Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

BACKGROUND: It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. METHODS: Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. RESULTS: Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60-63] years vs 64 [62-66] years, p < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic. CONCLUSION: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

Implementation of a Gene Panel for Genetic Diagnosis of Primary Ciliary Dyskinesia. / Implementación de un panel de genes para el diagnóstico genético de la discinesia ciliar primaria.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is characterized by an alteration in the ciliary structure causing difficulty in the clearance of respiratory secretions. Diagnosis is complex and based on a combination of techniques. The objective of this study was to design a gene panel including all known causative genes, and to corroborate their diagnostic utility in a cohort of Spanish patients. METHODS: This was a multicenter cross-sectional study of patients with a high suspicion of PCD, according to European Respiratory Society criteria, designed around a gene panel for massive sequencing using SeqCap EZ capture technology that included 44 genes associated with PCD. RESULTS: We included 79 patients, 53 of whom had a diagnosis of confirmed or highly probable PCD. The sensitivity of the gene panel was 81.1%, with a specificity of 100%. Candidate variants were found in some of the genes of the panel in 43 patients with PCD, 51.2% (22/43) of whom were homozygotes and 48.8% (21/43) compound heterozygotes. The most common causative genes were DNAH5 and CCDC39. We found 52 different variants, 36 of which were not previously described in the literature. CONCLUSIONS: The design and implementation of a tailored gene panel produces a high yield in the genetic diagnosis of PCD. This panel provides a better understanding of the causative factors involved in these patients and lays down the groundwork for future therapeutic approaches.

[Bronchial hyperresponsiveness to methacholine assessed by means of tracheal auscultation of healthy children aged under 4 years]. / Estudio de la hiperrespuesta bronquial a la metacolina mediante la auscultación traqueal en niños sanos menores de 4 años.

OBJECTIVE: To assess the safety of the tracheal auscultation method for measuring bronchial hyperresponsiveness in healthy unsedated children aged less than 4 years and to establish a range of normal bronchial hyperresponsiveness values. POPULATION AND METHODS: The study population consisted of healthy children aged between 6 months and 4 years. A methacholine bronchial provocation test was administered to unsedated children, using the tidal volume breathing technique and applying an abbreviated protocol. The test was considered positive when wheezing was heard in the trachea, arterial oxygen saturation (SaO2) fell by 5% or more, or respiratory rate increased by 50% or more. RESULTS: A total of 16 children were studied. Ages ranged from 8 to 47 months, with a mean (SD) of 23.5 (12.2) months. There was no response to the methacholine in 11 children. In the other 5 children, there was a positive response at a concentration of 8 mg/mL. Response to the test was considered positive on the basis of tracheal wheezing in 3 cases, tracheal wheezing and a fall in SaO2 in 1 case, and a fall of SaO2 of 5% or more in 1 case. SaO2 never fell below 93%. CONCLUSIONS: As a means for assessing bronchial hyperresponsiveness, the tracheal auscultation method is appropriate, is simple to apply, and can be safely administered to unsedated children aged less than 4 years. The lowest concentration at which a response to methacholine occurs in healthy children of this age group is 8 mg/mL.

Estudio de la hiperrespuesta bronquial a la metacolina mediante la auscultación traqueal en niños sanos menores de 4 años / Bronchial hyperresponsiveness to methacholine assessed by means of tracheal auscultation of healthy children aged under 4 years

Objetivo: Valorar la seguridad del método de la auscultación traqueal para medir la hiperrespuesta bronquial en niños sanos menores de 4 años de edad, sin sedación, y establecer valores de normalidad. Población y métodos: Se incluyó en el estudio a niños sanos de entre 6 meses y 4 años de edad. Se les realizó una prueba de provocación bronquial con metacolina mediante la técnica de la respiración a volumen corriente, en niños no sedados, utilizando un protocolo acortado. Se consideró positiva la prueba cuando se auscultaron sibilantes en la tráquea, la saturación arterial de oxígeno (SaO2) disminuyó un 5% o más, o bien aumentó la frecuencia respiratoria un 50% o más. Resultados: Se estudió a 16 niños de 8 a 47 meses de edad (mediana: 23,5 meses; desviación estándar: 12,2 meses). En 11 niños no hubo respuesta a la metacolina, y en 5 la respuesta fue positiva a la concentración de 8 mg/ml. La prueba se consideró positiva en 3 casos por la auscultación de sibilancias traqueales, en uno por la auscultación de sibilancias y descenso de la SaO2, y en otro por un descenso de la SaO2 del 5% o superior. En ningún caso la SaO2 disminuyó por debajo del 93%. Conclusiones: El método de la auscultación traqueal es sencillo, adecuado y seguro para valorar la presencia de hiperrespuesta bronquial en niños menores de 4 años de edad, sin necesidad de sedarlos. La concentración mínima a la que los niños sanos de esta edad responden a la metacolina es 8 mg/ml

Objective: To assess the safety of the tracheal auscultation method for measuring bronchial hyperresponsiveness in healthy unsedated children aged less than 4 years and to establish a range of normal bronchial hyperresponsiveness values. Population and methods: The study population consisted of healthy children aged between 6 months and 4 years. A methacholine bronchial provocation test was administered to unsedated children, using the tidal volume breathing technique and applying an abbreviated protocol. The test was considered positive when wheezing was heard in the trachea, arterial oxygen saturation (SaO2) fell by 5% or more, or respiratory rate increased by 50% or more. Results: A total of 16 children were studied. Ages ranged from 8 to 47 months, with a mean (SD) of 23.5 (12.2) months. There was no response to the methacholine in 11 children. In the other 5 children, there was a positive response at a concentration of 8 mg/mL. Response to the test was considered positive on the basis of tracheal wheezing in 3 cases, tracheal wheezing and a fall in SaO2 in 1 case, and a fall of SaO2 of 5% or more in 1 case. SaO2 never fell below 93%. Conclusions: As a means for assessing bronchial hyperresponsiveness, the tracheal auscultation method is appropriate, is simple to apply, and can be safely administered to unsedated children aged less than 4 years. The lowest concentration at which a response to methacholine occurs in healthy children of this age group is 8 mg/mL