Evaluation of Electrical Impedance Tomography for the Diagnosis of Chronic Rejection in Lung Transplants Recipients (CLAD)

Evaluation of Electrical Impedance Tomography for the Diagnosis of Chronic Rejection in Lung Transplants Recipients

Evaluation of Electrical Impedance Tomography for the Diagnosis of Chronic Rejection in Lung Transplants Recipients

Electrical impedance tomography (EIT) is non-invasive and provides functional imaging of the lung and it could be a useful tool to diagnose chronic lung allograft dysfunction (CLAD) and specially Bronchiolitis Obliterans Syndrome (BOS). Hence, for this study, the investigators aim to show that EIT would provide an accurate diagnostic CLAD with an ability to to distinguish BOS from Restrictive Allograft Syndrome (RAS) and to stage BOS accurately when compared to FEV1 the current gold standard. The investigators are also aiming to provide physiological data in lung transplant recipients with chronic rejection.

Lung transplantation is the only treatment option available for patients affected by end-stage lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis or idiopathic pulmonary fibrosis, not responding to maximal medical therapy. Despite the advance in the surgical techniques, immunosuppression treatment and prevention of acute cellular rejection episodes as well as opportunistic infections, the long terms outcomes following lung transplant remain unsatisfactory. Chronic lung allograft dysfunction (CLAD) is the first cause of long term mortality in lung transplant recipients responsible of 5 years mortality post-surgery of 50%. CLAD can lead to chronic respiratory failure and can presents in two different phenotypes: Restrictive forms of CLAD were all lung volumes are decreased (commonly called RAS, Restrictive Allograft Syndrome) that has been recently associated with antibodies mediated rejection. A more common form of obstructive CLAD has been identified as the well-known and defined Bronchiolitis Obliterans Syndrome (BOS). In patients with BOS, the progressive obliteration and a narrowing of the distal airways result in breathlessness, airflow obstruction and air trapping. Currently, Forced Expiratory Volume at 1 second (FEV1) measurement is the gold standard to assess BOS severity. This test is non invasive and easily performed at bedside. Thus, it only gives a broad idea of the regional consequences of BOS as may be influenced by large airway obstructions. Chest computed tomography (CT) gives more detailed imaging of the regional consequences of BOS but is time-consuming and expose patients to radiations. Others imaging techniques such as ventilation/perfusion scintigraphy have been studied but cannot be performed at bedside. As to date there is no curative treatment for BOS, preventive treatments such as long term azithromycin, bronchodilators, inhaled steroids or plasmapheresis have to be started at early stage of the disease to improve outcomes for the recipients Electrical impedance tomography (EIT) is a new technology that involves wearing a belt of sensors around the chest that provides information on how well the lungs are being filled with air by the ventilator. It allows the assessment of these differences, which previously required the use of invasive equipment to obtain. Information is gained by repeatedly injecting small alternating electric currents (usually 5 mA) at high frequency of 50 - 80 kHz through a system of skin electrodes (usually 16) applied circumferentially around the thorax in a single plane between the 4th and 6th intercostal space. While an adjacent pair of electrodes 'injects' the current ('adjacent drive configuration'), all the remaining adjacent passive electrode pairs measure the differences in electric potential. A resistivity (impedance) image is reconstructed from this data by a mathematical algorithm using a two dimensional model and a simplified shape to represent the thoracic cross-section. The resulting image possesses a high temporal and functional resolution making it possible to monitor dynamic physiological phenomena (e.g. delay in regional inflation or recruitment) on a breath by breath basis. It is important to realize that the EIT images are based on image reconstruction techniques that require at least one measurement on a well-defined reference state. All quantitative data are related to this reference and can only indirectly quantify (relative) changes in local lung impedance (but not absolute). EIT can be used in mechanically ventilated patients to assess recruitment and to optimise ventilator settings to reduce risk of iatrogenic ventilator associated lung injury. To date, EIT has never been used in lung transplant recipients.

A 1:1 randomisation will be performed to decide the order of the administration of salbutamol and CPAP. All participants will receive both interventions in a cross-over fashion. Salbutamol nebulisation will be given during 15 minutes using 5mg of salbutamol. Assessments on CPAP will be performed at 3 different level of pressure. Each participant will then have continuous assessment of the following whilst self venting: Spirometry - FEV1, FVC, MVV Muscle strength measurements: MIP, MEP, SNIP Borg scale, mMRC, Visual Analogue Scale for breathlessness Electrical impedance tomography EMGpara Transcutaneous measurement of CO2 and 02 level End-tidal CO2 monitoring Pneumotachography

All participants will have continuous monitoring - salbutamol nebulisation will be given during 15 minutes using 5mg of salbutamol. Assessments on CPAP will be performed at 3 different level of pressure during this time.

Using EIT to distinguish between restrictive and obstructive different phenotypes in recipients of lung transplants

Following administration of salbutamol whilst using CPAP taking EITresults to determine if there is a change in the lungs

Comparing Lung measurements taken during the EIT test with the CT results of the participants to ascertain if there is any correlation

Comparing lung measurements taken during the EIT test with those taken during neural respiratory drive during the intervention

Comparing lung measurements taken during the EIT test with the Neural respiratory drive results taken and the participants breathlessness

Comparing the obstructive allograft syndrome EIT results to the restrictive allograft syndrome results.

Inclusion Criteria: Bilateral lung transplant recipient Time from lung transplantation > 6 months A chest CT scan (HRCT) performed as part of their standard care in the last 3 months A bronchoscopy with BAL and Biopsies performed as part of their standard care in the last 3 months For group with CLAD: a drop in lung function assessed on FEV1 or FVC For group without CLAD: an unchanged lung function Exclusion Criteria: Pregnancy Body mass index > 40kg/m2 Significant physical or psychiatric comorbidity that would prevent compliance with trial protocol Allergy to salbutamol Patient with intra-bronchial or intra-tracheal metallic stent Evidence of acute infection or acute cellular rejection. In addition 10 healthy volunteers will be recruited