Monitoring Disease Progression in Idiopathic Pulmonary Fibrosis


Monitoring Disease Progression in Idiopathic Pulmonary Fibrosis

In medical terms, “disease progression” means that a disease is getting worse over time. IPF is a disease that progresses over time.

IPF gets worse at different speeds for different people. For some people, the disease gets worse slowly (“slowly progressing disease”). For other people, the disease gets worse more quickly (“rapidly progressing disease”). Researchers are not sure why some people with IPF have rapidly progressing disease and others have slowly progressing disease. Some research suggests there may be genetic differences between patients with the two different types.1

Doctors use a variety of tests to monitor disease progression in IPF. The tests are usually done at the time of diagnosis, and then repeated after certain time periods (for example, every few months). The test results can help show if a person’s disease stayed stable (did not get worse) during that time, or if it progressed (got worse).

The following are some key tests that doctors use to monitor disease progression in IPF. Some of these tests are also used to evaluate patients during clinical trials of medications for IPF.  

FORCED VITAL CAPACITY

What is forced vital capacity (FVC)?

Forced vital capacity (FVC) is the total amount of air a person can exhale rapidly and with maximum force after taking the deepest breath possible. FVC is measured in liters using a lung function test called spirometry.2

What is “percent predicted FVC”?

The results of the FVC part of the spirometry test are often reported as “percent predicted FVC”. This score is based on gender, age, and height. 

Lower scores indicate worse lung function. A person with a percent predicted FVC of 100% has all of the lung function that would be predicted for a healthy person of the same gender, age, and height. A person with a percent predicted FVC of 70% has only 70% of the lung function that would be predicted for a healthy person of the same gender, age, and height. 

Can FVC help with monitoring disease progression?

Yes. Changes in percent predicted FVC score are helpful for monitoring disease progression. 

The percent predicted FVC score can change a little bit from test to test, even in a healthy person. This is normal. But, an absolute decline of 10 percentage points is considered a “meaningful” drop.3 For example, a patient who had a percent predicted FVC of 50% at diagnosis, and who now has a score of 40%, has gotten worse over time. A drop of less than 10 percentage points is usually called “stable disease”. That is the definition of “stable disease” that was used for clinical trials of the two anti-fibrotic medications pirfenidone and nintedanib.

In 2017, a large research study pooled the data from 1,132 IPF patients who received placebo in 6 clinical trials of nintedanib and pirfenidone. The patients were tracked for an average of 60 weeks (about 14 months). The study found that an absolute decline of 10 percentage points in percent predicted FVC was associated with an increased risk of death during the study follow up.4 A decline ranging from 5 percentage points to less than 10 percentage points was not associated with increased risk of death during the study. 

These results support the threshold of 10 percentage points as a “meaningful” drop for patients with IPF. 

DIFFUSING CAPACITY OF THE LUNGS FOR CARBON MONOXIDE (DLCO)

What is diffusing capacity of the lungs for carbon monoxide (DLCO)?

This pulmonary function test is used to estimate the transfer of oxygen from the alveoli (air sacs) in the lungs to the red blood cells in the bloodstream. The diffusing capacity of the lungs (DL) of oxygen is technically very difficult to measure. However, the diffusing capacity of carbon monoxide (DLCO) is much easier to measure, and it gives a good estimate for oxygen. The test is safe because the amount of carbon monoxide that is inhaled is very small. 

What is “percent predicted DLCO”?

Just like for FVC, the results of the DLCO test are often reported as “percent predicted DLCO”. This score is based on ethnicity, gender, age, and height. 

Lower scores indicate worse oxygen transfer in the lungs. A person with a percent predicted DLCO of 100% has all of the oxygen transfer that would be predicted for a healthy person of the same ethnicity, gender, age, and height. A person with a percent predicted DLCO of 70% has only 70% of the oxygen transfer that would be predicted for a healthy person of the same ethnicity, gender, age, and height. 

 A DLCO result that is 80% of the predicted value or higher is within normal limits. 

Can DLCO help with monitoring disease progression?

Yes. As with FVC, DLCO may change a little bit from test to test. However, a drop in the percent predicted DLCO score of 15% or more means that lung damage has worsened.

In a large study from Europe, 714 IPF patients in the EMPIRE registry were tracked for a median of 63 months (over 5 years). At the start of the study, the average percent predicted DLCO was 45%. The authors found that a drop in percent predicted DLCO of 15 percentage points or more at month 12 after study start was associated with over a three-fold increased risk of death during the study as compared to a drop of less than 15 percentage points.5

Do FVC and DLCO scores always track together?

Not always. Sometimes the FVC score declines over 6 months or a year, while the DLCO score stays stable. This is especially true if the DLCO score is 40% of predicted or lower. Accurate testing of DLCO at lower scores is more challenging. 

Research suggests that the percent predicted FVC is more sensitive for showing disease progression than the percent predicted DLCO.5 For this reason, DLCO scores are not used at the primary endpoint in clinical studies of new medications for IPF, but may be used as secondary endpoints.

HIGH-RESOLUTION COMPUTED TOMOGRAPHY (HRCT)

What is high-resolution computed tomography (HRCT)? 

HRCT is an imaging study performed in a medical center or hospital. Computer software is used to construct a detailed three-dimensional image from many two-dimensional x-ray images of the lungs. Most people with IPF have very distinctive lung patterns on HRCT. These signs show the formation of scar tissue around the air sacs and supportive tissues of the lungs.6 HRCT is often used to help diagnose IPF

Can HRCT results help with monitoring disease progression?

This question is being studied by many researchers in the field of IPF. 

HRCT is useful for helping diagnose IPF, and taking new scans over time is useful to see if lung fibrosis is becoming worse or staying stable. However, researchers still do not have enough data to understand how to predict life expectancy or make predictions about disease progression using HRCT scans alone. This is an area of active research.7

Do HRCT scan results track with FVC scores?

Not always. In fact, a major barrier to using HRCT to monitor disease progression is that scores on FVC and other pulmonary function tests do not always track with the way the lungs look on HRCT images.

For example, one study enrolled 98 patients with IPF who were diagnosed using HRCT alone between January 2008 and January 2012. HRCT scans and spirometry were performed every 6 months for the first year after diagnosis. 

HRCT images were scored by two different radiologists for how severe the lung fibrosis appeared for each patient at each scan. The scores were then averaged to give a final score for each patient at each scan.8

At the first 6-month testing, the researchers found that there were 62 patients whose FVC scores and HRCT scores both stayed stable. There were 30 patients whose FVC scores stayed stable while their HRCT fibrosis scores became worse. For 3 patients, the FVC score became worse and the HRCT fibrosis score stayed stable. For another 3 patients, FVC scores and HRCT fibrosis scores both became worse. 

All patients whose HRCT fibrosis scores became worse at month 6 or at month 12 had a two-fold increased risk of death during the study compared to those whose HRCT scores stayed stable. This was true even for the 30 patients for whom the FVC score stayed stable while the HRCT fibrosis score became worse. These patients still had an increased risk of death. 

The study suggests that HRCT might pick up disease progression before FVC testing does. Still, many more studies will need to be done to help develop a standard scoring system and to help researchers understand the meaning of various scores. 

For these reasons, HRCT scan results are not used as a primary clinical trial endpoint for drug development in IPF, but they may be used as a secondary endpoint. The latest studies are using computer algorithms to interpret HRCT scan results, which may provide a way to make the results more predictive of mortality risk.9

SIX-MINUTE WALK TEST (6-MWT)

What is the six-minute walk test (6-MWT)?

The 6-MWT is a simple walking test that measures the distance that a person is able to walk in 6 minutes. Two markers are set on the floor 100 feet apart in an obstacle-free corridor. The patient walks back and forth between the markers for a total of 6 minutes, circling around each marker instead of making a sudden turn. 

The score for the 6-MWT is the number of meters walked. A score at diagnosis of less than 250 meters has been associated with a two-fold increase in risk of death in the following 6 months.10

Can the 6-MWT help with monitoring disease progression?

Yes. A decline of 50 meters or more in 6-MWT distance indicates disease progression and an increase in mortality risk.

A large study of 748 patients with IPF looked at 6-MWT distance at the start of the study and again 24 weeks later. Patients with a decline of 50 meters or more in the distance walked at week 24 compared to study start had over a three-fold increased risk of mortality in the following year.10

One drawback to using the 6-MWT to help monitor disease progression is that the test can be affected by factors other than IPF, like age, weight loss or gain, peripheral arterial disease, musculoskeletal problems, depression, and difficulties with memory or concentration. 

Do 6-MWT test results track with FVC scores?

Yes, changes in 6-MWT distance at different time points do generally track with changes in percent predicted FVC scores.

A large study of 338 patients with IPF tracked 6-MWT and spirometry results from the study start to the end of the study at 48 weeks. The researchers found that 6-MWT scores, percent predicted FVC scores, and percent predicted DLCO scores all generally tracked together for these patients.11

The 6-MWT is often used as a secondary endpoint in clinical trials of medications for IPF.  

PATIENT REPORTED OUTCOMES

What are patient reported outcomes?

None of these tests described above measure symptoms that are often very important and significant to patients, like coughing, fatigue, and breathlessness. It can happen that clinical tests show that lung function is stable and the 6-MWT is stable, but the patient feels quite distressed by daily symptoms. 

Patient reported outcomes usually are questionnaires about symptoms. Some examples are St. George’s Respiratory Questionnaire, The King’s Brief Interstitial Lung Disease Questionnaire, and The University of California San Diego Shortness of Breath Questionnaire.  

Can patient reported outcomes be used to help monitor disease progression?

This question is currently being studied by researchers. Certainly, these questionnaires can show whether symptoms are becoming worse or staying the same over time. Such questionnaires are often used as secondary endpoints in clinical trials of medications for IPF. However, researchers are still working on understanding how patient reported outcomes may track with FVC, DLCO, HRCT, and 6-MWT results.12

References

  1. Selman M, Carrillo G, Estrada A, Mejia M, Becerril C, et al. Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression patternPLoS One. 2007;2(5): e482.
  2. Moore, VC. Spirometry: step by stepBreathe. 2012;8:232-240.
  3. Ley B. Clarity on endpoints for clinical trials in idiopathic pulmonary fibrosisAnn Am Thorac Soc. 2017;14:1383-1384.
  4. Paterniti MO, Bi Y, Rekić D, et al. Acute exacerbation and decline in forced vital capacity are associated with increased mortality in idiopathic pulmonary fibrosisAnn Am Thorac Soc. 2017;14(9):1395-1402.
  5. Doubková M, Švancara J, Svoboda M, et al. EMPIRE Registry, Czech Part: Impact of demographics, pulmonary function and HRCT on survival and clinical course in idiopathic pulmonary fibrosisClin Respir J. 2018;12(4):1526-1535.
  6. Raghu G, Remy-Jardin M, Myers JL, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68.
  7. Gruden JF. CT in idiopathic pulmonary fibrosis: diagnosis and beyondAm J Roentgenol. 2016;206(3):495–507.
  8. Oda K, Ishimoto H, Yatera K, et al. High-resolution CT scoring system-based grading scale predicts the clinical outcomes in patients with idiopathic pulmonary fibrosisRespir Res. 2014;15(1):10. 
  9. Clukers, J., Lanclus, M., Mignot, B. et al. Quantitative CT analysis using functional imaging is superior in describing disease progression in idiopathic pulmonary fibrosis compared to forced vital capacityRespir Res. 2018;19:213.
  10. du Bois RM, Albera C, Bradford WZ, et al. 6-Minute walk distance is an independent predictor of mortality in patients with idiopathic pulmonary fibrosisEur Respir J. 2014;43(5):1421-1429. 
  11. Nathan SD, du Bois RM, Albera C, et al. Validation of test performance characteristics and minimal clinically important difference of the 6-minute walk test in patients with idiopathic pulmonary fibrosisRespir Med. 2015;109(7):914-922.
  12. Moor CC, Heukels P, Kool M, Wijsenbeek MS. Integrating patient perspectives into personalized medicine in idiopathic pulmonary fibrosisFront Med (Lausanne). 2017;4:226.