The first thing to know is that there is currently no test for PCD that picks up 100% of cases or that can totally rule PCD out.

The second thing to be aware of is that diagnostic practices for PCD vary by country and sometimes even by region within a country. A ‘good’ diagnostic option in the US may not be available in other countries and there are diagnostic tests done very well outside of the US that are not at all reliable in the US.

The third thing to know is that the diagnostic option chosen by your physician is likely based on what will be covered by health services or insurance, which may or may not necessarily represent what they consider the optimal diagnostic approach. This is especially the case in the US, where there are hundreds of sites attempting to make the diagnosis of PCD and thousands of private and public insurance providers involved.

The US is an outlier in PCD diagnosis, largely due to our very fractured healthcare system. In countries with national healthcare systems, patients are funneled into expert centers. With the patient community focused in these centers, it becomes possible to resource and train personnel on diagnostic techniques. An example of this is high-speed videomicroscopy (HSVM), a diagnostic tool used extensively in Europe, UK, and Australia, but not in the US. This is because it is an art, it takes a long time and significant dedication to become proficient at it, and in the US, every site would insist on providing the service whether they could do it well or not because insurance would require ‘in-network’ processing. This would be a nightmare and the diagnoses derived from this in North America, outside of a couple of sites, would be completely unreliable. (Please note: This is exactly the point of having a US PCD Clinical and Research Centers Network, so we can focus resources in sites that can develop expertise in PCD and eventually incorporate some of these other diagnostic tools).

This is sadly often the case in the US with ciliary biopsy, as well. When it is done well at a center that knows what they are doing, it will still miss PCD at least 30% of the time, because PCD genes do not result in visible ultrastructural changes at least 30% of time (this includes some ‘biggies’–common PCD genes like DNAH11 that look entirely normal in a biopsy sample and would be missed by biopsy alone).

We need to be honest about the fact that biopsies (in the US) are often done very poorly because insurance dictates where the sample is processed and every site will feel the need to comply with insurance requirements without fully understanding the challenges. Ciliary biopsy is a labor-intensive, finicky process requiring a number of steps be done successfully to achieve the desired result. A mistake or problem at any step may render the result useless, and there are lots of opportunities for things to go wrong. Often it is the very first step—collecting an adequate sample—that goes wrong. The best processing in the world will not yield a useful sample for biopsy if no cilia are actually present. Flawed processing, too few images for review, and misinterpretation of structural anomalies are examples of other issues with ciliary biopsy. The result is a significant number of US patients who have been misdiagnosed—either told they have PCD when they do not or told they do not have it when they do—on the basis of a faulty biopsy diagnosis. So not only does biopsy not pick up 30% of PCD when done well, it’s yield of good diagnoses is, in fact, even lower because it is often not done well (in the US). PCD experts in North America suggest that biopsies done here may pick up 30-50% of PCD. This is an appallingly low yield for a supposed ‘gold standard’ test. For research, it has become necessary for PCD expert sites to overread every single biopsy. This will also be the case for our soon-to-launch registry—every biopsy will be reviewed by PCD experts prior to inclusion in the registry.

There are a handful of North American sites that do a good job with PCD biopsy, but they are disappearing at a rapid rate because the test is labor-intensive, requires significant resources, and may not result in a useful sample despite best efforts. In the US, where healthcare is a profit-driven enterprise, ciliary biopsy often represents a financial loss for labs, not profit. Many of them simply can’t justify doing biopsies any more, or doing them the way they should be done.

Nasal nitric oxide (nNO) is a useful screening tool for PCD but is mostly available only at academic and research centers. In the US and parts of Canada, it is not approved for diagnosis and must be done under a research protocol. NNO has been validated only when done using what is known as ‘chemiluminescent’ technology. These devices are very expensive and special training is required, using validated protocols. Values derived outside of these protocols are not useful for establishing the diagnosis. For instance, in the US, there are some clinics using the small handheld devices used to measure nitric oxide at the mouth for asthma to screen for PCD. This is not a valid way to measure NO for PCD, as NO from the lower airways that comes out of the mouth is artificially low and could lead to false positive (mis)diagnoses. Some sites create their own nasal version for measuring NO with these devices. There are two problems with this: 1.) These devices are intended to capture increased levels of NO seen in asthma and the technology they use is not as sensitive at picking up the extremely low levels seen in PCD. They are a bit of a ‘blunt instrument’ for nasal NO, using a mean score (mixing both high and low values) that has been shown in research to result in false positives. 2.) Validation studies done for nNO require a ‘closed palate’ technique in children over five. The goal is to collect NO only from the sinuses. Rigged devices may not be adequate to restrict the measurement to nasal NO only.  NO device manufacturers have expressed an interest in developing the nNO capabilities of smaller, cheaper devices, but so far this has not been done and these devices are not validated for PCD diagnosis.

Lastly, nNO is most useful in patients older than five but can be done in younger patients as well. At PCD centers in North America, Europe, and Australia nNO data is being collected starting in infants to see if valid cutoffs can be established. The PCDF position is that nNO is very useful, and it is another diagnostic tool in the arsenal, but like most PCD tests, it cannot stand alone–and in the US, it cannot be used by itself to establish diagnosis because it is not yet FDA approved for PCD diagnosis–and whenever possible should be used as part of a matrix testing approach that includes several tests.

The one exception to the requirement for multiple tests is genetic testing. If you have a positive genetic test for PCD (two pathogenic variants on a single gene, one from mom, one from dad OR single variants on identified X-linked/other genes) no other testing is required to confirm the diagnosis. However, other testing may still be useful for establishing the clinical consequences (i.e. what ultrastructural defect or nasal NO impact is produced) of your genetic profile and most physicians will still want additional supportive testing.

Because of our unique problems with diagnosis in the US, we encourage genetic testing for PCD. When done in patients with the correct clinical picture (meet all the criteria for PCD), current genetic tests pick up 70-75% of all PCD. Some diagnostic yield rates are lower (some papers say 40%), but it is very important to note that in a recent clinical trial for a drug in PCD that used very careful inclusion criteria (only enrolled patients that had clearly defined histories suggestive of PCD), the diagnostic yield for genetic testing actually exceeded 75%. If a site is ordering PCD genetic tests on every child in their practice with bad ears, there will be many negative results. That is most likely a reflection on choosing inappropriate candidates for PCD testing, not of the unreliability of the test itself.

That said, we still do not know every gene associated with PCD, nor do we know every PCD-causing variant on these genes. We are up to more than 40 PCD-associated genes with new genes or new variants on existing genes being identified all the time. It is challenging for genetic testing companies to keep up. Also, the new genes being discovered primarily affect tiny percentages of the patient population—1% or fewer—so there may be less sense of urgency to get them on panels since very few patients will benefit from this testing. Still, we just heard that Invitae and Prevention Genetics in the US and Blueprint Genetics in Canada have added more genes to their PCD panels, bringing the number of genes tested up to 38 (these panels often include non-PCD genes, as well, which is why some will say ‘41 genes’—be sure to look at the actual genes on the panel) so these are very comprehensive genetic tests.

Most individuals (in the US and Canada, I don’t know the status of testing coverage in Europe, UK or Australia) who want genetic testing for PCD can get coverage for it. Exceptions tend to be state, federal and VA plans, which is incredibly frustrating. These plans will pay thousands of dollars for repeated, unreliable biopsies, but will not cover much cheaper, more reliable genetic testing. They often have a policy of not covering any genetic testing for anything, period, which is very hard to fight. Some private insurers are now implementing similar ‘no genetic testing’ policies. Several test providers offer very reasonable rates for families whose insurance won’t cover. One site offers a complete PCD panel, plus CFTR (for cystic fibrosis) for $250.

Genetic testing for PCD has its own issues, largely related to faulty interpretation of genetic test results from sites not familiar with PCD. The two biggest issues we see related to misdiagnosis of genetic testing are: 1.) Not understanding variants of uncertain significance (VUSs) vs. pathogenic variants and making a misdiagnosis of PCD based on VUSs. 2.) Not understanding the recessive nature of most genetic causes of PCD and making a misdiagnosis based on pathogenic variants on two or more separate genes (e.g. one pathogenic variant on DNAH11 and the second one on DNAH5). Neither of these situations constitutes a genetic diagnosis of PCD. This does not mean that the person does not have PCD, just that they do not genetic proof of the diagnosis. 

Given this, why would people want to have genetic testing? It’s important to remember that genetic testing is not just for diagnosis. It is also becoming more and more important for targeting therapeutic development (see Kalydeco, Orkambi and Trikafta for CF—all developed to target specific genetic defects). Genetic information is also important to establish genotype/phenotype correlations, meaning determining whether your genetic profile is likely to result in more or less severe disease. Right now, we have limited information related to this for only a couple of PCD genes. We need to understand this picture for all PCD genes.

In the US, there are only two FDA-approved methods for diagnosing PCD: Ciliary biopsy and genetic testing. Any other testing is supplementary, but it cannot be used to formally diagnose PCD. There are a lot of patients stuck in a no-man’s land with diagnosis, as they have inconclusive biopsy and genetic testing. This does not mean you do not have PCD—just that until laboratory verification occurs, you will likely be classified as ‘probable’ or ‘possible’ PCD, not confirmed. This should not impact treatment in any way.

PCD diagnosis is still a challenge and still subject to regional and insurance limitations. Groups in Europe, Australia, and North America create diagnostic guidelines knowing that this is an evolving area and any recommendation is based solely on ‘what we know now’ and will almost certainly change with time. There are additional exciting diagnostic techniques, including immunofluorescent assay, that are used at sites in Europe and that we hope to incorporate at a few PCD center sites in North America, so stay tuned. PCD diagnosis is getting better and better all the time.