Fibered Confocal Fluorescence Microscopy Imaging in Patients With Diffuse Parenchymal Lung Diseases

Diffuse parenchymal lung diseases (DPLD) represent a large and heterogeneous group of disorders encompassing a collection of pulmonary diseases that affect the interstitium including the alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues. This spectrum of disease is encountered not only in pulmonary medicine as a collection of idiopathic conditions, but also in transplant medicine (solid organ and haematological), infectious disease (atypical pneumonias) and rheumatology (connective tissue disease/vasculitis). Although new techniques such as high resolution computed tomography (HRCT) and insights into the pathogenesis have led to a better understanding of DPLD, clinical diagnosis, management and prognostication remains a challenge.

The current diagnostic standard of DPLD is a correlation between clinical course, radiological features on HRCT and pathological findings. Even in idiopathic pulmonary fibrosis (IPF) where a typical usual interstitial pattern on HRCT is pathognomonic without the requirement of pathology, this is only diagnostic in 80% of patients, and an atypical pattern on HRCT does not preclude a diagnosis of IPF. As such the final diagnosis often hinges on histopathological confirmation which traditionally requires a surgical lung biopsy under general anaesthetic via thoracoscopy or thoracotomy. This entails significant morbidity and mortality in this group of patients who already have respiratory compromise. Minimally invasive endoscopic procedures such as bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) via flexible bronchoscopy have increasingly been used in the majority of cases as a substitute to surgical biopsy. This unfortunately is not entirely a benign procedure either - BAL can worsen hypoxaemia, and TBLB may lead to significant bleeding or pneumothorax in around 5% of patients. Furthermore, the diagnostic yield of TBLB is severely limited because of the small size of tissue and the blind nature of choosing target bronchopulmonary segments to biopsy. Other limitations include significant inter-observer variation in interpretation of the histology, and the problem of ''sampling error'': the possibility that a biopsy specimen was taken from an area not representative of the predominant disease process. These limitations are reflected in the low diagnostic yields reported - in immunocompromised patients, the diagnostic yield of either BAL or TBLB was 38% with a 13% complication rate, and diagnostic yields of <50% with TBLB have been reported in hypersensitivity pneumonitis and about 30% in usual interstitial pneumonia.

A definitive diagnosis is essential in the management of diffuse parenchymal lung diseases. Infectious aetiologies necessitate antimicrobial therapy while immune mediated causes are managed by immunosuppression. Drug induced pathology will require a revision of current medication while fibrotic conditions can be managed expectantly. Prognostication is also markedly altered by aetiology and diagnosis. The gap in current medical practice is the availability of minimally invasive procedures with few complications and a high diagnostic fidelity.

Fibered confocal fluorescence microscopy (FCFM) (CellvizioR Lung, MaunaKea Technologies, France) is a new, safe and minimally invasive technique that can be used to obtain real time high-resolution, microstructural images of lobular and alveolar lung structures in living humans. FCFM provides a clear, in-focus image of a thin section within a biological sample, where the microscope's objective is replaced by a flexible fiberoptic miniprobe. The technique makes it possible to obtain high-quality images from endogenous or exogenous tissue fluorophores, through a fiberoptic probe of 1.4mm diameter that can be introduced into the working channel of a standard, flexible bronchoscope. This could potentially provide diagnostic information on fibrosis and inflammation of the distal air spaces associated with diffuse parenchymal lung diseases without the need for lung biopsies.

Current data and imaging for pulmonary FCFM is available in normal alveoli of both smokers and non-smokers. Pathological lung FCFM imaging for DPLD has yet to be published. In patients scheduled for bronchoscopy as part of regular clinical care/diagnostic workup, the investigators will offer the patient concurrent fibered confocal fluorescence microscopy imaging to be performed during the bronchoscopic procedure. The investigators aim to identify and catalogue distinct and discriminating features seen on images obtained from FCFM in this group of patients, and to correlate these findings with specific HRCT features and pathological findings if available. The investigators hope to be able to demonstrate reproducibility of FCFM image interpretation, with minimal intra and inter observer variability and high Kappa values. Eventually the investigators hope to define diagnostic criteria and patterns for FCFM image interpretation to correlate with specific DPLD entities, thereby creating an atlas of FCFM for DPLD. This would enhance our current diagnosis and management of DPLD with minimal additional risks to the patients.

Inclusion criteria

• Patients 21 years old and older diagnosed with suspected diffuse parenchymal lung disease (multi-lobar pulmonary infiltrates)
• Patients scheduled for bronchoscopy as part of regular clinical care/diagnostic workup
• Ability and willingness to sign informed consent

Exclusion criteria

• Contraindications to bronchoscopic evaluation eg. Haemodynamic instability, respiratory failure, uncorrected coagulopathy
• Suspected/confirmed pregnancy