Transbronchial cryobiopsy followed by as-needed surgical lung biopsy versus immediate surgical lung biopsy for diagnosing interstitial lung disease (the COLD study): a randomised controlled trial.

BACKGROUND: An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB. METHODS: The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed. FINDINGS: Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy. INTERPRETATION: In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers.

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.

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.

The potential of electronic nose technology in lung transplantation: a proof of principle.

Exhaled breath analysis using eNose technology holds promise as a point-of-care indicator of clinical status after lung transplantation. This case study invites further exploration of eNose technology in the field of lung transplantation. https://bit.ly/3wgQ3DE.

Long-term outcome and bridging success of patients evaluated and bridged to lung transplantation on the ICU.

BACKGROUND: Evaluating and bridging patients to lung transplantation (LTx) on the intensive care unit (ICU) remains controversial, especially without a previous waitlist status. Long term outcome data after LTx from ICU remains scarce. We compared long-term survival and development of chronic lung allograft dysfunction (CLAD) in elective and LTx from ICU, with or without previous waitlist status. METHODS: Patients transplanted between 2004 and 2018 in 2 large academic Dutch institutes were included. Long-term survival and development of CLAD was compared in patients who received an elective LTx (ELTx), those bridged and transplanted from the ICU with a previous listing status (BTT), and in patients urgently evaluated and bridged on ICU (EBTT). RESULTS: A total of 582 patients underwent a LTx, 70 (12%) from ICU, 39 BTT and 31 EBTT. Patients transplanted from ICU were younger than ELTx (46 vs 51 years) and were bridged with mechanical ventilation (n = 42 (60%)), extra corporeal membrane oxygenation (n = 28 (40%)), or both (n = 21/28). Bridging success was 48% in the BTT group and 72% in the EBTT group. Patients bridged to LTx on ICU had similar 1 and 5 year survival (86.8% and 78.4%) compared to elective LTx (86.8% and 71.9%). This was not different between the BTT and EBTT group. 5 year CLAD free survival was not different in patients transplanted from ICU vs ELTx. CONCLUSION: Patients bridged to LTx on the ICU with and without prior listing status had excellent short and long-term patient and graft outcomes, and was similar to patients electively transplanted.

Evaluation of a Home Monitoring Application for Follow Up after Lung Transplantation-A Pilot Study.

Home spirometry after lung transplantation is common practice, to monitor graft function. However, there is little experience with online home monitoring applications with direct data transfer to the hospital. We evaluated the feasibility and patient experiences with a new online home monitoring application, integrated with a Bluetooth-enabled spirometer and real-time data transfer. Consecutive lung transplant recipients were asked to evaluate this home monitoring application for three months in a pilot study. Home spirometry measurements were compared with in-hospital lung function tests (the forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) at the end of the study. Ten patients participated. The home and hospital spirometry measurements showed a high correlation, for both the FEV1 (r = 0.99, p < 0.01) and FVC (r = 0.99, p < 0.01). The adherence and patient satisfaction were high, and the patients preferred the home monitoring application over the current home spirometer, with a difference of 1.4 ± 1.5 points on a scale from 0 to 10 (p = 0.02). Online home monitoring with direct data transfer is feasible and reliable after lung transplantation and results in high patient satisfaction. Whether the implementation of online home monitoring enables the earlier detection of lung function decline and improves patient and graft outcomes will be the subject of future research.