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!
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?
These are the last words I will utter about the month referred to above. After this, I shall erase this time from my memory and speak of it no more.
I should have known. It had been nineteen months since my last confession, I mean, hospitalization due to complications of cystic fibrosis. This may or may not have been due to the fact that I might have been enrolled in a research study involving a now famous potentiator in combination with an up and coming corrector of my f’ed up CFTR protein. I cannot confirm nor deny that I have been a research subject for a large amount of those nineteen months. I have been sworn to secrecy by the research Gods who don’t want study subjects blabbering all over social media about their experiences. So maybe I’ve been in a study, maybe not. I could tell you, but then I would have to kill all of you, which would be hard and very illegal.
It had become a frequent topic of conversation in our house. “Mom, it’s been so long since you’ve had pneumonia! What’s up with that?” To which I would respond, “I know…where is some wood to knock on?” My IV pole gathered dust, and I actually ran out of the thousands of little plastic bags that IV drugs are packaged in, which I had been collecting over the years.
When I passed the 12 month mark, I started to get a bit overconfident, I now admit. I hadn’t gone for over a year in years! It seemed that every 4-6 months prior, I would get slammed with the two-by-four named cystic fibrosis, and end up in the hospital, followed by home IV’s, followed by a short(ish) period of feeling sorry for myself, and then start all over again to become fit and healthy. It was a dance that I had down pat.
So, when my throat was a bit sore for a couple of days, I said it was the heater. And when I started to cough more than usual and felt tight, I decided it must be time to switch inhaled antibiotics…the colistin was getting to me. It took the fever to knock some sense into me. “Oh yeah, Julie…you do have this small underlying issue. Perhaps if it looks like a duck, it might be a duck?” What a great diagnostician I am.
So exactly one week from a 45 minute jog/walk, I am calling my doctor to tell him I need an x-ray. First, let’s talk about that 45 minutes. You probably don’t get this unless you, too, have this stupid, f’ing, ridiculous disease. In my twenties, a 45 minute jog was no biggie, Yes, it took longer for me than most to work up to this, but my lungs weren’t that bad and I ran frequently. In my thirties, I could still jog continuously for 45 minutes, presuming I had been diligently training for months. In my forties, not a chance. I had to switch to the jog/walk side of the street. And it was a chore. I did it…because I knew it was keeping me alive. But it almost always sucked, and was only worth it when it was over. To be clear, I am now 53. A forty-five minute jog/walk meant I was the fittest (endurance-wise) that I could be. I’m not kidding myself, these lungs aren’t ever again going to do much better than that.
Back to the phone call. From being at the top of my game one week prior, I had been slammed out of the blue by the railroad tie named cystic fibrosis. In a literal heap of piss-poor-protoplasm, I held on to my phone, listening unbelievingly to the message on my doctor’s line, “I will be out of town and away from the office until….” forever from then. I needed an x-ray. The fever was now accompanied by an elephant sitting on my right chest wall, poking a sizzling hot tire iron into my ribs with every inhalation.
Ok, I thought. This is why God made cell phones. Fortunately, he answered (my doctor, not God) and ordered the needed test. Of course, I didn’t really need an x-ray. I knew exactly what it would show. I was screwed. Not just because of the pneumonia, but because my guy was out of town. This meant an ER visit, followed by treatment by people who don’t know me or my CF. Never a good combination and to be avoided at all cost.
So I did what any sane person who had a partner who worked at another hospital would do. I packed my bags, my Vest, and my dogs and drove an hour north to be admitted at Barb’s hospital in Marin. At least they know me, and I am treated extremely well. It helps to have friends in high places. Plus I’m pretty sure Barb would not allow them to let me die. I landed in solitary confinement, with all visitors required to gown, glove and mask before entering. Flu? Who knew? MRSA…absolutely…droplet and contact precautions in place.
The dance commenced. In went the PICC. Drip drip drip went the triple antibiotics. The dilaudid was supplied as requested (thank you). Into the room came the meals, out of the room they left, untouched. The Boost supplement pile grew. The showerless days passed. The colon moved nary a muscle. The fevers remitted. The cough morphed from dry and painful to loose and rattley. The form that looked back at me from the tiny mirror above the sink grew smaller and smaller. I managed a walk around the ward. Then another outside to the circle in front of the hospital. I couldn’t believe how weak I was and how those 30 or so steps did me in. 45 minutes, my ass. Finally, the home IV “lesson” was given (I still laugh as I remember this…I’m sorry but I have a PhD in this stuff by now), and it was discharge day.
But this is where things got weird. Normally, after a week or so of IV’s, I’m feeling pretty good and anxious to pull the PICC. Yes, I do it myself. Not this time. I couldn’t eat. I couldn’t sleep. The antibiotics were killing me. One of them, levofloxacin, was causing every tendon in my shoulders, hands and knees to ache and feel as though they could rupture at any moment. The other two were trashing my kidneys. Like any legitimate doctor-patient, I decided I should refresh my memory about the signs of uremia (kidney failure). I read on Dr Google about a new fun fact that I never learned in medical school. There is something called “uremic frost” which occurs on the skin of people who are in florid renal failure. Oddly, it looks EXACTLY like my skin looks after a good hard sweat. And of course, I was sweating a fair amount. So I was pretty certain I was going to need a kidney transplant before a lung transplant…a first in the CF literature, I was certain.
Days went by. Friends brought food (thank you, you know who you are). I couldn’t really eat it. The scale dipped to 100 pounds. This is when I freaked out. Tears came. Swear words were frequent. What the hell was wrong? Why couldn’t I eat? Why was I disappearing? Why did I hurt absolutely everywhere? Where was a single molecule of ATP? I had none.
Finally, I decided that I couldn’t take the antibiotics anymore. A ten day course was all I could take this time. Sure, I’m normally supposed to do at least two weeks, sometimes three. I would have to take my chances and hope 10 days was enough. Never before had the collateral damage of antibiotics been worse than the infection itself. This was a whole new world. I think perhaps it is a product of years of antibiotic use multiplied by years of age.
But even stopping the antibiotics didn’t do the trick. I still abhorred the idea of food. I just wanted to sleep. Then, the fever came back. I kid you not. My heart fell into my slippers when I saw it was 100.1. I was frantic. I swear I took my temp at least once every 5 minutes, wondering what the hell I was going to do if it grew any higher. Back to the ER? Barb was out of town. Then the chest pain came back and I knew. I wasn’t just screwed, I was royally screwed. I even told the kids that night that I was probably going to have to go into the ER the next morning. It was a Saturday night. The boys could go to “other mom” but what was I going to do with the dogs? What antibiotics could they even use this time? I had pretty much been through them all. These were the thoughts rolling around in my brain that sleepless night.
Then…I woke up to no pain and no fever. Not quite believing it, I continued my obsessive temperature taking throughout the day. Nothing. The next day…the same. I went for a walk. It was short, and veeeeery slow. Then I realized that I was slightly hungry. Wow…that was a strange feeling. I ate a bowl of soup. Then another. What was that fever and pain? Who knows. A bit of atelectasis maybe? The Universe messing with me? I’ll never know, but that last week was a whole new dance step.
Fast forward to today, the last day of the worst month in a very long time. I’ve gained back half of the weight. I walked an hour today. This, too, passed. Now I’m well into the very well rehearsed last part of the dance…getting back to that 45 minutes. The last memory I have is of New Year’s Eve.
Months ago, I was very inspired by a blog post I read from the Unknown Cystic. If you don’t know him, I highly recommend that you check out his blog. I’m not sure how he did this with a bag over his head, but he built a treadmill desk, and proceeded to log miles and miles each day as he toiled at his at home job. This little nugget percolated through my brain over the summer, as I tried to figure out how to do something similar.
Then, the back thing happened, and suddenly it hurt to sit down for long periods of time. So a percolating idea became much more urgent. As I have the carpentry skills of a basset hound, and not a tool more complex than a phillips screw driver (which one is that?), I went the pathetically lazy route and bought the damn thing–other than the treadmill, which I had. If you read Unknown Cystic’s articles, you will see how he did it and be much more impressed.
Here’s all I had to do:
1) Convince my teenage sons to bring the treadmill inside for me. This was not as easy as you might think, but eventually they caved and proved that they were much stronger than their mother.
2) Order a TrekDesk on Amazon. Ching.
3) Drag the 80 pound box through your house to office. This is not recommended if you have a herniated disk, but boys were unavailable.
4) Assemble desk. This is supposed to be easy, and I guess since I was able to do it, it must be.
5) Lift desk up and over treadmill–again, not recommended with disk herniation.
6) Start walking. Get a FitBit or something like it, and try to create a new record every day.
7) Say goodbye to back pain and hello to foot and leg fatigue (but this gets better)