IDIOPATHIC PULMONARY FIBROSIS

MONITORING THE CLINICAL COURSE OF DISEASE

IPF Prognosis

At Time of Diagnosis(Baseline)

Physiologic• Gas exchange• Desaturation• Pulmonary hemodynamics

Radiologic• HRCT score• HRCT pattern

Pathologic• Pattern• Extent

Follow Up(Dynamic)

Physiologic • Forced vital capacity• Gas exchange• Dyspnea

Clinical Predictors IPF

Age: Poorer prognosis Median survival for patients younger than age 50 years

was more compared with those between 50–60 years,60-70 years and above 70 years1

Sex : More common in men, but sex differences in survival

have been inconsistent

1.Am J Respir Crit Care Med 2001;164:1171–1181.

Clinical Predictors IPF

Ethnicity: Limited data; earlier study suggested higher mortality of

whites compared with blacks

Smoking status: Non-smokers had a higher survival rate than former

smokers and all smokers (current and former)

Am J Respir Crit Care Med 2011;183:431–440.

Clinical Predictors IPF

Dyspnea: MRC chronic dyspnea score and the CRP dyspnea score at baseline and change in score at 6 and 12 months shown to be significant

Physical findings: Digital clubbing significantly associated with reduced survival; BMI has shown an inverse association with survival

Impact of comorbidities: pulmonary hypertension, emphysema, bronchogenic carcinoma, gastroesophageal reflux and significant coronary artery disease may also affect outcome in IPF

Am J Respir Crit Care Med 2011;183:431–440.

Physiologic Predictors

Most consistently associated with prognosis are FVC, TLC, and DLCO

Confounding by obstructive lung disease, especially emphysema

Composite physiologic index : may account for emphysema in IPF combining FVC, DLCO, and FEV1 into a formula that correlates better with disease extent by CT than any individual pulmonary function test ; may be a more accurate predictor of survival

Impact of Baseline FVC and DLCO on Risk of Mortality

Forced Vital Capacity

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

≥ 90 80–89 70–79 60–69 50–59 40–49

0

5

10

15

20

25

35

30

% Predicted FVC

Dea

ths

in P

lace

bo

Gro

up

s (%

)

Diffusion Capacity forCarbon Monoxide

≥ 50 40–49 30–39 20–29 10–19

0

5

10

15

20

25

35

30

% Predicted DLCO

Dea

ths

in P

lace

bo G

roup

s (%

)

Retrospective analysis , n= 168 patients who received placebo as part of a randomized trial evaluating the efficacy of interferon -1b among IPF patients with IPF. DLCO was predictive for death, with a progressive increase in deaths as the predicted DLCO decreased. In contrast, predicted FVC at baseline was not predictive for mortality.

Baseline diffusing capacity at presentation and survival

0

25

50

75

100

0 36

Time (months)

12 24

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

Sur

viva

l (%

)

P = 0.03

N= 104 patients with fibrotic idiopathic interstitial pneumonia (UIP = 63; NSIP = 41). Survival was better in patients with a DLCO of more than 35% predicted (n = 76) than patients with DLCO of less than 35% predicted (n = 28). In the latter group, survival did not differ between UIP and NSIP (P = 0.28).Am J Respir Crit Care Med. 2003;168:531-537.

Survival in relation to the magnitude of serial change in FVC Studies have demonstrated that 6- to 12-month changes

in FVC and DLCO are highly predictive of outcome

Clinically significant changes in FVC and DLCO have typically been considered greater than 10% and greater than 15%, respectively

Even marginal declines in FVC at 6 months (5–10%) are associated with higher risk for mortality

Survival in relation to the magnitude of serial change in FVC at 6 months

Improved indicates an increase in percent predicted FVC of 10 or greater (n = 9). Decline 0–10% indicates that the change in percent predicted FVC was marginal (n = 50), and decline >10% indicates a decrease in percent predicted FVC of 10 or greater (n = 22).

Kaplan-Meier survival estimates for 6-month change in FVC % predicted (n = 79).

FVC may be the most appropriate single prognostic parameter, given its ease of measurement, reproducibility, and ability to predict prognosis at baseline and over time, with even minor changes providing prognostic information

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.

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

N= 41 patients with UIP who remained under follow-up at 12 months relative to serial 12-month changes in total gas transfer (DLCO). Mortality was substantially higher in patients with a change in DLCO of more than 15% compared with those with stable/improved DLCO (P < 0.0005).

(P = 0.0005)

n = 21

n = 20

Time (months)

Stable(Change of less than 2 points)

Improved (Decrease of 2 points or greater)

Declined(Increase of 2 points or greater)

Change in dyspnea score as a dynamic predictor of survival

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 (

%)

Patients with improvement in dyspnea scores had the greatest survival while those with declines in dyspnea scores had the lowest survival. Similar results were obtained for changes in dyspnea scores over 12 months.

Physiologic Predictors: Exercise testing Both distance walked and desaturation during the 6MWT

found to predict mortality, and a composite of the product of distance and desaturation in one study predicted mortality better than either measure alone1

Change in 6MWD is highly predictive of mortality (decline in 6MWD>50 m over 24wk is associated with a fourfold increase in risk of death at 1 year [P , 0.001])2

Abnormal heart rate recovery after 1 minute of rest after the 6MWT may be a novel and powerful predictor of mortality3

1.Respir Med 2006;100:1734–1741.2.Am J Respir Crit Care Med 2010;181:A1103.3. Chest 2009;136:841–848.

Radiographic Predictors

HRCT : overall extent of fibrosis has been consistently shown to correlate with disease severity parameters on pulmonary function tests and prognosis

UIP pattern on HRCT: worse prognosis in patients with IPF compared with those with atypical HRCT findings

Am J Respir Crit Care Med 2008;177:433–439.Thorax 2003;58:143–148.

Survival Time Is Influenced by Both Histologic and HRCT Appearance at Presentation

HRCT Biopsy Median Survival

Definite/probable UIP UIP 2.08 years

Indeterminate UIP or definite/probable NSIP

UIP 5.76 years

Definite/probable NSIP NSIP > 9 years

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

Fibroblastic foci and their quantification has been shown to predict survival

worst prognosis

Biomarker Predictors

Blood B-type natriuretic peptide was shown to be a better predictor of

survival1

Albumin levels negatively correlate with prognosis in many diseases and predict survival2

Circulating fibrocyte levels are elevated in IPF and increase further during acute exacerbations3

Higher Krebs von den Lungen-6 (KL-6 )levels may have reduced survival4

High serum levels of both surfactant proteins A and D (SP-A and SP-D) - increased mortality5

Serum chemokines CCL-18 levels6

1.Respir Med 2009;103:180–186.2.Chest 2009;135:929–935.3.Respir Crit Care Med 2009;179:588–594. 4.Respirology 2006;11:164–168.5.Am J Respir Crit Care Med 1999;160:1843–1850.6.Am J Respir Crit Care Med 2009;179:717–723.

Biomarker Predictors

BAL fluid Neutrophilia in BAL at baseline shown to independently predict 1-year

mortality1

Matrix metalloproteinases (MMPs- 3, 7, 8, and 9) appear to be elevated in both blood and BAL fluid in patients with IPF2

BAL fluid elevated CCL-2, 17, 22 produced by alveolar macrophages, SP-A and SP-D4 shown to be a strong and independent predictor of mortality3

1.Eur Respir J 2009;33:77–84.2.Respiration 2009;78:285–292.3.Chest 2008;133:226–232.4.Am J Respir Crit CareMed 2000;162:1109–1114.

Monitoring Patients with IPF

Every 3 to 6 months monitor for : Worsening Symptoms Worsening Oxygenation (Spirometry, DLco , 6 MWT) Progression of Fibrosis from Baseline on HRCT Complications and Comorbidities

Presence of any of the following changes is consistent with progressive disease:

Am J Respir Crit Care Med 2011; 183:788–824.

Progressive dyspnea (objectively assessed) Progressive, sustained decrease from baseline

in absolute FVC and/or absolute DLCO (corrected for hemoglobin)

Progression of fibrosis from baseline on HRCT Acute exacerbation Death from respiratory failure

Individual predictors of survival in IPF

Am J Respir Crit Care Med 2011; 183: 788–824.

Schematic pathway :clinical management of patients with IPF

Am J Respir Crit Care Med 2011; 183:788–824.

Summary

IPF is a disease of multiple pathways ;combination therapy likely to be most successful.

Clinical predictors useful in describing natural history of IPF, however disease progression remains difficult to predict

FVC may be the most appropriate single prognostic parameter providing prognostic information

Similar to the diagnosis of IPF, prognosis of individual patients will likely best be determined using a multidisciplinary approach

THE END