The relationship between gut and nasopharyngeal microbiome composition can predict the severity of COVID-19 (preprint)

BackgroundCoronavirus disease 2019 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that displays great variability in clinical phenotype. Many factors have been described to be correlated with its severity but no specific determinants of infection outcome have been identified yet, maybe due the complex pathogenic mechanisms. The microbiota could play a key role in the infection and in the progression and outcome of the disease. Hence, SARS-CoV-2 infection has been associated with nasopharyngeal and gut dysbiosis and higher abundance of opportunistic pathogens. MethodsTo identify new prognostic markers for the disease, a multicenter prospective observational cohort study was carried out in COVID-19 patients that were divided in three cohorts according to their symptomatology: mild (n=24), moderate (n=51) and severe/critical (n=31). Faecal and nasopharyngeal samples were taken and the microbiota was analysed. ResultsMicrobiota composition could be associated with the severity of the symptoms and the linear discriminant analysis identified the genera Mycoplasma and Prevotella as severity biomarkers in nasopharyngeal samples, and Allistipes, Enterococcus and Escherichia in faecal samples. Moreover, M. salivarium was defined as a unique microorganism in COVID-19 patients nasopharyngeal microbiota while P. bivia and P. timonensis were defined in faecal microbiota. A connection between faecal and nasopharyngeal microbiota in COVID-19 patients was also identified as a strong positive correlation between P. timonensis (faeces) towards P. dentalis and M. salivarium (nasopharyngeal) was found in critically ill patients. ConclusionsThis ratio could be used as a novel prognostic biomarker for severe COVID-19 patients.

Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study

Background The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19. Methods We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero (<1 N1 copies per mL), VIR-N1-Low (1–2747 N1 copies per mL), and VIR-N1-Storm (>2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis. Findings 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16–0·55;p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26–0·57;p<0·0001, compared with the VIR-N1-Storm group). Interpretation The presence of a so-called viral storm is associated with increased all-cause death in patients admitted to the intensive care unit with severe COVID-19. Preventing this viral storm could help to reduce poor outcomes. Viral storm could be an enrichment marker for treatment with antivirals or purification devices to remove viral components from the blood. Funding Instituto de Salud Carlos III, Canadian Institutes of Health Research, Li Ka-Shing Foundation, Research Nova Scotia, and European Society of Clinical Microbiology and Infectious Diseases. Translation For the Spanish translation of the see Supplementary Materials section.

Risk factors for developing ventilator-associated lower respiratory tract infection in patients with severe COVID-19: a multinational, multicentre study, prospective, observational study.

Around one-third of patients diagnosed with COVID-19 develop a severe illness that requires admission to the Intensive Care Unit (ICU). In clinical practice, clinicians have learned that patients admitted to the ICU due to severe COVID-19 frequently develop ventilator-associated lower respiratory tract infections (VA-LRTI). This study aims to describe the clinical characteristics, the factors associated with VA-LRTI, and its impact on clinical outcomes in patients with severe COVID-19. This was a multicentre, observational cohort study conducted in ten countries in Latin America and Europe. We included patients with confirmed rtPCR for SARS-CoV-2 requiring ICU admission and endotracheal intubation. Only patients with a microbiological and clinical diagnosis of VA-LRTI were included. Multivariate Logistic regression analyses and Random Forest were conducted to determine the risk factors for VA-LRTI and its clinical impact in patients with severe COVID-19. In our study cohort of 3287 patients, VA-LRTI was diagnosed in 28.8% [948/3287]. The cumulative incidence of ventilator-associated pneumonia (VAP) was 18.6% [610/3287], followed by ventilator-associated tracheobronchitis (VAT) 10.3% [338/3287]. A total of 1252 bacteria species were isolated. The most frequently isolated pathogens were Pseudomonas aeruginosa (21.2% [266/1252]), followed by Klebsiella pneumoniae (19.1% [239/1252]) and Staphylococcus aureus (15.5% [194/1,252]). The factors independently associated with the development of VA-LRTI were prolonged stay under invasive mechanical ventilation, AKI during ICU stay, and the number of comorbidities. Regarding the clinical impact of VA-LRTI, patients with VAP had an increased risk of hospital mortality (OR [95% CI] of 1.81 [1.40-2.34]), while VAT was not associated with increased hospital mortality (OR [95% CI] of 1.34 [0.98-1.83]). VA-LRTI, often with difficult-to-treat bacteria, is frequent in patients admitted to the ICU due to severe COVID-19 and is associated with worse clinical outcomes, including higher mortality. Identifying risk factors for VA-LRTI might allow the early patient diagnosis to improve clinical outcomes.Trial registration: This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.

Key Factors Associated With Pulmonary Sequelae in the Follow-Up of Critically Ill COVID-19 Patients.

INTRODUCTION: Critical COVID-19 survivors have a high risk of respiratory sequelae. Therefore, we aimed to identify key factors associated with altered lung function and CT scan abnormalities at a follow-up visit in a cohort of critical COVID-19 survivors. METHODS: Multicenter ambispective observational study in 52 Spanish intensive care units. Up to 1327 PCR-confirmed critical COVID-19 patients had sociodemographic, anthropometric, comorbidity and lifestyle characteristics collected at hospital admission; clinical and biological parameters throughout hospital stay; and, lung function and CT scan at a follow-up visit. RESULTS: The median [p25-p75] time from discharge to follow-up was 3.57 [2.77-4.92] months. Median age was 60 [53-67] years, 27.8% women. The mean (SD) percentage of predicted diffusing lung capacity for carbon monoxide (DLCO) at follow-up was 72.02 (18.33)% predicted, with 66% of patients having DLCO<80% and 24% having DLCO<60%. CT scan showed persistent pulmonary infiltrates, fibrotic lesions, and emphysema in 33%, 25% and 6% of patients, respectively. Key variables associated with DLCO<60% were chronic lung disease (CLD) (OR: 1.86 (1.18-2.92)), duration of invasive mechanical ventilation (IMV) (OR: 1.56 (1.37-1.77)), age (OR [per-1-SD] (95%CI): 1.39 (1.18-1.63)), urea (OR: 1.16 (0.97-1.39)) and estimated glomerular filtration rate at ICU admission (OR: 0.88 (0.73-1.06)). Bacterial pneumonia (1.62 (1.11-2.35)) and duration of ventilation (NIMV (1.23 (1.06-1.42), IMV (1.21 (1.01-1.45)) and prone positioning (1.17 (0.98-1.39)) were associated with fibrotic lesions. CONCLUSION: Age and CLD, reflecting patients' baseline vulnerability, and markers of COVID-19 severity, such as duration of IMV and renal failure, were key factors associated with impaired DLCO and CT abnormalities.

A differential therapeutic consideration for use of corticosteroids according to established COVID-19 clinical phenotypes in critically ill patients.

OBJECTIVE: To determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes. DESIGN: A secondary analysis derived from multicenter, observational study. SETTING: Critical Care Units. PATIENTS: Adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. INTERVENTIONS: Corticosteroids vs. no corticosteroids. MAIN VARIABLES OF INTEREST: Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). We performed a multivariate analysis after propensity optimal full matching (PS) for whole population and weighted Cox regression (HR) and Fine-Gray analysis (sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. RESULTS: A total of 2017 patients were analyzed, 1171 (58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR: 1.0; 95% CI: 0.98-1.15). Corticosteroids were administered in 298/537 (55.5%) patients of "A" phenotype and their use was not associated with ICU mortality (HR=0.85 [0.55-1.33]). A total of 338/623 (54.2%) patients in "B" phenotype received corticosteroids. No effect of corticosteroids on ICU mortality was observed when HR was performed (0.72 [0.49-1.05]). Finally, 535/857 (62.4%) patients in "C" phenotype received corticosteroids. In this phenotype HR (0.75 [0.58-0.98]) and sHR (0.79 [0.63-0.98]) suggest a protective effect of corticosteroids on ICU mortality. CONCLUSION: Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate dose. Only patients with the highest inflammatory levels could benefit from steroid treatment.

A differential therapeutic consideration for use of corticosteroids according to established COVID-19 clinical phenotypes in critically ill patients Una consideración terapéutica diferencial para el uso de corticoesteroides en COVID-19 según los diferentes fenotipos clínicos establecidos en pacientes críticos

Objective To determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes. Design A secondary analysis derived from multicenter, observational study. Setting Critical Care Units. Patients Adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. Interventions Corticosteroids vs. no corticosteroids. Main variables of interest Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). We performed a multivariate analysis after propensity optimal full matching (PS) for whole population and weighted Cox regression (HR) and Fine-Gray analysis (sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. Results A total of 2017 patients were analyzed, 1171 (58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR: 1.0;95% CI: 0.98–1.15). Corticosteroids were administered in 298/537 (55.5%) patients of “A” phenotype and their use was not associated with ICU mortality (HR = 0.85 [0.55–1.33]). A total of 338/623 (54.2%) patients in “B” phenotype received corticosteroids. No effect of corticosteroids on ICU mortality was observed when HR was performed (0.72 [0.49–1.05]). Finally, 535/857 (62.4%) patients in “C” phenotype received corticosteroids. In this phenotype HR (0.75 [0.58–0.98]) and sHR (0.79 [0.63–0.98]) suggest a protective effect of corticosteroids on ICU mortality. Conclusion Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate dose. Only patients with the highest inflammatory levels could benefit from steroid treatment.

[Team-specific impacts of the corona pandemic on intensive care medicine personnel of a maximum care hospital]. / Teamspezifische Auswirkungen der Corona-Pandemie auf Mitarbeiter:innen der Internistischen Intensivmedizin eines Krankenhauses der Maximalversorgung.

The ongoing strain on personnel in the healthcare system during the COVID-19 pandemic is considerable and poses major emotional and psychological challenges for the personnel. In a team evaluation (physicians and nurses), team-specific stress, possible relief strategies, positive and negative experiences, and wishes for improvement of the situation in an intensive care unit were collected. While both occupational groups perceived equally high emotional stress intensities, nursing additionally perceived high stress intensities in the organizational and physical areas. Thus, the occupational group of nurses proves to be the most stressed by the COVID-19 pandemic. The findings presented here can be used to derive instructions for future actions.

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study.

Background: The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods: Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings: Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation: Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. Funding: ISCIII, UNESPA, CIBERES, FEDER, ESF.

RUXOLITINIB AS A TREATMENT STRATEGY FOR SARS-CoV-2 PNEUMONIA: CLINICAL EXPERIENCE IN A REAL-WORLD SETTING (preprint)

Introduction: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19 cases. Methods: We analysed the data obtained for an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The dose used was determined based on physician’s criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured. Results: A total of 287 patients administered ruxolitinib were reported at 22 sites in Mexico from March to June 2020; 80.8% received 5 mg BID and 19.16% received 10 mg BID ruxolitinib. At the beginning of treatment, 223 patients were on oxygen support, 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. There was a statistically significant improvement measured as a reduction by 2 points (initial 5.39 ± 0.93, final 3.67± 2.98, P value = 0.0001) on the 8-point ordinal scale. There were a total of 74 deaths. Serious adverse events were presented in 6.9% of the patients. Conclusion: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality.

Dexamethasone as risk-factor for ICU-acquired respiratory tract infections in severe COVID-19.

PURPOSE: Dexamethasone is the only drug that has consistently reduced mortality in patients with COVID-19, especially in patients needing oxygen or invasive mechanical ventilation. However, there is a growing concern about the relation of dexamethasone with the unprecedented rates of ICU-acquired respiratory tract infections (ICU-RTI) observed in patients with severe COVID-19. METHODS: This was a multicenter, prospective cohort study; conducted in ten countries in Latin America and Europe. We included patients older than 18 with confirmed SARS-CoV-2 requiring ICU admission. A multivariate logistic regression and propensity score matching (PSM) analysis was conducted to determine the relation between dexamethasone treatment and ICU-RTI. RESULTS: A total of 3777 patients were included. 2065 (54.7%) were treated with dexamethasone within the first 24 h of admission. After performing the PSM, patients treated with dexamethasone showed significantly higher proportions of VAP (282/1652 [17.1%] Vs. 218/1652 [13.2%], p = 0.014). Also, dexamethasone treatment was identified as an adjusted risk factor of ICU-RTI in the multivariate logistic regression model (OR 1.64; 95%CI: 1.37-1.97; p < 0.001). CONCLUSION: Patients treated with dexamethasone for severe COVID-19 had a higher risk of developing ICU-acquired respiratory tract infections after adjusting for days of invasive mechanical ventilation and ICU length of stay, suggesting a cautious use of this treatment.

ICU-Acquired Pneumonia Is Associated with Poor Health Post-COVID-19 Syndrome.

BACKGROUND: Some patients previously presenting with COVID-19 have been reported to develop persistent COVID-19 symptoms. While this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the incidence and factors associated with the characteristics of persistent COVID-19. On the other hand, these patients very often have intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence on poor health post-COVID 19 syndrome in ICU-discharged patients. METHODS: This prospective, multicentre, and observational study was carrid out across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge. RESULTS: A total of 1255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP). Patients requiring invasive mechanical ventilation had more persistent post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, development of ICUAP, and ARDS were independent factors for persistent poor health post-COVID-19. CONCLUSIONS: Persistent post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay, development of ICUAP, and ARDS all comprised independent factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-COVID-19.

Aspergillus Tracheobronchitis in COVID-19 ARDS Patients – A Cohort Study (preprint)

Background: Coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome patients are at risk for fungal infections, especially aspergillosis and mucormycosis. COVID-19-associated pulmonary aspergillosis (CAPA) is differentiated in a pulmonary form and Aspergillus tracheobronchitis (ATB). During the first wave of the pandemic, bronchoscopy for diagnosing Aspergillus superinfections was rarely performed in COVID-19 patients, so that detailed on data on ATB in CAPA patients is scarce. We analyzed prevalence and mortality of tracheobronchitis in patients with CAPA.Methods: We conducted a retrospective, single-centre study at the 14-bed intensive care unit (ICU) of the Department I of Internal Medicine of the University Hospital of Cologne, Germany from March 2020 to February 2021. CAPA patients were identified by twice weekly analysis of tracheal aspirates for Aspergillus growth, Aspergillus DNA (PCR) and galactomannan combined with serum galactomannan testing. In case of positive results, bronchoscopy with the examination of trachea and lower airways and bronchoalveolar lavage followed.Findings: A total of 69 COVID-19 patients were admitted to the ICU, with 17 patients developing probable CAPA. All CAPA patients received bronchoscopy resulting in a clinical diagnosis of tracheobronchitis in 8 patients with signs of tracheal lesions, pseudomembranes or vulnerable bloody trachea. Seven bronchoalveolar lavages revealed culture and eight PCR positivity for Aspergillus fumigatus. In 7 of 8 tracheobronchitis patients, bronchoalveolar lavage samples tested positive for galactomannan antigen optical density index of >0.5. The overall mortality of CAPA patients was 52.9% and the overall mortality of ATB patients was 75%.Interpretation: Our data indicate a substantial prevalence of tracheobronchitis in this single-center cohort of CAPA patients. To facilitate early diagnosis bronchoscopic tracheal examination is crucial as computed tomography lacks diagnostic accuracy to enable timely initiation of therapy.Funding Information: This work was in part supported by the German Registry of COVID-19 Autopsies (www.DeRegCOVID.ukaachen.de), funded by the Federal Ministry of Health (ZMVI1-2520COR201), and the project DEFEAT PANDEMICs, funded by the Federal Ministry of Education and Research (01KX2021).Declaration of Interests: PK reports grants or contracts from German Federal Ministry of Research and Education and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. SvS none. JGB reports scientific grants and travel expenses from Kite/Gilead outside the submitted work. FF has a clinician scientist position supported by the deans office, medical faculty, University of Cologne. JSG none. FP none. BB reports honoraria, travel expenses and advisory role from/for Astellas, Celgene, Johnson & Johnson, Kite/Gilead, MSD, Novartis, Pfizer, Takeda and financing of scientific research by Astellas, Celgene, Kite/Gilead, MSD and Takeda outside the submitted work. DAE received honoraria from Sanofi and TAKEDA outside the submitted work. ASV reports travel grants from Gilead Sciences outside the submitted work. OK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead and Pfizer and receipt of equipment, materials, drugs, medical writing, gifts or other services by Pfizer, MSD, Basilea, Gilead, Virotech and Wako Fujifilm outside the submitted work. PB none. MK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead, MSD and Pfizer outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al 344 Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley outside the submitted work.Ethics Approval Statement: Patients with CAPA were included in the FungiScope® global registry for emerging invasive fungal infections (https://www.clinicaltrials.gov; National Clinical Trials identifier NCT01731353), which was approved by the local ethics committee of the University of Cologne, Cologne, Germany (identifier 05-102).

Spanish Asthma Management Guidelines (GEMA) v.5.1. Highlights and Controversies

In this fifth phase of development, the contents of the Spanish Asthma Management Guidelines (GEMA), which include versions 5.0 and 5.1, have undergone a thorough review. The aim here is to set the main changes in context. These could be summarized as follows: DIAGNOSIS: new FENO cut-off and severity classification based on treatment needed to maintain control;INTERMITTENT ASTHMA: a more restrictive concept and treatment extended to include a glucocorticoid/adrenergic combination as needed;MILD ASTHMA: glucocorticoid/adrenergic therapy as needed as an alternative in case of low therapeutic adherence to conventional fixed-dose steroids;SEVERE ASTHMA: readjustment of phenotypes, incorporation of triple therapy in a single inhaler, and criteria for selection of a biologic in severe uncontrolled asthma;OTHERS: specific scoring in childhood asthma, incorporation of certain organizational aspects (care circuits, asthma units, telemedicine), new sections on COVID-19 and nasal polyposis. Resumen La quinta fase de la Guía Española para el Manejo del Asma (GEMA) que incluye las versiones 5.0 y 5.1, ha efectuado una profunda revisión de su contenido. El presente texto tiene como objetivo contextualizar los principales cambios. Estos se podrían resumir en: DIAGNÓSTICO: nuevo punto de corte de FENO y clasificación de gravedad basada en el tratamiento necesario para mantener el control;ASMA INTERMITENTE: concepto más restrictivo y tratamiento ampliado a combinación de glucocorticoide/adrenérgico a demanda;ASMA LEVE: tratamiento con glucocorticoide/adrenérgico a demanda como alternativa si baja adhesión terapéutica a esteroide fijo clásico;ASMA GRAVE: reajuste de los fenotipos, incorporación de la triple terapia en un solo inhalador y criterios para la selección del fármaco biológico en asma grave no controlada;OTROS: puntualizaciones concretas en asma infantil, incorporación de determinados aspectos organizativos (flujos entre niveles asistenciales, unidades de asma, telemedicina), nuevas secciones de COVID-19 y de poliposis nasal.

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients.

BACKGROUND: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. METHODS: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. RESULTS: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). CONCLUSIONS: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.

ICU-Acquired Pneumonia is a Risk Factor of a Poor Health Post-Covid-19 Syndrome (preprint)

Background: . Some patients who had previously presented with COVID-19 have been reported to develop persistent COVID-19 symptoms. Whilst this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the prevalence and risk factors and characteristics of persistent COVID_19 . On other hand these patients have very often intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence in the poor health post-Covid 19 syndrome in ICU discharged patients Methods: This prospective, multicentre and observational study was done across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge. Results: A total of 1,255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP) Patients requiring invasive mechanical ventilation had persistent, post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, and development of ICUAP were independent risk factors for persistent poor health post-COVID-19. Conclusions: : Persistent, post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay and the onset of ICUAP comprised all independent risk factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-Covid 19

E-learning in "innovation, creativity and entrepreneur ship": Exploring the new opportunities and challenges of technologies

Keywords: Innovation, Creativity, Entrepreneurship, E-learning, Teaching ABSTRACT Companies and society demand professionals be able to provide creative solutions with added value as well as to implement them in order to face the arising challenges in the increasingly dynamic environment. In this context, the School of Industrial Engineering (ETSII) at Polytechnic University of Valencia (UPV) is aware of the opportunities offered by new information and communication technologies to support teachers in this task while enhancing students' generic outcomes. Alhabeeb & Rowley (2018) defines e-learning as: "an approach to teaching and learning, representing all or part of the educational model applied, that is based on the use of electronic media and devices as tools for improving access to training, communication and interaction and that facilitates the adoption of new ways of understanding and developing learning"(p. 1). Ghiringhelly and Quacquarelly (2003) considered the e-learning design a complex process integrated by four stages: identification of training objectives, detection of training needs, creation of design team and selection of learning content.

COVID-19 and intracranial hemorrhage: a multicenter case series, systematic review and pooled analysis (preprint)

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts on hemostasis and microvasculature. Correspondingly, antithrombotic therapy is frequently used for prophylaxis or treatment of thromboembolic complications as well as in the context of extracorporeal membrane oxygenation (ECMO). However, reports of intracranial hemorrhage (ICH) associated with Coronavirus disease 2019 (COVID-19) have also emerged. In the light of the dilemma between thromboembolic and hemorrhagic complications, we sought to systematically investigate incidence, mortality, radiological subtypes and clinical characteristics of ICH in COVID-19 patients.Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. Furthermore, we performed a pooled analysis including a prospectively collected cohort of critically ill COVID-19 patients with ICH as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive care of COVID-19).Results: Our literature review revealed a total of 217 citations. After selection process, 79 studies and a total of 477 patients were included. Median age was 58.8 years (95% CI 54.8 years-62.9 years; I2 = 85,6%). 23.3% patients experienced critical stage of COVID-19 (95% CI 8.9% − 61.2%, I2 = 53.8%). 62.7% patients were on anticoagulation (95% CI 38.2% − 103.0%, I2 = 82,6%), and 27.5% patients received ECMO (95% CI 5.8% − 130.2%, I2 = 92.7%). Microbleeds (51.1%, 95% CI 31.1% − 84.2%, I2 = 85.1%), subarachnoid hemorrhage (SAH) (26.6%, 95% CI 16.8% − 42.0%, I2 = 61.2%) and intraparenchymal hemorrhage (IPH) (33.7%, 95% CI 23.3% − 48.8%, I2 = 63.7%) were most frequently documented as ICH subtypes. Incidence was at 0.85% (95% CI 0.36%-1.99%; I2 = 97.5%) and mortality at 52.18% (95% CI 40.40%-67.39%; I2 = 51.7%), respectively.Conclusion: ICH in COVID-19 patients is rare, but has a very poor prognosis. Different subtypes of ICH seen in COVID-19 support the assumption of heterogenous and multifactorial pathomechanisms contributing to ICH in COVID-19. Further data and pathophysiological insights are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.

Deciding between cash-based and in-kind distributions during humanitarian emergencies

PurposeThe purpose of this paper is to provide an analytical model to decide between cash-based and in-kind distributions during emergency responses considering the needs of beneficiaries and market conditions. To allow the switch between modalities, a preparedness framework for humanitarian organizations (HOs) is provided.Design/methodology/approachA mathematical model is proposed to help humanitarian responders make quantitative decisions on the type of programs to implement in emergency responses. The model was applied to a field response by an international HO during the COVID-19 emergency in Colombia.FindingsCash-based and in-kind distributions are not mutually exclusive response modalities during emergencies, and the real needs of beneficiaries and market effects should be included in the modality selection decision to improve program effectiveness.Research limitations/implicationsThe research is focused on short-term immediate response to emergencies;the proposed model assumes favorable market conditions and limits the aid options to direct in-kind and multipurpose cash assistance, excluding other types of cash transfers.Practical implicationsThe research outlines practical preconditions to operationalize switching between programs during an emergency. The study provides evidence that HOs should consider dynamics decision tools to select aid modalities and evaluate their response depending on market conditions.Social implicationsConsidering aid modality as a dynamic decision and including the needs from beneficiaries in the choice can have profound impact in the dignifying of humanitarian response to emergencies.Originality/valueThe quantitative model to decide between aid modalities is a novel approach to include beneficiaries' needs and market dynamics into humanitarian supply chain research. The preparedness framework closes the gap between the emergency preparedness literature and the operational constraints that organizations face for fast program implementation.