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Conquering Chronic Lung Infection In Cystic Fibrosis Patients
Cystic fibrosis (CF) is one of the most common genetic disorders in the world. The disease infects nearly 70,000 people worldwide and approximately one in 30 Americans is a carrier. CF is caused by mutations in the human cystic fibrosis transmembrane regulator (CFTR) gene, and more than 2,000 mutations have been characterized in people with CF (PwCF). CFTR mutations cause physiologic changes that result in chronic lung infections, the major culprit of which is an unusual phenotype of Pseudomonas aeruginosa called "mucoid."
For decades, chronic lung infection has been responsible either directly or indirectly for 70% of pre-mature deaths in PwCF. However, the seminal discovery of the CFTR gene in 1989 led to the development of small molecules that can modulate the activity of CFTR. The 2019 approval of the small molecule-based medication Trikafta has provided hope to PwCF and their families for a much-prolonged life span. This oral drug modifies the activity of the aberrant CFTR proteins in 90% of PwCF. It is given twice daily either as granules for children 2–6 years of age, or as tablets for those older than 6. It is well tolerated but can have liver toxicity and a wide array of drug-drug interactions.
Two scientists, Peter Gilligan, Ph.D., former Director of the Clinical Microbiology-Immunology Laboratories at the University of North Carolina (UNC) Hospitals and Rhianna Lee, Ph.D., who works in the Marsico Lung Institute/UNC Cystic Fibrosis Center, describe the battle to fight CF lung disease and the remarkable advances science has made in this fight.
Why is CF of particular and personal interest to you?Gilligan: As I approach my 50th college reunion, it is a time of reflection. Any reflection of that time must include my roommate of four years, Leon. Unknown to me, Leon was living on borrowed time when I met him, for he had cystic fibrosis. In 1969, the median life expectancy of a PwCF was 14 years. Leon's dream was to graduate from Holy Cross, which we did proudly in 1973. He passed away four years later. His life and experience battling CF have provided inspiration for my scientific journey, which continues to this day.
Lee: I was 8 years old when I first heard the words cystic fibrosis. The diagnosis was given as the reason for my brother's sudden hospitalization. He was 3 months old at the time, but those words have defined each moment of his life—and mine—ever since. At the time, I knew very little about the disease or its implications, only that my parents were fearful of what CF could mean for my brother. I sat with him through countless breathing treatments, encouraged him during hospital stays and, all the while, gleaned hope from the impact that research was having on his prognosis. By the age of 12, I decided to one day be a part of the research that was actively changing my brother's life.
Pathophysiology of CF lung diseaseThe airway epithelium serves as a vital barrier between the body and the outside world, protecting against uptake of inhaled particles, chemicals, allergens and pathogens. Inhaled materials are trapped in secreted mucus and removed from the airways through a process known as mucociliary clearance (MCC), in which motile cilia beat in a coordinated fashion to move particulates up and out of the respiratory tract. Proper hydration of the airway epithelium and the overlying mucus layer is key to productive MCC.
The CFTR gene encodes for an epithelial ion channel, which conducts chloride (Cl-) and bicarbonate (HCO3) out of epithelial cells and into the airway lumen. Water follows these molecules, thus hydrating the airway surface layer (ASL) and mucus layer covering the airway epithelium. In CF, absent or dysfunctional CFTR leads to a dehydrated ASL and buildup of a thick, sticky mucus, which cannot be transported by MCC. Pathogens become trapped in these abnormal lung secretions, leading to chronic infection and persistent inflammation.
The major pathogen responsible for chronic lung infection in CF patients is mucoid Pseudomonas aeruginosa (PA), which grows as microcolonies in the CF airway. These microcolonies are composed of gram-negative bacilli encased in the polysaccharide, alginate, and aggregated in biofilms. Alginate gives colonies their mucoid appearance.
Mucoid PA is refractory to MCC, phagocytosis and antimicrobial therapy allowing the establishment of chronic infection, often leading to chronic inflammation. The combination causes progressive damage to the lung architecture, resulting in ever-worsening lung function. Over a period of years, this eventually leads to either lung transplantation or death. Other important pathogens encountered in chronic CF lung infections include Staphylococcus aureus (especially methicillin resistant strains), Burkholderia cepacia complex, Mycobacterium abscessus complex and the fungus Aspergillus fumigatus. PwCF also experience acute infections with respiratory viruses such as Respiratory syncytial virus RSV and influenza, although the impact of viruses on chronic bacterial infections is less certain. Interestingly, COVID-19 has not been a significant cause of morbidity and mortality in PwCF, with mild disease being the norm.
Treatment of CF lung disease Small molecule CFTR modulatorsThe landscape of CF treatment shifted dramatically with the development of small molecule CFTR modulators, which address the underlying cause of disease by correcting protein folding, trafficking, function or stability. This results in improved MCC, limiting chronic infection, especially due to mucoid PA. The first CFTR modulator, Kalydeco, was approved in 2012 for PwCF carrying at least one copy of the G551D variant. Kalydeco is highly effective, rescuing about 11% of pulmonary function—measured as the forced expired volume in one second, or FEV1. However, only ~4% of the CF population was eligible for this treatment, based on the genotype criteria that were initially established.
The next big breakthrough occurred in 2015, when Orkambi was approved for PwCF carrying two copies of the F508del variant. F508del is the most common CFTR variant, so this covered about 50% of the CF population. However, Orkambi was less effective than Kalydeco, rescuing only ~3% of pulmonary function in clinical trials in 2017. Through in vitro studies of CFTR function, Kalydeco eligibility was expanded to include 23 relatively rare CFTR variants, extending modulator treatment to another 6% of the population.
Then in 2018, Symdeco was approved, showing marginal improvements over Orkambi. Finally in 2019, the blockbuster drug, Trikafta, was approved for PwCF carrying at least one copy of the F508del, the most frequent variant covering ~80% of the CF population. Moreover, Trikafta is the most effective CFTR modulator developed to date, correcting ~14% of pulmonary function in trials.
Overall, CFTR modulators have been extremely successful in extending life expectancy and improving the quality of life for 90% of PwCF, but developing therapies for the remaining 10% has proven challenging. This group harbors a wide range of exceptionally rare CFTR variants. In fact, more than 1,200 CFTR variants are carried by five or fewer people worldwide. For these individuals, a well-powered clinical trial will never be possible. This group also includes CFTR variants that cause premature termination codons, which produce little to no CFTR protein and, thus, little to no drug target. As the field shifts its focus toward the long list of rare, untreated CFTR variants, it becomes clear that extending life-changing treatment to all PwCF will require a new approach to drug design and development.
Prior to CFTR modulators, the care of CF patients targeted the mobilization of respiratory airway secretions, the eradication of bacterial pathogens and treatment of pulmonary exacerbations.
Mobilization of airway secretionsBecause the thick, mucous secretions found in CF airways are an ideal habitat for certain bacteria, such as P. Aeruginosa and S. Aureus, mobilization and clearance of airway secretions has been an important treatment for PwCF. For many years, a standard treatment was to have a family member percuss the back and chest of the PwCF to mobilize the thick, sticky mucous secretions. A more modern approach to this treatment requires the patient to wear an oscillating vest that mobilizes the secretions. After chest physiotherapy, the patient typically uses a nebulizer to deliver treatments including DNAse and hypertonic saline making mucous less sticky, more watery and easier to expectorate.
Antimicrobial eradication of pseudomonas aeruginosaTo prevent the establishment of chronic PA infection, eradication therapy using aerosolized antimicrobials has become a standard of care in CF patients, with tobramycin being the most used antimicrobial. However, eradication is somewhat of a misnomer, since the primary goal of this strategy is to delay the onset of chronic infection. The decline in the prevalence of P. Aeruginosa in PwCF suggests that this approach, along with genetic modifiers, has delayed the establishment of infection.
Treatment of pulmonary exacerbationThe length and quality of life in PwCF is based on the frequency of pulmonary exacerbation. It is an acute manifestation of chronic lung infections characterized by fever; increased cough, sputum production and respiratory rate; weight loss and declining respiratory function, as measured by spirometry. People with frequent exacerbations tend to have more frequent hospitalizations, a poorer quality of life and shorter lifespans. Exacerbations are typically treated with two or three intravenous (IV) antimicrobials for 14 days. This treatment does not "cure" the infection. Rather it reduces clinical symptoms and may restore some lung function. However once chronic infection is established, damage to lung architecture is relentless, eventually leading to lung transplantation or death, over a period of years to decades.
When will there be a cure for CF lung disease?The detection of the CFTR gene in 1989 raised hope that gene therapy could be successful in reversing the genetic defect in this gene. A 1995 proof of concept clinical trial of the transfer of a normal CFTR gene into nasal epithelial cells using an adenovirus vector was unsuccessful. Multiple trials have followed with none showing significant success.
Double lung transplantation is a proven "cure" for CF lung disease. First done extensively in the 1990s, the median life expectancy of CF transplant recipients has steadily increased, reaching 9.5 years by 2018. However, the 2021 U.S. CF patient registry reports that complication of lung transplantation was second only to chronic lung infection as a cause of death. With the wide availability of triple CFTR modulators, the number of CF lung transplants has plummeted. Clearly CFTR modulators are judged to be better options than CF lung transplantation in the care of most PwCF.
The success of highly effective CFTR modulators highlights the importance of correcting the underlying cause of CF. While modulators act at the protein level, a long-term cure will require looking upstream to correct the genetic defect at the DNA level. Theoretically, this could be achieved by one of three approaches:
The largest barrier facing each of the three approaches is delivery.
The airway epithelium serves a vital protective role by keeping foreign particles out of the human body. Unfortunately, these mechanisms cannot distinguish between harmful inhaled particles and those that are therapeutically delivered. Thus, airway mucus and MCC represent a major barrier to effective delivery of gene editing, gene therapy or cell therapy vectors. Methods to overcome the airway epithelial barrier safely and temporarily must be developed for successful gene correction or replacement.
Lee: Since my brother's diagnosis in 2001 to now, life expectancy for CF has increased by nearly 20 years. This advancement can be credited to the development of better airway clearance techniques, antimicrobial treatments and highly effective CFTR modulators. The latter demands particular recognition. Trikafta undoubtedly changed the trajectory of my brother's life. Though stories like his are cause for great celebration, the sobering reality is that many PwCF are still waiting for their breakthrough therapies. Their continued fight against CF and the hope provided by recent breakthroughs inspires me and many others to continue working toward a cure for CF.
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Is Cystic Fibrosis Contagious?
For a person to develop cystic fibrosis, both their parents must carry the gene mutation. As such, the condition is not contagious.
Cystic fibrosis (CF) is a genetic condition that causes a buildup of thick, sticky mucus in the lungs and digestive system. This results in blockages, infections, or damage to the organs and tissues involved in breathing and digestion.
This article explores the causes of CF and explains why the condition is not contagious.
It also discusses CF symptoms and treatments as well as the outlook for people living with the condition. Finally, the article answers some frequently asked questions about CF.
Cystic fibrosis (CF) is a genetic condition. It occurs due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene provides instructions for the CFTR protein, which is involved in regulating the consistency of mucus.
The CFTR protein exists in every mucus-producing organ of the body, including the:
The CFTR protein controls the movement of sodium and water across cell membranes. In people without CF, the CFTR protein helps produce thin, free-flowing mucus. In people with CF, the faulty CFTR protein produces thick, sticky mucus.
The thick, sticky mucus in the respiratory and digestive systems can cause complications, such as blockages, infections, and organ damage.
For a person to develop CF, they must inherit a faulty CFTR gene from each parent. If both parents have the faulty gene, there is a 1 in 4 chance their offspring will have CF.
Because CF is a genetic condition, it is not contagious. This means it is not possible for a person to contract CF from someone who has the condition.
People with CF often experience a chronic cough. This might lead other people to believe CF may be contagious. However, this cough is a symptom of CF. The condition cannot be transmitted to others.
Cross-infection occurs when one person with CF transmits an infection to another person with CF. This is much more likely to occur in indoor settings.
However, cross-infection can also happen at outdoor gatherings if two people with CF come into close contact.
To avoid cross-infection, doctors recommend people with CF stay at least 6 feet away from one another.
According to the Cystic Fibrosis Foundation, people with CF who do not live together should also avoid the following:
CF is a genetic condition that occurs when a person inherits two faulty copies of the CFTR gene — one from each parent.
If both parents carry a faulty copy of the CFTR gene, there is a 1 in 4 chance their offspring will have CF.
People with a family history of CF may choose to have genetic screening before having children. Genetic screening can determine whether an individual has a copy of the faulty CFTR gene that causes CF.
However, current genetic tests do not screen for all possible mutations in the CFTR gene.
Anyone with a family history of CF can speak with a doctor to learn more.
Around 35,000 people in the United States have CF. The symptoms may vary from one person to another, but some possible signs and symptoms include:
People with CF may also experience bowel problems, such as:
There is currently no cure for CF. However, treatments can help manage the condition and improve quality of life. According to the National Heart, Lung, and Blood Institute, treatments aim to:
Treatment options that can help loosen mucus in the airways and ease breathing include:
The National Health Service in the United Kingdom notes that people with CF may benefit from consulting with a dietitian. Since CF can affect a person's digestive system, digesting food and absorbing nutrients can be difficult. A dietitian may recommend:
In some cases, people with advanced CF may require surgical procedures, such as a lung or liver transplant.
Although there are many treatments for CF, the condition can cause serious long-term health problems.
Moreover, some of the treatments for CF can be intensive, and this may have negative effects on a person's mental health and overall well-being.
According to the American Lung Association, the current average life expectancy for people with CF is around 40 years. However, this number continues to grow as new research emerges.
Data from the 2021 Cystic Fibrosis Foundation Registry predicts that around half of babies born with CF in 2021 will go on to live 65 years or more.
The outlook for people with CF can depend on many factors, including whether they have other health conditions. Anyone living with CF can speak with a doctor to learn more about their unique outlook.
Below are answers to some frequently asked questions about CF.
Is it safe to be around someone with cystic fibrosis?CF is a genetic condition caused by a mutation in a certain gene. The condition is not contagious. People without CF cannot contract it from someone who has CF.
However, people with CF can transmit certain infections to other people with CF via cross-infection. To prevent cross-infection, doctors recommend people with CF who do not live together avoid close contact.
Can you kiss someone with cystic fibrosis?A person cannot get CF from kissing someone who has the condition.
However, people with CF are more susceptible to certain infections. As such, a person who has an infection should avoid kissing a person with CF. This can help protect the person with CF from contracting dangerous infections.
How is cystic fibrosis transmitted?Parents can transmit CF to their offspring through DNA. Specifically, if both parents carry the CFTR gene mutation that causes CF, there is a 1 in 4 chance their offspring will have CF.
Does cystic fibrosis need isolation?People with CF typically develop frequent lung infections. They may need to isolate themselves from people with active infections to help reduce their risk of becoming sick.
However, it is not necessary for people with CF to remain isolated at all times.
Cystic fibrosis (CF) is a genetic condition that damages mucus-producing organs, such as the lungs, and the organs of the digestive system.
It occurs due to inheriting a faulty CFTR gene from each parent. The condition is not contagious. People with CF cannot transmit the disease to individuals who do not have it.
People with CF often develop breathing difficulties and frequent lung infections. They may also develop bowel problems or malnutrition.
The treatment for CF involves airway clearance techniques, medications, and lifestyle modifications. Anyone living with CF should speak with a doctor to learn more about their treatment plan and outlook.
What To Know About The Sweat Test For Cystic Fibrosis
The sweat test involves measuring the amount of chloride in sweat. Doctors may use the sweat test to help diagnose cystic fibrosis, as cystic fibrosis causes higher amounts of chloride in sweat.
The sweat test can be useful for diagnosing cystic fibrosis in babies, children, and adults. A doctor may order a sweat test if a person has symptoms of cystic fibrosis or as part of a newborn screening test.
Read on to learn more about the sweat test. This article discusses how it can help diagnose cystic fibrosis, what the test involves, who might need it, and more.
The sweat test is a test that measures the amount of chloride a person has in their sweat.
Each person's body contains two copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The genes produce the CFTR protein.
When a person has cystic fibrosis, the CFTR protein does not work properly. This can cause chloride, which is a component of salt, to become trapped in the cells.
This can result in more chloride in a person's sweat. If the sweat test detects higher chloride levels, this can indicate cystic fibrosis.
Learn more about diagnosing cystic fibrosis.
The sweat test involves placing pads soaked in the chemical pilocarpine on the lower arm or leg. This helps to stimulate sweat production.
A small electrical current will then be passed through the pads for about 5 minutes. This helps the chemical to seep into the skin. It does not cause any pain.
Afterward, the sweat will be collected with a piece of gauze, filter paper, or a small plastic coil. This will typically last for about 30 minutes.
A doctor may order a sweat test if a child or adult has symptoms of cystic fibrosis. They may also recommend the test if a person has a family history of cystic fibrosis.
The sweat test may also be carried out as part of newborn screening tests. Babies in the United States are screened for a variety of conditions after birth, including cystic fibrosis.
If the heel prick test indicates that the baby might have cystic fibrosis, a doctor may order a sweat test to confirm the diagnosis.
Learn about cystic fibrosis and genetics.
A doctor may recommend not applying any creams or lotions to the arms or legs in the 24 hours before the sweat test.
A person will typically not need to do anything else to prepare for a sweat test.
If the sweat test measures a low level of chloride salts, then this typically suggests that the person does not have cystic fibrosis.
If the sweat test measures a high level of chloride, then this may indicate cystic fibrosis. A doctor may then order blood tests to confirm the diagnosis.
In some cases, the results may be inconclusive. If this is the case, a person may need to take another sweat test.
A sweat test is a test that can help with diagnosing cystic fibrosis. It measures the levels of chloride a person has in their sweat.
The test involves placing pilocarpine-soaked pads on the skin and passing a weak electrical current through the pad. Afterward, the sweat will be collected to test the level of chloride.
A person may need this test if they have symptoms or a family history of cystic fibrosis. It may also be necessary if a baby's heel prick test suggests that cystic fibrosis might be possible.
A high level of chloride can indicate cystic fibrosis. Blood tests can then help to confirm the diagnosis.
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