LCI and the future of cystic fibrosis

Cystic fibrosis (CF) is one of the most common genetic diseases in the United States. Though it’s commonly considered a pulmonary disease, cystic fibrosis is a genetic disease that affects many organs. At the root, cystic fibrosis is caused by a defective transport protein known as the cystic fibrosis transmembrane conductance regulator (CFTR) in cell membranes that allows for the transfer of water and salt ions across the cell membrane. When the CFTR protein is dysfunctional, the lack of water transport results in unusually thick mucus in the body. This is what causes its infamous reputation, where many people with CF encounter issues in their gastrointestinal tract, pancreases, and lungs. Still, there can be more consequences for people with CF, but the focus of this blog will remain on the pulmonary implications of CF.

Cystic fibrosis has traditionally been monitored using FEV1

Since lung disease has such a profound effect on patient’s quality of life, lung function tests are usually used to evaluate CF lung disease and the success (or failure) of interventions. Historically, forced expiratory volume in one second (FEV1) as measured by spirometry has been the gold standard for evaluating the progression of CF lung disease, as well as the primary endpoint for interventional clinical trials.^* FEV1 can be a powerful measure, but like all measures, it has limitations: FEV1 mostly captures what’s happening in the large airways, which is crucial, but not the whole picture. It’s important to have alternative and complementary tools to understand the holistic picture of how CF is damaging a patient’s lungs. FEV1 is also not extremely sensitive, so when FEV1 decline is occurring, it coincides with clinical symptoms. In other words: Patients can tell when their FEV1 has declined because they can already feel it. Depending on what has caused FEV1 decline in a patient, it can sometimes be recovered. But over time, most people with CF will experience severe decline in their lung function, resulting in many instances of oral and intravenous antibiotics before finally ending in either a bilateral lung transplant or death.

Looking ahead

Fortunately, the world of CF looks a lot different today compared to even a decade ago. Recent therapeutics called CFTR modulator therapies, which include drugs such as Trikafta, have gone a long way in significantly improving the quality of life and prognosis for many people in the CF community. This has led to an unprecedented stability for most patients on CFTR modulators. But the newness and success of CFTR modulators (several modulators have been approved by the US Food and Drug Administration to treat patients with varying CF-causing mutations) have been met with some unexpected consequences. Since FEV1 has been used as the primary measurement of monitoring lung disease and patients are seeing unexpected stability in their FEV1, there is increased urgency for alternative, more sensitive ways of monitoring patients and the impact of interventions. Lung clearance index (LCI), measured during the multiple breath washout (MBW) test,^* might just be one solution to this problem.

The promise of lung clearance index

Using MBW tests to measure LCI to determine early lung disease in cystic fibrosis and other obstructive pulmonary diseases has been extensively documented in the literature.^* But what are MBW tests? What is LCI? Why is this a promising complementary approach to spirometry and FEV1 in cystic fibrosis?

One limitation of spirometry is that it requires forced expiration of air. MBW tests, alternatively, are performed while the patient restfully breathes, lessening the burden on patients who might struggle to forcefully expel air. LCI — like FEV1 in spirometry — is just one of the measures captured during MBW tests.

In clinical practice the nitrogen (N₂) washout is the most common form of MBW. During the N₂ MBW test, the patient is switched from breathing ambient air to inhalation of 100% oxygen. During this phase the N₂ is washed out breath by breath; i.e. the nitrogen concentration in the exhaled air decreases with each breath. LCI, then, is defined as “the number of lung volume turnovers needed to reduce the concentration of the tracer gas N₂ to 1/40^th of the initial concentration,” which provides an assessment of the patient’s ventilation inhomogeneity.^* As one paper reviewing the use of LCI in Italian people with CF articulates, LCI’s promise lies in its ability to “allow indirect investigation of the small airways; the site where, from a pathophysiologic point of view, the disease begins.”^*

It should be noted that some evidence has indicated that LCI is more variable in patients with more advanced lung disease.^* Just as FEV1 has its limitations, so does LCI, underscoring the importance of establishing normalized values and repeatability of proposed measures^* and using complementary measurements when evaluating the progression of lung disease. But for any proposed guidance to be effective, it must be accessible. A device like the EasyOne Pro® LAB is portable and capable of conducting not only spirometry, but also multiple breath washout tests, offering a comprehensive method of quantifying both large and small airway disease.^*

It is promising that people with CF are faring better than ever before, but with improved health comes a newfound need to better capture the full scope of a patient’s lung disease to prevent further decline and ensure patients with CF live long, healthy, stable lives. There is more to learn about LCI and its ability to measure early lung disease in CF, but with the health of the average person in the CF community more stable than in the past and LCI's promise as a more sensitive measurement, LCI should be prioritized in the clinic and in research in the coming years.