PCD diagnosis has historically been a daunting task, relying primarily on interpretation of ciliary ultrastructural biopsies. Recent advancement in our knowledge about PCD genetics and the emergence of a characteristic phenotype for most cases of PCD has greatly improved PCD diagnosis.
From the PCDF Consensus Statement: “PCD is a rare disorder; consequently, only a limited number of centers have extensive experience in the diagnosis and management of PCD. Research over the past decade has led to a revolution in diagnostic approaches, including nNO and genetic testing. Nevertheless, many PCD patients are still undiagnosed or misdiagnosed. To date, only limited studies have addressed management of PCD, and there have been no large, randomized clinical trials to direct therapy. Therefore, this review article includes consensus recommendations from PCD physicians in North America for diagnosis, monitoring and management of PCD.”
Making the Diagnosis
PCD diagnosis generally requires a ‘matrix’ approach using multiple diagnostic modalities. These are described below.
A careful history is the most important first step in the diagnostic work up for primary ciliary dyskinesia (PCD). Based on data collected through the Genetic Disorders of Mucociliary Clearance Consortium (GDMCC) and published in the PCD Foundation Consensus Guidelines available here, there are four hallmark features of PCD:
- Chronic cough (often wet sounding) and sputum production from the first months of life
- Chronic nasal congestion from the first months of life, progressing to chronic sinusitis with age
- Neonatal respiratory distress
- Laterality (organ placement) defects, including situs inversus totalis, situs ambiguus/heterotaxy
and congenital heart defects
In addition, chronic otitis media with effusion–often with hearing loss–is nearly universal in PCD, especially during childhood. While this feature was not statistically significant in distinguishing PCD from non-PCD, if it occurs in conjunction with the above features, it can reinforce the clinical picture.
According to the PCDF Consensus Statement, “Genetic testing for disease-causing mutations associated with PCD is recommended as part of a panel of diagnostic PCD tests.” There are currently 38 known genes associated with PCD, which counts for an estimated 75% of patients who have this disease. Ultimately, the goal is to provide therapies targeted at specific genes, so a confirmed PCD diagnosis via a genetic panel will be increasingly important.
NOTE: Information on clinical genetic testing for PCD can be found here.
Per the 2015 consensus statement, high-speed videomicroscopy, which is an examination of cilia waveform from a ciliary biopsy, can be sufficient in providing a clinical diagnosis for PCD. However, there is a caveat: this test must be performed by a qualified medical professional who has experience with high speed videomicroscopy technology. If this test is performed by a medical technician who is not an expert, there is a chance of either a false-negatives or a false-positive result, both of which can potentially be harmful to the patient.
Transmission Electron Microscopy (TEM)
PCDF Consensus Statement: “Respiratory epithelial biopsy with TEM processing for ultrastructural examination of ciliary axonemes is a proven technique for PCD diagnosis and is recommended as part of a panel of diagnostic tests for PCD. Disease-causing TEM defects in the outer dynein arms, outer and inner dynein arms, inner dynein arms with microtubule disorganization, radial spokes, or central apparatus provide confirmation of PCD diagnosis. However, TEM studies with normal ciliary ultrastructure do not rule out PCD, as certain PCD gene mutations can result in normal ultrastructure, or subtle abnormalities (particularly those involving the central apparatus and radial spokes) that are not readily recognized on TEM.”
When performed by experienced technologists and analyzed by pathologists familiar with ciliary defects, TEM can yield usable diagnostic results in about 70% of cases. In reality, however, this ‘ideal’ situation is very rare and the yield of reliable results is much lower at most centers. Therefore, the PCD Foundation recommends that all patients with suspected PCD be directed to PCD Foundation Clinical and Research Network Centers for TEM as part of a larger PCD diagnostic workup.
Nasal Nitric Oxide (nNO) Measurement
For reasons not yet known, the vast majority of individuals with PCD have very low levels of nitric oxide in their sinus cavities. This is not just a small difference, it is a marked and significantly lower level than seen in people without PCD.* Because this finding has been verified in numerous studies around the world, measuring the nasal nitric oxide (nNO) level in individuals thought to have PCD can be a useful screening tool to help a physician decide whether or not PCD is a likely diagnosis. In the US, nNO testing cannot be used to make the diagnosis; nor can it be used to exclude PCD. It is a screening test only that will help prioritize decisions about next diagnostic steps.
nNO is a biological test, similar to the ‘sweat test’ in cystic fibrosis. It appears, with few exceptions (see below), to be a very accurate and sensitive screen for PCD, as long as it is done using validated SOPs by trained operators, and is recommended by the PCD Foundation as an adjunct to the diagnostic workup in our clinical centers. Like all tests, it’s value relies on it being performed and interpreted correctly. PCDF centers are site visited to ensure nNO testing follows standard operating procedures.
*There are a few notable exceptions:
-Individuals with PCD from RSPH1 mutations can have normal nNO. It is not known if other yet-to-be-
discovered genes will have similar nNO results.
-Some individuals with cystic fibrosis will also have low nNO. CF should be ruled out prior to doing
nNO testing for PCD.
Immunofluorescence Testing (IF)
Immunofluorescence testing (IF) uses antibodies to detect missing dynein arm proteins along the ciliary axoneme. While IF may be used as an additional tool to make a PCD diagnosis, it is not recommended to be used as the only test to confirm PCD.
Confirming the Diagnosis
The PCDF consensus recommendations states that “many physicians incorrectly diagnose PCD or eliminate PCD from their differential diagnosis due to inexperience with diagnostic testing methods. Thus far, all therapies used for PCD are unproven through large clinical trials.” The statement continues: “patients often receive false-positive or false-negative PCD diagnoses, as physicians are unaware of the pitfalls commonly encountered with ciliary electron microscopy, PCD molecular genetic panels, ciliary motility studies, and nasal nitric oxide testing.”
Although gene-specific therapies are not available at this time, it is important to confirm (or rule out) a PCD diagnosis so that patients can be on an optimal treatment regimen to manage their disease. Therefore, it is critical that all diagnostic tests are performed by experienced technicians, preferably at one of our many PCDF Clinical Centers located all across the the U.S. and Canada.
Genetic Testing Resources
There are a number of options for genetic testing for PCD, including genetic laboratory services at individual academic sites and commercial genetic testing vendors. Individual physician preference and insurance requirements often dictate which genetic testing provider is used. The list below represents commercial vendors* (vs. in-house academic labs) that offer PCD genetic testing panels.
PLEASE NOTE: This information is provided as an informational resource only and should not be viewed as an endorsement for any particular test or vendor.
- Ambry Genetics http://www.ambrygen.com/
- Fulgent Diagnostics https://www.fulgentgenetics.com/
- Invitae https://www.invitae.com/en/
- McLendon Clinical Laboratory http://www.uncmedicalcenter.org/mclendon-clinical-laboratories/available-tests/primary-ciliary-dyskinesia-pcd-mutation-testing/
- Prevention Genetics https://www.preventiongenetics.com/
*Vendors—if you would like to be included on this list, please forward information to the PCD Foundation at firstname.lastname@example.org.