PCD Foundation Blog

One of the best things about this meeting has been the really practical information presented. Keeping neb equipment clean was an interesting topic covered by Dr. Gwen Huitt. For inhaled antibiotics (TOBI, colistin, etc.) National Jewish recommends using only a Pari (http://www.pari.com/) neb cup with filter (which is pretty standard, I believe) and the DeVilbiss Pulmo-Aide nebulizer machine, available online at http://www.devilbisshealthcare.com/index.jsp.

Pari neb cups can be boiled for sterilization, but the tubing is another matter. Since people with bronchiectasis are prone to “water” bugs like Pseudomonas and NTMs, it it important that the tubing be kept dry. Dr. Huitt recommends having seven sets of tubing, one for each day of the week. After use, she has her patients jerry-rig a blow drying system for the tubing by taking a standard rubber glove, cutting a slit in one fingertip and inserting one end of the tubing in the slit. A standard hair dryer is then attached to the wrist end of the glove and hot, dry air blown through the glove and into the tubing for one minute. Then leave the tubing in the open air until the next use. Both Dr. Huit and the RT strongly suggested NOT bagging up tubing for storage, but leaving it out in the air.

Some patients have also pulled their neb cup off the tubing at the end of a treatment and allowed the compressor to keep running for several minutes to dry the tubing. This also seems to work, but the hot, dry air of the blow dryer appears to be the most effective at curtailing bug growth.

*Please note–the following is not intended as an endorsement of any particular form of airway clearance, but is provided for informational purposes only.

At the NTM conference, a respiratory therapist (RT) from National Jewish talked about their preferences for airway clearance and highlighted the need for diligent, daily therapy. This talk was given in the context of patients with bronchiectasis and NTM infections, but much of what she presented would apply equally well to PCD patients.

First off, they really like the Vest (any brand) and the blue (for pediatric or low lung volume patients) or the green (adults) original versions of the Acapella. They are not so keen on the Acapella Choice (the cleanable one) at this point because it tends to break easily. Apparently, the manufacturer is working on this and hopefully will be able to come up with a solution to the breaking issue. The treatment regimen they like is Vesting for 10 minutes, followed by five blows (exhaling only) on the Acapella, followed by huff coughing, then repeat x 1 (for a total of 20 minutes Vest time).

The speaker was very clear about the fact that any form of airway clearance is better than nothing and they don’t want to discourage people from doing whatever therapy they find most effective. However, National Jewish does not generally prescribe IPV devices for patients with bronchiectasis because the “jack hammer” effect can lead to hemoptysis in these patients. Also, cough alone is not as effective in bronchiectatic airways because they become “floppy” and can collapse from the pressure of coughing, trapping mucus. PEP devices like the Acapella essentially use positive pressure to stent the airway open, so mixed with with cough or Vest to loosen secretions you may get good results. The speaKer also made a strong point about not confusing lack of productive cough with failure of treatment and suggested that airway clearance is happening with therapy regardless of whether you notice a demonstrable result.

The blue and green Acapella devices cannot be boiled or sanitized, so it is crucial that you only exhale into them and don’t breath in. For those of us (like me) who have difficulty walking and chewing gum at the same time, remembering not to inhale could present a challenge! Acapella is a vibratory PEP (positive expiratory pressure) device. Other devices in this category include the Flutter valve and the Quake. The Flutter is the old standard, but it is positioning-dependent, meaning that it’s effectiveness is strongly impacted by user ability. The Quake is a newer PEP device that allows the user to control the amount of vibration using a hand-turned crank that looks a bit like a fishing reel. The Quake also requires a certain amount of coordination–must exhale and turn the crank simultaneously–so it is not appropriate for everyone.

Postural drainage (tipping upside down) works great for some people and they do it a lot at National Jewish to help people get sputum samples up. However, you need to be sure you don’t have any reflux issues before embarking on a postural drainage regimen and it is always a good idea to do it on an empty stomach to prevent aspiration!

Coming up next…

“What’s Growing in Your Nebulizer?” or “How I Learned to Stop Worrying and Love My Tubing.”

So you may be wondering why non-tuberculous mycobacterial (NTM) infections (MAC, absessum, MAI, etc.) are of interest to people with PCD. NTMs are nasty and destructive bugs in the same family as Tuberculosis (TB) and there is increasing evidence that bronchiectasis-causing disorders contribute to acquisition of these bugs. At Family Day this summer, Dr. Knowles presented a slide indicating that 20% of PCD patients over the age of 29 in a small review had some form of NTM. Since that review, NTM has also been cultured from adolescent PCD patients. The current recommendation is that all PCD adults and adolescents, regardless of whether they are symptomatic or not, be cultured for NTMs annually. This requires a specialized culture called an AFB culture. There are several labs that do quality cultures. Contact the PCD Foundation for more information.

Patients wanting to participate in NIH-sponsored research now have a resource to help with travel costs.  Angel Flights/Mercy Medical Airlift has established an office at the Office of Rare Diseases in Bethesda, MD to better serve patients participating in research studies (like the PCD study [GDMCC]).

Here are the guidelines:

*Flights must be for research, evaluation or treatment.
*The appointment must already be set prior to calling Angel Flights.
*Flights are primarily for people who are 300-1,000 miles from the
target medical site, but there are occasionally resources for people
traveling longer distances.
*Financial need is considered, but the terms can be flexible.

The contact person at Angel Flights/Mercy Medical Airlift for GDMCC study participants is Marita Eddy.  Here is her phone number: 301-451-9646

Angel Flights/Mercy Medical Airlift also wants us to let our group members know that they accept and greatly appreciate donations of frequent flyer miles for United Airlines.  If you have miles you would like to donate on a different carrier, there are airline miles exchange sites on the Internet.

I received a letter from Genentech/Novartis outlining a new warning about Xolair.  This is an update from the Feb. 2007 FDA alert, which merely encouraged people to fully read the package insert that comes with Xolair.  Here is Genentech’s warning:

“Anaphylaxis, presenting as bronchospasm, hypotension, snycope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of Xolair.  Anaphylaxis occurred as early as after the first dose of Xolair, but also has occurred beyond 1 year after beginning regularly administered treatment.* Because of the risk of anaphylaxis, patients should be closely observed for an appropriate period of time after Xolar administration, and health care providers administering Xolair should be prepared to manage anaphylaxis that can be life-threatening.**Patients should also be informed of the signs and symptoms of anaphylaxis and instructed to seek immediate medical care should symptoms occur.”

Anaphylactic reactions can be deadly within minutes.  Neither the FDA nor Genentech is providing guidelines for who is at risk, so we have to assume that any user could potentially have an anaphylactic response to Xolair.  If you or your child is currently using this medication, please discuss this warning with your physician.  If you would like copies of the actual letter from Genentech, let me know and I can get them to you.

*This means that because even if you have used Xolair with no problems in the past, you still may experience anaphylaxis at some point.
**This means careful observation after each dose of Xolair

Since 2005, the Genetic Alliance and other patient advocacy groups have been working to get legislation passed that would protect individuals with genetic disorders (and their blood relatives) from discrimination in insurance coverage and in the workplace.  The resulting bill called “GINA” has received broad support from both parties.  The bill (details at link below) has been passed in the House of Representatives.  It looked to be a slam-dunk in the Senate, as well, but Oklahoma Senator Tom Coburn (a physician) has put a hold on the bill meaning that it won’t even be considered for an up or down vote.  Senator Coburn’s office has not provided an explanation for this action yet.  President Bush has already indicated that he will sign this bill into law if it is passed in the Senate.  The only hold-up now is Senator Coburn’s hold.

According to Senator John Kyl (R-AZ), enacting GINA requirements will result in little to no direct cost to taxpayers.  The biggest opponents of this legislation have been the health insurance industry and employer groups who would like to reserve the right to deny costly services to persons with genetic disorders.

Genetic Alliance is requesting that patients impacted by this legislation contact Senator Coburn (if they are from Oklahoma) or contact the Republican leadership in the Senate to request that they persuade Senator Coburn to release the hold.

Here is the bill:
http://rpc.senate.gov/_files/L2GeneticNondisDBJS021605.pdf

Here is Senator Coburn’s legislative aide email (if you live in OK):
courtney_cox at coburn.senate.gov

Senate leadership contacts for non-OK residents:
Trent Lott (R-MS)                  Phone 202.224.6253
Mitch McConnell (R-KY)           Phone 202.224.2541

It seems a bit ridiculous that we have to fight to prevent discrimination due to our genes.  However, the threat of discrimination in the U.S. is real.  Here is an example, the International Classification of Disease (ICD) now in its 10th revision, is used by the majority of the world to categorize disease and to keep medical statistics.  It does this by assigning numerical codes (PCD has not be given a specific code yet, that is a different problem).  In the 10th edition, the ICD distinguished the numerical codes for genetic diseases by putting a letter “V” in front of them.   These so-called “V” codes were great for countries with national health plans where all patients are covered regardless of their condition.  However, in the U.S. where ICD-10 codes are used for private insurance reimbursement, it is feared that V codes will prove to be “handy guide to discrimination” by insurance providers, allowing them to easily deny claims submitted using a  V code.  Please note–this has not happened yet–this is merely an example of why Genetic Alliance, the AMA, and other professional groups have been fighting for GINA for nearly 3 years now.

If you have the ability to make a call or send an email, please consider it.

Michele

Johnny L. Carson, Director

Department of Pediatrics Ultrastructure Laboratory

The University of North Carolina at Chapel Hill

While many in the PCD community know the significance of ultrastructural analysis of cilia and flagella in the diagnosis of PCD, most have never even seen one much less have an awareness of how they work and why they are useful for this purpose. Electron microscopes come in two varieties, transmission and scanning. While both varieties use an electron beam to generate an image, they function in fundamentally different ways. Scanning electron microscopes allow us to see surface topography at high resolution and while they are useful scientific instruments for a variety of purposes, they are not used to make the diagnosis of PCD. The transmission electron microscope (TEM) is the type used for analysis of cilia in the diagnosis of PCD. The word “transmission” refers to the transmission of electrons through the specimen to generate an image on a photographic plate. You may ask, “Why can’t we just use a light microscope to analyze cilia for PCD?” The reason is that the structures we need to examine in cilia are small molecules beyond the limits of resolution of light microscopes. What does this mean? In order to produce an image, whether it is on the retina of the human eye, a photographic plate, or a chip in a digital camera, light has to interact with the object being imaged. Visible light moves in the form of waves that interact with an object to be imaged in ways that cause the regularity of those waves to be interrupted. This is called diffraction. It is important that the object being imaged is able to interact with light in a way that causes diffraction. Think of a series of waves washing up along a beach. If the waves crash against a boulder, the interaction creates a large splash. In contrast, if these large waves wash over a small seashell, hardly a ripple is evident. While the cilium might be considered analogous to the boulder, the small structures within the cilium (the seashell) are too small to interact with light waves in order to image them effectively. For that purpose, we choose electrons. Electrons exhibit some of the same properties as light waves but they have much smaller wave forms capable being diffracted by much smaller structures. Thus, electrons can interact with the “fine structure” of the cilium in a way that makes it possible to obtain images of exceedingly high detail down to the molecular and sometimes atomic levels. The benefit of the electron microscope is not that it can magnify thousands or millions of times, but rather at those magnifications, one can appreciate the fine details of the specimen.

Electrons are not easy to produce, at least for electron microscopic purposes. The electron beam itself is generated from a tungsten filament, not much different in appearance from an ordinary light bulb filament. The hard part is focusing this beam of high energy electrons coherently. The path of an electron in air is less than two inches. However to be effective for electron microscopy, the beam must be focused through a series of large electromagnetic lenses. In order to generate the electron beam, electrons are literally boiled off of the filament tip under high voltage, anywhere from fifty thousand to one million volts. To accommodate the large lenses in doing their job, the beam must be directed through a long tube, the column, constantly maintained under a high vacuum. The specimen is positioned in the column among the lenses and the image focused onto a phosphorescent screen for examination. Historically, a conventional plate film camera was positioned directly below the viewing screen but in newer microscopes digital cameras are used. Depending on the application, transmission electron microscopes range in price from approximately $100,000 to millions of dollars. The purchase price is just for starters. The operation and maintenance of these sophisticated instruments generally requires at least one full time on-site technician for management as well as the purchase of a hefty service contract to troubleshoot complex problems that inevitably occur. For this reason, most electron microscopes are found in large multi-user facilities that allow the operational costs to be shared.

Unlike a light microscope in which a specimen can simply be positioned on a glass slide and examined, the processing of a specimen for TEM introduces a whole new level of complexity to this technology. In order for electrons to generate an image, the specimen must be treated with chemicals containing osmium, lead, and uranium in a way that deflects their “transmission” through the specimen making them “electron dense”. Water is also removed from the specimen by passing it through alcohol and the specimen is infiltrated with liquid plastic that is then allowed to polymerize in a small plastic capsule about the size of a pencil eraser. Processing a single specimen to the point of being ready to examine in the electron microscope usually requires about one week. A specialized instrument, an ultramicrotome, is used to shave extremely thin sections from the block that are then placed on a copper mesh for positioning in the microscope.

Proficiency in electron microscopy is a blend of science, art, eye-hand coordination (and sometimes a little luck). Professional electron microscopists have a good educational background in biology, chemistry, and physics. There are educational programs for aspiring students who should expect to spend 18-24 months to master the basic skills of electron microscopy theory and practice. This may sound like a daunting commitment but for the electron microscopist every specimen is a new and unexplored trail.

The electron microscope is one of the key instruments in the scientist’s tool box. In terms of PCD, this disease languished in obscurity and misunderstanding for three quarters of a century awaiting the advent of routine biological electron microscopy. Since that time, many new ultratructural discoveries have contributed to our knowledge of the pathophysiologic basis of PCD. Moreover and of equal importance to knowing what PCD is, electron microscopic studies have been central to achieving an understanding of what PCD isn’t. Also in recent years, studies of cilia characterizing fundamental mechanisms of motility and transport also laid an important scientific foundation that has led to an emerging knowledge of their role as sensory organelles. This has opened up the study of entire new cellular landscapes with the discovery than cilia play a significant role in a number of other human health syndromes collectively known as ciliopathies. While cilia exhibit a certain uniformity of structure and exist widely across both the plant and animal kingdoms, it will be interesting to learn whether there are unifying characteristics that link these motility and sensory functions in both health and disease. The emergence of the electron microscope as a routine instrument of research allowed us to see structures in cilia that are the misshapen product of gene mutations in PCD. Inevitably, the ongoing revolution of molecular biology will reveal to us the genetic basis of PCD and technological improvements in electron microscopes and ultrastructural technologies will continue to be an important tool in this quest.

Copyright Johnny L. Carson 2007

E-mail: jcarson@med.unc.edu

It is getting to be more and more important to understand the distinction between primary and secondary ciliary defects.* Here is a brief overview:

When you Hear PCD, Think Proteins

Primary or inherited defects are the result of genetic mutations that impact the production or expression of specific proteins. In the case of PCD (which includes KS, SI, ciliary aplasia, etc), those proteins are important in building the structure of cilia and flagella. They are also turning out to be very important in regulating organ placement and development. We have yet to discover what other things may be impacted by these proteins. If, because of a genetic mutation, your body can not make or use a protein adequately–EVERY SYSTEM THAT RELIES ON THAT PROTEIN WILL BE AFFECTED. PCD is not “selective.” You won’t have some cilia that work and others that don’t. You either have the functioning protein or you don’t, so it is a global or systemic problem for which there is no fix until we come up with treatments that work at the genetic level–thus the importance of genetic research.

Also, a faulty protein is with you forever so the problems associated with PCD, unlike SCD, are almost always apparent from birth or shortly thereafter. You won’t develop PCD over time–it is with you from day one. Granted, it may take a few months to recognize that the symptoms are not typical, but if your PCD symptoms started when you were an adolescent or only as an adult, you most likely do not have PCD.

Different Ultrastructural Changes

Secondary ciliary dyskinesia mimics PCD in symptoms. There may also be ultrastructural changes in ciliary biopsies in SCD, but these changes are very different and distinct from primary changes and a pathologist familiar with the two conditions will be able to distinguish between them. Every time anyone has a cold, they experience secondary ciliary dyskinesia. Any viral or bacterial insult will damage and/or destroy cilia. Repeated infections resulting in SCD can have the appearance of genetic ciliary dysfunction, but they are not the same. People with SCD can eventually recover fully functional cilia, assuming the underlying infection or condition can be treated adequately–people with PCD can not. Treatments for SCD and PCD may be very similar or even identical, but that does not mean they are the same disorder.

PCD vs. SCD What Difference Does it Make?

So why does it matter? There are several reasons:

1.) The long-term outlook is different. PCD is progressive and, for many, debilitating. If my child had SCD (or I did) and there was the possibility that whatever is causing the condition could be “cured,” I’d want to know that.

2.) PCD is genetic. It runs in families. Telling someone with SCD that they have PCD will give them the mistaken impression that they are at risk of passing on the genetic mutation that causes PCD when they are not.

3.) If someone is sick enough to have symptoms of SCD, it is important to find out what the actual cause is so that it can be treated appropriately. Clearly, something is wrong. If it is mislabeled PCD, then the true problem may never be identified.

4.) New information about the PCD phenotype (physical expression of the protein defect) is coming to light all the time. For instance, recent papers indicate that some of the proteins associated with PCD are also implicated in congenital heart disease. The new recommendation is that all people with PCD have a thorough cardiac evaluation. Because these proteins are not an issue in SCD, this recommendation does not apply to individuals with SCD. People with SCD who have been misdiagnosed with PCD are then put through an expensive, frightening and unnecessary cardiac evaluation.

5.) Millions of dollars are going into defining the “phenotype” of PCD–what the disease looks like and how it responds over time. This effort will be compromised if people who don’t actually have the genetic mutation are included in the data collection.

If You Think You May be Misdiagnosed

It is frustrating for all of us that the diagnostic picture in PCD is so mangled right now. However, the clinical picture of PCD, and the fact that it is a distinct clinical entity that can be distinguished from other conditions like SCD, is getting clearer all the time. Hopefully, this information will start to make its way into clinical practice so patients don’t have to face the frustration of misdiagnosis as often as they do now–and it is very common. The best way to be sure of your diagnosis is to participate in the research program or to contact one of the six PCD clinical centers who have expertise in this area. These centers are also valuable resources for information about collecting, preparing and analyzing ciliary biopsies for centers not affiliated with the PCD studies.

*PCD—Primary Ciliary Dyskinesia (inherited)

SCD—Secondary Ciliary Dyskinesia (acquired)

Michele

One of our biggest challenges, as people who care about PCD, is raising awareness about the disorder–not just in the medical community, but also with the general public. We all have had the experience of saying PCD or Kartagener’s and seeing eyebrows raise in confusion. For me, I generally try to describe PCD by saying “it’s like CF” or “it’s a little like really bad asthma,” trying to find a common frame of reference, but I’m always aware that those comparisons don’t do justice to accurately describing PCD. I’m convinced that one day PCD will have the same name recognition as cystic fibrosis–we just have to be persistent and creative in finding opportunities to raise awareness. Here is a really neat story from Kansas City that illustrates how patients can find/make these opportunities.
High school student Ashli from Olathe, Kansas was diagnosed with PCD last October after a lifetime of illness. Like many PCD families, Ashli and her mom, Vicki Bicknell, were very frustrated about the delay in diagnosis and the pervasive lack of awareness about PCD, even among the specialists Ashli had seen throughout her life. This frustration translated into motivation to get involved in PCD awareness. Ashli’s Ethics Class at Olathe South High School was looking for ideas for a community service project for the students. This was a comprehensive project, getting the students involved in choosing a cause, fundraising for their selected cause, and providing all the support services (marketing, public outreach, etc) that go into creating a successful event.
Bravely sharing her personal experience, Ashli spoke to her class about PCD and about the importance of patient organizations to support disease education and research efforts. Her presentation moved her class to choose the PCD Foundation for their Ethics Class project. Ashli, her mother, her classmates and her teachers worked very hard to organize a fundraising effort, soliciting donations from local companies and selling donated items on behalf of the PCD Foundation. They also arranged for an educational seminar to be held in the Olathe South High School auditorium and invited speakers from the PCD Foundation to talk about PCD, the importance of rare diseases research and why patient organizations are important. Local media outlets were invited and the session was taped for possible use in future news or print media stories. About 300 students, faculty and interested individuals attended the seminar. Johnny Carson, PhD (UNC) voluteered his time to come to Kansas City and explain what happens in PCD and how he got involved in PCD research. He highlighted that rare disease research makes a positive impact on everyone–not just the people with the rare diseases, and encouraged the students to get involved in fundraising and support for rare diseases research and also to consider pursuing education in the research sciences. Meghan Manion and Ashli Barker spoke about their personal experiences and what it’s like growing up with a rare chronic illness They were very open about the challenges and encouraged students to ask questions. I shared my experiences from the parent perspective and talked about starting a patient foundation (and took the opporunity to share darling baby pictures of Meghan!).

Ashli, with the full support of her mother and teachers, put a tremendous amount of time and effort into this event and did a phenomenal job of organizing a very comprehensive PCD awareness program. As a result, $4,000 was raised for the PCD Foundation and now the young people of Olathe, Kansas are more informed than many medical experts about PCD!
It was a real honor for us to be invited to speak about PCD (my favorite subject) and to hopefully encourage the next generation to consider choosing education/career paths that may help people with rare diseases. Special thanks to Johnny C., Meghan M., Mrs. Ruth Ann Falls, Mrs. Birch and the rest of the Olathe South High School administration and especially to Ashli Barker and Vicki Bicknell!

Michele