A value-based approach to optimize red blood cell transfusion in patients receiving extracorporeal membrane oxygenation.

INTRODUCTION: The risk, cost, and adverse outcomes associated with packed red blood cell (RBC) transfusions in patients with cardiopulmonary failure requiring extracorporeal membrane oxygenation (ECMO) have raised concerns regarding the overutilization of RBC products. It is, therefore, necessary to establish optimal transfusion criteria and protocols for patients supported with ECMO. The goal of this study was to establish specific criteria for RBC transfusions in patients undergoing ECMO. METHODS: This was a retrospective cohort study conducted at Stanford University Hospital. Data on RBC utilization during the entire hospital stay were obtained, which included patients aged ≥18 years who received ECMO support between 1 January 2017, and 30 June 2020 (n = 281). The primary outcome was in-hospital mortality. RESULTS: Hemoglobin (HGB) levels >10 g/dL before transfusion did not improve in-hospital survival. Therefore, we revised the HGB threshold to ≤10 g/dL to guide transfusion in patients undergoing ECMO. To validate this intervention, we prospectively compared the pre- and post-intervention cohorts for in-hospital mortality. Post-intervention analyses found 100% compliance for all eligible records and a decrease in the requirement for RBC transfusion by 1.2 units per patient without affecting the mortality. CONCLUSIONS: As an institution-driven value-based approach to guide transfusion in patients undergoing ECMO, we lowered the threshold HGB level. Validation of this revised intervention demonstrated excellent compliance and reduced the need for RBC transfusion while maintaining the clinical outcome. Our findings can help reform value-based healthcare in this cohort while maintaining the outcome.

Epidemiology of Lower Respiratory Tract Infections and Community-Acquired Respiratory Viruses in Patients with Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation: A Retrospective Cohort Study.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS)-chronic graft-versus-host disease (cGVHD) affecting the lungs-is an uncommon complication of allogeneic hematopoietic cell transplant (HCT). The epidemiology and complications of lower respiratory tract infections (LRTIs) and community-acquired respiratory viruses (CARVs) in these patients are poorly understood. OBJECTIVES: We aim to characterize the epidemiology of LRTIs in patients with BOS complicating HCT. We also aim to explore the association of LRTIs and CARV detection on lung function in BOS patients. STUDY DESIGN: Adult patients with BOS at Stanford Health Care between January 2010 and December 2019 were included in this retrospective cohort study. LRTI diagnosis was based on combined clinical, microbiologic, and radiographic criteria, using consensus criteria where available. RESULTS: Fifty-five patients with BOS were included. BOS was diagnosed at a median of 19.2 (IQR 12.5-24.7) months after HCT, and patients were followed for a median of 29.3 (IQR 9.9-53.2) months from BOS diagnosis. Twenty-two (40%) patients died after BOS diagnosis; 17 patients died from complications of cGVHD (including respiratory failure and infection) and 5 died from relapsed disease. Thirty-four (61.8%) patients developed at least one LRTI. Viral LRTIs were most common, occurring in 29 (52.7%) patients, primarily due to rhinovirus. Bacterial LRTIs-excluding Nocardia and non-tuberculous mycobacteria (NTM)-were the second most common, occurring in 21 (38.2%) patients, mostly due to Pseudomonas aeruginosa. Fungal LRTIs, NTM, and nocardiosis occurred in 14 (25.5%), 10 (18.2%), and 4 (7.3%) patients, respectively. Median time to development of the first LRTI after BOS diagnosis was 15.3 (4.7-44.7) months. Twenty-six (76.5%) of the 34 patients who developed LRTIs had infections due to more than one type of organism-fungi, viruses, Nocardia, NTM, and other bacteria-over the observation period. Patients with at least one LRTI had significantly lower forced expiratory volume in one second percent predicted (FEV1%) (37% vs. 53%, p = 0.0096) and diffusing capacity of carbon monoxide (DLCO) (45.5% predicted vs. 69% predicted, p = 0.0001). Patients with at least one LRTI trended toward lower overall survival (OS) (p = 0.0899) and higher non-relapse mortality (NRM) (p = 0.2707). Patients with a CARV detected or LRTI diagnosed after BOS-compared to those without any CARV detected or LRTI diagnosed-were more likely to have a sustained drop in FEV1% from baseline of at least 10% (21 [61.8%] versus 7 [33.3%]) and a sustained drop in FEV1% of at least 30% (12 [36.4%] versus 2 [9.5%]). CONCLUSIONS: LRTIs are common in BOS and associated with lower FEV1%, lower DLCO, and a trend toward decreased OS and higher NRM. Patients with LRTIs or CARVs (even absent lower respiratory tract involvement) were more likely to have substantial declines in FEV1% over time than those without. The array of organisms-including P. aeruginosa, mold, Nocardia, NTM, and CARVs-seen in BOS reflects the unique pathophysiology of this form of cGVHD, involving both systemic immunodeficiency and structural lung disease. These patterns of LRTIs and their outcomes can be used to guide clinical decisions and inform future research.

The safety and tolerability of pirfenidone for bronchiolitis obliterans syndrome after hematopoietic cell transplant (STOP-BOS) trial.

Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive airway fibrosis leads to a 5-year survival of 40%. Treatment options for BOS are limited. A single arm, 52-week, Phase I study of pirfenidone was conducted. The primary outcome was tolerability defined as maintaining the recommended dose of pirfenidone (2403 mg/day) without a dose reduction totaling more than 21 days, due to adverse events (AEs) or severe AEs (SAEs). Secondary outcomes included pulmonary function tests (PFTs) and patient reported outcomes (PROs). Among 22 participants treated for 1 year, 13 (59%) tolerated the recommended dose, with an average daily tolerated dose of 2325.6 mg/day. Twenty-two SAEs were observed, with 90.9% related to infections, none were attributed to pirfenidone. There was an increase in the average percent predicted forced expiratory volume in 1 s (FEV1%) of 7 percentage points annually and improvements in PROs related to symptoms of cGVHD. In this Phase I study, treatment with pirfenidone was safe. The stabilization in PFTs and improvements in PROs suggest the potential of pirfenidone for BOS treatment and support the value of a randomized controlled trial to evaluate the efficacy of pirfenidone in BOS after HCT. The study is registered in ClinicalTrials.gov (NCT03315741).

Head-to-head Comparison of Qualitative Radiologist Assessment With Automated Quantitative Computed Tomography Analysis for Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplantation.

PURPOSE: Computed tomography (CT) findings of bronchiolitis obliterans syndrome (BOS) can be nonspecific and variable. This study aims to measure the incremental value of automated quantitative lung CT analysis to clinical CT interpretation. A head-to-head comparison of quantitative CT lung density analysis by parametric response mapping (PRM) with qualitative radiologist performance in BOS diagnosis was performed. MATERIALS AND METHODS: Inspiratory and end-expiratory CTs of 65 patients referred to a post-bone marrow transplant lung graft-versus-host-disease clinic were reviewed by 3 thoracic radiologists for the presence of mosaic attenuation, centrilobular opacities, airways dilation, and bronchial wall thickening. Radiologists' majority consensus diagnosis of BOS was compared with automated PRM air trapping quantification and to the gold-standard diagnosis of BOS as per National Institutes of Health (NIH) consensus criteria. RESULTS: Using a previously established threshold of 28% air trapping on PRM, the diagnostic performance for BOS was as follows: sensitivity 56% and specificity 94% (area under the receiver operator curve [AUC]=0.75). Radiologist review of inspiratory CT images alone resulted in a sensitivity of 80% and a specificity of 69% (AUC=0.74). When radiologists assessed both inspiratory and end-expiratory CT images in combination, the sensitivity was 92% and the specificity was 59% (AUC=0.75). The highest performance was observed when the quantitative PRM report was reviewed alongside inspiratory and end-expiratory CT images, with a sensitivity of 92% and a specificity of 73% (AUC=0.83). CONCLUSIONS: In the CT diagnosis of BOS, qualitative expert radiologist interpretation was noninferior to quantitative PRM. The highest level of diagnostic performance was achieved by the combination of quantitative PRM measurements with qualitative image feature assessments.

Harnessing the Potential of Multiomics Studies for Precision Medicine in Infectious Disease.

The field of infectious diseases currently takes a reactive approach and treats infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (eg, immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in "omics" technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (ie, prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (ie, transcriptomics, epigenomics, metabolomics, proteomics) hold the promise to identify patients at increased risk of infection and enable risk-stratifying approaches to be applied in the clinic. Integration of patient-specific data using machine learning improves the effectiveness of prediction, providing the necessary technologies needed to propel the field of infectious diseases medicine into the era of personalized medicine.

Machine Learning Algorithms to Differentiate Among Pulmonary Complications After Hematopoietic Cell Transplant.

BACKGROUND: Pulmonary complications, including infections, are highly prevalent in patients after hematopoietic cell transplantation with chronic graft-vs-host disease. These comorbid diseases can make the diagnosis of early lung graft-vs-host disease (bronchiolitis obliterans syndrome) challenging. A quantitative method to differentiate among these pulmonary diseases can address diagnostic challenges and facilitate earlier and more targeted therapy. STUDY DESIGN AND METHODS: We conducted a single-center study of 66 patients with CT chest scans analyzed with a quantitative imaging tool known as parametric response mapping. Parametric response mapping results were correlated with pulmonary function tests and clinical characteristics. Five parametric response mapping metrics were applied to K-means clustering and support vector machine models to distinguish among posttransplantation lung complications solely from quantitative output. RESULTS: Compared with parametric response mapping, spirometry showed a moderate correlation with radiographic air trapping, and total lung capacity and residual volume showed a strong correlation with radiographic lung volumes. K-means clustering analysis distinguished four unique clusters. Clusters 2 and 3 represented obstructive physiology (encompassing 81% of patients with bronchiolitis obliterans syndrome) in increasing severity (percentage air trapping 15.6% and 43.0%, respectively). Cluster 1 was dominated by normal lung, and cluster 4 was characterized by patients with parenchymal opacities. A support vector machine algorithm differentiated bronchiolitis obliterans syndrome with a specificity of 88%, sensitivity of 83%, accuracy of 86%, and an area under the receiver operating characteristic curve of 0.85. INTERPRETATION: Our machine learning models offer a quantitative approach for the identification of bronchiolitis obliterans syndrome vs other lung diseases, including late pulmonary complications after hematopoietic cell transplantation.

Physiology of the Assisted Circulation in Cardiogenic Shock: A State-of-the-Art Perspective.

Mechanical circulatory support (MCS) has made rapid progress over the last 3 decades. This was driven by the need to develop acute and chronic circulatory support as well as by the limited organ availability for heart transplantation. The growth of MCS was also driven by the use of extracorporeal membrane oxygenation (ECMO) after the worldwide H1N1 influenza outbreak of 2009. The majority of mechanical pumps (ECMO and left ventricular assist devices) are currently based on continuous flow pump design. It is interesting to note that in the current era, we have reverted from the mammalian pulsatile heart back to the continuous flow pumps seen in our simple multicellular ancestors. This review will highlight key physiological concepts of the assisted circulation from its effects on cardiac dynamic to principles of cardiopulmonary fitness. We will also examine the physiological principles of the ECMO-assisted circulation, anticoagulation, and the haemocompatibility challenges that arise when the blood is exposed to a foreign mechanical circuit. Finally, we conclude with a perspective on smart design for future development of devices used for MCS.

Iron: an essential nutrient for Aspergillus fumigatus and a fulcrum for pathogenesis.

PURPOSE OF REVIEW: Aspergillus fumigatus is a ubiquitous saprophytic fungus that can cause life-threatening invasive aspergillosis in immunocompromised patients. Apart from the immune status of the host only a few characterized virulence factors have been identified. In this review, we describe the role of iron in the manifestation of A. fumigatus virulence. RECENT FINDINGS: We gathered recent clinical evidence suggesting that tissue iron overload increases the risk of invasive aspergillosis occurrence. Furthermore, we summarize the mechanisms that A. fumigatus employs to achieve iron homeostasis and their importance in A. fumigatus proliferation in vitro. We describe two recent in-vivo models that clearly demonstrate the importance of iron in A. fumigatus growth and invasion. SUMMARY: Based on these recent findings, therapy aimed at managing A. fumigatus iron homeostasis locally could make conditions more favorable to the host.

Microhemorrhage-associated tissue iron enhances the risk for Aspergillus fumigatus invasion in a mouse model of airway transplantation.

Invasive pulmonary disease due to the mold Aspergillus fumigatus can be life-threatening in lung transplant recipients, but the risk factors remain poorly understood. To study this process, we used a tracheal allograft mouse model that recapitulates large airway changes observed in patients undergoing lung transplantation. We report that microhemorrhage-related iron content may be a major determinant of A. fumigatus invasion and, consequently, its virulence. Invasive growth was increased during progressive alloimmune-mediated graft rejection associated with high concentrations of ferric iron in the graft. The role of iron in A. fumigatus invasive growth was further confirmed by showing that this invasive phenotype was increased in tracheal transplants from donor mice lacking the hemochromatosis gene (Hfe-/- ). The invasive phenotype was also increased in mouse syngrafts treated with topical iron solution and in allograft recipients receiving deferoxamine, a chelator that increases iron bioavailability to the mold. The invasive growth of the iron-intolerant A. fumigatus double-knockout mutant (ΔsreA/ΔcccA) was lower than that of the wild-type mold. Alloimmune-mediated microvascular damage and iron overload did not appear to impair the host's immune response. In human lung transplant recipients, positive staining for iron in lung transplant tissue was more commonly seen in endobronchial biopsy sections from transplanted airways than in biopsies from the patients' own airways. Collectively, these data identify iron as a major determinant of A. fumigatus invasive growth and a potential target to treat or prevent A. fumigatus infections in lung transplant patients.

Enhanced Electrochemical Sensing with Carbon Nanotubes Modified with Bismuth and Magnetic Nanoparticles in a Lab-on-a-Chip.

Iron plays an especially important role in human physiological functions and pathological impairments. The superior properties of carbon nanotubes (CNTs) and their modification with bismuth and magnetic nanoparticles as developed in this work have led to an extraordinary and novel material to facilitate ultrasensitive detection in the nanomolar range. Here, we present the development of an electrochemical sensor for detection of ferrous (Fe2+) and ferric (Fe3+) iron by means of CNTs modified with bismuth and magnetic nanoparticles for higher sensitivity of detection. The sensor fabrication includes microfabrication methodologies, soft lithography, and electrodeposition. Cyclic voltammetry and differential pulse voltammetry are used for the electroanalytical studies and detection of the ions in samples. The sensor has a dynamic range of detection from 0.01 nm to 10 mm. The performance of the sensor with modified CNTs was explored for sensitivity and specificity. CNTs, modified with bismuth and magnetic nanoparticles by means of electrodeposition, enhanced the detection limit significantly down to 0.01 nm.

Microvascular injury after lung transplantation.

PURPOSE OF REVIEW: Airway microvessel injury following transplantation has been implicated in the development of chronic rejection. This review focuses on the most recent developments in the field describing preclinical and clinical findings that further implicate the loss of microvascular integrity as an important pathological event in the evolution of irreversible fibrotic remodeling. RECENT FINDINGS: When lungs are transplanted, the airways appear vulnerable from the perspective of perfusion. Two vascular systems are lost, the bronchial artery and the lymphatic circulations, and the remaining vasculature in the airways expresses donor antigens susceptible to alloimmune-mediated injury via innate and adaptive immune mechanisms. Preclinical studies indicate the importance of hypoxia-inducible factor-1α in mediating microvascular repair and that hypoxia-inducible factor-1α can be upregulated to bolster endogenous repair. SUMMARY: Airway microvascular injury is a feature of lung transplantation that limits short-term and long-term organ health. Although some problems are attributable to a missing bronchial artery circulation, another significant issue involves alloimmune-mediated injury to transplant airway microvessels. For a variety of reasons, bronchial artery revascularization surgery at the time of transplantation has not been widely adopted, and the current best hope for this era may be new medical approaches that offer protection against immune-mediated vascular injury or that promote microvascular repair.

Effects of Iron Chelators on the Formation and Development of Aspergillus fumigatus Biofilm.

Iron acquisition is crucial for the growth of Aspergillus fumigatus. A. fumigatus biofilm formation occurs in vitro and in vivo and is associated with physiological changes. In this study, we assessed the effects of Fe chelators on biofilm formation and development. Deferiprone (DFP), deferasirox (DFS), and deferoxamine (DFM) were tested for MIC against a reference isolate via a broth macrodilution method. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to DFP, DFM, DFP plus FeCl3, or FeCl3 alone. A preformed biofilm was exposed to DFP with or without FeCl3. The DFP and DFS MIC50 against planktonic A. fumigatus was 1,250 µM, and XTT gave the same result. DFM showed no planktonic inhibition at concentrations of ≤2,500 µM. By XTT testing, DFM concentrations of <1,250 µM had no effect, whereas DFP at 2,500 µM increased biofilms forming in A. fumigatus or preformed biofilms (P < 0.01). DFP at 156 to 2,500 µM inhibited biofilm formation (P < 0.01 to 0.001) in a dose-responsive manner. Biofilm formation with 625 µM DFP plus any concentration of FeCl3 was lower than that in the controls (P < 0.05 to 0.001). FeCl3 at ≥625 µM reversed the DFP inhibitory effect (P < 0.05 to 0.01), but the reversal was incomplete compared to the controls (P < 0.05 to 0.01). For preformed biofilms, DFP in the range of ≥625 to 1,250 µM was inhibitory compared to the controls (P < 0.01 to 0.001). FeCl3 at ≥625 µM overcame inhibition by 625 µM DFP (P < 0.001). FeCl3 alone at ≥156 µM stimulated biofilm formation (P < 0.05 to 0.001). Preformed A. fumigatus biofilm increased with 2,500 µM FeCl3 only (P < 0.05). In a strain survey, various susceptibilities of biofilms of A. fumigatus clinical isolates to DFP were noted. In conclusion, iron stimulates biofilm formation and preformed biofilms. Chelators can inhibit or enhance biofilms. Chelation may be a potential therapy for A. fumigatus, but we show here that chelators must be chosen carefully. Individual isolate susceptibility assessments may be needed.

Application of a non-amplification-based technology to detect invasive fungal pathogens.

Current diagnostic techniques for fungal diseases could be improved with respect to sensitivity, specificity, and timeliness. To address this clinical need, we adapted a non-amplification-based nucleic acid detection technology to identify fungal pathogens. We demonstrate a high-specificity, detection sensitivity, reproducibility, and multiplex capacity for detecting fungal strains.

Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles.

Airway tissue ischemia and hypoxia in human lung transplantation is a consequence of the sacrifice of the bronchial circulation during the surgical procedure and is a major risk factor for the development of airway anastomotic complications. Augmented expression of hypoxia-inducible factor (HIF)-1α promotes microvascular repair and alleviates allograft ischemia and hypoxia. Deferoxamine mesylate (DFO) is an FDA-approved iron chelator which has been shown to upregulate cellular HIF-1α. Here, we developed a nanoparticle formulation of DFO that can be topically applied to airway transplants at the time of surgery. In a mouse orthotopic tracheal transplant (OTT) model, the DFO nanoparticle was highly effective in enhancing airway microvascular perfusion following transplantation through the production of the angiogenic factors, placental growth factor (PLGF) and stromal cell-derived factor (SDF)-1. The endothelial cells in DFO treated airways displayed higher levels of p-eNOS and Ki67, less apoptosis, and decreased production of perivascular reactive oxygen species (ROS) compared to vehicle-treated airways. In summary, a DFO formulation topically-applied at the time of surgery successfully augmented airway anastomotic microvascular regeneration and the repair of alloimmune-injured microvasculature. This approach may be an effective topical transplant-conditioning therapy for preventing airway complications following clinical lung transplantation.

Efficacy of transthoracic echocardiography for diagnosing heart failure in septic shock.

BACKGROUND: Cardiac dysfunction occurs in up to 80% of patients with septic shock. Transthoracic echocardiography (TTE) is an ideal tool for the detailed characterization of cardiac function. Its feasibility is perceived to be poor in critically ill patients, but this has never been studied. To address this question, the authors evaluated the efficacy of TTE to diagnose heart failure in septic shock. METHODS: This was a retrospective study. Patients admitted to the intensive care unit with septic shock and who had a TTE within 72 hours of intensive care unit admission were identified by a computer algorithm and validated by chart review. Echocardiography images were reviewed by a single cardiologist blinded to clinical outcomes. Clinical information was collected from patients' medical record. RESULTS: Seventy-six patients met the studies' inclusion criteria. The feasibility of TTE to calculate left ventricular ejection fraction was 90% and to assess diastolic function was 74%. Significant mitral regurgitation or aortic stenosis was the most frequent impediments for the assessment of diastolic function. Seventy-four percent of all patients showed some type of cardiac dysfunction (left or right ventricular systolic dysfunction and/or left ventricular diastolic dysfunction). In regression analyses, TTE feasibility was not impacted by factors previously associated with poor image acquisition: high body mass index, mechanical ventilation, tachycardia, advanced age or high severity of illness. CONCLUSIONS: This study demonstrated that TTE is a useful tool to assess myocardial function in critically ill patients and suggested its potential to assist in the management of patients with septic shock.

Aspergillus fumigatus invasion increases with progressive airway ischemia.

Despite the prevalence of Aspergillus-related disease in immune suppressed lung transplant patients, little is known of the host-pathogen interaction. Because of the mould's angiotropic nature and because of its capacity to thrive in hypoxic conditions, we hypothesized that the degree of Aspergillus invasion would increase with progressive rejection-mediated ischemia of the allograft. To study this relationship, we utilized a novel orthotopic tracheal transplant model of Aspergillus infection, in which it was possible to assess the effects of tissue hypoxia and ischemia on airway infectivity. Laser Doppler flowmetry and FITC-lectin were used to determine blood perfusion, and a fiber optic microsensor was used to measure airway tissue oxygen tension. Fungal burden and depth of invasion were graded using histopathology. We demonstrated a high efficacy (80%) for producing a localized fungal tracheal infection with the majority of infection occurring at the donor-recipient anastomosis; Aspergillus was more invasive in allogeneic compared to syngeneic groups. During the study period, the overall kinetics of both non-infected and infected allografts was similar, demonstrating a progressive loss of perfusion and oxygenation, which reached a nadir by days 10-12 post-transplantation. The extent of Aspergillus invasion directly correlated with the degree of graft hypoxia and ischemia. Compared to the midtrachea, the donor-recipient anastomotic site exhibited lower perfusion and more invasive disease; a finding consistent with clinical experience. For the first time, we identify ischemia as a putative risk factor for Aspergillus invasion. Therapeutic approaches focused on preserving vascular health may play an important role in limiting Aspergillus infections.

Propofol infusion syndrome resuscitation with extracorporeal life support: a case report and review of the literature.

We report a case of propofol infusion syndrome (PRIS) in a young female treated for status epilepticus. In this case, PRIS rapidly evolved to full cardiovascular collapse despite aggressive supportive care in the intensive care unit, as well as prompt discontinuation of the offending agent. She progressed to refractory cardiac arrest requiring emergent initiation of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (CPR). She regained a perfusing rhythm after prolonged (>8 hours) asystole, was weaned off ECMO and eventually all life support, and was discharged to home. We also present a review of the available literature on the use of ECMO for PRIS.