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Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19.Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death.IP-10 had the best prognostic performance: baseline concentrations 2000 pg/ml or higher predicted equally well to suPAR (sensitivity 85.0 %; negative predictive value 96.6 %). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000 pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations.IP-10 concentrations of 2,000 pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14 days from hospital admission for COVID-19 and they may guide anakinra treatment.gov, NCT04680949 and NCT04357366.

Objective: The clinical profile, management and outcome of infective endocarditis (IE) may be influenced by socioeconomic issues. Methods: A nationwide prospective study evaluated IE during the era of deep economic crisis in Greece. Epidemiological data and factors associated with 60-day mortality were analyzed through descriptive statistics, logistic and Cox-regression models. Results: Among 224 patients (male 72.3%, mean age 62.4 years), Staphylococcus aureus (n = 62; methicillin-resistant S. aureus (MRSA) 33.8%) predominated in the young without impact on mortality (p = 0.593), whilst Enterococci (n = 36) predominated in the elderly. Complications of IE were associated with mortality: heart failure [OR 2.415 (95% CI: 1.159–5.029), p = 0.019], stroke [OR 3.206 (95% CI: 1.190–8.632), p = 0.018] and acute kidney injury [OR 2.283 (95% CI: 1.085–4.805), p = 0.029]. A 60-day survival benefit was solely related to cardiac surgery for IE during hospitalization [HR 0.386 (95% CI: 0.165–0.903), p = 0.028] and compliance with antimicrobial treatment guidelines [HR 0.487 (95% CI: 0.259–0.916), p = 0.026]. Compared with a previous country cohort study, history of rheumatic fever and native valve predisposition had declined, whilst underlying renal disease and right-sided IE had increased (p < 0.0001); HIV infection had emerged (p = 0.002). No difference in rates of surgery and outcome was assessed. Conclusions: A country-wide survey of IE highlighted emergence of HIV, right-sided IE and predominance of MRSA in the youth during a severe socioeconomic crisis. Compliance with treatment guidelines promoted survival.

Contains fulltext : 237989.pdf (Publisher’s version ) (Closed access) BACKGROUND: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO(2)/FiO(2)), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO(2)/FiO(2). In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING: Sobi.

Early recognition of risk and start of treatment may improve unfavorable outcome of COVID-19. In the SAVE-MORE double-blind randomized trial, 594 patients with pneumonia without respiratory dysfunction at risk as defined by plasma suPAR (soluble urokinase plasminogen activator receptor) ≥ 6 ng/ml were 1:2 randomized to subcutaneous placebo or 100 mg anakinra once daily for 10 days; 85.9% were co-administered dexamethasone. After 28 days, anakinra-treated patients were distributed to lower strata of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) (adjusted odds ratio-OR 0.36; 95%CI 0.26–0.50; P

BackgroundIn a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure.MethodsIn the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Progression Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints.ResultsAnakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; PConclusionsEarly start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia.(Sponsored by the Hellenic Institute for the Study of SepsisClinicalTrials.govidentifier,NCT04680949)

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml−1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26–0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P, The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1α/β inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor.

Summary Healthcare workers (HCWs) have been recognized as a high-risk group for infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This study estimated their risk of infection based on hospital characteristics. Factors significantly associated with increased risk for SARS-CoV-2 infection were: working in a non-referral hospital compared with a coronavirus disease 2019 (COVID-19) referral hospital, working in a hospital with a high number of employees, and working in a hospital with an increased number of patients with COVID-19. This study revealed gaps in infection control in the non-referral hospitals. There is an urgent need for continuous training in infection control practices. Compliance of HCWs with the use of personal protective equipment should also be addressed.

COVID-19 pandemic caused a major crisis, affecting and straining health care systems, including some very advanced ones. The pandemic may have also indirectly affected access to health care for patients with other conditions, not related to COVID-19, even in countries not overwhelmed by an outbreak.We analyzed and compared visits to the emergency room (ER) department during the same calendar period of 2019 and 2020 (from March 1 to March 31 of each year) in our hospital, a medium size, tertiary center, located in the center of Athens, which is not a referral center for COVID-19.Total ER visits were reduced by 42.3% and the number of those requiring hospitalization by 34.8%. This reduction was driven by lower numbers of visits for low risk, non-specific symptoms and causes. However, there was a significant decrease in admissions for cardiovascular symptoms and complications (chest pain of cardiac origin, acute coronary syndromes, and stroke) by 39.7% and for suspected or confirmed GI hemorrhage by 54.7%. Importantly, number of ER visits for infections remained unchanged, as well as the number of patients that required hospitalization for infection management; only few patients were diagnosed with COVID-19.During the initial period of the pandemic and lock-down in Greece, there was a major decrease in the patients visiting ER department, including decrease in the numbers of admissions for cardiovascular symptoms and complications. These observations may have implications for the management of non-COVID-19 diseases during the pandemic.

One hundred and fifty-seven patients undergoing high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) for hematopoietic malignancies and solid tumors were randomly assigned to receive (Group A) or not (Group B) prophylaxis with ciprofloxacin, orally, and vancomycin, intravenously. Prophylactic antibiotics were given from day 0 until resolution of neutropenia or the appearance of a febrile event. Furthermore, patients in both groups received once a day fluconazole, orally. The primary end-point of our study was the incidence of neutropenic febrile episodes attributed to infection. One hundred and twelve (71.3%) patients developed neutropenic fever, 50 (56.2%) in Group A and 62 (91.2%) in Group B (P < 0.001) with the majority (82%) of patients developing fever of unknown origin. Patients on prophylactic antibiotics had a significantly lower rate of bacteremias (5.6%) than did those randomized to no prophylaxis (29.4%) (P = 0.005) and, when developing neutropenic fever, they had a lower probability of response to first-line empirical antibiotics (P = 0.025). Prophylactic administration of ciprofloxacin and vancomycin reduced the incidence of neutropenic fever in patients receiving HDT with ASCT, however, without affecting the total interval of hospitalization, time to engraftment, or all-cause mortality. Therefore, our results do not support the use of antibiotic prophylaxis for patients undergoing HDT and ASCT.

Background. Influenza is associated with an increased risk for serious illness, hospitalization, and mortality in infants aged

One hundred and fifty-seven patients undergoing high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) for hematopoietic malignancies and solid tumors were randomly assigned to receive (Group A) or not (Group B) prophylaxis with ciprofloxacin, orally, and vancomycin, intravenously. Prophylactic antibiotics were given from day 0 until resolution of neutropenia or the appearance of a febrile event. Furthermore, patients in both groups received once a day fluconazole, orally. The primary end-point of our study was the incidence of neutropenic febrile episodes attributed to infection. One hundred and twelve (71.3%) patients developed neutropenic fever, 50 (56.2%) in Group A and 62 (91.2%) in Group B (P < 0.001) with the majority (82%) of patients developing fever of unknown origin. Patients on prophylactic antibiotics had a significantly lower rate of bacteremias (5.6%) than did those randomized to no prophylaxis (29.4%) (P = 0.005) and, when developing neutropenic fever, they had a lower probability of response to first-line empirical antibiotics (P = 0.025). Prophylactic administration of ciprofloxacin and vancomycin reduced the incidence of neutropenic fever in patients receiving HOT with ASCT, however, without affecting the total interval of hospitalization, time to engraftment, or all-cause mortality. Therefore, our results do not support the use of antibiotic prophylaxis for patients undergoing HOT and ASCT. Am. J. Hematol. 85:863-867, 2010. (C) 2010 Wiley-Liss, Inc.

Multiple Myeloma (MM) is a disease of the elderly and due to the aging population an increasing number of patients are diagnosed at the age ≥80 year. The management of these octogenarians is challenging due to their frailty as a result of co-morbidities and of age-related deterioration of organ function (lung, renal, cardiac). Indeed, age ≥80 year alone is a sufficient parameter to define frailty, according to IMWG recommendations. Thus, most octogenarians are not eligible and are not recruited in clinical trials. The aim of our study was to analyze the disease characteristics and treatment outcomes of patients ≥80 years of age. All patients with symptomatic MM since 1994, who received at least one dose of any therapy and were followed in our center (University of Athens, Greece) were included in the analysis. Among 610 consecutive patients, 84 (14%) were ≥80 years of age. During these 20 years, there was a steady increase in the proportion of patients ≥80 years who were treated for MM (10% during the 1994-1999 period, 12% during 2000-2005, 14% during 2006-2010 and 16% after 2011). Compared to patients ≤65 years and those 66-79 years, octogenarians had more often moderate or severe renal impairment (p Patients ≤65 years received more often bortezomib-based regimens upfront (61% vs 15% vs 11% respectively, p The median overall survival (OS) was 66% at 5 years for patients ≤65 years, 46 months for those 66-79 years and only 19.5 months for octogenarians (p In conclusion, myeloma patients ≥80 years present with poor prognostic features, which are probably related to non-MM related conditions, since high risk MM features (such as adverse cytogenetics) are less common. The management of octogenarians should take into account not only myeloma but also their general condition. A comprehensive geriatric assessment should routinely be performed in these patients, in order to identify those most vulnerable and those most likely to tolerate and benefit from novel therapies. Disclosures No relevant conflicts of interest to declare.

Growth differentiation factor-15 (GDF-15) is a member of the TGF-beta family, which is involved in several pathological conditions, including inflammation, cancer, cardiovascular, pulmonary and renal diseases. GDF-15 has prognostic value in patients with cardiovascular disorders and adds prognostic information to conventional prognostic factors, such as NT-proBNP and high-sensitivity troponin (hs-TnT). Cardiac involvement is the most important determinant of prognosis in patients with AL amyloidosis and cardiac biomarkers have major prognostic importance in AL. The aim of the study was to explore the value of GDF-15 in patients with AL amyloidosis. We measured the circulating levels of GDF-15, NT-proBNP and hs-TnT in 77 patients with newly diagnosed AL amyloidosis, before and 3 months post frontline treatment. GDF-15 was measured by a novel pre-commercial immunoassay (Roche Diagnostics). Patients' median age was 68 years; most patients had cardiac (61%) or renal involvement (74%); 61% had NT-proBNP >1284 pg/ml and 46% had hsTnT>54 ng/ml. Median eGFR was 57 ml/min/1.73m2, 52% had eGFR 1200 pg/ml (the upper limit of normal for individuals without cardiovascular disease). GDF-15 correlated with NT-proBNP (r=0.538, p7575 pg/ml) had a very poor outcome (median overall survival (OS) 3 months) compared to patients with GDF-15 levels below the upper quartile (p=0.01; see the Figure). Among other cardiac markers, hs-TnT >54 ng/ml (12 vs >48 months, p=0.001) and NT-proBNP >1284 pg/ml (11 vs >48 months, p We also evaluated changes in the levels of GDF-15, NT-proBNP and hs-TnT in patients who received lenalidomide after 3 months of treatment. In these patients NT-proBNP often increases without obvious deterioration of cardiac function, thus complicating the assessment of cardiac response early, during the course of therapy. GDF-15 levels did not change significantly either in patients with hematological response (p=0.998) or those without hematological response (p=0.774). However, NT-proBNP levels increased substantially both in those with hematological response (p=0.05) and in those without hematological responses (p=0.013). Similarly, hs-TnT levels increased in non-responders (p=0.006) and did not change in patients with hematological response (p=0.251). As GDF-15 reflects heart and renal defects, we further evaluated whether GDF-15 could be associated with the risk of progression to ESRD and need for dialysis. Using ROC analysis, GDF-15 >median was identified to better discriminate patients which had a shorter time to dialysis (29 months vs not reached, p=0.001, see the Figure; with 38% vs. 8% progressing to ESRD, respectively). eGFR< 60 ml/min/m2 was also a strong predictor of ESRD (p=0.004). However, in multivariate analysis which included GDF-15 >median, eGFR 5 g/day, only GDF-15 was independently associated with a higher risk of ESRD requiring dialysis (HR: 4.25, 95% CI 1.01-18, p=0.045). In conclusion, GDF-15 is a novel biomarker with prognostic implications for different outcomes in patients with AL; it is associated with a high risk of early death, with OS and also with renal outcome. More importantly GDF-15 adds prognostic information independent of the traditional cardiac biomarkers and thus, its measurement in larger series of patients is recommended. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Severe renal impairment (RI) in MM patients is a medical emergency. Immediate antimyeloma therapy and appropriate supportive measures are needed because these patients are at high risk for early death and other complications associated with their renal dysfunction. Antimyeloma therapy may improve renal function in a significant proportion of patients and the choice of treatment may also be guided by the degree of RI. For the evaluation of the recovery of renal function IMWG has proposed specific criteria (Dimopoulos et al, JCO 2010), which are based on changes of calculated GFR. A new formula for the estimation of GFR has been used by nephrologists as a more accurate method of renal function assessment (CKD-EPI formula). In order to evaluate the currently available IMWG criteria, by using the new CKD-EPI formula, we assessed renal response in patients with newly diagnosed MM who presented with severe RI. We also evaluated simplified criteria for renal response and compared patient outcomes with the IMWG criteria. We analyzed the outcomes of 105 consecutive patients who presented with severe RI (eGFR Most patients (68%) were >65 years of age; 36% were >75 years, while 92% had ISS-3 disease. Primary therapy with bortezomib-based regimens was given in 38% of patients, 43% received IMiD-based therapy (34% thalidomide- and 9% lenalidomide-based) and 19% high dose dexamethasone and conventional chemotherapy (CC) regimens. When GFR was calculated by the MDRD formula then 51% had stage 4 and 49% had stage 5 RI, while by the CKD-EPI formula, 49% had stage 4 and 51% stage 5 RI. Thus, RI stage change between stage 4 & 5 occurred in only 2% of patients with the use of CKD-EPI vs. MDRD equation. According to the IMWG criteria, with GFR calculated by the MDRD formula, 36 (34%) patients achieved CRrenal, 8 (7.5%) PRrenal and 33 (31%) MRrenal. When GFR was calculated by the CKD-EPI formula, then 35 (33%) patients achieved a CRrenal, 8 (7.5%) PRrenal and 34 (32%) MRrenal; only in 3 patients (3%) there was a discrepancy in the quality of renal response between the two equations. Major renal response (CR+PRrenal) was more frequent with bortezomib (57.5% vs. 34% for IMiDs vs. 26% for high dose Dexa+CC, p=0.034). When we applied the proposed simplified renal response criteria, then 47 (45%) patients were considered responders; responses were more frequent in patients treated with bortezomib (62.5% vs. 35% for IMiDs vs. 32% for high dose Dexa+CC, p=0.016). The median survival for all patients who presented with severe RI was 31 months (95% CI 16-46). Early death (65 years (p=0.022). The median survival of patients who presented with stage 4 vs. stage 5 RI was similar (31 vs. 38 months, p=0.230). For patients who survived at least 2 months, the median survival of the patients who achieved ≥PRrenal was 53 months (by MDRD and CKD-EPI) vs. 43 months for patients who had minor renal response vs. 42 months for patients who did not have a renal response, by the IMWG criteria. Among patients who survived at least 2 months, median survival of the responders according to the proposed simplified renal response criteria was 53 vs. 44 of the non responders (p=0.3). There was no difference in the performance of either criteria for overall survival, risk of death at 6 or 12 months, with either of the formulas for eGFR calculation. We conclude that in unselected MM patients with severe RI, the criteria for the improvement of renal function can be simplified without any significant change in their prognostic significance. The GFR calculated by the CKD-EPI can also be used for the assessment of renal response in patients with MM. Disclosures: No relevant conflicts of interest to declare.

Abstract 3334 Poster Board III-222 High dose melphalan (HDM) with autologous stem cell transplantation (ASCT) is the standard of care for eligible patients with multiple myeloma (MM) aged up to 65 years. This procedure is accompanied by a high incidence of neutropenic fever and infections that represent a leading cause of morbidity in these patients. The aim of this study was to evaluate the impact of prophylactic antibiotic administration after ASCT on the rate of infections and neutropenic fever. As of June 2009, 126 MM patients who underwent ASCT in our institution were randomized to receive or not prophylactic antibiotics post-ASCT. The prophylactic antibiotic regimen included IV vancomycin at a dose of 1000 mg once daily and ciprofloxacin at a dose of 500 mg, PO, twice daily. The administration of prophylactic antibiotics was started on day 0 of ASCT and continued until resolution of neutropenia or until the occurrence of a febrile event. In addition, all patients, irrespective of randomization, received fluconazole 200 mg, PO, once daily, and valacyclovir 500 mg, PO, once daily. G-CSF was given to all patients until resolution of neutropenia. When temperature exceeded 38°C for more than 1 hour, peripheral blood and urine samples were collected for microbiologic cultures, a chest X-ray was performed and empirical antibiotic treatment with IV wide spectrum antibiotics including amikacin, ceftazidime and therapeutic dose of vancomycin was started. This empirical therapy was later modified individually, according to cultures and sensitivity data. If patient remained febrile for 3-5 days after this initial treatment, a second-line regimen consisting of a carbapenem with a glycopeptide in the majority of cases was administered, until fever resolution. In the case of a proven or suspected fungal or viral infection, appropriate antifungal or antiviral therapy was administered. Sixty-nine (54%) patients were randomized to receive antibiotic prophylaxis. These patients had a significantly lower incidence of neutropenic fever post-ASCT compared to those who received only supportive care (58% versus 92%; p0.5×109/L: 9.6 versus 10.7, p25×109/L: 9.7 versus 11.8, p Disclosures No relevant conflicts of interest to declare.