Even a disease as deadly as idiopathic pulmonary fibrosis (IPF) can start out as just a cough. But as the condition progresses, a person might experience up to 500 respiratory spasms per day. Breathing becomes difficult, as does sleeping. A chronic lack of oxygen increases blood pressure in the lungs. Within 3–5 years of diagnosis, if untreated, a person will experience respiratory failure and die. As the term idiopathic signals, the cause of the disease is not clear, although both genetics and the environment are thought to have a role (see ‘Idiopathic no more?’).
IPF develops more or less in silence, and so it is hard to catch early. “There’s underdiagnosis. People often come to see us pulmonologists when it’s too late,” says Gisli Jenkins, a respiratory physician at Imperial College London.
Nature Outlook: Lung health
Attempts to treat the condition — or at least alleviate its symptoms — have largely focused on fibrosis, the formation of scar tissue around the tiny air sacs in the lung known as alveoli. So far, it’s been a rough ride. Treatment with a combination of anti-inflammatory drugs, which was the standard of care for many years, is now not advised because a clinical study1 in 2012 concluded that it not only failed to improve outcomes, but also increased mortality.
In 2014, two treatments were approved by the US Food and Drug Administration (FDA) and have become the current standard of care. The first, nintedanib, targets myofibroblasts — the cells that cause fibrosis in an attempt to repair escalating damage in the lung. Nintedanib inhibits three receptor types that promote these cells’ activity to prevent more damage.
The drug slows down the decrease in forced vital capacity (FVC) — the maximum amount of air a person can forcibly exhale after taking the deepest possible breath. But there is no evidence that it reduces mortality, and it causes burdensome side effects, such as diarrhoea.
Idiopathic no more? Idiopathic pulmonary fibrosis (IPF) is a misnomer, according to pulmonologist Paul Wolters at the University of California, San Francisco. The term idiopathic means that the condition has arisen for no known reason. But that “might falsely convey that there is little or no understanding for the cause or pathogenesis” of IPF, Wolters and his colleagues wrote in a 2018 paper arguing against the continued use of the term6. They pointed to “genetic, environmental, cellular, and molecular mechanisms” as being likely culprits in the onset of IPF. Indeed, says Wolters, a combination of genetic and environmental factors are the cause of most cases of the condition. He thinks that “in some people, it’s entirely genetics, 100%. In others, it’s injury causing failure of the epithelium. But genetics are at the root”. The strongest genetic risk factor for IPF might be a common variant in the promoter region of the MUC5B gene, which one study found in more than one-third of people who have the condition7. It causes overproduction of mucin protein in the small airways. This causes excess mucus, which impairs the lung’s clearance mechanisms and creates a microenvironment that leaves lung epithelial cells more vulnerable to damage by inhaled particles or microorganisms, and primes the tissue for fibrosis. Although MUC5B confers risk on a larger number of people, it is the rare, high-impact mutations that cause the most severe forms of the disease. These mutations are often found in genes that are essential for maintaining the telomeres at the ends of chromosomes. Among these mutations, those in TERT and TERC are key. These genes code for the core components of the enzyme telomerase. They affect the cell’s ability to maintain its telomeres with each cell division, which leads to accelerated telomere shortening and premature cellular ageing. These effects are particularly damaging to the lung’s epithelial stem cells, which must divide regularly to repair everyday damage. Shorter telomeres are also commonly found in people with IPF who don’t have these mutations. Other rare mutations might affect genes, such as SFTPC and SFTPA2, that produce surfactant proteins. These changes cause crucial proteins to misfold during production inside the lung’s epithelial cells. Such misfolding causes intense cellular stress, which, in turn, triggers a process called the unfolded protein response. This usually results in programmed cell death, or apoptosis, and the release of signals that initiate a fibrotic response in the surrounding tissue. Efforts to reduce the environmental insults that people experience might have an impact. Asbestos, and dust from compounds such as coal and silica are known to be risk factors, as is smoking. “Reducing the environmental contribution to idiopathic pulmonary fibrosis would be huge,” says Gisli Jenkins at Imperial College London. But “the challenge is always convincing any politician in any country that a disease with a latency period of 20–30 years is something they need to deal with, when the electoral cycle is only 4–5 years”.
The second drug, pirfenidone, reduces the activity of the signalling molecule TGF-β, which typically impels fibroblasts to transform into the myofibroblasts that exacerbate fibrosis. Treatment prolongs progression-free survival by about 25%, and reduces mortality by about half after one year of treatment. But it also has unpleasant side effects, similar to those of nintedanib.
Generic variants of pirfenidone have been available since 2022. The main patents for nintedanib have now expired in Europe and are due to expire in the United States in 2026, paving the way for more affordable generic options. Yet the persistent side effects of these drugs could limit the impact of this opportunity. Many people who take IPF therapies have to change their diets and worry about finding toilets when outside the home.
Less than half of people with IPF in the United States are taking either medication, according to Toby Maher at the University of Southern California in Los Angeles. “Pulmonologists have been very reluctant to prescribe drugs that they know patients will struggle to tolerate,” says Maher, who is a pulmonologist and lead investigator on several clinical trials for IPF therapies.
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