PCD on the Move 2017 (OTM 2017), the fourth annual North American scientific meeting dedicated to primary ciliary dyskinesia (PCD), focused on how to move ciliary/PCD science into practical applications to improve the quality of life for individuals with PCD.
PCD OTM began in 2014 as a way to keep our growing network of centers informed of advances in basic and clinical science in PCD. Adult patients and family members are welcome, as well, and represent the patient voice in these meetings. Because of our very close working relationships with the international PCD community, the meeting rapidly became international in scope and over the years we have had attendees from Australia, Belgium, Brazil, Germany, Japan, and Saudi Arabia.
This sort of international collaboration is absolutely essential for research progress with a genetically complex and rare disorder like PCD. It will not just ‘take a village’ to understand PCD, it will take the entire world. Perhaps the most important aspect of international collaboration is the ongoing effort to identify genes involved in PCD and related disorders. For those of us who are affected individuals or family members, this genetic work could not be more vital. Gene identification has been and will continue to be useful as part of the diagnostic workup for PCD, but that is just one reason to continue this important work. The real value in understanding PCD genetics is that once we know which genes are involved and understand what they are supposed to do, we can figure out how genetic mutations in PCD alter the normal function of a gene. The difference between what a gene is supposed to and how a PCD mutation interferes with proper function may provide a target for therapies. This is not theoretical any more. In cystic fibrosis (CF) using this exact approach has resulted in the development of some spectacularly effective therapies that will dramatically change the treatment course and outcomes of CF.
In PCD, clinical trials to test therapies will also require international collaboration because clinical trials require lots of participants and no single country or region has enough identified patients on their own. For example, the current CLEAN-PCD study requires 36 sites in 8 countries to enroll 150 eligible patients. Clinical studies are very, very expensive to do and critically important for the international PCD community.
With this background information, you now understand the focus of the sessions and presentations at PCD OTM 2017.
Wednesday, August 23
PCD Nuts & Bolts Session
The opening session of OTM 2017 provided a broad overview of the basics on PCD for medical professionals, allied health partners, clinical centers and families new to the diagnosis of PCD. This overview included describing the clinical features of PCD, current recommendations for diagnosis and treatment (North American), as well as hands on opportunities to try different airway clearance options and to measure nasal nitric oxide.
Basic and Translational Science Session
This is always a fantastic session with ‘cutting edge’ scientific presentations designed to get attendees thinking about how to translate the rapidly expanding body of basic science about cilia into actual practice for diagnosing and caring for patients.
Our keynote speaker for this session was Dr. Heymut Omran from the University of Muenster, Germany. Dr. Omran is a long-time research collaborator, heads large European PCD research networks, and is an international leader in gene identification for disorders of cilia, including PCD. He highlighted that, unlike cystic fibrosis (CF) which is caused by mutations on a single gene, there are now 39 genes (and counting) known to cause PCD. It is not a single disease entity, but rather a collection of related disorders with similar features currently captured under the umbrella term ‘primary ciliary dyskinesia.’ As we identify more genes and start to understand what they actually do, we may need to rethink how we describe this group of disorders. He also reinforced the idea that discovery of respiratory disorders caused by gene defects in motile cilia is in its infancy and all the genes we know now represent what could be considered ‘classic PCD.’ This is just the tip of the iceberg in terms of genetic disorders of motile cilia in the respiratory tract and efforts to identify atypical, variant or milder forms of respiratory cilia disease, which are likely to be quite common, have not yet even begun.
Other talks in this session focused on creating good animal models to study ciliary function for PCD and looking at cilia genes associated with congenital heart and laterality (sided-ness and situs) defects.
The final talk focused on creating an organized system to collect and analyze the volumes of genetic data currently being generated by PCD genetic testing to rapidly share information and aid with identification of PCD genes and disease-causing mutations.
Thursday, August 24
Thursday’s sessions focused on diagnosis of PCD, recognizing clinical features of the disorder and efforts to help patients understand and cope with the challenges of PCD. Additionally, young investigators presented reports on unique and challenging patient cases.
The morning diagnosis session reviewed what we know about nasal nitric oxide (nNO) as a screening tool for PCD. NNO is a very sensitive and specific tool—when done correctly—for most, but not all, forms of classic PCD. We do not yet know if it will prove to be as effective for milder or variant forms. Like all known PCD diagnostic tests, it will not pick up all cases of PCD and needs to be used as part of a battery of tests. It should be done at expert centers familiar with PCD and only with validated standard operating procedures (SOPs) for performing the test.
Immunofluorescent (IF) staining is another very promising diagnostic tool that has been used extensively in Germany for years and is now done in other European sites. This test uses antibodies created to ‘stick to’ specific proteins (that correspond to the proteins different PCD genes should be making) which are tagged with fluorescent dye. The antibodies are introduced to a sample of cilia and if the tagged protein does not light up, it is likely the protein is not being produced—thus likely positive for PCD. IF can now be done for almost all PCD genes/proteins and the PCDF is very interested in incorporating this diagnostic test at some of our clinical centers.
Analysis of ciliary ultrastructure from a biopsy sample of cilia is still considered the ‘gold standard’ for PCD diagnosis in the medical literature. This is unfortunate, as the talk on electron microscopy (EM) demonstrated. Even under the best of circumstances at centers that really do an excellent job producing and analyzing biopsy samples, at least 30% of all cases of PCD will be missed (false negative) because the affected structures cannot be visualized by EM. On the other side, ciliary ultrastructural defects that occur due to non-PCD related infection and inflammation are often incorrectly labeled PCD (false positive). While biopsy with EM will continue to play a role in PCD diagnosis, its status as the ‘gold standard’ for PCD diagnosis really needs to be challenged, especially as more comprehensive genetic testing becomes available and with improved access to better tests like immunofluorescent staining.
Genetic counseling is a vital component of comprehensive care for families who receive a genetic diagnosis and we closed the session on diagnosis with a fantastic talk from a genetic counselor who works with families at our Minneapolis PCD site. She discussed the importance of educating families about inheritance patterns, prognosis for future health, family planning, and testing for carrier status in other family members. Genetic counselors can also provide assistance to physicians in interpreting genetic results and helping develop communication strategies to share information with families.
Fellows Case Reports Session
Four unique PCD cases were presented during this session.
The first case focused on PCD complicated by a rare fungal infection, Aspergillus fumigatus, generally seen in patients with compromised immune systems and not in PCD patients. A full immune system workup is underway in this patient to determine whether they have a co-occurring immunodeficiency in addition to PCD.
The second case featured a young child in Saudi Arabia who presented with classic features of PCD, but also with a neural tube defect. Genetic workup revealed a defect in RSPH9 (a gene affecting the radial spokes). This was the first report of neural tube defect in a patient with an RSPH9 defect.
The third case highlighted the importance of early diagnosis in PCD so that appropriate care can be instituted to try to prevent early acquisition of severe disease. In this case, hallmark features of PCD in an infant, including prolonged neonatal respiratory distress and upper lobe atelectasis went unrecognized and the child was not diagnosed with PCD (due to CCDC40 mutations) until age 3, by which time she already had extensive bronchiectasis and had undergone lobectomy. The importance of identifying what we now know to be strong markers for the PCD in the neonatal period was discussed.
The fourth case really demonstrated the wide variation in PCD presentation, not just between genes, but between different mutations on the same gene. This case was of a man, age 82, with four biological children who had a lifelong history of upper and lower respiratory disease. He had also smoked for 25 years prior to quitting at age 40. He was diagnosed with severe COPD based on his respiratory issues and smoking history. However, lung x-ray revealed situs inversus totalis, so PCD genetic testing was done, revealing two novel mutations on DNAH5, a gene normally associated with severe outer dynein arm defects and male infertility.
Clinical Features and Manifestations of PCD Session
The first talk in this session focused on paying careful to attention to the phenotype—or clinical presentation—of classic PCD, which is remarkably consistent given the large number of genes responsible for the disorder. Data analysis from the large North American GDMCC study indicated that the clinical features that most accurately predicted an ultimate diagnosis of PCD include year-round, wet sounding cough starting in the first year of life; year-round nasal congestion starting in the first year of life; any laterality or sidedness defect; and neonatal respiratory distress. A patient presenting with a history of these four features has a high likelihood of PCD. Even after removing laterality defects, the remaining three features make a strong case for suspicion of PCD. Ear issues are very common in PCD, but they are also common in the general population so including ear infections in the probability calculations was not helpful for predicting PCD. It is, however, important to remember that ear issues are a prominent clinical problem in PCD.
GDMCC 5905, an ongoing genetics study, was discussed next. This study uses whole exome sequencing to attempt to identify novel genes and mutations from patients who exhibit the clinical phenotype of PCD, but who are currently undiagnosed because no available testing captures their underlying defect.
ENT issues in PCD cause untold misery in patients, yet we have almost no data to support any practice or therapy for ear, nose and sinus problems in PCD and approaches to ENT issues vary dramatically by country. The next talk presented data from an ongoing longitudinal study at the University of Toronto that marks the first systemic effort in North America to create an evidence base to direct therapeutic practices for ENT issues in PCD.
Early literature on what we now call PCD focused on Kartagener syndrome—a subset of PCD characterized by situs inversus totalis. We now know that PCD can be associated with an array of organ and laterality defects and that the incidence of congenital heart defects in people with PCD and situs ambiguus (non-typical and non-situs inversus) is significantly elevated. The final talk of this session focused on ongoing research to understand the role of cilia in determining organ placement.
Friday, August 25
Last conference day! The focus was on adult issues in PCD, including challenging infections, advanced lung disease/bronchiectasis and sub/infertility in females with PCD.
Adult Issues in PCD
Highlights of the ‘challenging infections’ presentation: PCD is a progressive disorder, so it is no surprise that respiratory infections may become more severe and harder to treat in adult patients. Studies of the lung microbiome of patients with PCD demonstrate a clear pattern of increasingly difficult to treat infections, including acquisition of multiply-resistant organisms. Despite this, infection control guidelines are lacking in PCD compared to other disorders, like cystic fibrosis. In the absence of evidence, there is consensus that common sense approaches to prevent patient-to-patient transmission of infections should be implemented in clinical settings and in any setting where patients might be exposed to each other. This is especially important for patients with pan-resistant organisms or active infections that could be spread to other patients. Look for an upcoming post that goes into this topic in-depth.
PCD bronchiectasis may start in childhood, but dealing with advancing bronchiectasis is especially challenging for adults with PCD. The presentation on bronchiectasis focused on how patients with advanced bronchiectasis can be helped to manage their daily care. There was consensus that adult PCD bronchiectasis care in the US is sub-par, in general, and that this needs to be an area of focus for the PCD centers network.
It is unclear whether reports of subfertility and increased risk of ectopic pregnancy in females with PCD are accurate because until recently have been no efforts to carefully and systematically collect data on this topic. To address this, the next speaker shared data from a University of Muenster review of adult female PCD patients and found that most who wanted to achieve pregnancy were able to do so, even without reproductive assistance. This represents a small patient group, but includes patients with PCD caused by several different mutations. There is broad agreement that fertility issues in PCD—both male and female—is an area that need further study.
Research and Future Directions
The first talk in this session was an overview of the ongoing CLEAN-PCD study, including goals of the study, study design, revisions to the inclusion criteria and recruitment targets vs. actual recruitment. This is a larger topic, so look for an upcoming post with more details.
Dr. Michael Knowles from UNC, Chapel Hill closed the meeting with an excellent talk recapping progress in PCD research to date and highlighting what we can look forward to in the future. His talk was videotaped and will be posted to the website as soon as some minor editing is completed.