Approach to suspected donor-derived infections

Prevention of donor-derived disease among pediatric solid organ transplant recipients requires judicious risk-benefit assessment. Comprehensive guidelines outline specific donor risk factors and post-transplant monitoring strategies to prevent and mitigate transmission of HIV, hepatitis B, and hepatitis C. However, elimination of unanticipated donor-derived infections remains challenging. The objectives of this review are to (1) define risk of anticipated vs. unanticipated disease transmission events in pediatric solid organ transplant recipients; (2) discuss donor presentations that confer greater risk of unanticipated disease transmission; (3) develop a matrix for consideration of donor acceptance; and (4) discuss limitations and future directions for donor screening. Although solid organ transplant confers inherent risk of infection transmission, the risk of significant disease transmission events may be mitigated by a comprehensive approach including donor assessment, consideration of recipient need, post-transplant monitoring, and early intervention

Usefulness of gene expression profiling of bronchoalveolar lavage cells in acute lung allograft rejection.

BackgroundChronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD.MethodsWe performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC).ResultsDifferential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29-4.53).ConclusionsBAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD

β-Herpesviruses in Febrile Children with Cancer

These viruses should be included in the differential diagnosis of febrile disease

Febrile Neutropenia in Children: Etiologies, Outcomes, and Risk Factors with Prolonged Fever

Most studies of children with prolonged fever and neutropenia (PFN) have focused on invasive fungal disease (IFD) as the etiology of fever and not on other causes. Data are lacking regarding risk factors and adverse outcomes in pediatric cancer patients with PFN compared with those whose fevers resolve more rapidly. Retrospective medical record review was performed for all cancer patients with febrile neutropenia (FN) in the pediatric oncology unit at University of Chicago Medicine Comer Children’s Hospital from March 2009 to July 2016. Resolving febrile neutropenia (RFN), lasting less than 96 hours, and PFN episodes (≥ 96 hours) were compared to identify risk factors and outcomes associated with PFN. A total of 572 FN episodes were identified in 265 patients. PFN occurred in 119 (21%) FN episodes (50 patients) and RFN occurred in 453 (79%) FN episodes (215 patients). In multivariable analysis, autologous stem cell transplant (odds ratio [OR] 6.5, P 39°C at the time of presentation (OR 2.4, P<0.01) and absolute monocyte count (AMC) <100 cells/m3 (OR 2.7, P=<0.01) were independently associated with PFN. Pneumonia, neutropenic enterocolitis and IFD were more common etiologies of fever in PFN compared with RFN. Patients with PFN were more likely to be admitted to the pediatric intensive care unit [OR 3, (95%CI, 1.66%-5.28%), P<0.001] and had a trend toward higher 30-day mortality [OR 3.8, (95%CI, 0.52%-29.32%), P=0.07]. Patients with PFN are at increased risk for serious illness and death. A better understanding of the etiologies of PFN other than IFD is needed to be able to appropriately diagnose and treat this high-risk group

The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation

Despite recent advances, cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality. Research in the field and development of prior consensus guidelines supported by The Transplantation Society has allowed a more standardized approach to CMV management. An international multidisciplinary panel of experts was convened to expand and revise evidence and expert opinion-based consensus guidelines on CMV management including prevention, treatment, diagnostics, immunology, drug resistance, and pediatric issues. Highlights include advances in molecular and immunologic diagnostics, improved understanding of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immunosuppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations

Recommended curriculum for subspecialty training in transplant infectious disease on behalf of the American Society of Transplantation Infectious Diseases Community of Practice Educational Initiatives Working Group

R. Avery, H. Clauss, L. Danziger-Isakov, J. Davis, K. Doucette, D. van Duin, J. Fishman, F. Gunseren, A. Humar, S. Husain, C. Isada, K. Julian, D. Kaul, D. Kumar, S. Martin, M. Michaels, M. Morris, F. Silveira, A. Subramanian. Recommended curriculum for subspecialty training in transplant infectious disease on behalf of the American Society of Transplantation Infectious Diseases Community of Practice Educational Initiatives Working Group. Transpl Infect Dis 2010: 12: 190–194. All rights reservedThe American Society of Transplantation Infectious Diseases (ID) Community of Practice has established an education workgroup to identify core components of a curriculum for training specialists in transplant ID. Clinical, laboratory, and research training form the triad of components on which an additional year of ID training, dedicated to the care of solid organ and hematopoietic stem cell transplant recipients, should be based. The recommended training environment would have access to adequate numbers of transplant patients, along with qualified faculty committed to teaching specialized fellows in this area. The learning objectives for both inpatient and outpatient clinical training are presented. The laboratory component requires trainees to attain expertize in utilizing and interpreting cutting-edge diagnostics used in transplant medicine. The research component may involve basic science, and translational or clinical research individualized to the trainee. Finally, suggestions for evaluation of both the fellows and the training program are provided.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79192/1/j.1399-3062.2010.00510.x.pd

TCR cross-reactivity and allorecognition: new insights into the immunogenetics of allorecognition

Alloreactive T cells are core mediators of graft rejection and are a potent barrier to transplantation tolerance. It was previously unclear how T cells educated in the recipient thymus could recognize allogeneic HLA molecules. Recently it was shown that both naïve and memory CD4+ and CD8+ T cells are frequently cross-reactive against allogeneic HLA molecules and that this allorecognition exhibits exquisite peptide and HLA specificity and is dependent on both public and private specificities of the T cell receptor. In this review we highlight new insights gained into the immunogenetics of allorecognition, with particular emphasis on how viral infection and vaccination may specifically activate allo-HLA reactive T cells. We also briefly discuss the potential for virus-specific T cell infusions to produce GvHD. The progress made in understanding the molecular basis of allograft rejection will hopefully be translated into improved allograft function and/or survival, and eventually tolerance induction

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events