This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

Background We tested the hypothesis that changes in our transplant practice have improved outcomes over the last decade. To explore correlates of improved outcomes, we analyzed the frequency and severity of graft-versus-host disease and hepatic, renal, pulmonary and infectious complications. Methods During 1993–1997 and 2003–2007, 1418 and 1148 patients received their first allogeneic transplants at our Center. Outcome measures included non-relapse mortality, recurrent malignancy, overall mortality, and the frequency and severity of major complications across this decade. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for severity of illness at the time of transplantation. Results In comparing outcomes during 1993–1997 and 2003–2007, we observed statistically significant decreases in the hazards of day -200 non-relapse mortality (by 60%), overall non-relapse mortality (by 52%), relapse or progression of malignancy (by 21%), and overall mortality (by 41%), after adjusting for components of the PAM score. Similar results were seen when the analyses were confined to patients receiving myeloablative conditioning therapy. We found statistically significant declines in the risk of more severe GVHD, disease caused by infections (viral, bacterial, and fungal), and damage to the liver, kidneys, and lungs. Conclusions We document a substantial reduction in the hazard of death related to allogeneic hematopoietic cell transplantation as well as improved long-term survival over the last decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD.

Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .).

Factors that increased risks for IA after engraftment included receipt of T celldepleted or CD34-selected stem cell products, receipt of corticosteroids, neutropenia, lymphopenia, GVHD, CMV disease, and respiratory virus infections. Very late IA (> 6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraft-

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then, there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aim to support clinical research and drug development. The main changes compared to previous definitions are the introduction of a "probable disease" category and to incorporate quantitative nucleic acid testing in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts between scientists, regulators, and industry can provide a platform for this work.

Cytomegalovirus (CMV) continues to cause major complications after hematopoietic cell transplantation (HCT). Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. Here, we review aspects of CMV treatment and prevention in HCT recipients, including currently used drugs and diagnostics, ways to optimize preemptive therapy strategies with quantitative polymerase chain reaction assays, the use of prophylaxis, management of CMV disease caused by wild-type or drugresistant strains, and future strategies. IntroductionCytomegalovirus (CMV) remains one of the most important complications after allogeneic hematopoietic stem cell transplantation (HCT). It can cause multiorgan disease in recipients of stem cell transplants, including pneumonia, hepatitis, gastroenteritis, retinitis, and encephalitis, and the disease can develop both early and late after the transplantation procedure. [1][2][3] Seropositivity for CMV remains a risk factor for transplantation-related mortality in patients who receive a transplant from an unrelated donor despite major advances in early diagnosis and management. [4][5][6] The pathogenesis of CMV infection and disease is complex with several interactions between CMV and the immune system. The interaction is mediated through several mechanisms, including the virus having effects on HLA expression, cytokine production, and expression of adherence molecules. These interactions can explain the increased risk of secondary bacterial and fungal infections in patients with CMV infection. 7 Another possible effect of the interaction with the immune system is the described association between CMV and acute and chronic graft-versus-host disease (GVHD). It has been documented that patients with acute GVHD are at an increased risk of CMV disease. [8][9][10] However, CMV infection has been reported as a risk factor for acute GVHD in patients receiving T cell-depleted grafts, and for chronic GVHD. 4,[11][12][13] CMV reactivation is controlled by CMV-specific T cells. 14,15 However, recent studies also suggest that natural killer (NK) cells play a role in protecting against CMV, because donor-activating killer immunoglobulin-like receptor (KIR) genes have been associated with protection from CMV reactivation in the recipient. 16,17 Prevention of primary CMV infection Pretransplantation strategiesDetermining the CMV serologic status. CMV serologic status should be assessed as early as possible when a patient is being considered for allogeneic HCT. There is an advantage for patients who are CMV seronegative when coming to transplantation, and, in some situations, it might be logical to test the patient's status at the time of diagnosis of a disease that may require HCT in the future. If a patient is found CMV seronegative, a strategy to provide "CMV-safe" blood products should be used.Donor selection. Patients who are CMV seronegative before tran...

Highlights d Early B cell responses to SARS-CoV-2 spike protein are analyzed from a COVID-19 patient d Most antibodies target non-neutralizing epitopes outside the RBD d A potent neutralizing mAb blocks the interaction of the S protein with ACE2 d Neutralizing antibodies are minimally mutated

Ganciclovir effectively prevents cytomegalovirus (CMV) disease in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT), but lateonset CMV disease is increasingly observed. We designed a prospective cohort study to define the incidence and risk factors for late CMV infection in patients who undergo HSCT. CMV-seropositive patients were studied prospectively for CMV infection (quantitative pp65 antigenemia, quantitative CMV-DNA, blood culture), T-cell immunity (CMV-specific CD4 ؉ T-helper and CD8 ؉ cytotoxic Tlymphocyte responses, CD4 and CD8 Tcell count, absolute lymphocyte count), and other transplantation-related factors. Univariate and multivariable analyses were used to assess the risk for late CMV infection and disease and to assess overall survival. Late CMV disease developed in 26 of 146 (17.8%) patients a median of 169 days after transplantation (range, 96-784 days); the mortality rate was 46%. Thirty-eight percent of patients surviving late disease had a second episode a median of 79 days after the first episode. At 3 months after transplantation, preceding detection of CMV pp65 antigenemia, CD4 T-cell counts lower than 50 cells/ mm 3 , postengraftment absolute lymphopenia levels lower than 100 lymphocytes/mm 3 , undetectable CMV-specific T-cell responses, and graft-versus-host disease (GVHD) were associated with late CMV disease or death. After 3 months, continued detection of pp65 antigenemia or CMV DNA in plasma or peripheral blood leukocytes and lymphopenia (fewer than 300 lymphocytes/mm 3 ) were strong predictors of late CMV disease and death. In conclusion, CMV viral load, lymphopenia, and CMV-specific T-cell immunodeficiency are predictors of late CMV disease and death after allogeneic stem cell transplantation. Prevention strategies should be targeted at patients in whom CMV reactivated during the first 3 months and those with poor CMV-specific immunity or low CD4 counts. (Blood. 2003;101: 407-414)