It has been truly gratifying to see the growth of interest in PCD research over the past decade. This interest holds the promise of exciting new technologies and therapies that will improve PCD diagnostics and quality of life. However, sometimes excitement over possibilities can lead to misinterpretation of what is actually useful in the clinical setting (i.e. at your physician’s office). There is a difference between technologies or therapies that are currently being evaluated for use (research) and those for which scientific evaluation has been done and they have been validated for use with actual patients (clinical practice).
Diagnosis of PCD is a challenging problem and one that has led to a number of advances in recent years. Many of these advances are still in the ‘being scientifically evaluated’ stage, which means they are in the research arena—not appropriate for, or available in, the clinical setting yet, except as part of a clinical trial at specific participating centers. To clarify the status of diagnostic tests in PCD, it is useful to divide the tests into those that have passed scientific ‘muster’ (been validated through research studies) and have been approved by regulatory authorities for use with patients vs. those still in the process of validation:
Validated and approved (FDA or other regulatory body) for PCD diagnosis:
1. Biopsy of cilia with electron microscopic assessment of ciliary ultrastructure (aka ‘biopsy’)
2. Genetic test showing known biallelic (one from each parent) PCD mutations on a confirmed PCD gene
Adjunct testing that may be useful, but cannot be used to make the diagnosis alone (diagnosis must be confirmed with one of the tests above):
3. Nasal nitric oxide measurement (validated standard operating procedures (SOPs) available; must be done at expert center)
4. Immunofluorescent assay test for ciliary proteins (validated assays available; must be done at expert center)
5. High-speed videomicroscopy (no standard operating procedures yet established or validated; must be done at expert center)
As you can see, there are only two tests that are actually approved for making a clinical diagnosis of PCD—ciliary biopsy and genetics. The other tests on the list can be helpful—sometimes extremely helpful—when trying to determine the likelihood of PCD or not PCD, but they cannot on their own establish the diagnosis. Most of them are also considered ‘research’ and not clinical tests. This means that they have not yet been validated for use in a clinical setting and can only be used under a research protocol. Their value in the clinical setting has yet to be firmly established or ‘validated.’
Every diagnostic option on this list has limitations. There is no single test that can pick up all cases of PCD and there are some forms of PCD for which no reliable test currently exists. In these cases, physicians may have to resort to diagnosing ‘likely’ or ‘probable’ PCD based on the evidence they are able to gather using available technology. This is frustrating for many families (and for many physicians), but relying on unvalidated tests that may or may not provide a reliable result will not reduce this frustration. It is more likely to compound it by introducing additional opportunities for misdiagnosis.
Understanding the nature of PCD is important. It is not uncommon for us to hear families say ‘it must be PCD—I have/my child has all the symptoms.’ But while symptoms commonly seen in PCD may lead a doctor to suspect the disorder, PCD is not just a set of symptoms. It is a group of distinct genetic disorders. The diagnosis is made based on the presence of specific PCD genetic defects and not on PCD-like symptoms. This is similar to cystic fibrosis. Many children have repeated lung infections and fail to gain weight. However, no one would diagnose these children as having cystic fibrosis on the basis of symptoms alone without convincing evidence from validated tests (sweat test, CF genetic testing, nasal potential difference, etc.) done at a CF certified site proving that a CF mutation is responsible for symptoms. Since we don’t know all the genes involved in PCD yet, other indications of PCD genetic defects—like specific ultrastructural changes on biopsy or very low nasal NO or distinctly impaired ciliary beat patterns—can provide evidence for a genetic defect. But diagnoses made this way must be done very, very carefully, by people with a great deal of experience because it is very easy to misinterpret these tests and mistake ‘acquired’ or ‘non-genetic’ changes for PCD changes.
Getting the diagnosis right is important for many reasons. First and foremost, PCD is a genetic disorder and the diagnosis carries implications for families. Second, a misdiagnosis of PCD will interfere with additional investigation to find the real reason for symptoms and possibly delay appropriate treatment. Finally, ‘un-diagnosis’ is a traumatic experience for families and one that can often be avoided by evaluation at an expert center.
In summary, PCD is a disorder of specific genetic mutations -- not just a set of symptoms-- that is currently difficult to diagnose. There are only two approved tests for confirming the diagnosis of PCD: 1.) Biopsy of cilia with transmission electron microscopic (TEM or EM) analysis of ultrastructure, or 2.) Genetic testing that demonstrates biallelic PCD mutations. Other PCD tests like video analysis of ciliary beat and nasal nitric oxide measurement are not diagnostic on their own and are often performed as part of a clinical trial to evaluate their reliability. Results from these research tests cannot establish the diagnosis of PCD and they must be confirmed by an approved, validated test.
This article was medically reviewed by a member of the PCDF Medical and Scientific Advisory Board prior to publication