Just as we all remember where we were and what we were doing when JFK died, I remember where I was in 1989 when I learned that the gene coding for CF had been identified. It was a BIG day. Everyone in the CF world was convinced that a cure was just around the corner. I was a medical student and soon to be resident at Stanford, and couldn’t wait to be a subject in gene therapy studies.
Of course, that didn’t exactly pan out as expected. Inserting a corrected version of this newly identified gene was much more complicated than anyone could guess, and gene therapy as a cure for CF is still a long way off. But, 25 years later, as a result of sequencing the gene and determining the structure and function of the protein it coded for, we are having another BIG, BIG day.
Everyone in the above-mentioned CF world has been anticipating the day that Vertex Pharmaceuticals would announce the results of their two phase 3 combination trials of Kalydeco (ivacaftor) with VX809 (lumicaftor). These were huge studies, not just in the sense of numbers of patients (1000 total), but also in the significance of the results. Kalydeco had already proven to be a huge success for a small number of people with a rare CF mutation, G551d. “Blue Lightening” as some fondly refer to it, at the cost of over 300K per year, has proven to be a literal life saver for people with this mutation. You can argue for days about the price–and many , many people have deep concerns about this–but you can’t argue that Kalydeco has been a game changer. By correcting the defective gene product itself, Vertex has proven that the long awaited CF “cure” is quite possibly just around the corner.
I put cure in quotes because taking a Vertex drug is NOT going to undo what has been done. Scarred lungs will remain scarred. Treatments to contain chronic infections will continue to be necessary. Pancreatic enzymes will still need to be replaced. CF-related diabetes will continue to need management with insulin. By “cure,” what I mean is “contained,” or managed chronically, just as diabetes or high blood pressure are managed.
But these combination studies, named TRAFFIC AND TRANSPORT, were going for the BIG money (pun intended), deltaf508 homozygotes, the most common genotype to cause CF. Yours truly is a double delta f508, and I was a subject in the study. Now that the results are published, I can talk about my experience.
I still don’t know if I got the drugs during the first six months, as I was blinded. But when I rolled over to the open label portion of the study, when i knew for a fact that I was taking both drugs, I immediately got sick and ended up with pneumonia. Then, two months later, the same thing happened. And then, the same thing happened again. In sum, three rounds of pneumonia in four months.
Coincidence? Maybe. Prior to rolling over to open label, it had been 19 months since I had needed IV’s for pneumonia. So I don’t know for sure…but I had to stop the trial, and I’m not about to take those two drugs together again until I have a LOT more information.
But my story is not what Vertex is reporting today, so I’ll stop there. Vertex says that they have achieved their primary endpoint of absolute improvement of FEV1 of about 3%. In addition, secondary endpoints of weight gain and decreased pulmonary exacerbations were statistically significantly achieved. This is big! Wall street is going crazy. Facebook is exploding. Champaign corks are popping!
A lot of people are going to make a lot of money.
A 3% change in FEV1 is not a ton. As a comparison, Pulmozyme studies showed an improvement of about 6% in FEV1. Kalydeco improved FEV1 in G551d folks by about 10%. According to Dr. Bonnie Ramsey, one of the lead investigators in these trials, patients probably wouldn’t even notice a 3% improvement. So why is 3% a game changer? And why is this a BIG, BIG day?
Today is a BIG, BIG day and I will always remember where I was (sitting on the toilet, of course) when I read the press release, because today we know for sure that it can be done! It can be done for the most common form of the disease, not just in the lucky (?) few with G551d. It’s as if we’ve been running a marathon for 25 years, slogging along, runners (patients) dying left and right, trying to cure or control this damn disease, and suddenly today, the finish line is in sight.
The delta f508 mutation leads to a misfolded protein (CFTR) which mostly gets chewed up and spit out by the cell’s quality control mechanisms before it can ever get to where it needs to go, the cell membrane. Here, even the very few CFTR that make it to the target site don’t function correctly to allow chloride ions to traverse the membrane. That’s why we need at least two drugs…one to help with the folding and one to help with the functioning.
But there are two areas within the CFTR protein that are misfolded. Lumicaftor (809) corrects one of them. Then Ivacaftor (Kalydeco) corrects the functioning (partially) of the protein at the membrane.
So 3% is not huge, but better correctors are just around the corner, including second generation correctors that fix the second misfolding site in the dd508 mutated gene product. People, the end is near, and the race is on! Vertex is madly working on other correctors, as are big pharmaceuticals like Pfizer and Genzyme. Competition is really, really good. There will now be a sprint to the finish line because everyone wants to be the big winner in CF. The game has changed. The slog is now a sprint. Everybody wants to be the company that does for delta f508 what Kalydeco has done for G551d, or better!
The race is on, and now we are going to watch capitalism work, for better or worse. CF patients and investors in the correct company will win. People who actually have to pay the astronomical prices for these medicines will lose.
My Quantified Self Experiment: Can Heart Rate Variability Be Useful In Predicting A CF Exacerbation?
There is a movement afoot. It goes by a few names; quantified self, biohacking, and biologging are a few. The quantified self website has a tagline which sums up the purpose of this movement quite well, “self knowledge through numbers.” By using technology, usually in the form of wearable tracking devices, data is acquired which allows the self-tracker to understand herself better.
A simple example is the popular Fitbit, which is a device worn somewhere on the body, depending on the model, that tracks steps taken over the course of the day. It’s fancier than a simple pedometer (the original self-tracker), in that it has a built in accelerometer, so the user can wirelessly sync to her computer dashboard and record sleep, calories expended, steps and miles walked, floors climbed, most active time of the day, and of course even connect with fellow fitbit friends. It’s really amazing what you can track these days.
My recent foray into self-tracking involves first-thing-in-the-morning measurement of my heart rate variability, or HRV. I learned about the value of this measurement through my obsessive thinking about and planning my latest “comeback.” After the third bout of pneumonia this year, I guess I needed more than the usual amount of motivation, and was looking into the latest and greatest fitness gear/technologic toys to spice up the process a bit.
HRV measurement is definitely not new, but using it to enhance one’s training is a relatively recent phenomenon. It’s been used for years in professional athlete circles, but easy to use cellphone apps for the masses are new. There are a few, but the one I chose is called “Bioforce.” Using a bluetooth enabled Polar heartrate monitor strap and this iPhone app, I’ve been watching my HRV steadily “improve” as I’ve slowly but surely increased my training intensity since rolling out of my room in the wheelchair (why do they have that rule?).
So what is HRV? In brief, there is a normal rhythm to the heartbeat that is a bit different from the constant “lub dub, lub dub, lub dub” that you might imagine. Your heart rate is under the control of your autonomic nervous system, which is a good thing or else you’d have to consciously contract your heart with every beat. The autonomic control of heart rate depends on a delicate balance between the sympathetic nervous system (think “fight or flight”) and the parasympathetic nervous system (think “rest and digest”). As you inhale, the sympathetic nervous system is more in control, and as you exhale, the parasympathetic nervous system prevails. As a result, when you inhale, heart rate speeds up just a smidge, and as you exhale, it slows down. So when a regular heart rate monitor says your HR is 75, that is just an average of what it is over a given time period. Really, it probably ranges from about 70 to 80, depending on your breath cycle.
Now it gets simpler. A given measurement of HRV is a reflection of your autonomic nervous system, the balance of sympathetic and parasympathetic input, in the moment. Increased parasympathetic function is associated with higher HRV and aerobic capacity and has been shown to correlate to increased life expectancy (in “normals,” i.e. they don’t have CF).
Why is this useful? Well, when the body is stressed, sympathetic system is more prominent. This is why your heart and breathing rate increase, why you stop digesting food, why blood shunts to your muscles to get ready to fight. It’s all automatic. When you are relaxed, parasympathetic control leads to the opposite effects. So HRV can reflect your body’s state of stress.
Elite athletes use this measurement to tell them if they are overtraining. This is why HRV apps for your phone have been created. A given daily measurement will let them know whether they should train hard that day, or take it easy because their sympathetic control is too high, warning them that they are approaching the overtrained state.
But HRV can also reflect the body’s state of inflammation, because there is a linkage between inflammation and the sympathetic nervous system. This is a bit complicated, because obviously you can have low grade inflammation and not have a flight or fight response. But remember, we are talking about measuring a fine balance here, and a significant inflammatory process (such as a CF exacerbation) could very well tip the balance a bit, and this could be picked up by a measure of HRV, especially if you are your own control. At least, this is my hypothesis.
So this is my N of 1 trial. Basically, N of 1 is a clinical trial in which a single patient is the entire trial. I am running my own case study. And N of 1 trials are what the quantified self movement is all about.
What have I learned so far? Well, for the first few days out of the hospital, my HRV was extremely low (green line is HRV, yellow line is heart rate, and blue is average). This makes sense, as I was stressed and my body was WAY stressed. Gradually, it has increased, with downward blips here and there:
The colors of the bars on the bottom of the graph have meaning if you are an elite athlete and basing your day’s training on your HRV. Green means go hard, amber means take it easy, and red means take a day off because your body is in the danger zone of too much sympathetic input.
Here is what I have learned so far: My HRV goes down (bad) if I drink any amount of alcohol the night before. This saddens me. It also goes down if I am dehydrated, which is likely related. As you can see, I am supposed to take today off from training, but my take away is that the second bottle of Fat Tire last night was a really bad idea.
Okay, so I know I’m a nerd. But I’m going to keep this up and watch what happens when I get sick the next time. Maybe I’ll have an early warning. We’ll see.
These types of experiments can be very enlightening. What would be really cool though would be if those of us with specific questions (CF related) could share with others our experiences, and get immediate feedback from others with similar questions. Do you think we could uncover some interesting results? Think of the surfers’ experiences leading to the development of hypertonic saline. More to follow!
One of my father’s favorite sayings was, “I’m in pretty good shape for the shape that I’m in.” He was being funny of course, but these days, I can totally relate. It’s all about perspective. Today, I’m thinking about what it means to be “fit” as I walk at a snail’s pace on my treadmill and suck saltwater into my lungs, which are being violently shaken by my therapy vest.
If you use the biologic definition of fitness,
The genetic contribution of an individual to the next generation’s gene pool relative to the average for the population, usually measured by the number of offspring or close kin that survive to reproductive age.
then I’m toast. These genes were surgically stopped in their tracks decades ago. On purpose.
If you get a bit less Darwinian, fitness could be described as:
The capability of the body of distributing inhaled oxygen to muscle tissue during increased physical effort.
This is getting closer to what I’m after. But living with cystic fibrosis takes a special kind of fitness not intimated by either definition. My favorite description of fitness is one I heard on a podcast yesterday, which was something like,
The ability to do what you need to do, given the exigencies of your life, and to have a little left over for emergencies.
In other words, to be in good shape for the shape that you are in.
The “exigencies” of our lives include things like constant immunological battles in our lungs, defective insulin production, and shitty (pun intended) digestion, to name a few.
To be fit with CF means to be able to thrive, given all of these complications…and then, to have something left should an emergency occur.
I have a CFit client who is a perfect example of CF fitness. This woman is a runner, and also lifts weights and dabbles in Crossfit. She’s hardcore. She related a story to me the other day which left me amazed.
She was running with a group of people crossing a bridge, when they noticed a child stuck on a log in the water below. This was in Florida, and the water was swampy and apparently the home of many crocodiles. The kid was unable to swim to safety, and was in a precarious position, to say the least.
So my client took off at a sprint, as she needed to run nearly a mile to get to where she could enter the water. Then, she had to swim to the kid and keep him/her (I’m not sure) from being swept into crocodile territory until help arrived.
Now that is fitness!
If you are reading this thinking, “that could never be me,” you are missing my point. If you have CF and are simply moving more each day in attempt to improve your health, then you are an athlete in training. You don’t need to be a child-rescuing ninja. If you don’t like to run, then walk, or swim, or cycle, or lift weights, or swing a kettlebell, or play badminton, or… something! Prepare for that emergency. It may be a kid in danger, but more likely, it’s the next exacerbation. Whatever it is, it will be in your best interest to be stronger than you are right now. Unless you are my ninja CFit client…she’s already in pretty good shape for the shape that she’s in.
It was a little over a month ago that I lay on my weight bench in the garage with tears of frustration streaming down my face. I had just completed a 15 minute “workout” consisting of a few unweighted lunges, some hip bridges, and 3 sets of 5 reverse abdominal curls. This was all I could do, since I still had a PICC line in my arm and couldn’t chance any upper body work (I’ve learned that important life lesson). As it turned out, the 3 exercises I chose were clearly enough, as my heart rate after the last rep was about 300 bpm and I felt like if I rolled off the bench right then, I might have to call my son in to help me up.
I was a mess.
I suppose I had a good reason for the tears. This was the third bout of pneumonia in just four months, and I was sick and tired of being sick and tired. It was also my first attempt at any form of exercise other than easy walking in well over a month, and my physical fragility was frightening. Normally when I exercise, I am a bit of a taskmaster. I push myself pretty hard and usually do more than I set out to do. But today was different. I was a complete wimp.
I was nearly at the end of my course of antibiotics and the PICC was coming out in two days. This meant that I had been receiving medications to eradicate lung infections for four of the the last five weeks. That is a lot of antibiotics. There was likely not a viable bacterium to be found in my body. Indeed, my cough was gone, the pain of pleural inflammation was gone, and I could actually eat again. But, where was my mojo? I still felt like crap, and this was the kicker. Normally, at the end of a course of IV’s, I am raring to go, having planned my fitness regimen for the next three months. This time was different, and I was worried.
Of course, my partner reminded me that I would get better…that I always did…and that I needed to be patient. My rational mind knew this, but my emotional self kept whispering, “What if this is it? The beginning of the end? Your 53 year good luck streak has to end sometime…”. I hate that voice.
So, ten pounds of muscle mass down (which was obvious as I watched my legs trembling as I got up from the bench), I vowed to give my secret weapon the old college try and to stop listening to emotional self until the end of the trial. Antibiotics are needed, as are pulmonary clearance and airway treatments. Sleep is king, and hydration and good caloric intake does wonders. But, the best medicine of all, at least in my experience, is daily exercise. It makes me breathe deeper. It gets me outside. It makes me cough up junk. It builds an appetite. It makes me, ahem….regular. But most of all, it feeds my soul.
So, tears now dried, I developed my plan. It was a modified version of my plans of the past…much easier…much slower progressing.
Walking is always the foundation of my recovery, and will be until the day I can’t walk anymore. But walking further than I should due to training for a half-marathon when sick was what landed me in the hospital with pneumonia number two, so I had to be cautious. I decided to cut in half the time I thought I should be able to walk, and add just a few weight training exercises only three days/week. These were front squats, kettlebell swings (only 10 at a time), and Turkish get-ups with a very light kettlebell. That’s it. I wanted to do more, but my shoulder was messed up (thanks to levoquin), and I had to be careful not to rupture a tendon.
So that’s what I did. Over time, my walks became walk/jogs, and my two kettlebell exercises proved to work magic, as I knew they would. Today, I’m doing swing intervals as easily as I was before the s&#t hit the fan back in January. My shoulder is getting stronger and I’m able to press again. I can breathe. I’m not coughing. I’ve gained back 6 pounds.
Yes, the antibiotics did wonders. Thank God (and Barb) I have insurance and great medical care! But there is no doubt in my mind that what converted me from that trembling, weak mess lying on my bench last month to today, looking forward to my get-ups and KB presses, is exercise. Exercise is medicine. Very slowly but surely, it works to build up strength and endurance, to improve appetite and thus enable weight gain, and to bring me out of the doldrums to enjoying my fantastically fortunate life.
I have a pet peeve. It is the word “compliance.”
This word is thrown around quite a bit in CF circles, especially among medical professionals. It is used frequently in research papers, where there is an understanding of what it means. Physicians and other researchers are very concerned that people with CF don’t always do everything that they are told to do to keep their disease and all of its various manifestations at bay. If someone fails to do all required treatments or take all medications or exercise daily, they are coined “non-compliant.” Did I say that I hate that word?
Just do me a favor and check out your friendly thesaurus to find other words that mean the same thing. Never mind, I’ll help you out. Here are a few: docile, easy, manageable, meek, submissive, yielding. In other words, spineless, with no worthwhile opinion on the matter. Now in the olden days, when Doctors were GOD (which is why I capitalized doctor), it was just assumed that one followed one’s doctor’s orders, no questions asked. But times have changed, and if you don’t believe me, turn on your TV and count how many different pharmaceuticals tell you, the patient, to “ask your doctor if this could be right for you.” Like it or not, patients are a very important part of the equation now. This is a good thing (not the television commercial part…that is a very crazy and ridiculous thing).
I’m not harping on CF doctors. I actually think most realize that the patient has very important information, like how much it is really possible for them to do in a given 24 hour period. So why can’t we drop the word?
I have an alternative. How about instead of the word compliance, we use “consistent.” How consistent someone is with their thrice daily aerosols, or 250 pills to swallow, or blood glucose monitoring, or airway clearance technique of choice, or exercise, or any of the myriad other things we must do daily, sounds SO much better than “compliant.” There is no judgement in the word consistent. It implies that we are all trying hard, but sometimes life gets in the way. Check out some of the synonyms of my substitute word: dependable, persistent, rational, steady, true, regular. I like dependable and steady so much more than meek and submissive, don’t you?
What say you, CF peeps?