Diagnosing primary ciliary dyskinesia: an international patient perspective

Laura Behan; Audrey Dunn Galvin; Bruna Rubbo; Sarah Masefield; Fiona Copeland; Michele Manion; Bernhard Rindlisbacher; Beatrice Redfern; Jane S. Lucas

doi:10.1183/13993003.02018-2015

Diagnosing primary ciliary dyskinesia: an international patient perspective

European Respiratory Journal ◽

10.1183/13993003.02018-2015 ◽

2016 ◽

Vol 48 (4) ◽

pp. 1096-1107 ◽

Cited By ~ 25

Author(s):

Laura Behan ◽

Audrey Dunn Galvin ◽

Bruna Rubbo ◽

Sarah Masefield ◽

Fiona Copeland ◽

...

Keyword(s):

Primary Ciliary Dyskinesia ◽

Task Force ◽

Past History ◽

Genetic Disorder ◽

Diagnostic Testing ◽

Delayed Diagnosis ◽

Patient Survey ◽

European Respiratory Society ◽

Medical Practitioners ◽

Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by progressive sino-pulmonary disease, with symptoms starting soon after birth. A European Respiratory Society (ERS) Task Force aims to address disparities in diagnostics across Europe by providing evidence-based clinical practice guidelines. We aimed to identify challenges faced by patients when referred for PCD diagnostic testing.A patient survey was developed by patient representatives and healthcare specialists to capture experience. Online versions of the survey were translated into nine languages and completed in 25 countries. Of the respondents (n=365), 74% were PCD-positive, 5% PCD-negative and 21% PCD-uncertain/inconclusive. We then interviewed 20 parents/patients. Transcripts were analysed thematically.35% of respondents visited their doctor more than 40 times with PCD-related symptoms prior to diagnostic referral. Furthermore, the most prominent theme among interviewees was a lack of PCD awareness among medical practitioners and failure to take past history into account, leading to delayed diagnosis. Patients also highlighted the need for improved reporting of results and a solution to the “inconclusive” diagnostic status.These findings will be used to advise the ERS Task Force guidelines for diagnosing PCD, and should help stakeholders responsible for improving existing services and expanding provision for diagnosis of this rare disease.

Download Full-text

Diagnosis of primary ciliary dyskinesia: summary of the ERS Task Force report

Breathe ◽

10.1183/20734735.008517 ◽

2017 ◽

Vol 13 (3) ◽

pp. 166-178 ◽

Cited By ~ 23

Author(s):

Claudia E. Kuehni ◽

Jane S. Lucas

Keyword(s):

Secondary Care ◽

Primary Ciliary Dyskinesia ◽

High Speed ◽

Task Force ◽

Diagnostic Testing ◽

List Type ◽

European Respiratory Society ◽

Term Infants ◽

Task Force Report ◽

Ciliary Dyskinesia

Key pointsPrimary ciliary dyskinesia (PCD) is a genetically and clinically heterogeneous disease characterised by abnormal motile ciliary function.There is no “gold standard” diagnostic test for PCD.The European Respiratory Society (ERS) Task Force Guidelines for diagnosing PCD recommend that patients should be referred for diagnostic testing if they have several of the following features: persistent wet cough; situs anomalies; congenital cardiac defects; persistent rhinitis; chronic middle ear disease with or without hearing loss; or a history, in term infants, of neonatal upper and lower respiratory symptoms or neonatal intensive care admission.The ERS Task Force recommends that patients should be investigated in a specialist PCD centre with access to a range of complementary tests: nasal nitric oxide, high-speed video microscopy analysis and transmission electron microscopy. Additional tests including immunofluorescence labelling of ciliary proteins and genetic testing may also help determine the diagnosis.Educational aimsThis article is intended for primary and secondary care physicians interested in primary ciliary dyskinesia (PCD), i.e. those who identify patients for testing, and those involved in diagnosing and managing PCD patients. It aims: to inform readers about the new European Respiratory Society Task Force Guidelines for diagnosing patients with PCDto enable primary and secondary care physicians to: identify patients who need diagnostic testing; understand the diagnostic tests that their patients will undergo, the results of the tests and their limitations; and ensure that appropriate care is subsequently delivered.

Download Full-text

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

European Respiratory Journal ◽

10.1183/13993003.01090-2016 ◽

2016 ◽

Vol 49 (1) ◽

pp. 1601090 ◽

Cited By ~ 202

Author(s):

Jane S. Lucas ◽

Angelo Barbato ◽

Samuel A. Collins ◽

Myrofora Goutaki ◽

Laura Behan ◽

...

Keyword(s):

Diagnostic Tests ◽

Primary Ciliary Dyskinesia ◽

High Speed ◽

Task Force ◽

Clinical Care ◽

Beat Frequency ◽

Diagnostic Methods ◽

Future Research ◽

European Respiratory Society ◽

Ciliary Dyskinesia

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no “gold standard” reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia.

Download Full-text

How to use nasal nitric oxide in a child with suspected primary ciliary dyskinesia

Archives of Disease in Childhood - Education and Practice ◽

10.1136/archdischild-2016-311468 ◽

2017 ◽

Vol 102 (6) ◽

pp. 314-318 ◽

Cited By ~ 2

Author(s):

Kim Simpson ◽

Malcolm Brodlie

Keyword(s):

Nitric Oxide ◽

Primary Ciliary Dyskinesia ◽

Clinical Utility ◽

Diagnostic Testing ◽

Older Children ◽

Tidal Breathing ◽

Closure Technique ◽

Nasal Nitric Oxide ◽

Ciliary Function ◽

Ciliary Dyskinesia

Measuring nasal nitric oxide (nNO) is increasingly used as part of testing for primary ciliary dyskinesia (PCD). The diagnosis of PCD is often delayed until after bronchiectasis is established and auditory damage has occurred. It is important that all paediatricians are aware of clinical features that are suggestive of PCD that should prompt diagnostic testing. nNO levels are recognised to be low in people with PCD and results generated by static chemiluminescence analysers using velum closure technique in older children have good sensitivity and specificity. However, to conclusively rule PCD in or out, further tests of ciliary function are required and assessment of cilia ultrastructure, immunohistochemistry studies and genotyping may also be indicated. These tests are more complex, invasive and expensive than nNO. nNO is less well studied in younger children where tidal breathing measurements are required. Portable nitric oxide analysers are also increasingly used in practice. This paper discusses when to consider PCD as a possible diagnosis in a child along with the indications, physiological and technical background and clinical utility of nNO as a test for PCD in children.

Download Full-text

Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106424 ◽

2019 ◽

Vol 57 (4) ◽

pp. 237-244 ◽

Cited By ~ 2

Author(s):

Sylvain Blanchon ◽

Marie Legendre ◽

Mathieu Bottier ◽

Aline Tamalet ◽

Guy Montantin ◽

...

Keyword(s):

Primary Ciliary Dyskinesia ◽

High Speed ◽

Genetic Disorder ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Central Complex ◽

Ciliary Beating ◽

Recovery Stroke ◽

Biallelic Mutations ◽

Ciliary Dyskinesia

BackgroundPrimary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype.MethodsWe prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV).ResultsSixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of DNAI1 mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of CCDC39 mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of RSPH1 mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF.ConclusionQuantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.

Download Full-text

Time trends in diagnostic testing for primary ciliary dyskinesia in Europe

European Respiratory Journal ◽

10.1183/13993003.00528-2019 ◽

2019 ◽

Vol 54 (4) ◽

pp. 1900528 ◽

Cited By ~ 5

Author(s):

Florian S. Halbeisen ◽

Amelia Shoemark ◽

Angelo Barbato ◽

Mieke Boon ◽

Siobhan Carr ◽

...

Keyword(s):

Time Trends ◽

Primary Ciliary Dyskinesia ◽

Diagnostic Testing ◽

Ciliary Dyskinesia

Download Full-text

Accuracy of diagnostic testing in primary ciliary dyskinesia

European Respiratory Journal ◽

10.1183/13993003.00749-2015 ◽

2015 ◽

Vol 47 (3) ◽

pp. 837-848 ◽

Cited By ~ 52

Author(s):

Claire L. Jackson ◽

Laura Behan ◽

Samuel A. Collins ◽

Patricia M. Goggin ◽

Elizabeth C. Adam ◽

...

Keyword(s):

Sensitivity And Specificity ◽

Primary Ciliary Dyskinesia ◽

High Speed ◽

Diagnostic Testing ◽

Standard Test ◽

Diagnostic Process ◽

Published Data ◽

Transmission Electron ◽

Repeated Sampling ◽

Ciliary Dyskinesia

Diagnosis of primary ciliary dyskinesia (PCD) lacks a “gold standard” test and is therefore based on combinations of tests including nasal nitric oxide (nNO), high-speed video microscopy analysis (HSVMA), genotyping and transmission electron microscopy (TEM). There are few published data on the accuracy of this approach.Using prospectively collected data from 654 consecutive patients referred for PCD diagnostics we calculated sensitivity and specificity for individual and combination testing strategies. Not all patients underwent all tests.HSVMA had excellent sensitivity and specificity (100% and 93%, respectively). TEM was 100% specific, but 21% of PCD patients had normal ultrastructure. nNO (30 nL·min−1 cut-off) had good sensitivity and specificity (91% and 96%, respectively). Simultaneous testing using HSVMA and TEM was 100% sensitive and 92% specific.In conclusion, combination testing was found to be a highly accurate approach for diagnosing PCD. HSVMA alone has excellent accuracy, but requires significant expertise, and repeated sampling or cell culture is often needed. TEM alone is specific but misses 21% of cases. nNO (≤30 nL·min−1) contributes well to the diagnostic process. In isolation nNO screening at this cut-off would miss ∼10% of cases, but in combination with HSVMA could reduce unnecessary further testing. Standardisation of testing between centres is a future priority.

Download Full-text