Safety and Outcome of High-Flow Nasal Oxygen Therapy Outside ICU Setting in Hypoxemic Patients With COVID-19.

OBJECTIVE: High-flow nasal oxygen (HFNO) therapy is frequently applied outside ICU setting in hypoxemic patients with COVID-19. However, safety concerns limit more widespread use. We aimed to assess the safety and clinical outcomes of initiation of HFNO therapy in COVID-19 on non-ICU wards. DESIGN: Prospective observational multicenter pragmatic study. SETTING: Respiratory wards and ICUs of 10 hospitals in The Netherlands. PATIENTS: Adult patients treated with HFNO for COVID-19-associated hypoxemia between December 2020 and July 2021 were included. Patients with treatment limitations were excluded from this analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Outcomes included intubation and mortality rate, duration of hospital and ICU stay, severity of respiratory failure, and complications. Using propensity-matched analysis, we compared patients who initiated HFNO on the wards versus those in ICU. Six hundred eight patients were included, of whom 379 started HFNO on the ward and 229 in the ICU. The intubation rate in the matched cohort ( n = 214 patients) was 53% and 60% in ward and ICU starters, respectively ( p = 0.41). Mortality rates were comparable between groups (28-d [8% vs 13%], p = 0.28). ICU-free days were significantly higher in ward starters (21 vs 17 d, p < 0.001). No patient died before endotracheal intubation, and the severity of respiratory failure surrounding invasive ventilation and clinical outcomes did not differ between intubated ward and ICU starters (respiratory rate-oxygenation index 3.20 vs 3.38; Pa o2 :F io2 ratio 65 vs 64 mm Hg; prone positioning after intubation 81 vs 78%; mortality rate 17 vs 25% and ventilator-free days at 28 d 15 vs 13 d, all p values > 0.05). CONCLUSIONS: In this large cohort of hypoxemic patients with COVID-19, initiation of HFNO outside the ICU was safe, and clinical outcomes were similar to initiation in the ICU. Furthermore, the initiation of HFNO on wards saved time in ICU without excess mortality or complicated course. Our results indicate that HFNO initiation outside ICU should be further explored in other hypoxemic diseases and clinical settings aiming to preserve ICU capacity and healthcare costs.

Clinical Characteristics and Outcomes of Immunocompromised Patients With Coronavirus Disease 2019 Caused by the Omicron Variant: A Prospective, Observational Study.

BACKGROUND: Illness after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is less severe compared with previous variants. Data on the disease burden in immunocompromised patients are lacking. We investigated the clinical characteristics and outcomes of immunocompromised patients with coronavirus disease 2019 (COVID-19) caused by Omicron. METHODS: Organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients infected with the Omicron variant were included. Characteristics of consenting patients were collected and patients were contacted regularly until symptom resolution. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed. RESULTS: 114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received 3 mRNA vaccinations. While only 1 patient died, 23 (20%) were hospitalized for a median of 11 days. A low SARS-CoV-2 immunoglobulin G (IgG) antibody response (<300 BAU [binding antibody units]/mL) at diagnosis, being older, being a lung transplant recipient, having more comorbidities, and having a higher frailty score were associated with hospital admission (all P < .01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% had a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of these patients, and 1 died. CONCLUSIONS: While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. In addition to vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients.

High Levels of Neutrophil Extracellular Traps Persist in the Lower Respiratory Tract of Critically Ill Patients With Coronavirus Disease 2019.

Lower respiratory tract (LRT) disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can deteriorate to acute respiratory distress syndrome (ARDS). Because the release of neutrophil extracellular traps (NETs) is implicated in ARDS pathogenesis, we investigated the presence of NETs and correlates of pathogenesis in blood and LRT samples of critically ill patients with COVID-19. Plasma NET levels peaked early after intensive care unit admission and were correlated with the SARS-CoV-2 RNA load in sputum and levels of neutrophil-recruiting chemokines and inflammatory markers in plasma samples. The baseline plasma NET quantity was correlated with disease severity but was not associated with soluble markers of thrombosis or with development of thrombosis. High NET levels were present in LRT samples and persisted during the course of COVID-19, consistent with the detection of NETs in bronchi and alveolar spaces in lung tissue from deceased patient with COVID-19. Thus, NETs are produced and retained in the LRT of critically ill patients with COVID-19 and could contribute to SARS-CoV-2-induced ARDS disease.

The Seraph®-100 Microbind Affinity Blood Filter Does Not Affect Vancomycin, Tacrolimus, and Mycophenolic Acid Plasma Concentrations.

Extracorporeal blood purification is considered an adjunct therapy in critically ill patients with life-threatening conditions such as sepsis and septic shock. It consists of cytokine removal, removal of endotoxins, a combination of both, or the removal of pathogens themselves. The latter technique was introduced for clinical application very recently. This case study describes a case of a 69-year-old female lung transplant recipient patient with a persistent VV-ECMO-related septic deep vein thrombosis with continuous renal replacement therapy-dependent acute kidney injury initiated on the Seraph®-100 Microbind Affinity Filter in order to control the persistent bacteraemia with coagulase-negative staphylococci. Drug plasma concentrations (vancomycin, tacrolimus, and mycophenolic acid) were measured before and after the device to calculate absorber-related drug clearance.

COVID-19 in solid organ transplant recipients: a single-center experience.

Solid organ transplant (SOT) recipients may be at risk for severe COVID-19. Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the effective treatment strategy for these patients is unknown. We describe our institutional experience with COVID-19 in SOT. Demographic, clinical, and treatment data were extracted from the electronic patient files. A total of 23 SOT transplant recipients suffering from COVID-19 were identified (n = 3 heart; n = 15 kidney; n = 1 kidney-after-heart; n = 3 lung, and n = 1 liver transplant recipient). The presenting symptoms were similar to nonimmunocompromised patients. Eighty-three percent (19/23) of the patients required hospitalization, but only two of these were transferred to the intensive care unit. Five patients died from COVID-19; all had high Clinical Frailty Scores. In four of these patients, mechanical ventilation was deemed futile. In 57% of patients, the immunosuppressive therapy was not changed and only three patients were treated with chloroquine. Most patients recovered without experimental antiviral therapy. Modification of the immunosuppressive regimen alone could be a therapeutic option for SOT recipients suffering from moderate to severe COVID-19. Pre-existent frailty is associated with death from COVID-19.

Impact of donor lung quality on post-transplant recipient outcome in the Lung Allocation Score era in Eurotransplant - a historical prospective study.

The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2 /FiO2  ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized.

High-dose posaconazole for azole-resistant aspergillosis and other difficult-to-treat mould infections.

BACKGROUND: Oral follow-up therapy is problematic in moulds with reduced azole-susceptibility, such as azole-resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L-AmB) is advocated by guidelines for the treatment of azole-resistant aspergillosis infections. Preclinical research indicates that high-dose posaconazole (HD-POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe. OBJECTIVES: To describe our experience with the use of oral HD-POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint. PATIENTS/METHODS: We review evidence supporting the use of HD-POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose. RESULTS: Sixteen patients were treated intentionally with HD-POS for voriconazole-resistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3-4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3-4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale. CONCLUSIONS: High-dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible.

Enhanced Bruton's tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis.

RATIONALE: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice. METHODS: B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis. RESULTS: More IgA+ memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = - 0.50). Bruton's tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA+ germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88). CONCLUSION: Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.

Lung allocation score: the Eurotransplant model versus the revised US model - a cross-sectional study.

Both Eurotransplant (ET) and the US use the lung allocation score (LAS) to allocate donor lungs. In 2015, the US implemented a new algorithm for calculating the score while ET has fine-tuned the original model using business rules. A comparison of both models in a contemporary patient cohort was performed. The rank positions and the correlation between both scores were calculated for all patients on the active waiting list in ET. On February 6th 2017, 581 patients were actively listed on the lung transplant waiting list. The median LAS values were 32.56 and 32.70 in ET and the US, respectively. The overall correlation coefficient between both scores was 0.71. Forty-three per cent of the patients had a < 2 point change in their LAS. US LAS was more than two points lower for 41% and more than two points higher for 16% of the patients. Median ranks and the 90th percentiles for all diagnosis groups did not differ between both scores. Implementing the 2015 US LAS model would not significantly alter the current waiting list in ET.

Ten-Year Survival in Patients with Idiopathic Pulmonary Fibrosis After Lung Transplantation.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal fibrosing lung disease with a median survival of approximately 3 years after diagnosis. The only medical option to improve survival in IPF is lung transplantation (LTX). The purpose of this study was to evaluate trajectory data of IPF patients listed for LTX and to investigate the survival after LTX. METHODS AND RESULTS: Data were retrospectively collected from September 1989 until July 2011 of all IPF patients registered for LTX in the Netherlands. Patients were included after revision of the diagnosis based on the criteria set by the ATS/ERS/JRS/ALAT. Trajectory data, clinical data at time of screening, and donor data were collected. In total, 98 IPF patients were listed for LTX. During the waiting list period, 30 % of the patients died. Mean pulmonary artery pressure, 6-min walking distance, and the use of supplemental oxygen were significant predictors of mortality on the waiting list. Fifty-two patients received LTX with a median overall survival after transplantation of 10 years. CONCLUSIONS: This study demonstrated a 10-year survival time after LTX in IPF. Furthermore, our study demonstrated a significantly better survival after bilateral LTX in IPF compared to single LTX although bilateral LTX patients were significantly younger.

Incidence of viral respiratory pathogens causing exacerbations in adult cystic fibrosis patients.

Respiratory infections caused by respiratory viruses are common in paediatric cystic fibrosis (CF) patients and are associated with increased morbidity. There is only little data on the incidence of viral respiratory pathogens causing exacerbations in the adult CF patient population. In this observational pilot study we show, by using molecular as well as conventional techniques for viral isolation, that during 1 y a viral pathogen could be isolated in 8/24 (33%) adult CF patients who presented with a pulmonary exacerbation. This result shows that there is a considerable incidence of viral pathogens in pulmonary exacerbations in adult CF patients. Newly identified viruses such as pandemic influenza A/H1N1, human metapneumovirus, human bocavirus, and human coronavirus NL63 were not detected in our population, except for 1 human coronavirus NL63.

Diagnostic accuracy of eNose 'breathprints' for therapeutic drug monitoring of Tacrolimus trough levels in lung transplantation.

In order to prevent long-term immunity-related complications after lung transplantation, close monitoring of immunosuppressant levels using therapeutic drug monitoring (TDM) is paramount. Novel electronic nose (eNose) technology may be a non-invasive alternative to the current invasive procedures for TDM. We investigated the diagnostic and categorization capacity of eNose breathprints for Tacrolimus trough blood plasma levels (TACtrough) in lung transplant recipients (LTRs). We performed eNose measurements in stable LTR attending the outpatient clinic. We evaluated (1) the correlation between eNose measurements and TACtrough, (2) the diagnostic capacity of eNose technology for TACtrough, and (3) the accuracy of eNose technology for categorization of TACtroughinto three clinically relevant categories (low: <7µg ml-1, medium: 7-10µg ml-1, and high: >10µg ml-1). A total of 186 measurements from 86 LTR were included. There was a weak but statistically significant correlation (r= 0.21,p= 0.004) between the eNose measurements and TACtrough. The root mean squared error of prediction for the diagnostic capacity was 3.186 in the training and 3.131 in the validation set. The accuracy of categorization ranged between 45%-63% for the training set and 52%-69% in the validation set. There is a weak correlation between eNose breathprints and TACtroughin LTR. However, the diagnostic as well as categorization capacity for TACtroughusing eNose breathprints is too inaccurate to be applicable in TDM.

Diagnostic performance of electronic nose technology in chronic lung allograft dysfunction.

BACKGROUND: There is a need for reliable biomarkers for the diagnosis of chronic lung allograft dysfunction (CLAD). In this light, we investigated the diagnostic value of exhaled breath analysis using an electronic nose (eNose) for CLAD, CLAD phenotype, and CLAD stage in lung transplant recipients (LTR). METHODS: We performed eNose measurements in LTR with and without CLAD, visiting the outpatient clinic. Through supervised machine learning, the diagnostic value of eNose for CLAD was assessed in a random training and validation set. Next, we investigated the diagnostic value of the eNose measurements combined with known risk factors for CLAD. Model performance was evaluated using ROC-analysis. RESULTS: We included 152 LTR (median age 60 years, 49% females), of whom 38 with CLAD. eNose-based classification of patients with and without CLAD provided an AUC of 0.86 in the training set, and 0.82 in the validation set. After adding established risk factors for CLAD (age, gender, type of transplantation, time after transplantation and prior occurrence of acute cellular rejection) to a model with the eNose data, the discriminative ability of the model improved to an AUC of 0.94 (p = 0.02) in the training set and 0.94 (p = 0.04) in the validation set. Discrimination between BOS and RAS was good (AUC 0.95). Discriminative ability for other phenotypes (AUCs ranging 0.50-0.92) or CLAD stages (AUC 0.56) was limited. CONCLUSION: Exhaled breath analysis using eNose is a promising novel biomarker for enabling diagnosis and phenotyping CLAD. eNose technology could be a valuable addition to the diagnostic armamentarium for suspected graft failure in LTR.

Current Perspectives on the Management of Herpesvirus Infections in Solid Organ Transplant Recipients.

Solid organ transplant recipients (SOTRs) are at high risk of human herpesvirus (HHV)-related morbidity and mortality due to the use of immunosuppressive therapy. We aim to increase awareness and understanding of HHV disease burden in SOTRs by providing an overview of current prevention and management strategies as described in the literature and guidelines. We discuss challenges in both prevention and treatment as well as future perspectives.

Detection of Bacterial Colonization in Lung Transplant Recipients Using an Electronic Nose.

Background: Bacterial colonization (BC) of the lower airways is common in lung transplant recipients (LTRs) and increases the risk of chronic lung allograft dysfunction. Diagnosis often requires bronchoscopy. Exhaled breath analysis using electronic nose (eNose) technology may noninvasively detect BC in LTRs. Therefore, we aimed to assess the diagnostic accuracy of an eNose to detect BC in LTRs. Methods: We performed a cross-sectional analysis within a prospective, single-center cohort study assessing the diagnostic accuracy of detecting BC using eNose technology in LTRs. In the outpatient clinic, consecutive LTR eNose measurements were collected. We assessed and classified the eNose measurements for the presence of BC. Using supervised machine learning, the diagnostic accuracy of eNose for BC was assessed in a random training and validation set. Model performance was evaluated using receiver operating characteristic analysis. Results: In total, 161 LTRs were included with 80 exclusions because of various reasons. Of the remaining 81 patients, 16 (20%) were classified as BC and 65 (80%) as non-BC. eNose-based classification of patients with and without BC provided an area under the curve of 0.82 in the training set and 0.97 in the validation set. Conclusions: Exhaled breath analysis using eNose technology has the potential to noninvasively detect BC.

Humoral and cellular immune responses after COVID-19 vaccination of lung transplant recipients and patients on the waiting list: a 6-month follow-up.

Background: Data on cellular response and the decay of antibodies and T cells in time are scarce in lung transplant recipients (LTRs). Additionally, the development and durability of humoral and cellular immune responses have not been investigated in patients on the waitlist for lung transplantation (WLs). Here, we report our 6-month follow-up of humoral and cellular immune responses of LTRs and WLs, compared with controls. Methods: Humoral responses to two doses of the mRNA-1273 vaccination were assessed by determining spike (S)-specific IgG antibodies and neutralizing antibodies. Cellular responses were investigated by interferon gamma (IFN-γ) release assay (IGRA) and IFN-γ ELISpot assay at 28 days and 6 months after the second vaccination. Results: In LTRs, the level of antibodies and T-cell responses was significantly lower at 28 days after the second vaccination. Also, WLs had lower antibody titers and lower T-cell responses compared with controls. Six months after the second vaccination, all groups showed a decrease in antibody titers and T-cell responses. In WLs, the rate of decline of neutralizing antibodies and T-cell responses was significantly higher than in controls. Conclusion: Our results show that humoral and cellular responses in LTRs, if they develop, decrease at rates comparable with controls. In contrast, the inferior cellular responses and the rapid decay of both humoral and cellular responses in the WL groups imply that WLs may not be protected adequately by two vaccinations and repeat boostering may be necessary to induce protection that lasts beyond the months immediately post-transplantation.