HHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant.

Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT.

Diffuse Alveolar Hemorrhage in Hematopoietic Cell Transplantation.

Diffuse alveolar hemorrhage (DAH) is a morbid syndrome that occurs after autologous and allogeneic hematopoietic cell transplantation in children and adults. DAH manifests most often in the first few weeks following transplantation. It presents with pneumonia-like symptoms and acute respiratory failure, often requiring high levels of oxygen supplementation or mechanical ventilatory support. Hemoptysis is variably present. Chest radiographs typically feature widespread alveolar filling, sometimes with peripheral sparing and pleural effusions. The diagnosis is suspected when serial bronchoalveolar lavages return increasingly bloody fluid. DAH is differentiated from infectious causes of alveolar hemorrhage when extensive microbiological testing reveals no pulmonary pathogens. The cause is poorly understood, though preclinical and clinical studies implicate pretransplant conditioning regimens, particularly those using high doses of total-body-irradiation, acute graft-versus-host disease (GVHD), medications used to prevent GVHD, and other factors. Treatment consists of supportive care, systemic corticosteroids, platelet transfusions, and sometimes includes antifibrinolytic drugs and topical procoagulant factors. Therapeutic blockade of tumor necrosis factor-α showed promise in observational studies, but its benefit for DAH remains uncertain after small clinical trials. Even with these treatments, mortality from progression and relapse is high. Future investigational therapies could target the vascular endothelial cell biology theorized to contribute to alveolar bleeding and pathways that contribute to susceptibility, inflammation, cellular resilience, and tissue repair. This review will help clinicians navigate through the limited evidence to diagnose and treat DAH, counsel patients and families, and plan for future research.

Outcomes in quality improvement and patient safety training: moving from in-person to synchronous distance education.

BACKGROUND: The COVID-19 pandemic necessitated increased synchronous distance education (SDE) in graduate medical education, presenting challenges for Quality Improvement and Patient Safety (QIPS) best practices, which call for integration with daily clinical care and investigation of real patient safety events. OBJECTIVE: To evaluate educational outcomes for QIPS training after conversion of a mature, in-person curriculum to SDE. METHODS: 68 postgraduate year (PGY)-1 residents were surveyed before and after the SDE Culture of Patient Safety training in June 2020, and 59 PGY-2s were administered the Quality Improvement Knowledge Application Tool-Revised (QIKAT-R) before and after the SDE QIPS seminar series in July-August 2020. Values before and after training were compared using sign tests for matched pairs (PGY-1) and Wilcoxon signed-rank tests (PGY-2). RESULTS: 100% (68 of 68) of PGY-1s and 46% (27 of 59) of PGY-2s completed precourse and postcourse surveys. Before the course, 55 PGY-1s (81%) strongly agreed that submitting patient safety event reports are a physician's responsibility, and 63 (93%) did so after (15% increase, p=0.004). For PGY-2s, the median composite QIKAT-R score was 17 (IQR 14.5-20) before and 22.5 (IQR 20-24.5) after the seminars, with a median difference of 4.5 (IQR 1.5-7), a 32% increase in QIPS competency (p=0.001). CONCLUSIONS: Patient safety attitudes and quality improvement knowledge increased after SDE QIPS training at comparable levels to previously published results for in-person training, supporting SDE use in future hybrid curricula to optimise educational value and reach.

Maximizing Career Advancement During the COVID-19 Pandemic: Recommendations for Postgraduate Training Programs.

The ongoing novel Coronavirus disease 2019 (COVID-19) pandemic has created many threats as well as opportunities for the career development of physicians-in-training. Institutional responses to the demand for patient care reduced the time many residents have to pursue clinical electives, scholarship projects, and other experiences meant to clarify and advance their personal and professional goals. Moreover, many academic medical centers experienced profound fiscal losses that require thoughtful revisions to budgets and curricula. In this article, the authors recommend strategies for residency programs to mitigate these losses and capitalize on growth in virtual education, scholarship opportunities, and relationships arising from the pandemic. Drawing from career development guidelines from the National Career Development Association and existing literature about factors associated with positive career outcomes, the authors suggest leadership roles, curricula, and events that training programs can quickly and inexpensively implement to help residents grow as professionals, achieve personal training goals, produce scholarship, and attain future employment. To help trainees manage their careers, the authors recommend structured mentorship and education in career pathways and the preparation of job application materials. To foster attainment of specific knowledge and cultivate lifelong learning, the authors recommend leveraging existing resources to provide time, funding, academic coaching, and skills training for scholarship projects. To promote development of effective work relationships and community, the authors recommend appointment of a faculty champion for career advancement, scholarship showcases, attendance at virtual journal clubs, and networking through social media outlets. These recommendations for supporting career advancement may apply to early career faculty development as well as undergraduate and postgraduate medical education beyond the pandemic era. Outcomes studies will be needed to evaluate the impact of these recommendations.

Creating a Framework to Integrate Residency Program and Medical Center Approaches to Quality Improvement and Patient Safety Training.

Quality improvement and patient safety (QIPS) are core components of graduate medical education (GME). Training programs and affiliated medical centers must partner to create an environment in which trainees can learn while meaningfully contributing to QIPS efforts, to further the shared goal of improving patient care. Numerous challenges have been identified in the literature, including lack of resources, lack of faculty expertise, and siloed QIPS programs. In this article, the authors describe a framework for integrated QIPS training for residents in the University of Washington Internal Medicine Residency Program, beginning in 2014 with the creation of a dedicated QIPS chief resident position and assistant program director for health systems position, the building of a formal curriculum, and integration with medical center QIPS efforts. The postgraduate year (PGY) 1 curriculum focused on the culture of patient safety and entering traditional patient safety event (PSE) reports. The PGY-2 curriculum highlighted QIPS methodology and how to conduct mentored PSE reviews of cases that were of educational value to trainees and a clinical priority to the medical center. Additional PGY-2/PGY-3 training focused on the active report, presentation, and evaluation of cases during morbidity and mortality conferences while on clinical services, as well as how to lead longitudinal QIPS work. Select residents led mentored QI projects as part of an additional elective. The hallmark feature of this framework was the depth of integration with medical center priorities, which maximized educational and operational value. Evaluation of the program demonstrated improved attitudes, knowledge, and behavior changes in trainees, and significant contributions to medical center QIPS work. This specialty-agnostic framework allowed for training program and medical center integration, as well as horizontal integration across GME specialties, and can be a model for other institutions.

Incidence, Risk Factors, and Outcomes of Idiopathic Pneumonia Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Our current knowledge of idiopathic pneumonia syndrome (IPS) predates improved specificity in the diagnosis of IPS and advances in hematopoietic cell transplantation (HCT) and critical care practices. In this study, we describe and update the incidence, risk factors, and outcomes of IPS. We performed a retrospective cohort study of all adults who underwent allogeneic HCT at the Fred Hutchinson Cancer Research Center between 2006 and 2013 (n = 1829). IPS was defined using the National Heart, Lung, and Blood Institute consensus definition: multilobar airspace opacities on chest imaging, absence of lower respiratory tract infection, and hypoxemia. We described IPS incidence and mortality within 120 and 365 days after HCT. We examined conditioning intensity (nonmyeloablative versus myeloablative with high-dose total body irradiation [TBI] versus myeloablative with low-dose TBI) as an IPS risk factor in a time-to-event analysis using Cox models, controlled for age at transplant, HLA matching, stem cell source, and pretransplant Lung function Score (a combined measure of impairment in Forced Expiratory Volume in the first second (FEV1) and Diffusion capacity for carbon monoxide (DLCO)). Among 1829 HCT recipients, 67 fulfilled IPS criteria within 120 days (3.7%). Individuals who developed IPS were more likely to be black/non-Hispanic versus other racial groups and have severe pulmonary impairment but were otherwise similar to participants without IPS. In adjusted models, myeloablative conditioning with high-dose TBI was associated with increased risk of IPS (hazard ratio, 2.5; 95% confidence interval, 1.2 to 5.2). Thirty-one patients (46.3%) with IPS died within the first 120 days of HCT and 47 patients (70.1%) died within 365 days of HCT. In contrast, among the 1762 patients who did not acquire IPS in the first 120 days, 204 (11.6%) died within 120 days of HCT and 510 (29.9%) died within 365 days of HCT. Our findings suggest that although the incidence of IPS may be declining, it remains associated with post-transplant mortality. Future study should focus on early detection and identifying pathologic mediators of IPS to facilitate timely, targeted therapies for those most susceptible to lung injury post-HCT.

Human Herpesvirus 6B and Lower Respiratory Tract Disease After Hematopoietic Cell Transplantation.

PURPOSE: Human herpesvirus 6B (HHV-6B) DNA is frequently detected in bronchoalveolar lavage fluid (BALF) from immunocompromised subjects with lower respiratory tract disease (LRTD). Whether HHV-6B is a pulmonary pathogen is unclear. METHODS: We tested BALF for HHV-6B DNA using polymerase chain reaction in allogeneic hematopoietic cell transplantation (HCT) recipients who underwent a BAL for evaluation of LRTD from 1992 to 2015. We used multivariable proportional hazards models to evaluate the association of HHV-6B+ BALF with overall mortality, death from respiratory failure, and the effect of anti-HHV-6B antivirals on these outcomes. We used branched-chain RNA in situ hybridization to detect HHV-6 messenger RNA (U41 and U57 transcripts) in lung tissue. RESULTS: We detected HHV-6B+ BALF from 147 of 553 (27%) individuals. Subjects with HHV-6B+ BALF, with or without copathogens, had significantly increased risk of overall mortality (adjusted hazard ratio [aHR], 2.18; 95% CI, 1.41-3.39) and death from respiratory failure (aHR, 2.50; 95% CI, 1.56-4.01) compared with subjects with HHV-6B- BALF. Subjects with HHV-6B+ BALF who received antivirals within 3 days pre-BAL had an approximately 1 log10 lower median HHV-6B BALF viral load, as well as a lower risk of overall mortality (aHR, 0.42; 95% CI, 0.16-1.10), compared with subjects with HHV-6B+ BALF not receiving antivirals. We detected intraparenchymal HHV-6 gene expression by RNA in situ hybridization in lung tissue in all three tested subjects with HHV-6B+ BALF and sufficient tissue RNA preservation. CONCLUSION: These data provide evidence that HHV-6B detection in BALF is associated with higher mortality in allogeneic hematopoietic cell transplantation recipients with LRTD. Definitive evidence of causation will require a randomized prevention or treatment trial.

Early Onset Noninfectious Pulmonary Syndromes after Hematopoietic Cell Transplantation.

This article reviews the noninfectious pulmonary syndromes that cause morbidity and mortality early after hematopoietic cell transplantation with an emphasis on risk factors, clinical manifestations, treatment, and outcomes. The first section covers idiopathic pneumonia syndrome and its subtypes: peri-engraftment respiratory distress syndrome, diffuse alveolar hemorrhage, delayed pulmonary toxicity syndrome, and cryptogenic organizing pneumonia. The second section covers pulmonary toxicities of chemotherapies and immunosuppressive agents used in this setting. The final section covers less common syndromes, including pulmonary alveolar proteinosis, venous thromboembolism, pulmonary cytolytic thrombi, pulmonary venoocclusive disease, and transfusion-related acute lung injury.

Development and validation of a prehospital prediction model for acute traumatic coagulopathy.

BACKGROUND: Acute traumatic coagulopathy (ATC) is a syndrome of early, endogenous clotting dysfunction that afflicts up to 30% of severely injured patients, signaling an increased likelihood of all-cause and hemorrhage-associated mortality. To aid identification of patients within the likely therapeutic window for ATC and facilitate study of its mechanisms and targeted treatment, we developed and validated a prehospital ATC prediction model. METHODS: Construction of a parsimonious multivariable logistic regression model predicting ATC - defined as an admission international normalized ratio >1.5 - employed data from 1963 severely injured patients admitted to an Oregon trauma system hospital between 2008 and 2012 who received prehospital care but did not have isolated head injury. The prediction model was validated using data from 285 severely injured patients admitted to a level 1 trauma center in Seattle, WA, USA between 2009 and 2013. RESULTS: The final Prediction of Acute Coagulopathy of Trauma (PACT) score incorporated age, injury mechanism, prehospital shock index and Glasgow Coma Score values, and prehospital cardiopulmonary resuscitation and endotracheal intubation. In the validation cohort, the PACT score demonstrated better discrimination (area under the receiver operating characteristic curve 0.80 vs. 0.70, p = 0.032) and likely improved calibration compared to a previously published prehospital ATC prediction score. Designating PACT scores ≥196 as positive resulted in sensitivity and specificity for ATC of 73% and 74%, respectively. CONCLUSIONS: Our prediction model uses routinely available and objective prehospital data to identify patients at increased risk of ATC. The PACT score could facilitate subject selection for studies of targeted treatment of ATC.

The association between platelet transfusion and idiopathic pneumonia syndrome is unaffected by platelet product type.

BACKGROUND: Methods used to produce platelet (PLT) components, pooling of PLT-rich plasma (PRP-PLT) and apheresis (AP-PLT), may variably contribute to the pathogenesis and severity of idiopathic pneumonia syndrome (IPS). STUDY DESIGN AND METHODS: We performed a retrospective cohort study of 906 allogeneic hematopoietic cell transplant recipients to examine associations between PLT product type and risks of developing IPS and dying after IPS onset. Proportional hazards models included separate terms for the sum of all PLT transfusions and the sum of PRP-PLT units received in the 3 or 7 days before IPS onset. Similarly constructed models analyzed the outcome of time to death after IPS onset. All analyses were adjusted for known IPS risk factors. RESULTS: Patients received a median of three PRP-PLT transfusions (interquartile range [IQR], 0-6) and five AP-PLT transfusions (IQR, 1-13) while at risk for IPS. Seventy-five patients (8%) developed IPS by Posttransplant Day 120. The proportion of PRP-PLT transfusions was not associated with risk of developing IPS (3-day hazard ratio [HR] 0.98, 95% CI 0.74-1.29, p = 0.86; 7-day HR 1.00, 95% CI 0.86-1.15, p = 0.95) or dying after IPS onset (3-day HR 0.99, 95% CI 0.75-1.31, p = 0.97; 7-day HR 0.98, 95% CI 0.78-1.12, p = 0.47). CONCLUSION: The association between PLT transfusions and risk of developing IPS or dying after IPS onset does not differ according to PLT product type. Further research is required to identify potentially modifiable steps in PLT component production that contribute to IPS.

The Epidemiology of Transfusion-related Acute Lung Injury Varies According to the Applied Definition of Lung Injury Onset Time.

RATIONALE: Research that applies an unreliable definition for transfusion-related acute lung injury (TRALI) may draw false conclusions about its risk factors and biology. The effectiveness of preventive strategies may decrease as a consequence. However, the reliability of the consensus TRALI definition is unknown. OBJECTIVES: To prospectively study the effect of applying two plausible definitions of acute respiratory distress syndrome onset time on TRALI epidemiology. METHODS: We studied 316 adults admitted to the intensive care unit and transfused red blood cells within 24 hours of blunt trauma. We identified patients with acute respiratory distress syndrome, and defined acute respiratory distress syndrome onset time two ways: (1) the time at which the first radiographic or oxygenation criterion was met, and (2) the time both criteria were met. We categorized two corresponding groups of TRALI cases transfused in the 6 hours before acute respiratory distress syndrome onset. We used Cohen's kappa to measure agreement between the TRALI cases and implicated blood components identified by the two acute respiratory distress syndrome onset time definitions. In a nested case-control study, we examined potential risk factors for each group of TRALI cases, including demographics, injury severity, and characteristics of blood components transfused in the 6 hours before acute respiratory distress syndrome onset. MEASUREMENTS AND MAIN RESULTS: Forty-two of 113 patients with acute respiratory distress syndrome were TRALI cases per the first acute respiratory distress syndrome onset time definition and 63 per the second definition. There was slight agreement between the two groups of TRALI cases (κ = 0.16; 95% confidence interval, -0.01 to 0.33) and between the implicated blood components (κ = 0.15, 95% confidence interval, 0.11-0.20). Age, Injury Severity Score, high plasma-volume components, and transfused plasma volume were risk factors for TRALI when applying the second acute respiratory distress syndrome onset time definition but not when applying the first definition. CONCLUSIONS: The epidemiology of TRALI varies when applying two plausible definitions of acute respiratory distress syndrome onset time to severely injured trauma patients. A TRALI definition that standardizes acute respiratory distress syndrome onset time might improve reliability and align efforts to understand epidemiology, biology, and prevention.

An International Normalized Ratio-Based Definition of Acute Traumatic Coagulopathy Is Associated With Mortality, Venous Thromboembolism, and Multiple Organ Failure After Injury.

OBJECTIVES: Acute traumatic coagulopathy is associated with adverse outcomes including death. Previous studies examining acute traumatic coagulopathy's relation with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding, and single-center designs. In this study, we validated the admission international normalized ratio as an independent risk factor for death and other adverse outcomes after trauma and compared two common international normalized ratio-based definitions for acute traumatic coagulopathy. DESIGN: Multicenter prospective observational study. SETTING: Nine level I trauma centers in the United States. PATIENTS: A total of 1,031 blunt trauma patients with hemorrhagic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: International normalized ratio exhibited a positive adjusted association with all-cause in-hospital mortality, hemorrhagic shock-associated in-hospital mortality, venous thromboembolism, and multiple organ failure. Acute traumatic coagulopathy affected 50% of subjects if defined as an international normalized ratio greater than 1.2 and 21% of subjects if defined by international normalized ratio greater than 1.5. After adjustment for potential confounders, acute traumatic coagulopathy defined as an international normalized ratio greater than 1.5 was significantly associated with all-cause death (odds ratio [OR], 1.88; p < 0.001), hemorrhagic shock-associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p < 0.001), and multiple organ failure (OR, 1.38; p = 0.02). Acute traumatic coagulopathy defined as an international normalized ratio greater than 1.2 was not associated with an increased risk for the studied outcomes. CONCLUSIONS: Elevated international normalized ratio on hospital admission is a risk factor for mortality and morbidity after severe trauma. Our results confirm this association in a prospectively assembled multicenter cohort of severely injured patients. Defining acute traumatic coagulopathy by using an international normalized ratio greater than 1.5 but not an international normalized ratio greater than 1.2 identified a clinically meaningful subset of trauma patients who, adjusting for confounding factors, experienced more adverse outcomes. Targeting future therapies for acute traumatic coagulopathy to patients with an international normalized ratio greater than 1.5 may yield greater returns than using a lower international normalized ratio threshold.

The association between red blood cell and platelet transfusion and subsequently developing idiopathic pneumonia syndrome after hematopoietic stem cell transplantation.

BACKGROUND: Blood transfusions are common during hematopoietic stem cell transplantation (HSCT) and may contribute to lung injury. STUDY DESIGN AND METHODS: This study examined the associations between red blood cell (RBC) and platelet (PLT) transfusions and idiopathic pneumonia syndrome (IPS) among 914 individuals who underwent myeloablative allogeneic HSCT between 1997 and 2001. Patients received allogeneic blood transfusions at their physicians' discretion. RBCs, PLTs, and a composite of "other" transfusions were quantified as the sum of units received each 7-day period from 6 days before transplant until IPS onset, death, or Posttransplant Day 120. RBC and PLT transfusions were modeled as separate time-varying exposures in proportional hazards models adjusted for IPS risk factors (age, baseline disease, irradiation dose) and other transfusions. Timing of PLT transfusion relative to myeloid engraftment and PLT ABO blood group (match vs. mismatch) were included as potential interaction terms. RESULTS: Patients received a median of 9 PLT and 10 RBC units. There were 77 IPS cases (8.4%). Each additional PLT unit transfused in the prior week was associated with 16% higher IPS risk (hazard ratio, 1.16; 95% confidence interval, 1.09-1.23; p < 0.001). Recent RBC and PLT transfusions were each significantly associated with greater risk of IPS when examined without the other; only PLT transfusions retained significance when both exposures were included in the model. The PLT association was not modified by engraftment or ABO mismatch. CONCLUSION: PLT transfusions are associated with greater risk of IPS after myeloablative HSCT. RBCs may also contribute; however, these findings need confirmation.

Prohemostatic therapy: the rise and fall of aprotinin.

Aprotinin has been used clinically to enhance hemostasis for decades and was approved in the United States by the Food and Drug Administration in 1993 to reduce the transfusion requirement during coronary artery bypass surgery. Marketing of aprotinin ceased recently when observational studies and a randomized clinical trial reported increased cardiovascular toxicity in patients receiving this drug. The importance of prohemostatic therapy is reviewed in light of new information on long-term deleterious effects of blood transfusion, including increased risk of cardiovascular disease, malignancy, and infection possibly attributable to delivery of a load of red cell-derived redox-active iron. Weaknesses in design of clinical trials that failed to control adequately for such alternative mechanisms of toxicity complicate interpretation of risks versus benefits in clinical trials of aprotinin given to reduce transfusion requirement in the acute surgical setting. Properties and applications of aprotinin that may not have received sufficient attention in the decision to remove this drug from the therapeutic armamentarium are reviewed. Potential application of prohemostatic drugs, including aprotinin to special populations at risk for operative blood loss requiring transfusion, is illustrated by the description of nine patients with coagulopathies whose operative bleeding was managed effectively with aprotinin. This drug may remain safe and effective in patients at risk of bleeding with surgery. Beneficial effects of aprotinin seemingly unrelated to its prohemostatic properties, especially its apparent striking antineoplastic effects, warrant further study.