IPF Natural History andPrognostic Indicators

Learning Objective: Critically evaluate the prognostic indicators used in clinical practice

IPF Prognosis

At Time of Diagnosis(Baseline)

Clinical• Dyspnea

Physiologic• DLCO

• 6MWT desaturation• A-a gradient• Pulmonary hypertension

Radiologic• HRCT pattern

Follow Up(Dynamic)

Physiologic • Forced vital capacity• DLCO

Clinical • Dyspnea

Updated

Baseline Dyspnea

• Turner-Warwick – 220 cases– 4 level dyspnea scale– Survival: mild dyspnea (94 mo) vs moderate/severe

dyspnea (42 mo) (P < 0.03)

• King – 238 cases– 11 level dyspnea scale– Survival: Change of 2 levels associated with

increased hazard (1.23) of death; P = 0.006

Turner-Warwick M, et al.Thorax. 1980;35:171-180.

King TE, et al. AJRCCM. 2001;164:1171-1181.

Mortality According to Baseline Lung Function

King TE, et al. Chest. 2005;127:171-177.

DLco

≥ 50 40–49 30–39 20–29 10–19

% Predicted DLCO

0

5

10

15

20

25

35

30

< 1010–1920–2930–3940–4950–59

0

10

20

30

40

50

60

P(A-a)O2, mm Hg

n = 168

P(A-a)O2FVC

≥ 90 80–89 70–79 60–69 50–5940–49

0

5

10

15

20

25

35

30

% Predicted FVC

Dea

ths

(%)

16

3

33

44

65

7

0

14

42

59

32 2123

31

67

44

3

Baseline Diffusing Capacity at Presentation and Survival

Latsi PI, et al. Am J Respir Crit Care Med. 2003;168:531-537.

0

25

50

75

100

0 36

Time (months)

12 24

DLCO > 35% (n = 76)UIP: DLCO < 35% (n = 12)NSIP: DLCO < 35% (n = 16)

Su

rviv

al (

%)

P = 0.03

Updated

Lama VN, et al. Am J Respir Crit Care Med. 2003;168:1084-1090.

0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

Years

Su

rviv

al P

rob

abili

ty

Desaturators (SaO2 ≤ 88%, n = 44)

P = 0.0018

Nondesaturators (SaO2 > 88%, n = 39)

N = 83

Baseline Desaturation on 6MWT Predicts Decreased Survival in IPF

7431

Mean Pulmonary Artery Pressure: A Predictor of Survival in IPF Patients

Lettieri CJ, et al. Chest. 2006;129:746-752.

1.0

0.8

0.6

0.4

0.2

0.0

0 5

P < 0.001

Yes (mPAP > 25 mm Hg)

No (mPAP ≤ 25 mm Hg)

Years to Event

Cu

mu

lati

ve P

rob

abil

ity

to S

urv

ival

n = 54

n = 25

2 6

Flaherty KR, et al. Thorax. 2003;58:143-148.

Survival

HRCT definite UIP and biopsy UIP 2.1 yearsHRCT indeterminate and biopsy UIP 5.8 years

Baseline HRCT Appearance

Baseline HRCT Findings

• Sumikawa et al– 98 cases of IPF– Quantified various HRCT findings– Traction bronchiectasis and “fibrosis score” associated with

survival (HR 1.3 and 1.1, respectively)• Best et al

– 167 cases of IPF (Interferon beta trial)– Quantified various HRCT findings– Extent of fibrosis (combined reticulation and honeycombing)

associated with survival (HR 1.1)

Sumikawa H, et al. Am J Respir Crit Care Med. 2008;177:433-439.Best AC, et al. Radiology. 2008;246:935-940.

Updated

KL-6 May Predict Survival in IPF

Satoh H, et al. Journal of Internal Medicine. 2006;260:429–434.

Updated

KL-6 ≤ 1000 U/mLKL-6 ≤ 1000 U/mL

• Diffusing capacity for carbon monoxide (DLCO)

• Alveolar-arterial oxygen pressure gradient (P[A-a]O2)

• Desaturation during a 6-minute walk test (SpO2 < 88%)

• Presence of pulmonary hypertension (mPAP > 25 mm Hg)

• Definite IPF pattern on HRCT (fibrosis with honeycomb)

Baseline Factors Associated With Risk of Mortality in IPF

Other Predictors Under Investigation

• Number of fibroblastic foci1-3

• Surfactant proteins A and D4

• Duration of symptoms5

1. King TE, et al. Am J Respir Crit Care Med. 2001;164:1025-1031.2. Nicholson AG, et al. Am J Respir Crit Care Med. 2002;166:173-177. 3. Flaherty KR, et al. Am J Respir Crit Care Med. 2001;164:1722-1727.4. Greene KE, et al. Eur Respir J. 2002;19: 439-446.5. Selman M, et al. PLoS ONE. 2007;2(5): e482:1-11.

Updated

Declined(Decrease in % predicted of ≥ 10)

Dynamic Predictor: Decline in FVC Predicts Mortality

Collard HR, et al. Am J Respir Crit Care Med. 2003;168:538-542.

Stable(Change in % predicted < 10)

Improved (Increase in % predicted of ≥ 10)

Years121086420

0

20

40

60

80

100

Su

rviv

al (

%)

•Data collected every 6 months•Similar characteristics were seen in the 12-month follow up

n = 9

n = 50n = 22

Stable(Change of less than 2 points)

Improved (Decrease of 2 points or greater)

Declined(Increase of 2 points or greater)

Dynamic Predictor: Change in Dyspnea Score

Collard HR, et al. Am J Respir Crit Care Med. 2003;168:538-542.

Years121086420

0

20

40

60

80

100

n = 31

n = 33

n = 15

Similar characteristics were seen in the 12-month follow up

Su

rviv

al (

%)

Stable/improved DLCO

0

25

50

75

100

0 7212 24 36 48 60

Decline in DLCO

Su

rviv

al (

%)

Latsi PI, et al. Am J Respir Crit Care Med. 2003;168:531-537.

Mortality was substantially higher in patients with decrease in DLCO of more than 15%

(P = 0.0005)

n = 21

n = 20

Time (months)

Dynamic Predictor: Change in Diffusing Capacity (DLCO) at 12 Months

Prognostic Utility

Baseline (Severity)

Dynamic (Progression)

Dyspnea + +

FVC % +

DLCO % + +

A-a gradient +

6MWT – desaturation ( 88%) +

Pulmonary arterial pressure +

HRCT pattern +

Predicting Disease Progression

• While clinical predictors are useful in describing the natural history of IPF, disease progression in individuals remains difficult to predict

• Nearly half of the deaths in a large prospective randomized trial occurred prior to evidence of disease progression

Raghu G, et al. N Engl J Med. 2004;350:125-133.

Clinical Progression of IPF

Traditional View: Slow Decline

Emerging Paradigm: Heterogeneous Progression

Early Disease

Late Disease

Asymptomatic

Sta

te o

f H

ea

lth

Healthy

Sick

Time

Lu

ng

Fu

nc

tion

Normal

Low

Years

Acute Exacerbation

Slow Decline

Rapid Decline

Kim DS, et al. Proc Am Thoracic Soc. 2006;3:285-292.

Re

sp

ira

tory

F

un

cti

on

/Sy

mp

tom

s

0 1 2 3 4

Proposed Definition for Acute Exacerbation of IPF

• Acute, clinically significant deterioration of unidentifiable cause in a patient with underlying IPF

• Diagnostic criteria:– Previous or concurrent diagnosis of IPF– Unexplained worsening or development of dyspnea within 30 days– High-resolution computed tomography with new bilateral ground-glass

abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with UIP pattern

– No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage

– Exclusion of alternative causes, including the following:• Left heart failure• Pulmonary embolism• Identifiable cause of acute lung injuryx

• Patients with idiopathic clinical worsening who fail to meet all five criteria due to missing data should be termed ‘‘suspected acute exacerbations.’’

Collard HR, et al. Am J Respir Crit Care Med. 2007;176:636–643.

Radiograph of Acute Exacerbation

Images courtesy of Jeffrey A. Golden, MD.

Updated

Stable Acute Exacerbation

Low Magnification of AE Shows UIP

Image courtesy of Kirk Jones, MD.

CL

HCF

CL

Updated

Histopathology of Acute Exacerbation

Image courtesy of Kirk Jones, MD.

af

Histopathology of Acute Exacerbation

Image courtesy of Kirk Jones, MD.

HM

Take Home Messages

• Baseline factors associated with an increased risk of mortality– Low DLCO

– A-a gradient– Desaturation during a 6MWT (SpO2 < 88%)– Pulmonary arterial hypertension (mPAP > 25 mm Hg)– Honeycombing on HRCT

• Dynamic predictors of mortality– FVC – DLCO

– Dyspnea

• Prognostic indicators do not fully predict the course of disease for an individual patient