Pulmonary radioaerosol mucociliary clearance in primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) is a genetic condition affecting one in 10 000-40 000 people from birth [1]; cilia fail to beat, and the airway clearance of mucus and debris is severely impaired. If untreated, this results in progressive lung infection leading to bronchiectasis and ultimately respiratory failure. Additionally, delayed diagnosis has implications for genetic counselling, appropriate management of glue ear and fertility advice. Early diagnosis and appropriate treatment are believed to improve outcome. The diagnosis of PCD is highly specialised and results can remain inconclusive, despite state of the art equipment and diagnostic techniques. A European consensus statement [2,3] highlighted that there is no ''gold-standard'' diagnostic test; diagnosis requires expert review of clinical history and screening tests (nasal nitric oxide measurement) alongside analysis of ciliary function and ultrastructure [2]. It is recommended that ciliary activity of respiratory epithelial cells obtained by nasal or bronchial brushing is recorded using a high-speed video camera mounted on a microscope. The images are played back in slow motion to analyse ciliary beat pattern (CBP) and frequency (CBF). Transmission electron microscopy (TEM) is used to assess ciliary ultrastructure [4]. Diagnostic uncertainty can be caused by secondary damage of the epithelium during sampling or due to infection or inflammation of epithelia; this damage can lead to abnormalities of ultrastructure, CBF and CBP. Furthermore, diagnosis is hindered by normal ciliary ultrastructure in 3-30% of cases of PCD [5,6]. To improve diagnostic certainty, a variety of further investigations can be employed [2], including reanalysis of CBF, CBP and TEM following culture of the cells at an air-liquid interface [7,8], or using immunofluorescence microscopy [9] to identify ciliary proteins. A single-centre study has previously reported the use of pulmonary radioaerosol mucociliary clearance (MCC) in the diagnosis of PCD [10]. The method is based on clearance patterns after the inhalation of a radioaerosol tracer. It provides a whole-lung functional test for pulmonary radioaerosol MCC. The investigation is noninvasive and has been used in thousands of patients with other lung diseases, as young as ,5 years. The authors reported that MCC was an effective noninvasive functional test for PCD [10] but the study was preliminary, and the feasibility of this complex technique and interpretation of data have not been assessed in other centres. We therefore conducted a study to replicate the results using a standardised protocol. This study was approved by the National Research Ethics Service (South Central committee 11/ SC/0192) and all subjects gave written informed consent.

Cilia and Mucociliary Clearance

“…As expected, PCD patients show markedly reduced tracheobronchial clearance compared with healthy individuals (Walker et al 2014; Munkholm et al 2015). To compensate for the deficient mucociliary transport, patients with PCD rely almost entirely on cough clearance to remove secretions from their bronchial airways (Noone et al 1999).…”

Diagnosis and management of primary ciliary dyskinesia

“…Investigations providing additional information include radioaerosol MCC30 31 as an in vivo measure of ciliary function and immunofluorescence-labelled antibodies32 to demonstrate absence of cilia axonemal and cytoplasmic preassembly of proteins. EM tomography may be of assistance in identifying the ultrastructural defect where standard tomography has not resolved the abnormality 33.…”

Diagnosis of primary ciliary dyskinesia: searching for a gold standard

“…Expertise is essential to interpretation of genetic testing; the authors are aware of patients who have been misdiagnosed by interpretation-error of gene variants of unknown significance identified by commercial genetic testing. Additional tests that may be helpful when other diagnostic tests are inconclusive include: immunofluorescence labelling of ciliary proteins [23] and in vivo assessment of mucociliary clearance of radiolabelled aerosol [24,25].…”