Cystic Fibrosis Treatments and Medications

Treatment for cystic fibrosis (CF) has come a long way—sixty years ago, most patients with cystic fibrosis didn’t live until puberty. Now they grow up, graduate, go to college, have careers, and raise families. New drugs now target the basic mechanism of the disease rather than the consequences, and even more effective treatments are in the pipeline.

What is cystic fibrosis?

Cystic fibrosis (or mucoviscidosis) is an inherited condition that reduces the water content of secretions within the body, causing thick and sticky mucus which fills up and blocks the lungs and other organs. It is one of the most common heritable genetic disorder in Caucasians in the US.

Cystic fibrosis is inherited from both parents. A person must have two cystic fibrosis genes, one from the father and one from the mother, to manifest. People with one cystic fibrosis gene are “carriers” but do not have cystic fibrosis.

Patients with cystic fibrosis produce a defective protein, called CFTR (cystic fibrosis transmembrane conductance regulator), which is normally embedded in cell membranes and transports chloride ions into and out of cells. Chlorine is one part of table salt, or sodium chloride. When the cell does not move chlorine out of the cell, sodium doesn’t leave, either, because it’s electrically attracted to the chlorine. Water wants to be where the salt is, so it stays with the sodium and chlorine. Because of this, tissues responsible for secretions do not include enough water, so the secretions are sticky, thick, and can block vital organs.

This is the basic mechanism responsible for cystic-fibrosis-related diseases throughout the body:

• Mucus in the lungs is too sticky to clear out and provides a rich environment for bacteria growth, resulting in chronic lung infections, bronchial damage (bronchiectasis), and scarring (fibrosis). Chronic and progressive lung disease is the primary cause of death in 77% of CF patients.

• The pancreas secretes enzymes that digest food, but the secretions back up causing pancreatic insufficiency (87% of patients), insulin-dependent diabetes, and swelling of the pancreas (pancreatitis). Pancreatic insufficiency means patients with CF have difficulty digesting and absorbing nutrients, particularly fats, proteins, and fat-soluble vitamins.

• The liver serves many functions including secreting bile acid to help digestion. Bile acid obstruction is common in CF patients and results in fatty liver, cirrhosis (scarring), and gallbladder stones.

• Sticky mucus in the intestines causes thick stools that block the intestines (meconium ileus). Meconium ileus in a newborn is often the first sign of cystic fibrosis. Gastroesophageal reflux (GER) is also a common complaint and may contribute to lung infections.

• Thick secretions in the nose can cause nasal polyps as well as chronic swelling of the sinuses and nasal passages (rhinosinusitis).

• Nearly all men with cystic fibrosis (97%) will not have sperm in their ejaculate because of obstruction of the vas deferens, the duct that transports sperm to the urethra.

• Nutritional deficiency as a result of pancreatic insufficiency can result in bone loss, osteoporosis, and joint disease.

There are over 2000 genetic mutations that are responsible for cystic fibrosis. All are related to the CFTR protein. Based on the type of mutation, cystic fibrosis is divided into five classes of decreasing severity:

• Class 1 CF means cells are unable to produce working copies of CFTR proteins.

• Class 2 CF prevents cells from moving CFTR protein from where it’s made in the cell to the cell membrane and then locks it in place.

• Class 3 CF involves fully-formed but completely defective CFTR proteins on the cell membrane.

• Class 4 CF has fully-formed but partly defective CFTR proteins on the cell membrane.

• Class 5 CF has fully-formed and fully working CFTR proteins that are broken down too quickly by the cell.

The first three classes are the most severe cases. Seven in ten CF patients are class 2 CF patients with a single common mutation, the F508 mutation.

Approximately 30,000 people in the United States (1 in 11,000) have been diagnosed with CF. However, around 10 million people in the U.S. carry a cystic fibrosis gene. Risk factors for carrying a cystic fibrosis gene are limited to European descent or having relatives with cystic fibrosis.

The primary goal of treatment is to prevent and treat lung infections, maintain adequate nutrition, and manage other conditions as they arise. Patients born in 2018 can expect to live an average of 47 years, but life expectancy is more than 50 years in other countries.

How is cystic fibrosis diagnosed?

Cystic fibrosis diagnosis begins at birth. All newborns in the United States are screened for cystic fibrosis along with other conditions using a blood test, the Newborn Screening Test. For cystic fibrosis, the test will measure the amount of a certain pancreatic protein called trypsinogen using IRT (immunoreactive trypsinogen test) and, depending on the state, genetic testing.

The average age for diagnosis is 6 months, but nearly all patients are diagnosed before the age of 2. A definitive diagnosis of CF consists of

• Clinical evidence of cystic fibrosis

• Evidence of CFTR dysfunction

Clinical evidence of CF could be a positive IRT test or a sibling with CF. If not, the doctor will monitor for clinical signs of cystic fibrosis in the infant including intestinal blockage, jaundice, lung problems, or poor weight gain.

Evidence of CFTR protein dysfunction includes the sweat chloride test, a DNA test, or other tests used if the results are ambiguous.

Sweat chloride test

Patients with a defective CFTR protein do not reabsorb salt from the sweat before it leaves the body as other people do, so excessively salty sweat indicates a defective CFTR protein 99% of the time. Sweat chloride tests are accurate and inexpensive, so they are usually the first-line CFTR function test.

DNA test

A sweat test might show higher than normal salt levels, but not high enough for a CF diagnosis. A DNA test will then be used that looks for at least two copies of a cystic fibrosis mutation. There must be one copy on both chromosomes. The disease usually does not manifest if only one mutated gene is present.

CFTR tests

Neither the sweat test nor the DNA test is foolproof. There are over 2000 genetic mutations that cause cystic fibrosis, but DNA testing can only identify about 70 of the most common ones. To resolve questionable cases, one of two tests can measure the activity of the patient’s CFTR proteins by measuring voltage differences in the body’s tissues: the nasal potential difference (NPD) test and the intestinal current measurement (ICM).

Cystic fibrosis treatment options

The foundations of cystic fibrosis treatment are:

• Proactive prevention and treatment of lung infections

• Nutritional support

• Other conditions will be treated as they arise.

Most patients will be treated by a team of healthcare professionals at clinics that specialize in cystic fibrosis. This team will include pulmonologists, gastroenterologists, endocrinologists, nutritionists, nurses, and physical therapists.

Airway clearance

The centerpiece of CF treatment is to clear the lungs of mucus to prevent bacterial infection using physical therapy, exercise, and medications. Therapists and patients will regularly perform Airway Clearance Techniques (ACTs) involving inhaled mucus thinners followed by Chest Physical Therapy (CPT), such as striking the chest, coughing, vibration (a cystic fibrosis “vest”), or deep breathing techniques to bring the mucus out of the lungs.

Lung infection

Patients with CF are vulnerable to lung infections. Over time, serial lung infections damage the airways, reduce lung capacity, and eventually progress to lung failure. For this reason, doctors use a low threshold for lung infection diagnosis and hospitalize CF patients at the first sign of an acute infection. Infections are treated aggressively with oral and injected antibiotics, oxygenation, and airway clearance.

Diet

Pancreatic insufficiency means the digestive system is missing pancreatic enzymes that break down and aid the absorption of nutrients such as fat, proteins, and fat-soluble vitamins. CF patients require a high fat, high protein, and high-calorie diet as well as anywhere from 120% to 200% the normal RDA of vitamins and minerals. Oral pancreatic enzymes will be taken at meals to facilitate digestion and absorption.

Symptomatic treatment

Other conditions caused by cystic fibrosis, such as digestive problems, nasal and sinus problems, and liver problems, will be managed as they occur. The most serious are liver damage and cystic-fibrosis-related diabetes, both of which can reduce life expectancy.

CFTR modulator therapies

Mutation-specific medications go to the source of cystic fibrosis and improve CFTR function. For now, however, CFTR modulator therapies only help supplement symptomatic treatment and are not a cure for cystic fibrosis.

Surgery

Despite the best efforts of doctors, lung function will progressively decline and the lungs will eventually fail, requiring a lung transplant. The average life expectancy after lung transplantation is eight to nine years. Some CF patients may require a liver transplant because of progressive damage to the liver.

Cystic fibrosis medications

Most medications for cystic fibrosis treat or manage cystic-fibrosis-related diseases and conditions. They are effective at slowing down progressive damage to the lungs, organs, and other tissues in the body.

Mucus thinners

One of the primary goals of cystic fibrosis treatment is to clear mucus from the lungs using physical therapy combined with mucus thinners taken through an inhaler or nebulizer. Mucolytics, such as dornase alfa, break up substances in the mucus, making it less sticky and easier to expel. Secretolytics, such as inhaled hypertonic saline solution, make mucus more watery by drawing water out of the tissues and into the airways. The effects of mucus thinners are temporary, so cystic fibrosis patients need to perform physical airway clearance to clear the thinned mucus.

Bronchodilators

Bronchodilators, such as albuterol or ipratropium, increase the width of the airways to allow more airflow. These treatments help with breathing difficulties and improve shortness of breath.

Antibiotics

The single greatest threat of cystic fibrosis is serial lung infections that over time steadily damage the lungs. Aggressive antibiotic therapy is used at the first sign of infection and includes penicillins, cephalosporins, azithromycin, tetracyclines, clindamycin, vancomycin, or sulfa drugs, among others.

Pancreatic enzymes

Pancreatic insufficiency means that vital enzymes needed to digest and absorb nutrients are missing from the digestive system. Many CF patients need to take pancreatic enzymes at each meal to increase the digestion of foods and the absorption of fats, proteins, and nutrients by the intestines.

Vitamins

Cystic fibrosis patients need anywhere from 120% to 150% of the recommended daily allowance of vitamins to compensate for their lowered ability to digest and absorb nutrients. Fat-soluble (ADEK) vitamins are particularly important because CF patients often do not have enzymes that help transport fats across the intestinal walls. These vitamins are often taken as CF-specific multivitamins in a water-soluble format.

CFTR modulators

CFTR modulators directly address CFTR protein malfunction. Ivacaftor treats class 3 cystic fibrosis, which is caused by CFTR proteins on the cell membrane staying permanently closed. Ivacaftor is a “potentiator” that activates CFTR proteins and opens the chlorine channel. Lumacaftor, tezacaftor, and elexacaftor treat class 2 cystic fibrosis, which is due to the malformation of the CFTR protein. These drugs are “correctors'' and are always combined with ivacaftor. They help fix the protein, move it to the cell membrane, and put it into place. Ivacaftor then activates the protein and opens the chlorine channel. These effects only last for as long as the drugs are in the bloodstream, so they must be taken regularly to be effective.

Other medications

Cystic fibrosis affects systems and organs throughout the body, so many other types of drugs will be relied on to treat symptoms, such as anti-inflammatory medications, prokinetics to treat gastroesophageal reflux, laxatives for intestinal obstruction, bile acids for liver blockage, and insulin for diabetes.

What is the best medication for cystic fibrosis?

Cystic fibrosis is a complex condition that affects organs and tissues throughout the body. Cystic fibrosis care involves a team effort of physicians and other healthcare providers who will find the right combination of medications and therapies suitable to the patient’s situation. Some of the most common drug classes used are represented in the table below.

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Best medications for cystic fibrosis