Optimierte 25(OH)-Vitamin D-Serumspiegel für die Antikörper-abhängige NK Zell-Zytotoxizität gegen B Zell-Lymphome und Mamma-Karzinome

Sowohl bei B-Zell-Non-Hodgkin-Lymphomen (B-NHL) als auch beim Mamma-Karzinom ist ein höherer 25-Hydroxyvitamin D-Spiegel im Serum (25(OH)D) mit einem besseren Überleben assoziiert. Zudem profitieren Patienten auch prospektiv von einer Vitamin D (VD)-Substitution. Bei den B-NHL, die standardmäßig mit dem therapeutischen Antikörper (AK) Rituximab behandelt werden, konnte gezeigt werden, dass dieser Effekt zumindest teilweise auf einer gesteigerten Antikörper-abhängigen zellulären Zytotoxizität (ADCC) von Makrophagen beruht. Diese Arbeit hatte das Ziel zu prüfen, ob auch NK Zellen durch eine Substitution in ihrer ADCC verstärkt werden, ob sich dies auch für den Anti-HER2-AK Trastuzumab im Kontext des Mamma-Karzinoms reproduzieren lässt und bei welchen 25(OH)D-Spiegeln die ADCC-Steigerung, sofern vorhanden, ihr Optimum erreicht. Hierfür wurden 20 gesunde Probanden (10 Frauen, 10 Männer) mit 25(OH)D-Insuffizienz (< 20 ng/ml i.S.) rekrutiert und in vivo entlang des Referenzwerterahmens auf 30, 65 und 90 ng/ml substituiert. Auf allen vier Stufen wurden NK-Zellen isoliert und mit Zellen der Burkitt-Lymphom-Zelllinie Daudi und den Anti-CD20-AK Rituximab (RTX) respektive Obinutuzumab (GA101), sowie mit Mamma-Karzinom-Zellen der ZR-75-1-Linie und Trastuzumab, inkubiert. Anschließend erfolgte die Quantifizierung der Tumorlyse mithilfe eines photochemischen Laktatdehydrogenase-Nachweises. Durch die Substitution kam es zu keiner signifikanten Veränderung der ADCC gegen ZR-75-1. Demgegenüber konnte für die Anti-CD20-AK ein Effekt nachgewiesen werden, der jedoch auf die weiblichen Probanden beschränkt war. Hier führte die Substitution vom Insuffizienzbereich (Mittleres 25(OH)D ± Standardabweichung: 10,1 ± 5,6 ng/ml) auf mittlere Serumspiegel (66,4 ± 3,4 ng/ml) zu einer Steigerung der medianen Tumorlyse von 22,8 % auf 31,7 % (1 µg/ml RTX; p=0,016) bzw. von 33,4 % auf 44,0 % (1 µg/ml GA101; p=0,016). Die Substitution auf lediglich niedrig-normale VD3-Serumwerte (31,4 ± 4,0 ng/ml) zeigte hingegen keine signifikante Steigerung der Daudi-Lyse. Die Lyse bei hoch-normalen Serumspiegeln (92,6 ± 12,2 ng/ml) war im Vergleich zu der mittlerer VD3-Werte jedoch wieder signifikant schwächer mit 21,8 % gegenüber 31,7 % (1 µg/ml RTX; p=0,037) bzw. 37,2 % gegenüber 44,0 % (1 µg/ml GA101; p=0,037). Es konnte gezeigt werden, dass NK-Zellen von in vivo VD3-substituierten Frauen in vitro verstärkt zur ADCC mit RTX und GA101 befähigt sind. Dieser Effekt zeigt sich am stärksten bei einem mittleren 25(OH)D-Niveau von ca. 65 ng/ml. Wir empfehlen diesen Serumspiegel daher als Zielwert für künftige Interventionsstudien, die den Effekt von VD auf das Tumorüberleben bei B-NHL untersuchen. Zudem empfehlen wir, den 25(OH)D-Serumspiegel auch während der laufenden Therapie zu kontrollieren.For both B cell Non-Hodgkin Lymphoma (B-NHL) and breast cancer it was shown that higher 25-Hydroxyvitamin D (25(OH)D) serum levels are associated with better survival. Furthermore, patients also benefit prospectively from vitamin D (VD) substitution. This effect on B-NHL, usually treated with chemotherapy and the monoclonal therapeutic antibody (AB) rituximab, is at least partly explicable by a VD-mediated improvement in the antibody-dependent cellular cytotoxicity (ADCC) of macrophages. The aim of this study was to test whether VD improves ADCC of natural killer (NK) cells as well and whether this also applies to the anti HER2 AB Trastuzumab in the context of breast cancer. The paramount aim, however, was to determine the 25(OH)D level yielding maximum ADCC increase – if existing. Therefor, 20 healthy subjects (10 females, 10 males) with VD insufficiency (serum 25(OH)D < 20 ng/ml) were recruited and substituted along the reference range to the target values 30, 65 and 90 ng/ml. On all four levels a blood sample was drawn, NK cells were isolated and subsequently incubated with cells of the Burkitt’s lymphoma cell line Daudi and the anti CD20 ABs Rituximab (RTX) and Obinutuzumab (GA101) respectively and with breast cancer cells of the ZR-75-1 lineage together with the anti HER2 AB Trastuzumab. Tumor cell lysis was quantified using photochemical detection of lactate dehydrogenase. VD substitution led to no significant change in the ADCC against ZR-75-1. In contrast, for the anti CD20 ABs there was an effect, but it was limited to the female subjects. Substitution from insufficiency (mean 25(OH)D ± standard deviation: 10.1 ± 5.6 ng/ml) to intermediate levels (66.4 + 3.4 ng/ml) increased the median tumor lysis from 22.8 % to 31.7 % (1 µg/ml RTX; p=0,016) or 33.4 % to 44.0 % (1 µg/ml GA101; p=0,016) respectively. In contrast, substitution to low-normal 25(OH)D values (31.4 ± 4.0 ng/ml) yielded no significant increase in Daudi lysis. Compared to mid-range 25(OH)D level, lysis on high-normal level (92.6 ± 12.2 ng/ml) showed a significant decrease from 31.7 % to 21.8% (1 µg/ml RTX; p=0,037) or 44.0 % to 37.2 % (1 µg/ml GA101; p=0,037), respectively. These results suggest that NK cells of women in vivo substituted with VD show stronger cytotoxicity in vitro with RTX and GA101. This effect was strongest on 25(OH)D levels around 65 ng/ml. We recommend this serum level as the target value for future clinical studies assessing the impact of VD substitution on the outcome of B-NHL treated with ADCC-mediating antibodies like RTX or GA101. Furthermore, these studies should determine 25(OH)D serum level not only on prior to inclusion but also during therapy

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Association of Country Income Level With the Characteristics and Outcomes of Critically Ill Patients Hospitalized With Acute Kidney Injury and COVID-19

Introduction: Acute kidney injury (AKI) has been identified as one of the most common and significant problems in hospitalized patients with COVID-19. However, studies examining the relationship between COVID-19 and AKI in low- and low-middle income countries (LLMIC) are lacking. Given that AKI is known to carry a higher mortality rate in these countries, it is important to understand differences in this population. Methods: This prospective, observational study examines the AKI incidence and characteristics of 32,210 patients with COVID-19 from 49 countries across all income levels who were admitted to an intensive care unit during their hospital stay. Results: Among patients with COVID-19 admitted to the intensive care unit, AKI incidence was highest in patients in LLMIC, followed by patients in upper-middle income countries (UMIC) and high-income countries (HIC) (53%, 38%, and 30%, respectively), whereas dialysis rates were lowest among patients with AKI from LLMIC and highest among those from HIC (27% vs. 45%). Patients with AKI in LLMIC had the largest proportion of community-acquired AKI (CA-AKI) and highest rate of in-hospital death (79% vs. 54% in HIC and 66% in UMIC). The association between AKI, being from LLMIC and in-hospital death persisted even after adjusting for disease severity. Conclusions: AKI is a particularly devastating complication of COVID-19 among patients from poorer nations where the gaps in accessibility and quality of healthcare delivery have a major impact on patient outcomes

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

Background: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25–1.30]). Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Respiratory support in patients with severe COVID-19 in the International Severe Acute Respiratory and Emerging Infection (ISARIC) COVID-19 study: a prospective, multinational, observational study

International audienceBackground: Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs).Methods: This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support.Results: A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83-7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97-2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14-1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25-1.30]).Conclusions: In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable

Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low- and middle-income countries in an international registry

Background: COVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs). Objectives: The main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality. Methods: Adult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort received care, such as admission to the intensive care unit, mechanical ventilation, or inotropes or vasopressors; the basic-treatment cohort did not receive any of these interventions. Results: The study population included 495,682 patients from 52 countries, with 63% from LMICs and 85% in the basic treatment cohort. The frequency of coagulopathy complications was higher in HICs (0.76%-3.4%) than in LMICs (0.09%-1.22%). Complications were more frequent in the advanced-treatment cohort than in the basic-treatment cohort. Coagulopathy complications were associated with increased in-hospital mortality (odds ratio, 1.58; 95% CI, 1.52-1.64). The increased mortality associated with these complications was higher in LMICs (58.5%) than in HICs (35.4%). After controlling for coagulopathy complications, treatment intensity, and multiple other factors, the mortality was higher among patients in LMICs than among patients in HICs (odds ratio, 1.45; 95% CI, 1.39-1.51). Conclusion: In a large, international registry of patients hospitalized for COVID-19, coagulopathy complications were more frequent in HICs than in LMICs (developing countries). Increased mortality associated with coagulopathy complications was of a greater magnitude among patients in LMICs. Additional research is needed regarding timely diagnosis of and intervention for coagulation derangements associated with COVID-19, particularly for limited-resource settings