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Disease Course of IPF

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About IPF: Disease course

The disease course is unpredictable in patients with IPF

The disease course of IPF is heterogeneous and difficult to predict but typically involves progressive deterioration of lung function that may have periods of sudden decline1-5 

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
3. Martinez FJ et al. Ann Intern Med. 2005;142(12 Pt 1):963-967.
4. King TE et al. Am J Respir Crit Care Med. 2001;164(7):1171-81.
5. Selman M et al. PLoS One. 2007;2(5):e482.

IPF has multiple forms

The clinical course of IPF may take several forms1,5:
  • Slow physiologic worsening with increasing severity of dyspnea (slowly progressive course)
  • Rapid onset of symptoms and progression to death (rapidly progressive course)
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
5. Selman M et al. PLoS One. 2007;2(5):e482.

Slowly progressive IPF

  • The clinical course for many patients is defined by a relatively slow decline in lung function1 
  • Patients may experience symptoms, which typically include nonproductive cough and increasing dyspnea, for months or years before they see a physician2,6-7

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
6. Kim DS et al. Proc Am Thorac Soc. 2006;3(4):285-292.
7. ATS. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.

Rapidly progressive IPF

A subgroup of patients exhibit a rapidly progressive course and have shortened survival compared with patients on a slowly progressive clinical course5
 
Risk factors for rapidly progressive IPF5

5. Selman M et al. PLoS One. 2007;2(5):e482.

Rapid and slow forms of IPF look the same on diagnosis

At diagnosis, there are no distinguishing clinical characteristics between patients with the accelerated variant of IPF and those with the more common slowly progressive form5
 
5. Selman M et al. PLoS One. 2007;2(5):e482.

Gene expression profiles may offer a way to differentiate the various disease courses

One study that evaluated patients’ gene expression profiles found that accelerated disease was associated with upregulation of many genes5

morphogenesis
oxidative stress
cell proliferation
Cancer-associated genes
cell migration
apoptosis
fibroblast genes
smooth muscle cell genes

5. Selman M et al. PLoS One. 2007;2(5):e482.

Acute exacerbations can accelerate disease progression

  • Patients with IPF may experience periods of relative stability interspersed with periods of acute decompensation2,8
  • Acute exacerbations are associated with disease progression and increased risk of mortality9,10
  • See About IPF: Acute Exacerbations section for more detailed information

2. Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
8. Collard HR et al. Am J Respir Crit Care Med. 2007;176(7):636-643.
9. Song JW et al. Eur Respir J. 2011;37(2):356-363.
10. Kondoh Y et al. Sarcoidosis Vasc Diffuse Lung Dis. 2010;27(2):103-10.

Defining disease progression

The following changes are considered signs of disease progression in IPF1:

Progressive dyspnea (objective assessment)
Progression of fibrosis from baseline on HRCT
Death from respiratory failure
Progressive, sustained decrease from baseline in absolute DLco
Progressive, sustained decrease from baseline in absolute FVC
AE-IPF

FVC, forced vital capacity; HRCT, high-resolution computed tomography; DLco, diffusing capacity of carbon monoxide; AE-IPF, acute exacerbation of IPF.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

Clinical assessment is the most common way to monitor progression in patients with IPF

Changes in patients’ symptoms are the clearest way to mark a worsening of disease1

These symptomatic deteriorations are generally accompanied by reduced physiologic measurements1

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

HRCT is not commonly used to monitor disease progression

  • There are no official recommendations for routine HRCT scans to monitor IPF progression1
  • Repeat HRCT scans are generally performed at the discretion of the patient’s pulmonologist1
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

However, repeat HRCT scans can confirm disease progression

  • Worsening on HRCT has been correlated with increased mortality11-15
  • A patient who presents with worsening breathlessness can undergo HRCT to confirm disease progression or AE-IPF, as well as exclude other causes of dyspnea (eg, pneumonia, pneumothorax)1,16 
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
11. Shin KM et al. Radiology. 2008;249(1):328-337.
12. Sumikawa H et al. Am J Respir Crit Care Med. 2008;177(4):433-439.
13. Ambrosini V et al. Eur Respir J. 2003;22(5):821-826.
14. Akira M et al. AJR Am J Roentgenol. 1997;168(1):79-83.
15. Kim DS et al. Eur Respir J. 2006;27(1):143-150.
16. Collard HR et al. Am J Respir Crit Care Med. 2016;194(3):265-275.

Clinical trials often use surrogate endpoints to measure disease progression

Surrogate endpoints for all-cause mortality allow for smaller samples size to show benefit17
 
Surrogate Endpoints
  • Decline in FVC
  • Time to acute exacerbation
  • 52-week mortality
17. Raghu G et al. Am J Respir Crit Care Med. 2012;185(10):1044-1048.

Questionnaires are a surrogate marker of disease progression in clinical trials

Clinical trials often use questionnaires focused on patient symptoms to define disease progression, although their utility in clinical practice is not established18,19
 
18. Saketkoo LA et al. Thorax. 2014;69(5):428-436.
19. Bajwah S et al. Thorax. 2013;68(9):867-879.

Endpoints used in clinical trials may not be appropriate for evaluating IPF in the clinic

While certain parameters appear to be clinically useful, there is still significant debate as to which endpoints are appropriate for patients with IPF17
 
17. Raghu G et al. Am J Respir Crit Care Med 2012;185(10):1044-1048.

Patient-reported outcomes are not prognostic in IPF

Although evidence-based, patient-reported outcome measures of symptoms are prognostic in some other respiratory diseases, these measures have not been validated in IPF17
 
17. Raghu G et al. Am J Respir Crit Care Med 2012;185(10):1044-1048.

Predicting outcomes in IPF should focus on noting changes to patients’ physiology and symptoms

The following changes correlate with poor outcomes for individual patients9,10,20-22
 
Episode(s) of AE-IPF9,10
Desaturation during 6MWT (≤88%)20
Decreased FVC (≥10%)*21,22
Decreased DLco (≥15%)*22

*Recommended by ATS/ERS/JRS/ALAT.
6MWT, 6-minute walk test.

9. Song JW et al. Eur Respir J. 2011;37(2):356-363.
10. Kondoh Y et al. Sarcoidosis Vasc Diffuse Lung Dis. 2010;27(2):103-110.
20. Lama VN et al. Am J Respir Crit Care Med. 2003;168(9):1084-1090.
21. du Bois RM et al. Am J Respir Crit Care Med. 2011;184(12):1382-1389.
22. Zappala CJ et al. Eur Respir J. 2010;35(4):830-836.

Tracking these changes can facilitate appropriate timing of discussions regarding disease management

Discussions may include1:
  • Lung transplantation
  • Supplemental oxygen therapy
  • Palliative care
  • Hospice referral 
 1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.

Nothing can currently predict mortality in IPF

No agreed-upon, evidence-based, surrogate endpoints for all-cause mortality exist for IPF17

17. Raghu G et al. Am J Respir Crit Care Med. 2012;185(10):1044-1048.

An algorithm may help predict IPF-related mortality

  • The GAP model was developed using competing risks regression modeling23
  • Potential predictive variables were evaluated retrospectively in a cohort of 228 patients with IPF23  
GAP, gender-age-physiology.

23. Ley B et al. Ann Intern Med. 2012;156(10):684-691.

The GAP point-score model assigns values to subgroups of 4 categories

23. Ley B et al. Ann Intern Med. 2012;156(10):684-691.

Survival decreases with GAP stage

23. Ley B et al. Ann Intern Med. 2012;156(10):684-691.

Summary

  • IPF has a heterogeneous disease course that may be slowly progressing or rapidly progressing2,5
    • Acute exacerbations can cause rapid acceleration of disease progression9,10
  • Disease progression is generally monitored by clinical assessment of a patient’s symptoms1
  • Mortality in IPF is hard to predict1
    • However, certain factors are associated with poor patient outcomes23
1. Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2. Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
5. Selman M et al. PLoS One. 2007;2(5):e482.
9. Song JW et al. Eur Respir J. 2011;37(2):356-363.
10. Kondoh Y et al. Sarcoidosis Vasc Diffuse Lung Dis. 2010;27(2):103-110.
23. Ley B et al. Ann Intern Med. 2012;156(10):684-691.

References

1.Raghu G et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
2.Ley B et al. Am J Respir Crit Care Med. 2011;183(4):431-440.
3.Martinez FJ et al. Ann Intern Med. 2005;142(12 Pt 1):963-967.
4.King TE et al. Am J Respir Crit Care Med. 2001;164(7):1171-1181.
5.Selman M et al. PLoS One. 2007;2(5):e482.
6.Kim DS et al. Proc Am Thorac Soc. 2006;3(4):285-292.
7.ATS. Am J Respir Crit Care Med. 2000;161(2 Pt 1):646-664.
8.Collard HR et al. Am J Respir Crit Care Med. 2007;176(7):636-643.
9.Song JW et al. Eur Respir J. 2011;37(2):356-363.
10.Kondoh Y et al. Sarcoidosis Vasc Diffuse Lung Dis. 2010;27(2):103-110.
11.Shin KM et al. Radiology. 2008;249(1):328-337.
12.Sumikawa H et al. Am J Respir Crit Care Med. 2008;177(4):433-439.
13.Ambrosini V et al. Eur Respir J. 2003;22(5):821-826.
14.Akira M et al. AJR Am J Roentgenol. 1997;168(1):79-83.
15.Kim DS et al. Eur Respir J. 2006;27(1):143-150.
16.Collard HR et al. Am J Respir Crit Care Med. 2016;194(3):265-275.
17.Raghu G et al. Am J Respir Crit Care Med. 2012;185(10):1044-1048.
18.Saketkoo LA et al. Thorax. 2014;69(5):428-436.
19.Bajwah S et al. Thorax. 2013;68(9):867-879.
20.Lama VN et al. Am J Respir Crit Care Med. 2003;168(9):1084-1090.
21.du Bois RM et al. Am J Respir Crit Care Med. 2011;184(12):1382-1389.
22.Zappala CJ et al. Eur Respir J. 2010;35(4):830-836.
23.Ley B et al. Ann Intern Med. 2012;156(10):684-691.

See the GAP Model for Predicting Mortality Risk