Cell-Free DNA Maps Tissue Injury and Correlates with Disease Severity in Lung Transplant Candidates.

Rationale: Plasma cell-free DNA levels correlate with disease severity in many conditions. Pretransplant cell-free DNA may risk stratify lung transplant candidates for post-transplant complications. Objectives: To evaluate if pretransplant cell-free DNA levels and tissue sources identify patients at high risk of primary graft dysfunction and other pre- and post-transplant outcomes. Methods: This multicenter, prospective cohort study recruited 186 lung transplant candidates. Pretransplant plasma samples were collected to measure cell-free DNA. Bisulfite sequencing was performed to identify the tissue sources of cell-free DNA. Multivariable regression models determined the association between cell-free DNA levels and the primary outcome of primary graft dysfunction and other transplant outcomes, including Lung Allocation Score, chronic lung allograft dysfunction, and death. Measurements and Main Results: Transplant candidates had twofold greater cell-free DNA levels than healthy control patients (median [interquartile range], 23.7 ng/ml [15.1-35.6] vs. 12.9 ng/ml [9.9-18.4]; P < 0.0001), primarily originating from inflammatory innate immune cells. Cell-free DNA levels and tissue sources differed by native lung disease category and correlated with the Lung Allocation Score (P < 0.001). High pretransplant cell-free DNA increased the risk of primary graft dysfunction (odds ratio, 1.60; 95% confidence interval [CI], 1.09-2.46; P = 0.0220), and death (hazard ratio, 1.43; 95% CI, 1.07-1.92; P = 0.0171) but not chronic lung allograft dysfunction (hazard ratio, 1.37; 95% CI, 0.97-1.94; P = 0.0767). Conclusions: Lung transplant candidates demonstrate a heightened degree of tissue injury with elevated cell-free DNA, primarily originating from innate immune cells. Pretransplant plasma cell-free DNA levels predict post-transplant complications.

Association Between Patient Race and Ethnicity and Outcomes With COVID-19: A Retrospective Analysis From a Large Mid-Atlantic Health System.

BACKGROUND: Members of racial and ethnic minority groups have been disproportionately impacted by coronavirus-2019 (COVID-19). The objective of the study is to describe associations between race and ethnicity on clinical outcomes such as need for mechanical ventilation and mortality. METHODS: Retrospective cohort study of patients with severe COVID-19 infection admitted within a large, not-for-profit healthcare system in the mid-Atlantic region between March and July, 2020. Patient demographic data and clinical outcomes were abstracted from the electronic health record. Logistic regressions were performed to estimate associations between race and ethnicity and the clinical outcomes. RESULTS: The study population (N = 2931) was stratified into 1 of 3 subgroups: non-Hispanic White (n = 466), non-Hispanic Black (n = 1611), and Hispanic (n = 654). The average age of White, Black, and Hispanic patients was 69 ± 17.06, 64 ± 15.9, and 50 ± 15.53 years old, respectively (P < .001). Compared to White patients, Black and Hispanic patients were at increased odds of needing mechanical ventilation due to COVID-19 pneumonia (odds ratio [OR] Black = 1.35, 95% confidence interval [CI] = 1.04 to 1.75, P < .05; OR Hispanic = 1.43, 95% CI = 1.06 to 1.93, P < .05). When compared to White patients, Hispanic patients were at decreased odds of death (OR = 0.45, 95% CI = 0.32 to 0.63, P < .001). However, when adjusting for age, there were no statistically significant differences in the odds of death between these groups (adjusted OR [aOR] Black = 1.05, 95% CI = 0.80 to 1.38, P = .71; aOR Hispanic = 1.10, 95% CI = 0.76 to 1.60, P = .62). CONCLUSION: Our analysis demonstrated that Hispanic patients were more likely require mechanical ventilation but had lower mortality when compared to White patients, with lower average age likely mediating this association. These findings emphasize the importance of outreach efforts to communities of color to increase prevention measures and vaccination uptake to reduce infection with COVID-19.

The interplay of inflammation and coagulation in COVID-19 Patients receiving extracorporeal membrane oxygenation support.

OBJECTIVE: Bleeding and thrombosis are common complications during Extracorporeal Membrane Oxygenation (ECMO) support for COVID-19 patients. We sought to examine the relationship between inflammatory status, coagulation effects, and observed bleeding and thrombosis in patients receiving venovenous (VV) ECMO for COVID-19 respiratory failure. STUDY DESIGN: Cross-sectional cohort study. SETTINGS: Quaternary care institution. PATIENTS: The study period from April 1, 2020, to January 1, 2021, we included all patients with confirmed COVID-19 who received VV ECMO support. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Thirty-two patients were supported with VV ECMO during the study period, and 17 patients (53%) survived to hospital discharge. The ECMO nonsurvivors mean lactate dehydrogenase (LDH) levels were markedly elevated in comparison to survivors (1046 u/L [IQR = 509, 1305] vs 489 u/L [385 658], p = 0.003). Platelet/fibrinogen dysfunction, as reflected by the low Maximum Amplitude (MA) on viscoelastic testing, was worse in nonsurvivors (65.25 mm [60.68, 67.67] vs 74.80 mm [73.10, 78.40], p = 0.01). Time-group interaction for the first seven days of ECMO support, showed significantly lower platelet count in the nonsurvivors (140 k/ul [103, 170] vs 189.5 k/ul [ 146, 315], p < 0.001) and higher D-dimer in (21 µg/mL [13, 21] vs 14 µg/mL [3, 21], p < 0.001) in comparison to the survivors. Finally, we found profound statistically significant correlations between the clinical markers of inflammation and markers of coagulation in the nonsurvivors group. The ECMO nonsurvivors experienced higher rate of bleeding (73.3% vs 35.3%, p = 0.03), digital ischemia (46.7% vs 11.8%, p = 0.02), acute renal failure (60% vs 11.8%, p = 0.01) and bloodstream infection (60% vs 23.5%, p = 0.03). CONCLUSION: The correlation between inflammation and coagulation in the nonsurvivors supported with VV ECMO could indicate dysregulated inflammatory response and worse clinical outcomes.

Extracorporeal membrane oxygenation for COVID-19 induced hypoxia: Single-center study.

INTRODUCTION: The pandemic of the coronavirus disease 2019 (COVID-19) and associated pneumonia represent a clinical and scientific challenge. The role of Extracorporeal Membrane Oxygenation (ECMO) in such a crisis remains unclear. METHODS: We examined COVID-19 patients who were supported for acute respiratory failure by both conventional mechanical ventilation (MV) and ECMO at a tertiary care institution in Washington DC. The study period extended from March 23 to April 29. We identified 59 patients who required invasive mechanical ventilation. Of those, 13 patients required ECMO. RESULTS: Nine out of 13 ECMO (69.2%) patients were decannulated from ECMO. All-cause ICU mortality was comparable between both ECMO and MV groups (6 patients [46.15%] vs. 22 patients [47.82 %], p = 0.92). ECMO non-survivors vs survivors had elevated D-dimer (9.740 mcg/ml [4.84-20.00] vs. 3.800 mcg/ml [2.19-9.11], p = 0.05), LDH (1158 ± 344.5 units/L vs. 575.9 ± 124.0 units/L, p = 0.001), and troponin (0.4315 ± 0.465 ng/ml vs. 0.034 ± 0.043 ng/ml, p = 0.04). Time on MV as expected was significantly longer in ECMO groups (563.3 hours [422.1-613.9] vs. 247.9 hours [101.8-479] in MV group, p = 0.0009) as well as ICU length of stay 576.2 hours [457.5-652.8] in ECMO group vs. 322.2 hours [120.6-569.3] in MV group, p = 0.012). CONCLUSION: ECMO is a supportive intervention for COVID-19 associated pneumonia that could be considered if the optimum mechanical ventilation is deemed ineffective. Biomarkers such as D-dimer, LDH, and troponin could help with discerning the clinical prognosis in patients with COVID-19 pneumonia.

Baseline Lung Allograft Dysfunction After Bilateral Lung Transplantation Is Associated With an Increased Risk of Death: Results From a Multicenter Cohort Study.

Background: A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. Methods: This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. Results: BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; P = 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; P = 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; P = 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log10(donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: -0.0095 [0.0007] versus -0.0109 [0.0007]; P = 0.15). Conclusions: BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.

Extreme elevations of donor-derived cell-free DNA increases the risk of chronic lung allograft dysfunction and death, even without clinical manifestations of disease.

BACKGROUND: Lung transplant recipients are traditionally monitored with pulmonary function testing (PFT) and lung biopsy to detect post-transplant complications and guide treatment. Plasma donor-derived cell free DNA (dd-cfDNA) is a novel molecular approach of assessing allograft injury, including subclinical allograft dysfunction. The aim of this study was to determine if episodes of extreme molecular injury (EMI) in lung transplant recipients increases the risk of chronic lung allograft dysfunction (CLAD) or death. METHODS: This multicenter prospective cohort study included 238 lung transplant recipients. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. EMI was defined as a dd-cfDNA above the third quartile of levels observed for acute rejection (dd-cfDNA level of ≥5% occurring after 45 days post-transplant). EMI was categorized as Secondary if associated with co-existing acute rejection, infection or PFT decline; or Primary if not associated with these conditions. RESULTS: EMI developed in 16% of patients at a median 343.5 (IQR: 177.3-535.5) days post-transplant. Over 50% of EMI episodes were classified as Primary. EMI was associated with an increased risk of severe CLAD or death (HR: 2.78, 95% CI: 1.26-6.22, p = 0.012). The risk remained consistent for the Primary EMI subgroup (HR: 2.34, 95% CI 1.18-4.85, p = 0.015). Time to first EMI episode was a significant predictor of the likelihood of developing CLAD or death (AUC=0.856, 95% CI=0.805-0.908, p < 0.001). CONCLUSIONS: Episodes of EMI in lung transplant recipients are often isolated and may not be detectable with traditional clinical monitoring approaches. EMI is associated with an increased risk of severe CLAD or death, independent of concomitant transplant complications.

Palliative Care for Patients on Extracorporeal Membrane Oxygenation for COVID-19 Infection.

BACKGROUND: Critically ill patients with COVID-19 infection on extracorporeal membrane oxygenation (ECMO) face high morbidity and mortality. Palliative care consultation may benefit these patients and their families. Prior to the pandemic, our institution implemented a policy of automatic palliative care consultation for all patients on ECMO due to the high mortality, medical complexity, and psychosocial distress associated with these cases. OBJECTIVES: The main objective was to describe the role of the palliative care team for patients on ECMO for COVID-19 infection. The secondary objective was to describe the clinical outcomes for this cohort. DESIGN: Case series. SETTINGS/SUBJECTS: All patients age 18 or older infected by the novel coronavirus who required cannulation on ECMO from March through July of 2020, at an urban, academic medical center in the United States. Inter-disciplinary palliative care consultation occurred for all patients. RESULTS: Twenty-three patients (median age 43 years [range 28-64], mean body mass index 34.9 kg/m2 [SD 9.2], 65% Hispanic ethnicity) were cannulated on ECMO. Eleven patients died during the hospitalization (48%). Patients older than 50 years of age demonstrated a trend toward increased odds of death compared to those younger than 50 years of age (OR 9.1, P = 0.07). Patients received an average of 6.8 (SD 3.7) palliative clinical encounters across all disciplines. The actions provided by the palliative care team included psychosocial support and counseling, determination of surrogate decision maker (for 100% of patients), pain management (83%), and non-pain symptom management (83%). CONCLUSIONS: Here, we present one of the first studies describing the patient characteristics, outcomes, and palliative care actions for critically ill patients with COVID-19 on ECMO. Almost half of the patients in this cohort died during their hospitalization. Given the high morbidity and mortality of this condition, we recommend involvement of palliative care for patients/families with COVID-19 infection who are on ECMO. The impact of palliative care on patient and family outcomes, such as symptom control, satisfaction with communication, rates of anxiety, and grief experience merits further investigation.

A Multimodal Sepsis Quality-Improvement Initiative Including 24/7 Screening and a Dedicated Sepsis Response Team-Reduced Readmissions and Mortality.

OBJECTIVES: To evaluate if a hospitalwide sepsis performance improvement initiative improves compliance with the Centers for Medicare and Medicaid Services-mandated sepsis bundle interventions and patient outcomes. STUDY DESIGN: Retrospective analysis comparing 6 months before and 14 months after intervention. SETTING: Tertiary teaching hospital in Washington, DC. SUBJECTS: Patients admitted with a diagnosis of sepsis to a tertiary hospital. INTERVENTIONS: Implementation of a multimodal quality-improvement initiative. MEASUREMENTS AND MAIN RESULTS: A total of 4,102 patients were diagnosed with sepsis, severe sepsis, or septic shock during the study period, 861 patients (21%) were diagnosed during a 6-month preintervention period, and 3,241 (79%) were diagnosed in a 13-month postintervention period. Adjusted for patient case-mix, the prevalence of simple sepsis increased by 12%, but it decreased for severe sepsis and septic shock by 5.3% and 6.9%, respectively. Compliance with all sepsis bundle interventions increased by 31.1 percentage points (p < 0.01). All-cause hospital readmission and readmission due to infection were both reduced by 1.6% and 1.7 percentage points (p < 0.05). Death from any sepsis diagnosis was reduced 4.5% (p < 0.01). Death from severe sepsis and septic shock both was reduced by 5% (p < 0.01) and 6.5% (p < 0.01), respectively. CONCLUSIONS: After the implementation of multimodal sepsis performance initiatives, we observed a higher prevalence of sepsis secondary to screening but a lower prevalence of severe sepsis and septic shock, an improvement in compliance with the sepsis bundle interventions bundle, as well as reduction in hospital readmission and all- cause mortality rate.

Assessing the need for transfer to the intensive care unit for Coronavirus-19 disease: Epidemiology and risk factors.

BACKGROUND: Although many patients with coronavirus disease 2019 (Covid-19) require direct admission to the intensive care unit (ICU), some are sent after admission. Clinicians require an understanding of this phenomenon and various risk stratification approaches for recognizing these subjects. METHODS: We examined all Covid-19 patients sent initially to a ward who subsequently required care in the ICU. We examined the timing transfer and attempted to develop a risk score based on baseline variables to predict progressive disease. We evaluated the utility of the CURB-65 score at identifying the need for ICU transfer. RESULTS: The cohort included 245 subjects (mean age 59.0 ± 14.2 years, 61.2% male) and 20% were eventually sent to the ICU. The median time to transfer was 2.5 days. Approximately 1/3rd of patients were not moved until day 4 or later and the main reason for transfer (79.2%) was worsening respiratory failure. A baseline absolute lymphocyte count (ALC) of ≤0.8 103/ml and a serum ferritin ≥1000 ng/ml were independently associated with ICU transfer. Co-morbid illnesses did not correlate with eventual ICU care. Neither a risk score based on a low ALC and/or high ferritin nor the CURB-65 score performed well at predicting need for transfer. CONCLUSION: Covid-19 patients admitted to general wards face a significant risk for deterioration necessitating ICU admission and respiratory failure can occur late in this disease. Neither baseline clinical factors nor the CURB-65 score perform well as screening tests to categorize these subjects as likely to progress to ICU care.