 36 patients diagnosed of LMWH hemorrhages were identified. The median age of patients was 76 years (range: 39 to 94 years). In 11 (31%) patients, hemorrhage originated during an ambulatory treatment, which prompted hospital admission. All patients had one or more risk factors for hemorrhage: age > or = 65 years (34; 94%); co-morbidities with hemorrhagic risk (28; 78%); use of platelet anti-aggregants or NSAIDs (17; 47%); length of treatment > 7 days (17; 47%) and use of anticoagulant doses (16; 44%). Hemorrhages occurred most commonly in the gastrointestinal tract and muscles (24; 67%). Most patients had major hemorrhages (26; 72%); and in 5 cases hemorrhages were fatal. In no patient was the dose adjusted by anti-Xa activity monitoring. CONCLUSIONS: Most patients with LMWH hemorrhages have different risk factors for hemorrhage. A careful assessment of hemorrhagic risk factors on patients is needed when LMWH are used, particularly in the ambulatory setting. LMWH doses should be adjusted in patients with hemorrhagic risk factors.

Etiología y sensibilidad antibiótica de las infeccionesextrahospitalarias más frecuentes, excepto las del tracto respiratorioinferior / Aetiology and antibiotic sensitivity of the most frequent outpatient infections, except those of the lower respiratory tract

La difusión de los perfiles de sensibilidad antibiótica es una práctica recomendada para mejorar la prescripción de antibióticos y controlar la aparición y diseminación de resistencias. Durante el año 2001, se recogieron los datos de sensibilidad a antimicrobianos de los patógenos bacterianos aislados de urocultivos, coprocultivos y exudados óticos y la sensibilidad de Streptococcus pyogenes de los cinco primeros meses del 2002 en el área de salud de Pamplona, que atiende a una población de 389.489 habitantes. Se registraron los datos de dispensación de antibióticos en esa misma área de salud. Más del 80 por ciento de los 4.216 uropátogenos aislados fueron sensibles a amoxicilina-ac.clavulánico, cefalosporinas, fosfomicina y nitrofurantoina. El 98,3 por ciento de los 495 aislamientos de Salmonella Enteritidis fueron sensibles a cotrimoxazol y el 96,6 por ciento de los 474 de Campylobacter jejuni fueron sensibles a eritromicina. De las 173 bacterias aisladas en otitis media, el 95 por ciento fueron sensibles a amoxicilina. Los bacilos Gram negativos productores de otitis externa presentaron una sensibilidad superior al 80 por ciento para ciprofloxacino, gentamicina y polimixina B. El 22,5 por ciento de Streptococcus pyogenes fue resistente a eritromicina. El consumo de antimicrobianos en dosis diaria definida por cada mil habitantes y día (DHD) durante el año 2001 fue de 14,8. Contrasta la elevada prescripción de antibióticos de amplio espectro y de macrólidos con las limitadas indicaciones de estos antibióticos en el tratamiento empírico de los gérmenes prevalentes en el área estudiada. El conocimiento de la sensibilidad antibiótica de los microorganismos circulantes en cada área geográfica, es un dato necesario para la elección empírica del tratamiento antimicrobiano. (AU)

[Aetiology and antibiotic sensitivity of the most frequent outpatient infections, except those of the lower respiratory tract]. / Etiología y sensibilidad antibiótica de las infecciones extrahospitalarias más frecuentes, excepto las del tracto respiratorio inferior.

Reporting of antimicrobial susceptibility profiles is recommended in order to improve antibiotic prescribing policies and to avoid the emergence of bacterial resistance. During 2001, susceptibility data from bacterial isolates collected from urine, faeces and ear swabs and antimicrobial susceptibility for Streptococcus pyogenes during the first five months in 2002 were recorded in the Health Area of Pamplona (389,489 inhabitants) and compared against data for antibiotic prescriptions. More than 80% of bacteria from urine were susceptible to amoxicillin plus clavulanic acid, oral cephalosporins, fosfomycin and nitrofurantoin. Of the Salmonella Enteritidis isolates, 98.3% were susceptible to trimethroprim-sulfamethoxazole and 96.6% of Campylobacter jejuni to erythromycin. Amoxicillin remained susceptible for more than 95.5% of middle ear isolates. Gram-negative bacilli isolates from otitis externa swabs were susceptible to ciprofloxacin, gentamicin and polimyxin B in over 80% of cases. Of the Streptococcus pyogenes isolated, 22.5% were resistant to erythromycin. Antimicrobial consumption in defined daily doses per 1,000 inhabitants, day (DID) during 2001 was 14.8. Here, we highlight the over-prescription of some broad-spectrum antibiotics and macrolides for the empiric treatment of infectious diseases in our area. Knowledge of local susceptibility patterns is essential in order to inform empiric therapy.