SummaryThe degree of somatic hypermutation, determined as percent deviation of immunoglobulin heavy chain gene variable region sequence from the germline (IGHV%), is an important prognostic factor in chronic lymphocytic leukaemia (CLL). Currently, a cut-off of 2% deviation or 98% sequence identity to germline in IGHV sequence is routinely used to dichotomize CLL patients into mutated and unmutated groups. Because dissimilar IGHV% cut-offs of 1-5% were identified in different studies, we wondered whether no cut-off should be applied and IGHV% treated as a continuous variable. We analysed the significance of IGHV% in 203 CLL patients enrolled on the original frontline fludarabine, cyclophosphamide and rituximab (FCR) trial with a median of 10 years follow-up. Using the Cox Proportional Hazard model, IGHV% was identified as a continuous variable that is significantly associated with progression-free (PFS) and overall survival (OS) (P < 0Á001). Furthermore, we validated this finding in 323 patients treated with FCR off-protocol and in the total cohort (n = 535). Multivariate analysis revealed a continuous trend. Higher IGHV% levels were incrementally associated with favorable PFS and OS in both FCR-treated cohorts (P < 0Á001, both cohorts). Taken together, our data suggest that IGHV% is a continuous variable in CLL patients treated with FCR.Keywords: CLL, FCR, IGHV gene, immunoglobulin heavy chain gene.The mutation status of the immunoglobulin heavy chain variable region gene (IGHV) is an established prognostic factor in patients with chronic lymphocytic leukaemia (CLL). Fais et al (1998) identified the presence of somatic hypermutation (SHM) in CLL cells and the prognostic significance of the percent of SHM deviation from the germline sequence (IGHV%) in patients with CLL was described the following year (Damle et al, 1999;Hamblin et al, 1999). In recent years a cut-off value of 2% deviation from the germline sequence of IGHV (i.e. 98% identity) has been commonly used in clinical practice and, according to the current dogma, CLL patients with ≥2% deviation, or otherwise ≤98% identity, are considered 'mutated' (M-CLL), whereas CLL patients with <2% IGHV% deviation or >98% identity are considered research paper ª
Background Vancomycin-resistant enterococci (VRE) are major therapeutic challenges. Prospective contemporary data characterizing the clinical and molecular epidemiology of VRE bloodstream infections (BSI) are lacking. Methods VENOUS I is a prospective observational cohort of adult patients with enterococcal BSI in 11 US hospitals. We included patients with Enterococcus faecalis or E. faecium BSI with ≥1 follow-up blood culture(s) within 7 days and availability of isolate(s) for further characterization. The primary study outcome was in-hospital mortality. Secondary outcomes were mortality at days 4, 7, 10, 12, and 15 after index blood culture. A desirability of outcome ranking was constructed to assess the association of vancomycin resistance with outcomes. All index isolates were subjected to whole genome sequencing. Results 42 of 232 (18%) patients died in hospital and 39 (17%) exhibited microbiological failure (lack of clearance in the first 4 days). Neutropenia (HR 3.13), microbiological failure (HR 2.15), VRE BSI (HR 2), use of urinary catheter (HR 1.85), and Pitt BSI score ≥2 (HR 1.83) were significant predictors of in-hospital mortality. Microbiological failure was the strongest predictor of in-hospital mortality in patients with E. faecium bacteremia (HR 5.03). The impact of vancomycin resistance on mortality in our cohort changed throughout the course of hospitalization. E. faecalis ST6 was a predominant multidrug-resistant lineage, whereas a heterogeneous genomic population of E. faecium was identified. Conclusions Failure of early eradication of VRE from the bloodstream is a major factor associated with poor outcomes.
In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 “South African” variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-β) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4+ T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.
A 25-year-old woman with multiply-refractory Hodgkin lymphoma underwent a hematopoietic stem cell transplantation (HSCT) from her haploidentical mother. She received standard reduced-intensity conditioning with fludarabine, cyclophosphamide, and total body irradiation, followed by graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PT-Cy), tacrolimus, and mycophenolate mofetil. The transplant course was typical, with culture-negative fever consistent with cytokine release syndrome (CRS) responsive to empiric broad-spectrum antibiotics and tocilizumab, resolving following PT-Cy. Hematopoietic engraftment and recovery were uneventful. She was discharged on GVHD and antimicrobial prophylaxis. One month post-transplant, the patient was admitted for highgrade fevers, dry cough, abdominal pain, and nausea. Initial workup identified cytomegalovirus (CMV) reactivation, treated to resolution with ganciclovir; endoscopic evaluation of the upper and lower gastrointestinal tract was negative; positron emission tomography-computed tomography (PET/CT) identified only splenomegaly and an overall improvement in lymphadenopathy (Figure 1A-B).Fevers persisted; she became progressively dyspneic, then acutely hypoxic on hospital day ten; repeat chest CT showed widespread nodular infiltrates. Polymerase chain reaction detected Toxoplasma gondii in blood. Prompt anti-parasitic combination therapy was initiated. Hypoxemia progressed, requiring intubation, mechanical ventilation, paralytics, and prone positioning. Evaluation of bronchoalveolar lavage fluid Abstract Hemophagocytic lymphohistiocytosis (HLH) is a disorder of immune regulation, manifested by fever, pancytopenia, hyperferritiniemia, hypertriglyceridemia, and extensive hemophagocytosis involving the bone marrow and spleen. HLH can occur in adults with an underlying hematopoietic malignancy, or with systemic infections. HLH following hematopoietic stem cell transplantation (HSCT) is unusual, and the diagnosis may be challenging particularly because the diagnostic criteria in the HLH-2004 guidelines overlap with common post-transplant complications such as engraftment syndrome, graft-vs-host disease, and infections. HLH is commonly triggered by viral, bacterial and, less commonly, parasitic infections. Following HSCT, patients with latent Toxoplasma infection may develop systemic disease secondary to reactivation, and rarely this may lead to a HLH physiology, with a very high mortality rate. Herein we describe the successful management of disseminated toxoplasmosis associated with life-threatening HLH using tocilizumab and antimicrobial therapy. K E Y W O R D S allogeneic stem cell transplantation, disseminated toxoplasmosis, haploidentical, hemophagocytic lymphohistiocytosis, tociliumab
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