Editor’s Note: Please join me in welcoming two new guest writers to tl;dr! If there was ever a time I needed a post, say, about 8 years ago, it’s this one. This is literally everything you need to know to survive management of your first few cystic fibrosis patients, and not only have they been thorough with this post…but they’ve given us thorough with panache! So who are ‘they’?

Yoldine Meris is a P6 student from Arnold and Marie Schwartz College of Pharmacy and Health Science in Brooklyn, New York. She is interested in the pharmaceutical industry and hopes to attain a fellowship to further her clinical knowledge and become involved in Medical Affairs and Medical Education. In her spare time, she enjoys binge watching her favorite shows and gets ridiculously excited over character development.

She wrote this post in collaboration with Elizabeth Gavioli, PharmD, BCPS, BCGP, who is an Assistant Professor at Arnold and Marie Schwartz College of Pharmacy and Health Sciences, and a clinical specialist at Mount Sinai Beth Israel. She specializes in the adult cystic fibrosis, internal medicine, and palliative care populations. After a night of salsa dancing, Dr. Gavioli likes to explore all the foodie wonders in New York City.

Happy learning!

We think it’d be remiss if we started off this post without assigning everyone a pop-quiz. Because who doesn’t love a good pop quiz? Especially when you didn’t study. But what’s life without an unwanted surprise every now and then? Dull we say, so here we go:

What autosomal recessive disease went from primarily affecting the pediatric population to the adult population?

A. Cystic Fibrosis
B. Cystic Fibrosis
C. Cooties

See, that wasn’t so bad! Hopefully, you chose the correct answer, and if not, take a moment to re-read the title of this post. Don’t worry, we’ll wait…….

Now, as you, dear reader, medical student, pharmacy student, healthcare professional, concerned pedestrian, have probably gleaned, we’re going to delve into the nitty gritty of cystic fibrosis.

Cystic fibrosis (CF) is one of the more interesting [read: nasty] respiratory disorders out there. However, while it is a disease that primarily affects the lungs, the pathophysiology of the disease means multiple organ systems are also involved (later we’ll have another pop-quiz related to this! More fun!).

There is no known cure for CF. Currently, the only forms of therapy that exist are geared towards slowing down the progression of the disease and supportive care management.

Genetics of Cystic Fibrosis

So how does one even get CF? Is it dropped off on your doorstep like the stork-baby delivery service our parents erroneously tried to get us to believe? Not quite.

Here is where we make our high-school science teachers SUPER proud. We’re going to delve into the good-‘ol Punnett square concept.

CF is a rare autosomal recessive disease linked to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Every single person has two copies of this gene; it’s a vital component of our genetic makeup. What makes it autosomal recessive?

The actual disease requires that a child inherit at least one mutated copy of the gene from each parent. Meaning an individual must have TWO mutated CFTR genes to have CF.

Still with me? No? Here’s a visual:

May the odds be ever in your favor. (Image)

Epidemiology of Cystic Fibrosis

Most patients affected by CF are Caucasian, particularly those of Northern European ancestry and North American Caucasians. Less affected are African Americans > Native Americans > and Hispanics.

Don’t worry this post isn’t all bleak and terrible news. A lot of great advancements have been made since the 1950s when CF mostly affected children. In fact, as of 2014 more than half of the CF population is above 18, AND WAIT FOR IT……the average survival age is now over 40!

With 70,000 cases worldwide (30,000 in the US), that’s a pretty significant number of people who get to live into their adulthood. Of course, we’re not where we want to be yet, but those statistics definitely deserve a fist bump.

Etiology of Cystic Fibrosis

That CFTR gene we were discussing earlier? It helps regulate the activity of the CFTR protein, which in turn is responsible for regulating the transport of chloride, water, and bicarbonate across our cell membranes. Specifically, in the parts of our body that contain mucus membranes.

In a nutshell, this exchange of anions helps clear out mucus in our lungs, pancreas, and bile ducts. When the function of CFTR is compromised, ion exchange is also affected. As a result, mucus builds up, and the body has a hard time clearing it. This allows for inflammation and a supportive environment for bacterial growth. Think of it as creating the BEST environment for the WORST party to be thrown in your lungs.

Therefore, CF patients are frequently hospitalized with respiratory infections and pulmonary exacerbations. It’s also why these patients tend to be taking an alphabet soup of medications at once.

We won’t go into all the possible genetic mutations that can lead to CFTR dysfunction (read: it’s an obscene amount), but we will look at the two major ways that CF can present itself:

1. Classic - No functional CF protein (of which there are three variations)

Class 1 - No protein
Class 2 - No traffic
Class 3 - No function

2. Non-classic - Some functional CF protein (of which there are three more variations)

Class 4 - Less function
Class 5 - Less protein
Class 6 - Less stable

If you’re a visual person, click here for a neat breakdown by the CF Foundation. This comprises the six variations of CFTR dysfunction that can occur, and we find it easier to think of them in the above format because it helps with visualizing the pathophysiology behind a patient’s disease.

Classic CF is recognized as a more severe form of the disease. In classic CF, patients either have no CFTR protein or the CFTR protein that exists doesn’t work due to misfolding or some other structural abnormality. In contrast, patients with non-classic CF present with variations of the CFTR protein that have reduced function and less severe phenotypes.

Diagnosis of Cystic Fibrosis

The sooner a patient with CF can be diagnosed the better. But, how do we identify newborns or adults with CF you ask? Well, people with CF tend to be salty. No, that’s not shade. No, I didn’t mistype that; yes, you read that correctly (so please close out of the urban dictionary page you just opened).

Remember our little chat above about the transport of chloride and water anions across the cellular membrane? Yeah, that’s why.

The test used on every newborn in the United States is known as the quantitative pilocarpine iontophoresis (QPIT), but if you’re feeling less fancy, sweat chloride test means the same thing. Most people will have a sweat chloride level that is below 29 mmol/L. That’s the sweet spot [pun totally intended] to be in.

Patients with CF: Usually a sweat chloride test above 60mmol/L and presentation of symptoms is enough to diagnose a newborn with CF.

For patients who are in what we call the “grey area” of 30 to 59 mmol/L, further CFTR gene analysis, immunoreactive trypsinogen (IRT) testing, and a family history are needed.

Pop quiz number 2!

What organ systems does CF primarily affect?

A. Respiratory (lungs)
B. Gastrointestinal (pancreas, liver)
C. Musculoskeletal (bones)
D. Reproductive System
E. None of the above
F. All of the above

There’s a trick answer in there. Bonus points for NOT picking it.

Treatment of Acute Cystic Fibrosis

Pulmonary Exacerbations

The most common reason why CF patients are hospitalized is a pulmonary exacerbation, with infection being the primary cause and inflammation being the exacerbating factor. Although no clear definition exists for what is considered a pulmonary infection, generally, it’s accepted as increased breathlessness and fatigue, a reduced forced expiratory volume in 1 second (FEV1), and increased production of sputum and cough.

Due to the pathophysiology of CF, these patients tend to have mucus that is more viscous and harder to remove than the average individual. Again, this build up creates an environment ripe for microbial growth and bacterial infection. The most common organisms adult CF patients present with are P. aeruginosa > S. aureus (MSSA and MSRA) > S. maltophilia or Achromobacter. The order MATTERS.

The older the CF patient, the higher their likelihood of having an exacerbation induced by P. aeruginosa. S. aureus infections tend to predominate in younger patients. And because we’re overly generous on tl;dr, we’ve attached a beautiful and COLORFUL chart to show you the correlation.

Bacteria isolated during pulmonary exacerbations in CF patients by age. (Rule of thumb: if you see a color-coded chart it’s probably important. Learn it.) (Image)

Hopefully, you haven’t forgotten most of what you’ve learned from your infectious diseases course in school. But just in case you did, tl;dr provides a handy-dandy little cheat sheet on antibiotics and their corresponding bacterial coverage.

For S. aureus infections, we treat using antibiotics that provide gram-positive coverage. Remember to save your heavy-duty methicillin-resistant S. aureus antibiotics – such as vancomycin or linezolid – unless there’s a likelihood that the patient could have MRSA (i.e., IV antibiotic use in the past 90 days, recent hospitalization, etc.).

If MRSA antibiotics are started and your susceptibility tests come back showing that the patient has methicillin-susceptible S. aureus (MSSA), the patient should be de-escalated to the appropriate antibiotic. This is especially important because CF patients will naturally have cases of chronic colonization throughout their lifetime, and it’s important to optimize their therapy to prevent as little resistance as possible.

The same general rule applies for CF patients with P. aeruginosa infections. Optimize therapy and treat with the appropriate antibiotics. Aminoglycosides are one of the mainstays for gram-negative/P. aeruginosa coverage in this patient population, but there are also other acceptable choices. (Again, that handy cheat sheet).

No matter how much optimization is being done, some patients will inevitably present with multi-drug resistant infections, especially to P. aeruginosa. In these scenarios one of the most important things that should be running through your mind is SYNERGISM. Why? Cause SYNERGISM is SEXY. Erm…effective, that is.

Also, it might totally save your patient’s life. Choose antibiotics that have similar coverage but differing mechanisms of action.

In addition to bacterial infections, CF patients are also predisposed to fungal infections. Of note, the one you’re likely to see associated with CF is allergic bronco-pulmonary aspergillosis (ABPA). ABPA is a type of spore-bearing fungus and comes from the Aspergillus fumigatus mold. See this handy-dandy post for more information on fungal infections.

The few patients who present with ABPA have symptoms consistent with bacterial infection. Simple diagnostics to differentiate ABPA from other types of infection include a chest radiograph in the presence of antibacterial failure, an aspergillus skin prick test, or in-vitro presence of serum IgE antibody to the mold.

Treatment for ABPA involves systemic doses of the steroid prednisone 0.5-2 mg/kg/day for 1-2 weeks (followed by tapering). If necessary patients are also placed on oral itraconazole 5mg/kg/day (max dose 400 mg/day). Remember, itraconazole is one of your antifungals that requires therapeutic monitoring due to its pharmacokinetics. As a rule of thumb, azoles require liver function tests and hepatic monitoring.

Clinically, you might see antifungals being added as a dual part of treatment against ABPA; however, they are not considered first-line. Mostly, they allow for faster tapering off steroids. Additionally, an antifungal such as itraconazole only needs to be added if patients have relapsed or are slow to respond to corticosteroid therapy.

Maintenance of Pulmonary Function

As a precaution the clinical practice is to provide as much prophylactic treatment as is safe. There’s even an established order that best allows for mucus clearance and opening of the airways. It goes as follows:

Step 1: Open the airways as much as possible.

Typically, this is performed by using a short-acting bronchodilator such as albuterol. The albuterol will help to widen the inflamed airways in preparation for clearing the mucus.

Step 2: The thinner the better.

The two mucolytics approved for use in CF patients are hypertonic saline (7%) and dornase alfa. Both are inhaled solutions that work (separately) to thin out the viscous and hardened mucus in the airways.

Step 3: Cough up everything except your lung.

Airway clearance/compression vests are the second to last step of the process. They use what is called high-frequency chest wall oscillation. Basically, this is the sophisticated way of saying they vibrate your chest to loosen mucus.

The vest is turned on for 5-minute increments. After 5 minutes the patient turns it off and coughs to bring up the loosened mucus. The vest is then turned back on and the process repeats for approximately 30 minutes.

Step 4: Use antibiotics and anti-inflammatory agents.

You, when you hear the words, “Long-term antibiotics.”(Image)

One thing you’ll see in CF patients that we rarely accept in the general population is the use of 1-2 antibiotics as prophylaxis. And, if you’re a good pharmacist or clinician who’s been grilled on the over-use of antibiotics leading to resistance, you probably just clutched your pearls.

I know, I know, get out those smelling salts and take a deep breath. There IS an actual benefit in CF patients.

Tobramycin is a great choice (and the guideline-approved choice) because it provides P. aeruginosa coverage. If tobramycin is your prophylactic drug of choice, it’ll be dosed as a once daily inhalation for 28 days. The patient is then on an “off-period” for another 28 days before they repeat the therapy.

Alternatives include aztreonam and colistin to use during tobramycin’s “off period”.

Because inflammation tends to be secondary to infection in these patients, and a known contributor of exacerbations, anti-inflammatory agents are also utilized. The two guideline recommended drugs are azithromycin and ibuprofen.

The combo of azithromycin and inflammation is one of those clinical pearls you should gently polish and tuck away in your mental pocket for safe keeping. Azithromycin has great anti-inflammatory properties (and if you’re a super smart double chocolate chip fudge cookie, you’ll know that it’s sometimes used in asthma/COPD patients hospitalized for exacerbations).

What also makes it a great prophylactic choice in CF patients is that azithromycin is the only approved anti-inflammatory antibiotic capable of disrupting the protective bio-film of certain bacteria (i.e., P. aeruginosa). This increases its efficacy and likelihood of curtailing a possible infection in addition to its anti-inflammatory role.

Ibuprofen, on the other hand, is only recommended in patients who are between 6 – 17 years of age. There’s no benefit seen with administration in the adult population and the likelihood of complications (GI ulcers, kidney damage anyone?) doesn’t outweigh what little benefit there might be.

Gastrointestinal and Nutritional Care in Cystic Fibrosis

Because all cells that rely on CFTR are affected, patients typically have pancreatic and hepatobiliary issues that can cause metabolic and bone-related complications.

Patients with severe forms of CF have mucus buildup in utero and end up being born with pancreatic insufficiency (which essentially spelled early death before the discovery of ‘fancy’ supplements).

Their less severe counterparts can end up with pancreatic insufficiency as well, although this occurs later in life. The fibrotic condition of their pancreas means these patients are incapable of producing the enzymes necessary for digestion. Consequently, their nutrient absorption becomes impaired, particularly the absorption of fat-soluble vitamins like A, D, E, and K.

AND, because the chain of “what else can go wrong!?” doesn’t end there, due to their compromised absorption of essential vitamins and poor nutrition, CF patients are also at risk for low bone density and consequent fractures.

So, what do we do? Perhaps, throw the entire aisle of vitamins and supplements at them?

Well, as healthcare practitioners, particularly PHARMACISTS, we think we can apply a bit more nuance to their therapeutic regimen than that.

Let’s start with the pancreatic insufficiency. We’re going to recommend pancreatic enzymes. Zenpep® or Creon®, anyone? We won’t go into the specifics of dosing these drugs, but you must know this - it’s very patient specific. Typically, a nutritionist/dietician will be part of the CF care team and will help dose the enzymes based on meals, daily nutrition, and fat-intake.

Now let’s tackle bone density and fracture prevention. To help prevent bone-weakness and promote growth, we give daily vitamin D supplementation (800 – 1600 IU/day). The rule of thumb is to have patients take their supplements or vitamins with their meals.

The upside? Due to the genetics of their condition, chronic infections, and the strain of working harder to breathe, CF patients have increased energy intake. Their metabolism works faster than the average person. Basically, CF patients can get away with eating the way we’d all like to eat. But can’t.

There is no restriction on food, and the recommended caloric intake is 110% to 200% of patients who don’t have CF.

The downside? They have CF.

Welp. When everything you knew to be true no longer is. (Image)

Oh wait! Silly us, we almost forgot. If you’re treating a CF patient there’s another metabolic issue you should be cognizant about. Aside from helping with digestion, what function is the pancreas most commonly known for?

The fibrotic condition of a CF patient’s pancreas means their islet cells over time lose beta cell function.

Remember back to diabetes, beta cells are the primary cells in the pancreas that produce insulin.

Essentially, these patients end up developing CF-related diabetes (CFRD) due to pancreatic insufficiency.

Most CF patients will require bolus doses of rapid-acting insulin (lispro, aspartate) before their meals. According to the CFRD guidelines, basal insulins such as detemir or glargine are indicated when patients suffer from elevated glucose levels in the morning prior to breakfast.

CFRD is a mixture of both type 1 and type 2 diabetes, but it more closely emulates type 1 diabetes, in that patients are insulin deficient. Therefore, oral hypoglycemics WOULD NOT be a good choice in this patient population because the primary issue is insulin production. In this instance, insulin injection therapy would be the preferred and recommended option. Oral diabetes medications are just not shown to be effective.

Another organ affected by the impaired transport of salt and water anions is the liver. The CFTR protein isn’t a part of hepatic cells, but it is a part of the intra- and extra-hepatic bile ducts as well as the gallbladder.

The flow of bile from the gallbladder can be reduced with CFTR dysfunction leading to inflammation and, subsequently, fibrosis of the liver. Not all CF patients will develop hepatobiliary disease, but some do and that can translate to complications of biliary cirrhosis later in life.

A drug to consider in this situation would be ursodiol. Like the enzymes and vitamins, ursodiol is taken WITH meals. Dosing in the adult population is typically 300mg twice-a-day.

Reproductive System Effects in Cystic Fibrosis

We’ll just briefly touch on the differences of fertility in male and female patients with CF. The gist of what you should know is that in women, CF causes their cervical mucus to be a lot thicker than normal (that darn mucus is back at it again).

A thicker cervical mucus means that it’s harder for sperm to reach their eggs and for fertilization to occur. The poor nutrition status of a CF patient can also play a role in a woman’s ovulation cycle; however, they are still able to conceive if they choose.

In men, CF affects them by causing the blockage or absence of their vas deferens. What on earth is the vas deferens?

Basically, it’s a long tube that connects the region where sperm is produced to the ejaculatory ducts of the penis. In this instance, CF-men still produce sperm, but their delivery is compromised.

Assisted Reproductive Therapy (ART) is primarily recommended.

Whew! At this point you’re probably thinking you can’t possibly take in more information. When does this CF rollercoaster end!? If you’ve made it this far you’re basically an expert, now right?!

Not quite. We haven’t even hit the good stuff yet.

Targeted Therapy for Cystic Fibrosis

So here it is, the good stuff. The NEW stuff, the you-should-REALLY- REALLY-know-this stuff. Basically, new therapy that’s recently emerged to treat CF patients with specific genetic mutations.

The therapies available are grouped as modulators. Modulators can individually be categorized as either a corrector or a potentiator depending on which class of CF (and genetic mutation) they are designed to treat.

The first drug to take note of is ivacaftor (brand name: Kalydeco®).

Ivacaftor is a potentiator and is prescribed for patients who have non-classic Type 3 and 4 mutations. Alternatively, it’s for patients with a G551 gene mutation. These are our patients who do produce some CFTR protein; however, due to gating or conductance issues, they are either unable to transport chloride ions through the cell or what they can transport is a very small and limited amount.

As a potentiator, ivacaftor works by allowing the CFTR protein channel to remain open for (continual) ion transport.

Dosing is based on age, and for patients 6 years and older, it is recommended to take one tablet (150mg) twice a day with a fatty meal. The most common side effects attributable to this drug are headaches, nasal congestion, dizziness, and GI upset.

Our second and third drugs are known as correctors, and they’re prescribed in combination with ivacaftor for patients who have the more classic Type 2 (i.e., more severe) form of CF. This is where CFTR is produced, but due to a trafficking defect, functional CFTR at the cell membrane is absent. Most CF patients fall into this category due to a deletion of phenylalanine at the 508 location on the CFTR gene, alternatively known as F508del-CFTR.

Known as a corrector, lumacaftor provides stability and conformation to the F508del-CFTR protein, which in turn allows it to fold properly and make it past the endoplasmic reticulum check point to be trafficked up to the cellular membrane.

Orkambi® (lumacaftor 100mg/ivacaftor 125mg) is dosed for patients 12 years and older at two tablets twice a day with a fatty meal. Most common side effects? Dyspnea, fatigue, flatulence, increased creatinine phosphokinase, and GI upset.

Tezacaftor is the newest bad boy on the market. It is an analogue of lumacaftor and pharmacologically does the same exact thing. But with a slightly better pharmacokinetic profile. Like lumacaftor, tezacaftor is given in combination with ivacaftor.

Symdeko® (tezacaftor 100mg/ivacaftor 150mg) therapy is dosed a bit differently. Patients take one tablet of Symdeko® in the morning and one tablet of ivacaftor (150mg) in the evening. Each dose should be twelve hours apart and taken with a fatty meal. The most common side effects are headache, nausea, sinus congestion, and dizziness.

Combined Clinical Pearls
- AST/ALT levels should be monitored every 3 months for the first year of therapy, and then annually thereafter. Use with caution in patients with advanced liver disease.
- Patients will require ophthalmological exams at baseline then yearly thereafter due to the potential risk of cataracts.
- Be wary of your CYP3A4 inhibitors as dose adjustments will have to be made (e.g., azole antifungals).
- CYP3A4 inducers are considered Category X drug interactions and are not recommended in combination with CF targeted therapy.
- Counsel patients to AVOID grapefruit or Seville oranges.
- Abnormal respiration and chest discomfort can occur at onset of therapy (primarily with Orkambi®).

And remember, while these relatively new drugs are great, they can’t be applied to every patient. It’s important to be aware of their exact indications. Not every patient has the genetic mutations listed above.

Wrapping Up with Cystic Fibrosis

Drugs aside, the only other option for CF patients to gain healthier lungs is a transplant. The conversation surrounding this decision is one that typically occurs far in advance of the actual necessity for the procedure. But don’t be fooled, a lung transplant doesn’t solve everything. Patients will still have other CF complications, such as pancreatic insufficiency, and they will need to continue their maintenance therapies.

The importance of patients having their own CF team cannot be highlighted enough. It makes sense that a multi-organ disease should require a multidisciplinary team. Nurses, nutritionists, pharmacists, physicians, and other health care professionals all contribute towards the care for patients with CF.

And, lastly don’t forget to encourage ADHERENCE, ADHERENCE, ADHERENCE to keep these patients out of the hospital.

The Ultimate Guide to Cystic Fibrosis