Evolution of lung function testing in Cystic Fibrosis: Past, Present, & Future Perspectives

Cystic fibrosis (CF) affects over 40,000 Americans and over 100,000 people across the world, making it one of the most common genetic diseases. This condition is relatively well-known, especially considering it affects fewer people than most other well-known chronic diseases. It's recognized partly due to campaigns like Cystic Fibrosis Awareness Month in May.

CF is an autosomal recessive condition, meaning each parent must pass down a copy of the defective gene to their child. This gene is known as the CF gene, which codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial protein found in the lungs, liver, pancreas, digestive tract, and reproductive systems.^* When functioning correctly, the CFTR protein serves a fundamental role in the formation of mucus. When the CFTR protein is defective, mucus becomes excessively thick. Thick and viscous mucus has consequences: Inflammation and infection become serious concerns, leading to prolonged lung decline. Pulmonary function tests (PFTs) are essential for diagnosing, monitoring, and treating CF.

Throughout this blog, we’ll discuss the history of PFT usage in cystic fibrosis and what the future looks like.

Past

Cystic fibrosis, which was only distinguished from celiac disease in 1938,^* has unfortunately been such a deadly condition that the vast majority — really, all — of our understanding has been learned in the last several decades. Since the 1950s, when more specialized care centers were established, we have come to understand a lot about CF in a relatively short time. By the 1970s, clinicians had already established the utility of measuring lung mechanics in determining the clinical severity and overall well-being of children with CF.^*

Since these early milestones, spirometry has been the most used pulmonary function test in cystic fibrosis patients.^* While spirometry tests include many different measurements, the most established marker of CF lung disease is FEV₁, or forced expiratory volume in one second. This measurement is particularly relevant in CF since lung decline has usually been so precipitous and mostly in the larger airways, where FEV₁ mostly captures.^* FEV₁ has been shown to be such a useful measurement that simply conducting routine spirometry is associated with higher rates of diagnosis and treatment of CF exacerbations.^*

Present

Spirometry has been so effective in fact that the present situation would not be possible without it: FEV₁ has been a primary endpoint for major milestones in clinical trials in CF that have led to the approval of such blockbusters including Vertex’s Trikafta. This blockbuster, approved for approximately 90% of the population, has been transformative for many people with CF.^*

Today, spirometry remains a key part of clinical monitoring, treatment, and evaluation of interventions in cystic fibrosis. But as medicine advances alongside our understanding of the biological underpinnings of conditions, unexpected consequences can emerge. In the story of CF, there now exists a recently emerged divide in the community between people who have gleaned benefits from a new therapeutic class — of which Trikafta is a part — called highly effective modulator therapy (HEMT). Various HEMT drugs exist, but this transformative therapeutic class remains inaccessible for a not insignificant cohort: 10% of the CF community. For this subset, FEV₁ remains the most established marker of lung disease, and will be crucial for the advent of new drugs indicated for people not on HEMT.

But just as HEMT medications have benefited many people greatly, people with CF still have lung disease. As these therapies are not a cure, and for as long as long-term lung health remains a concern, the community will need reliable, and even more sensitive, markers of lung disease. Further, this is not just relevant to people on HEMT, but also for children, where lung disease is present often before any clinical signs or symptoms and spirometry can be difficult to perform.^*

Future

Walicka-Serzysko et al. sought to investigate the very question of what the future of PFTs will look like in cystic fibrosis. They evaluated contemporary clinical spirometry against the promising PFTs with multiple breath washout (MBW) and impulse oscillometry (IOS) in a cohort of Polish children. They found that MBW and IOS out-performed conventional PFTs including spirometry.^* Further, they found that children with “normal” FEV₁ measurements consistently had impaired LCI measurements, indicating LCI as a more sensitive marker of lung disease. The additional benefit of MBW is its passivity, reducing the burden on the patient while also providing a more sensitive measurement.

Conclusion

Spirometry has long been a necessary tool for managing cystic fibrosis in the clinic and in evaluating interventions. It remains necessary for the entirety of the CF community, though its use is changing as more effective treatments emerge. Other PFTs, notably the multiple breath washout PFT and the even-more sensitive measurement lung clearance index, appear to be the future of monitoring lung disease in CF.