Connor and Madeline are white. In fact, they're European by pedigree. No, they're not related (closely). But, they do share some relatively common heritage, as is true with anyone who kind of looks similar. Connor and Madeline decide to have a kid, and name the little baby girl Claire. As Claire grows, she suffers from recurrent respiratory infections, appears a little malnourished, and occasionally has very foul smelling stool. One day, Madeline gives Claire a kiss on the forehead and notices the Claire has incredibly salty skin. Claire has been sick for days, so Madeline brings her into the local pediatric clinic to get checked out. They find Claire has a rather hard time breathing, her lungs sound congested, she has a fever, and generally doesn't look healthy. Her SPO2 is concerning, as is her work of breathing. The clinic decides to call 911 for paramedics to care for Claire and bring her to a pediatric hospital. Here is your dispatch information:
3 Year Old Female
History of respiratory infections
Fever, low SPO2, and shortness of breath.
Upon arrival you see the little 3 year old girl a little spaced out. It's odd that you can see intercostal retractions on this child - she seems a little skinny for her age and size. Her SPO2 is indeed low, her work of breathing is up, she has secretions that will not clear well (they seem incredibly thick), and she has rhonchi and wheezing on auscultation. Claire currently has a fever of 102.0f.
What's the diagnosis? Is there any specific treatments needed? Or just routine care?
Let's talk about Connor and Madeline for a minute before we get back to Claire.
When it comes to our chromosomes, we have 23 pairs in total. Of those 23 pairs, 22 are autosomes, and the last pair are sex chromosomes (they determine male or female characteristics). Most genetic diseases are autosomal diseases, meaning that they are inherited due to a mutation, deletion, or addition of one of the 22 autosomal pairs, or a missense of one of the proteins that the DNA encodes. Down Syndrome, for example, occurs from having an extra chromosome in the 21st pair (making three chromosomes total), which is why Down syndrome is also named “Trisomy 21”. Which, by the way, occurs incredibly early in development long before the child received a vaccine. ;) Many genetic disease have a normal amount of chromosomes, and the sufferer inherits very specific mutation(s) from their parents. If a disease is autosomal dominant, the child only needs to inherit one copy of the mutated gene (either paternal or maternal). However, if the disease is autosomal recessive, this means that they must inherit 2 copies of the mutated gene - one maternal, one paternal. This is the case with Claire. Her two white parents both carried a mutated allele (alleles are gene variants) called CFTR. You could consider Claire a little unlucky, because she had a one out of four chance of inheriting this disease, which neither of her parents actually suffer from (25% chance). Here's how it works:
As you can see from the graph, you need to inherit two copies of the mutant allele (gene variant) to actually suffer from the disease. This was the case with Claire, and it's also why her parents don't have the same issue - they were only carriers of the mutation. People who share heritage are more likely to have the same mutation, which is why consanguinity causes so many more birth defects (and why statistically it's safest to have babies with someone who has a much different background than you).
So, what is this CFTR mutation that Claire inherited? CFTR is the Cystic fibrosis Transmembrane Conductance Regulator gene. This is the gene that is mutated in patients who have cystic fibrosis. It's far more common in the white population, with occurrences between 1 in 2,500 and 1 in 3,500. Cystic fibrosis does occur in black and asian populations, but its occurrence is far less at 1 in 17,000 and 1 in 31,000 respectively. Carrying one copy of the faulty gene is actually more common than you might think:
1 in 29 chance for Caucasians
1 in 46 chance for Hispanics
1 in 65 chance for African-Americans
1 in 90 chance for Asians
Well, enough scaring you about what might be lurking inside your genome. Let's talk about how cystic fibrosis actually works.
Cystic fibrosis makes it really difficult to keep chloride pumping in and out of cells properly. The main issue with this is that it causes substances in the body to become dehydrated (like mucus in the lungs). Here's what should normally happen (in a patient without CF):
Goblet cells secrete mucus that line the lung for protection. This mucus catches stuff like dust, bacteria, virus', dirt, etc.. Then, your multicilliated cells (those little hair-like projections) act like a brooms and brush the debris up and out of the lung. Pretty cool, right? Side point... those multicilliated cells are what become paralyzed when you smoke cigarettes. When you stop poisoning them with hot cigarette smoke, they start working again. That's why the recently cold-turkey non-smoker starts hacking up a lung. Alright, back to CF - how does this process get messed up in cystic fibrosis?
In a few ways:
The first thing to note is that because of that chloride channel that is diseased (mutated) in the CF patient, their mucus gets really dehydrated. Because the mucus gets so dehydrated and thick, the multicilliated cells have a super difficult time moving it anywhere. The mucus just basically sits around and collects dirty stuff without being able to transport it. So when a virus, bacteria, fungus, or whatever else makes it into the lungs, it has a chance to sit there and multiply. What about the DNA you see in the figure above?
The mucus in a CF patient is not like yours and mine. We already know this because of the lack of chloride transport that causes the mucus to be extra thick and dry. But, there is another way this is true as well. As the mucus sits in the lungs, the body is sending white blood cells to try and fight these infections that the mucus is collecting. However, the white blood cells get stuck there, and eventually burst. What spills out? DNA - and usually it ends up being long single strands. Now we have the regular proteins that hold our mucus together (mucoproteins with disulfide bonds), plus we have long strands of DNA (polymerized nucleotides) holding it together as well. This just adds insult to injury when it comes to how difficult this snot it to manage.
This is a good time to note that this kind of blockage does not only occur in the lungs, but it also occurs in the pancreatic duct and common bile duct as well. The CF patient may become malnourished due to a lack of digestive enzymes from the pancreas and lack of bile from the liver/gallbladder breaking down food in the duodenum - this causes steatorrhea (fatty stool). The nutrient rich foods pass through the body instead of getting absorbed by it. This is what leads to malnourishment (and parents may note very foul smelling bowel movements).
Oh, and one more interesting fact. These kids can be diagnosis by a "Sweat Chloride Test" that tests the amount of chloride (a component of salt) in their perspiration. If it's over a certain amount, there's a problem. Parents may notice that the child has very 'salty' tasting skin, especially if they break a fever.
Breaking Down Tough Snot
So, what can we do to help little Claire with her respiratory issues, or CF patients in general? If they're formally diagnosed, they're going to have a bunch of home treatments. Let's go over what they are, and they will help us understand how their symptoms are managed.
Albuterol nebulizer does a couple things. Obviously a bronchodilator, albuterol uses beta-2 to open up the lungs. It also adds moisture to mucus and makes it a little more mobile. Why didn't we mention ipratropium bromide (atrovent)? It's not a profound effect, but it can dry things out a little bit. Their mucus is already super dry, and we don't want to steer any more fluid away from the lungs.
Second: Nebulized (Hypertonic) Saline
It doesn't have to be hypertonic, but it probably should be. Hypertonic saline will cause fluid to flow into the mucus and water it down. This will make it more easily expectorated by the patient. The order of these treatments so far is actually pretty important. Notice how the albuterol was first? That's because saline can cause a reactive airway, and you want to add a bronchodilator first to try and prevent it. Hypertonic saline is much more likely to cause a reactive airway, but it can happen with isotonic saline as well.
Third: Dornase Alfa (Pulmozyme)
This is a pretty cool medication - it lyses DNA. Remember how the patient has those strands of DNA holding their mucus together? Pulmozyme will break apart those strands of DNA and make the mucus less viscous. This obviously isn't a medication we carry, but the patient is usually on daily treatments of this via nebulizer. Of note is that N-Acetylcysteine (Mucomyst) is not mentioned here - why not? N-Acetylcysteine breaks down disulfide bonds (the ones that hold together the mucoproteins). That's not the problem with these patients, so Mucomust will not really have any meaningful impact on the mucus consistency.
Fourth: Chest Physiotherapy
Have you ever started to transport a COPD patient, and as you're going down a bumpy road full of potholes, the patient starts coughing up a bunch of stuff? Or it seems like their rhonchi is starting to move up their lungs? It's almost like the bumpy ride is therapeutic for them. Actually, it probably is. CF patients receive 'chest PT' which is Chest Physiotherapy. You can receive it in a couple ways. The first and most common way is through a vibrating vest that basically works like a subwoofer - it pumps air in and out to vibrate the secretions while the patient takes nebulizers. The other way is simply chest percussion.
While we might not have a vest with us, manual percussion to help clear secretions and a bumpy transport might actually help a lot.
There is no cure for cystic fibrosis, and the daily treatments we noted above are really considered comfort care. Some will even consider these daily treatments 'palliative care'. And yes, these patients have reduced lifespans, but treatment is now making it possible for them to live longer lives with less symptoms. There is some gene therapy that may be available to specific types of CFTR mutations. Medications might be given in combination or alone:
“Ivacaftor functions as a potentiator of the CFTR protein for common gating mutations, allowing for an increase in chloride ion flow. Tezacaftor functions as a corrector to facilitate the folding and presentation of the mature CFTR protein to the cell surface. Elexacaftor is also a CFTR corrector that works at an alternate binding site than tezacaftor on the CFTR protein to further facilitate the functionality of the CFTR protein at the cell surface” (Ridley & Condren, 2020).
Gene therapies work by altering a host stem cell via lentiviral vectors (like the AIDS virus), forcing it to express CFTR for a time (maybe weeks to months), which can lessen symptoms.
Cystic fibrosis is a relatively common genetic disease. We may care for a very young and undiagnosed CF patient, or we may see an adult CF patient since these patients are living longer and longer as gene therapies advance. Our main take home point should be understanding how the disease works. Thick secretions that cause pulmonary shunt? How can we restore hydration to the mucus, dilate the lungs, and assist the patient in expectation? Generally, albuterol, (hypertonic) saline, and some type of chest physiotherapy is what we can provide. We may be called to care for a patient who is simply having an exacerbation of mucus plugs from their CF, or their may have a lung infection (which they get very commonly) that is exacerbating their underlining illness. In the sicker population, CPAP may also help ease pulmonary shunt, but watch out for when they need to get rid of that thick mucus - could they hold the mask on themselves? It might be worth a try to not secure the mask in place. HFNC would also be a great option (a heated and humidified high-flow nasal cannula).
Hopefully this blog gave you an introductory understanding of cystic fibrosis! As we expand our clinical knowledge, adding new diseases to our mental model will help us improve our pulmonary care!
Kristin Ireland, RRT, EMT
At first while reading through this blog I was having flash backs to Respiratory school! The in-depth knowledge is very specific but comprehensive in nature. When the results of Claire's illness was precipitated by the physiology of her unknown illness, treatments were far easier to conceptualize. I have personally treated these kids before and it’s horrible, even more so when you don’t really understand what is going on in their bodies. Although the blog appears to be almost too specific, the amount of information is at base minimum of what a practitioner would need to know in order to truly help these patients. The order of medication needs to be well thought out, and this cannot be done without understanding what this disease is and how it manifests at a young age. Another therapy I would like to mention is High Frequency Oscillation Devices such as Intrapulmonary Percussive Ventilation (IPV). This mode of therapy can administer the medications and the vibratory components intrapulmonary. Much like chest physiotherapy, IPV works from the inside. If you have ever seen a flutter valve, this is like that but on steroids. This machine can be hooked up to a ventilated (ETT or trach, I’ve done both) CF patient or by way of mouth piece and face mask. With its memorable archaic structure, the newer versions like the MetaNeb allow for settings that you can do alone or in combination like continuous high frequency oscillations (with scaling for intensity), with neb only, or with CPAP (flow intensity options). A practitioner can really specialize a CF patients experience from both the inside and outside. Just bouncing down the road works pretty well too!
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Bulletin Infovac-France. (2004). Archives De Pediatrie. doi:10.1016/s0929-693x(04)00105-8
Pelliccia, J. G., PhD. (2019). Cystic fibrosis. Magill’s Medical Guide (Online Edition).
Ridley, K., & Condren, M. (2020). Elexacaftor-Tezacaftor-Ivacaftor: The First Triple- Combination Cystic Fibrosis Transmembrane Conductance Regulator Modulating Therapy. Journal of Pediatric Pharmacology & Therapeutics, 25(3), 192–197. https://doi.org/ 10.5863/1551-6776-25.3.192
Sharma, N., & Cutting, G. R. (2020). The genetics and genomics of cystic fibrosis. Journal of Cystic Fibrosis, 19(Supplement 1), S5–S9. https://doi.org/ 10.1016/j.jcf.2019.11.003
Tsui, L. (2003). Cystic fibrosis (CF). In D. N. Cooper, Encyclopedia of the human genome. Wiley. Credo Reference: http://vlib.excelsior.edu/login?url=https://search.credoreference.com/content/ entry/wileyhg/cystic_fibrosis_cf/0?insti tutionId=1649