Low in‑hospital mortality rate in patients with COVID‑19 receiving thromboprophylaxis: data from the multicentre observational START‑COVID Register

Abstract COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease,and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years

Studio sulle isoforme di gamma-glutamiltransferasi (GGT) nei pazienti sottoposti a trapianto allogenico ed autologo di cellule staminali emopoietiche

Il trapianto di cellule staminali emopoietiche (CSE) è una procedura medica largamente impiegata al giorno d’oggi nel trattamento di molte patologie ematologiche, sia neoplastiche che non neoplastiche. Le due principali tipologie di trapianto vengono definite “allogenico” ed “autologo”, a seconda che le cellule staminali emopoietiche, reinfuse dopo opportune terapie di condizionamento, derivino rispettivamente da un donatore sano o dal paziente stesso. La GVHD (Graft-versus-host disease, “malattia del trapianto contro l’ospite”) è la principale complicanza immunologica del trapianto allogenico, ed è caratterizzata da una reazione di cellule immunocompetenti del donatore contro tessuti del ricevente. Le manifestazioni di tale affezione possono colpire diversi tessuti e organi, come cute, fegato, intestino, stomaco, occhio e cavo orale. Fino ad oggi sono stati studiati molti biomarcatori diagnostici per la GVHD; lo studio delle isoforme della gamma-glutammiltranferasi (GGT) come potenziale biomarcatore della GVHD è stato l’oggetto di questo studio. Abbiamo analizzato un totale di 65 pazienti sottoposti a trapianto di cellule staminali emopoietiche (51 trapianti allogenici e 14 autologhi) tra il 2008 e il 2013 presso la U.O. Ematologia Universitaria di Pisa, Centro Trapianti di Midollo. Per ciascun paziente abbiamo raccolto campioni di sangue venoso a tempi prestabiliti, a partire dal giorno d’inizio della chemioterapia di condizionamento. Nella maggior parte dei soggetti analizzati, soprattutto gli allo-trapiantati, abbiamo osservato un incremento della GGT totale. La frazione con maggiore incremento percentuale rispetto al valore basale risulta essere la m-GGT, caratteristica che distingue il nostro gruppo di studio dalla popolazione generale dei soggetti sani, dove la frazione prevalente è la f-GGT, e da altri gruppi di soggetti malati, ad esempio affetti da malattie epatiche, dove prevalgono le forme b-GGT e s-GGT. Si è poi valutato l’andamento delle frazioni di GGT nei pazienti che sviluppano GVHD, sia acuta che cronica, in seguito a trapianto allogenico. Abbiamo osservato come, soprattutto nei pazienti trattati con condizionamento mieloablativo, ci sia un aumento delle GGT totale al giorno +7 dal trapianto, correlato alla tossicità farmacologica, e come poi nel gruppo di pazienti che sviluppano GVHD si assiste ad un secondo picco di aumento della GGT totale, in corrispondenza della comparsa delle manifestazioni cliniche di GVHD, a cui contribuiscono maggiormente le isoforme b-GGT e s-GGT. Non abbiamo evidenziato differenze specifiche nell’incremento delle singole frazioni tra le varie manifestazioni cliniche di GVHD (cute, intestino, fegato, stomaco). I valori di GGT totale si normalizzano in seguito ad un’adeguata terapia immunosoppressiva nei pazienti responsivi al trattamento. Abbiamo osservato un aumento della GGT totale al giorno +7 post-trapianto anche per i pazienti sottoposti a condizionamenti a ridotta intensità (RIC), ma i valori massimi raggiunti sono minori rispetto ai trapianti mieloablativi; anche in questo caso prevalgono le isoforme b-GGT e s-GGT. Nei trapianti autologhi, la GGT si mantiene nella maggior parte dei casi all’interno del range di riferimento; quando aumenta, si ha un incremento consensuale di tutte le frazioni. Per quanto riguarda la mortalità trapianto correlata (TRM), abbiamo notato che nel gruppo dei pazienti deceduti, circa il 50% di tutti i soggetti indagati (molti dei quali erano ad alto rischio e pluritrattati), si ha un aumento di tutte le frazioni di GGT in corrispondenza del giorno +7 dal trapianto, dato che conferma precedenti studi sulla TRM; in particolare si ha un aumento della b-GGT rispetto alle altre isoforme. In conclusione, lo studio delle frazioni della GGT plasmatica nei soggetti sottoposti a trapianto di CSE ha rivelato una notevole diversità nel comportamento delle stesse nelle fasi immediatamente precedenti e seguenti alla procedura. Sebbene i risultati, allo stato attuale, appaiano ancora preliminari a causa della modesta numerosità campionaria in esame, è già evidente che ciascuna frazione assume nel tempo andamenti diversi non solo rispetto alle altre frazioni, ma anche rispetto all’esito della procedura e agli eventi associati alla GVHD. L’attribuzione di uno specifico significato fisiopatologico alle variazioni di ciascuna frazione di GGT potrebbe fornire in futuro un utile strumento diagnostico e prognostico nell’ambito dei trapianti di midollo.

Ruxolitinib Rapidly Reduces Acute Respiratory Distress Syndrome in COVID-19 Disease. Analysis of Data Collection From RESPIRE Protocol

Background: The Coronavirus disease (COVID-19) pandemic is causing millions of infections and hundreds of thousands of deaths worldwide. Cumulative clinical and laboratory evidence suggest that a subset of patients with severe COVID-19 may develop a cytokine storm syndrome during the course of the disease, with severe respiratory impairment requiring ventilatory support. One field of research nowadays is to identify and treat viral-induced hyperinflammation with drugs used in other clinical conditions characterized by an hyperinflammation status. These drugs might help to reduce COVID19 mortality. Methods: Ruxolitinib, a JAK1 and JAK2 inhibitor, has been successfully used to treat severe immune-mediated diseases, such as graft vs. host disease and Hemophagocytic lymphohistiocytosis. We used ruxolitinib in 18 patients with clinically progressive COVID-19 related acute respiratory distress syndrome, with a primary endpoint to rapidly reduce the degree of respiratory impairment and as a secondary endpoint to rapidly restore the PaO2/FiO2 ratio, as an evaluation of clinical status, and monitoring of drug related Adverse Events. Parameters of inflammation responses and organ functions were assessed and monitored. The treatment plan was ruxolitinib 20 mg bid for the first 48 h and subsequent two-step de-escalation at 10 mg bid and 5 mg bid for a maximum of 14 days of treatment. Results: Our data collection shows a rapid clinical response with no evolution from non-invasive ventilation to mechanical ventilation in 16/18 patients and no response in two patients (overall response rate-ORR 89%). Already after 48 h of ruxolitinib treatment 16/18 patients showed evident clinical improvement, and after 7 days of treatment 11/18 patients showed fully recovered respiratory function (pO2 > 98% in spontaneous breathing), 4/18 patients had minimal oxygen requirement (2-4 L/m), 1/18 patient showed stable disease, and 2/18 patient showed progressive disease. After 14 days, 16/18 patients showed complete recovery of respiratory function (ORR 89%). Compliance to ruxolitinib planned treatment was 100% and no serious adverse event was recorded. In our case series of 18 critically ill patients with COVID-19 and ARDS, administration of ruxolitinib resulted in a clinical improvement that concurred to modify the standard course of disease. Ruxolitinib can be a therapeutic option for patients with respiratory insufficiency in COVID-19 related ARDS. RESPIRE Study (Ruxolitinib for the treatment of acute rESPIratory distREss syndrome, ClinicalTrials.gov Identifier: NCT04361903)

Relapsed/Refractory Chronic Lymphocytic Leukemia Patients Treated with Fixed Duration Venetoclax-Rituximab: Assessment of Response with Ultrasound, and Relationship with Minimal Residual Disease

A fixed duration of venetoclax-rituximab (VenR) resulted in a significant benefit of both PFS and in the attainment of an undetectable minimal residual disease (uMRD) compared with bendamustine-rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. The 2018 International Workshop on CLL guidelines, outside the context of clinical trials, suggested ultrasonography (US) as a possible imaging technique to evaluate visceral involvement, and palpation to evaluate superficial lymph nodes (SupLNs). In this real-life study we prospectively enrolled N = 22 patients. Patients were assessed by US, to determine nodal and splenic response in R/R CLL patients treated with a fixed duration VenR. We found an overall response rate, complete remission, partial remission, and stable disease, of 95.4%, 68%, 27.3%, and 4.5%, respectively. Responses were also correlated with risk categories. The time to response, and the time to clearance of the disease in the spleen, in abdominal LN (AbdLNs), and in SupLNs were discussed. Responses were independent from LN size. The correlation between response rate with MRD were also investigated. US allowed to detect a substantial CR rate correlated with uMRD

The Multifaceted Haptoglobin in the Context of Adipose Tissue and Metabolism

Obesity is a low chronic inflammatory state because several inflammatory factors are increased in obese subjects, this having important implications for the onset of obesity-associated complications. The source of most of these inflammatory molecules is white adipose tissue (WAT), which upon excessive weight gain, becomes infiltrated with macrophages and lymphocytes and undergoes important changes in its gene expression. Haptoglobin (Hp), a typical marker of inflammation in clinical practice, main carrier of free hemoglobin, and long known to be part of the hepatic acute phase response, perfectly sits in the intersection between obesity and inflammation: it is expressed by adipocytes and its abundance in WAT and in plasma positively relates to the degree of adiposity. In the present review, we will analyze causes and consequences of Hp expression and regulation in WAT and how these relate to the obesity/inflammation paradigm and comorbidities