Cystic fibrosis

• 1. A Warning on the Skin

  ›

  Cystic fibrosis, a genetic disorder that mostly damages the lungs, was noticed by ordinary families long before anyone gave it a name. In the 18th century, literature from Germany and Switzerland carried a stark warning: "Woe to the child who tastes salty from a kiss on the forehead, for he is bewitched and soon must die." The authors blamed witchcraft. Yet they had spotted a genuine sign of a genuine illness. Cystic fibrosis, often shortened to CF, is the subject of this documentary, and it begins with that salty skin. What goes wrong inside a cell to produce it? Why does one inherited condition reach so many parts of the body? How did researchers track down the gene responsible, and why does a harmful mutation stay common in some populations? Finally, how did a disease with no cure become one that many people now live with well into adulthood?

  2116689

• 2. A Faulty Channel

  ›

  On the long arm of chromosome 7, at a spot labelled 7q31.2, sits a gene about 230,000 base pairs long. It encodes a protein 1,480 amino acids in length, the cystic fibrosis transmembrane conductance regulator, known as CFTR. The protein is anchored in the outer membrane of cells in the sweat glands, lungs, pancreas and the body's other exocrine glands. It forms a channel for chloride ions, and that channel matters for making sweat, digestive juices and mucus. When it fails, secretions that should be thin turn thick.

  Different mutations break the protein in different ways. Some produce a protein that folds badly and is destroyed before it ever reaches the cell membrane. Others halt production early and leave a truncated protein. Some make a protein that fails to use its ATP energy normally, lets chloride, iodide and thiocyanate cross poorly, or degrades faster than usual. Still others simply make fewer copies. Each defect is a different target for drugs.

  In the airways, the damage unfolds in a thin layer called airway surface liquid, where tiny hair-like cilia normally beat beneath a blanket of mucus. Healthy CFTR draws chloride into that layer. It also restrains a second channel, called ENaC, which lets sodium drain away. Without that restraint, sodium flows freely out of the liquid and into the cell, and water follows it. The layer shrinks, the cilia end up stranded in sticky mucus, and they can no longer sweep the airways clear. Small airways clog. The thick, nutrient-rich mucus also gives bacteria a place to hide from the immune system.

  Sweat glands run the process in reverse. Here the channel normally pulls chloride back out of the sweat duct, but a faulty one cannot. Chloride and sodium stay in the sweat and reach the skin as salt. In severe cases the loss of salt and fluid causes dehydration with dangerously low blood sodium.

  CFTR is not the only influence on how severe the disease becomes. Low circulating levels of a protein called mannan-binding lectin, which helps immune cells swallow microbes, are linked to a threefold higher risk of end-stage lung disease.

  4852535562

• 3. Lungs Under Siege

  ›

  By the age of 18, 80% of patients with classic CF are harboring Pseudomonas aeruginosa, and 3.5% are harboring Burkholderia cepacia. The bacterial cast changes over time. Staphylococcus aureus and Haemophilus influenzae move into the lungs first, and Pseudomonas eventually takes over. The thick mucus lets bacteria gather into communities called biofilms, which immune cells and antibiotics struggle to penetrate. Inside the lungs the microbes adapt and become resistant to commonly used drugs. One Pseudomonas form builds large colonies and is called mucoid Pseudomonas; it is rarely seen in people without CF.

  Specialists admit that the natural history of these infections is poorly understood. Each patient's microbial community differs, and it shifts across both space and time. What is clear is the damage. Repeated infection and inflammation gradually remodel the airways, and widened, scarred major airways, known as bronchiectasis, make breathing harder still.

  Symptoms arrive in stages. Children and teenagers often have a runny nose, nasal obstruction and nasal polyps. Later come shortness of breath and a chronic cough that produces sputum. In late adolescence or adulthood, severe signs appear: wheezing, clubbed fingers, bluish skin from low oxygen, coughing up blood, strain on the heart and collapsed lung. Lung problems cause death in 70% of people with CF.

  Other microbes join the assault. Allergic bronchopulmonary aspergillosis is a reaction to the common fungus Aspergillus fumigatus that worsens breathing. Mycobacterium avium complex, a group of bacteria related to tuberculosis, can scar the lungs and does not respond to common antibiotics. Long courses of antibiotics and corticosteroids may even help fungi take hold.

  Some of the worst strains spread from person to person. In the past, people with CF attended summer "CF camps" and other gatherings. Hospitals grouped them in shared areas, and routine equipment such as nebulizers was not sterilized between patients. Today patients are routinely kept apart in healthcare settings, and clinicians are encouraged to wear gowns and gloves.

  34686972

• 4. Beyond the Lungs

  ›

  Between 15% and 20% of newborns with CF arrive with the small intestine blocked by meconium, the first stool, and many need surgery to clear it. Some newborns also develop jaundice because the bile ducts are blocked. These early digestive crises point to the pancreas, where the same thick secretions do quiet, lasting harm.

  The pancreas makes digestive juices, and in CF the ducts that carry its enzymes to the duodenum become plugged. The result is irreversible damage and sometimes painful inflammation called pancreatitis. Faulty chloride secretion also reduces bicarbonate, so the acidic mixture leaving the stomach is not neutralized and the enzymes that do arrive work poorly. Fat goes undigested, stools become large and greasy, and the fat-soluble vitamins A, D, E and K are poorly absorbed. Exocrine pancreatic insufficiency affects 85-90% of patients, mainly those whose two copies of the gene are both severely broken. People with milder combinations keep enough pancreatic function to skip enzyme supplements, and they usually grow and develop excellently.

  The vitamin shortfalls have consequences of their own. Low vitamin K can disrupt blood clotting, which is why unexplained bruising in a young child may call for a clotting evaluation. Poor vitamin D uptake can weaken bones into osteoporosis. When the pancreas loses its insulin-making islet cells, a distinct condition called cystic fibrosis-related diabetes emerges. It shares features of type 1 and type 2 diabetes and is a principal complication outside the lungs.

  The liver is another casualty. Studies found liver disease in 18% of children at age two and 41% at age 12, with no significant rise after that. Thickened bile can block the bile ducts, and over time the liver may scar into cirrhosis. Around 5-7% of people have liver damage severe enough to cause symptoms, typically gallstones. Liver disease is the third-most common cause of CF-related death. Rectal prolapse, in which internal rectal membranes protrude, affects as many as 10% of children.

  Infertility completes the picture. At least 97% of men with CF are infertile but not sterile, mainly because the vas deferens is absent from birth. Around 20% of women with CF face fertility difficulties from thickened cervical mucus or malnutrition. Assisted reproduction can still help: sperm can be collected directly from the testicles, and a single sperm can be injected into an egg.

  2835364143

• 5. Carriers and Geography

  ›

  Up to one in 25 people of Northern European ancestry carries a single faulty copy of the CFTR gene and is otherwise mostly healthy. Disease appears only when two carriers have a child together, and each pregnancy between them carries a 25% chance of CF. That arithmetic produces about one case per 3,000 newborns in the affected ancestry. In the United States about one child in 3,500 is born with CF, and roughly 30,000 Americans live with it. Canada counts about 4,000.

  The mutations are strikingly varied. As of 2018, more than 1,900 had been described, yet only five exceed a 1% share among patients. The dominant one, ΔF508, deletes three nucleotides and removes the amino acid phenylalanine at position 508 of the protein. It accounts for about 70% of cases worldwide and 90% in the United States. The next four are far rarer: G542X at 2.4%, G551D at 1.6%, N1303K at 1.3% and W1282X at 1.2%.

  Carrier rates fall sharply elsewhere. About one in 46 Hispanic Americans, one in 65 African Americans and one in 90 Asian Americans carries a mutation. Ireland has the world's highest prevalence, at one in 1353, while Japan's is among the lowest, at one in 350,000. Finland is an exception within the Western world: only one in 80 people carries a mutation, and CF occurs in just 20 Finnish families. No ΔF508 carriers turned up among 171 Finns and 151 Saami people tested.

  The ΔF508 mutation may be as much as 52,000 years old, which raises a puzzle. Why would such a damaging allele persist? Sickle-cell anemia offers a model, because its carriers gain protection from another disease, a trade-off called heterozygote advantage. Cholera was an early suggestion, since the cholera toxin needs normal CFTR to work, but later studies did not confirm it. Typhoid was proposed because Salmonella Typhi also needs normal CFTR to enter cells, and no study in living organisms has confirmed that either. Another idea ties CF in Europe to cattle domestication, with carriers shielded from diarrhea caused by lactose intolerance before lactose tolerance arose.

  The tuberculosis hypothesis is the most intricate. Carriers may have low activity of an enzyme called arylsulphatase, which Mycobacterium tuberculosis needs to express its virulence. None of these ideas explains why CF is uncommon outside Europe, in places where cholera and typhoid are endemic.

  8511319

• 6. Hunting the Gene

  ›

  Descriptions that fit cystic fibrosis occur at least as far back as 1595, and one estimate places the disease's origin around 3,000 BC. Even so, medicine needed until the 1930s to see the whole picture. In the 19th century, Carl von Rokitansky described a case of fetal death from meconium peritonitis, a complication tied to blocked newborn bowels. In 1905, Karl Landsteiner described meconium ileus itself. In 1936, Guido Fanconi connected celiac disease, cystic fibrosis of the pancreas and bronchiectasis.

  The decisive step came in 1938, when Dorothy Hansine Andersen published an article titled "Cystic Fibrosis of the Pancreas and Its Relation to Celiac Disease: a Clinical and Pathological Study" in the American Journal of Diseases of Children. She was the first to describe the characteristic pancreatic damage and link it to the lung and intestinal disease so prominent in CF. She also first proposed that the condition was recessive, and she first used pancreatic enzyme replacement to treat affected children. The name itself refers to the fibrosis and cysts that form in the pancreas.

  In 1952, Paul di Sant'Agnese discovered abnormalities in the electrolytes of sweat. A sweat test was developed and refined over the following decade. In 1985, Hans Eiberg found the first linkage between CF and another genetic marker, paraoxonase, which showed that only one locus exists for the disease.

  Pinpointing the gene was hard because CFTR mutations are small, and classical genetics could not locate them directly. Researchers used protein markers and gene-linkage studies to map the mutation to chromosome 7. Then they used techniques called chromosome walking and chromosome jumping to identify and sequence the gene. In 1988, Francis Collins, Lap-Chee Tsui and John R. Riordan found the first mutation, ΔF508, on the seventh chromosome. In 1989, Tsui led a team at the Hospital for Sick Children in Toronto that discovered the gene responsible for CF. Later research found well over 1,000 different mutations that cause the disease.

  1621199

• 7. Testing and Diagnosis

  ›

  By 2010, every US state ran a newborn screening program for cystic fibrosis, and 21 European countries had programs in at least some regions. The first screen is usually a blood test for high levels of immunoreactive trypsinogen, or IRT. Carriers can have raised IRT, and so, rarely, can people with two normal gene copies. Because levels fluctuate, programs often use percentile cutoffs, such as the 95th percentile. False positives make newborn screening controversial. A positive result flags a high likelihood of CF but cannot establish the diagnosis alone.

  That job falls to the sweat test. An electric current drives a drug called pilocarpine into the skin to stimulate sweating, and the collected sweat is analyzed for salt. A chloride level above 60 mmol/L suggests that CFTR is not working, and the person is diagnosed with CF. A level below 30 mmol/L makes the diagnosis unlikely.

  Genetic testing adds a second layer. Many laboratories check for the 30-96 most common CFTR mutations, which identifies over 90% of people with CF. For milder cases, a nasal potential difference measurement can help. It tracks the voltage response of the nasal lining to certain drugs. A definitive diagnosis requires typical clinical features, a sibling with CF or a positive newborn screen, plus laboratory proof of CFTR dysfunction. Proof can be two elevated sweat chloride readings on separate days, two pathogenic variants, or an abnormal nasal measurement.

  Prenatal carrier testing follows a similar logic. The American College of Obstetricians and Gynecologists recommends that everyone thinking of becoming pregnant be tested for carrier status. Because the tests are expensive, one parent is often tested first, and the other is tested only if the first is a carrier. Most commercial tests look for 32 or fewer mutations, so a negative screen does not guarantee a child will be unaffected.

  If risk is high, the fetus can be tested through chorionic villus sampling or amniocentesis. The risk of fetal death is about one in 100 for the first procedure and one in 200 for the second, though a recent study suggests it may be closer to one in 1,600. For carrier couples, one economic analysis compared preimplantation genetic diagnosis with natural conception followed by prenatal testing. It found net economic benefits for the first approach up to a maternal age of around 40 years.

  8580828893

• 8. Treatment and Survival

  ›

  In 1959, the median age of survival for children with CF in the United States was six months. There is still no cure, but management has improved enormously over roughly 70 years. Care now centers on proactive treatment of airway infection, good nutrition and an active lifestyle, delivered at specialist multidisciplinary centers.

  Many people with CF take one or more antibiotics at all times, even when healthy. Inhaled tobramycin, colistin or aztreonam is often given for months. Drawbacks include antibiotic resistance, tinnitus and changes in the voice. Aminoglycoside antibiotics can damage hearing, balance or the kidneys, so blood levels are routinely measured and adjusted. Mucus is loosened with dornase alfa, which breaks down DNA in sputum, and inhaled 7% hypertonic saline. In chest physiotherapy, a respiratory therapist percusses the chest by hand several times a day, and devices can do the same job. These routines are effective but extremely time-consuming.

  When lung function fails, transplantation is an option. Both lungs must be replaced, because a remaining original lung could infect the new one. Among adults with CF, median survival after transplant is about nine years.

  The biggest shift came from CFTR modulators, oral drugs that target the defective protein itself. Ivacaftor, first approved in 2012, targets the G551D variant present in about 5% of patients and improves lung function by about 10%. In its first year on the market, its list price in the United States was over $300,000 per year. Lumacaftor/ivacaftor followed in July 2015, and ivacaftor/tezacaftor in 2018 at a announced list price of $292,000 per year.

  In 2019, the triple combination elexacaftor/tezacaftor/ivacaftor, marketed as Trikafta, was approved in the United States for patients over 12. Approval extended to children aged 6 and older in 2021, and Europe approved it in 2020 as Kaftrio. The Cystic Fibrosis Foundation called it "the single greatest therapeutic advancement in the history of CF." In a clinical trial, participants had 63% fewer pulmonary exacerbations and a 41.8 mmol/L drop in sweat chloride. A further combination, vanzacaftor/tezacaftor/deutivacaftor, sold as Alyftrek, was approved in the United States in 2024.

  Survival figures have climbed accordingly. Predicted median survival in the United States reached 65.4 years in 2024, up from 46.1 years in 2019 and 40.1 years in 2014. Canada's estimate reached 64.3 years in 2024, up from 52.7 in 2019 and 53.0 in 2014. Among American adults with CF in 2024-94% had graduated from high school, 64% held jobs and 47% were married or living with a partner.

  Research continues for people the modulators do not help. Gene therapy has shown limited success. Bacteriophage therapy, which uses viruses to destroy bacteria protected by biofilms, is being studied against multidrug-resistant infections. Antisense therapy is aimed at splicing and nonsense mutations such as G542X and W1282X, where too little CFTR protein is made for a modulator to correct.

  1913455095