idiopathic pulmonary fibrosis (ipf) - … · 2 idiopathic pulmonary fibrosis (ipf) most common...

1

Joseph P. Lynch, III, MD, FCCP, FERS

Holt and Jo Hickman Endowed Chair ofAdvanced Lung Diseases and Lung Transplantation

Professor of Clinical Medicine, Step IX

Division of Pulmonary & Critical Care Medicine, Clinical Immunology and Allergy

The David Geffen School of Medicine at UCLA

Idiopathic Pulmonary Fibrosis (IPF)

Disclosures (2018): speaker fees (Genentec)

Interstitial Lung Disease

Clinical features:

Cough

Dyspnea

Restrictive PFTs (low VC, TLC)

2

Idiopathic pulmonary fibrosis (IPF)

Most common interstitial lung disease

Usual interstitial pneumonia (UIP)

pattern on surgical lung biopsy

Nonspecific Interstitial Pneumonia

• Clinical features overlap with IPF

• Much better response to therapy

• Need surgical lung Bx to diagnose

• Distinguishing IPF from

NSIP and other ILDs

important since prognosis

and treatment differ

3


• Affects older adults (> 55 y)

Progression inevitable

• Mortality > 70% at 5 years

Years

Survival: UIP, NSIP, other ILDs

0 2 4 6 8 10 12 14 16 18

0

20

40

60

80

100

UIP

NSIP

Other ILD

Survival %

Mayo Clinic

Bjoraker, AJRCCM, 1998:157;199

4

Survival in UIP, NSIP and RBILD

RBILD

NSIP

UIP

Flaherty, Eur Respir J 2002;19;275

Survival in UIP and NSIP

Nicholson, AJRCCM 2000; 162: 2213

Brompton, UK

5

Interstitial Lung Diseases

> 150 causes

Infectious (TB, fungi, PCP)

Environmental (HP, metals; drugs)

Connective Tissue Disease (CTD)

Idiopathic (IPF, LIP, OP, sarcoidosis)

Interstitial Lung Disease

Laboratory evaluation

Serologies for CTD

Hypersensitivity pneumonia

Infection (PPD, histo, cocci IgG, IgM)

6

Environmental History

• Exposures (work, home, hobbies)

• Toxins, irritants (drugs, chemicals)

• Cigarette smoking (LCH; DIP, RB)

Drugs may cause pulmonary toxicity

Amiodarone

Methotrexate

Nitrofurantoin

Sulfasalazine

Chemotherapy

(Bleomycin; busulfan)

Pneumoconioses

Beryllium

Silica

Hard metals (cobalt, tungsten carbide)

Asbestos

7

IPF: Differential Diagnosis

Connective Tissue Disease

Pneumoconiosis

Chronic Hypersensitivity Pneumonia

Pulmonary Complications of CTD

• Interstitial Lung Disease may affect all CTDs

• Histological patterns same as idiopathic IPs

• Multiple patterns may be observed

8

Distinguishing IPF from other ILDs

Thin section HRCT scans

Surgical (VATS) Lung Biopsy

Interstitial Lung Disease (ILD)

Surgical lung biopsy essential to diagnose some ILDs (e.g., NSIP, HP)

Thin-section HRCT (1-2 mm) can diagnose some, but not all, cases IPF

Interstitial Lung Disease (ILD)

Thin-section (1-2 mm) HRCT in some cases may be pathognomonic

(e.g., IPF with honeycombing)

9

Honeycomb cysts (UIP)

Epidemiology of Idiopathic

Pulmonary Fibrosis (IPF)

Idiopathic Pulmonary Fibrosis

Primarily affects elderly

Not seen in children

10

Prevalence IPF according to age

3

177

0

20

40

60

80

100

120

140

160

180

200

35-44 75+

pre

vale

nce

pe

r 100

,000

Coultas, AJRCCM 1994:150;967

New Mexico

Age (years)


4

227

0

50

100

150

200

250

18-34 75+

pre

vale

nce

pe

r 100

,000

Raghu, AJRCCM 2006:174;810

USA (1996-2000)

Age (years)


1.12.6

6.4

19.3

0

5

10

15

20

25

18-34 35-44 45-54 55-64

pre

va

len

ce p

er

10

0,0

00

Raghu, Eur Respir J 2016:48;179

USA (2004-2010) age 18-64 (> 40 million adults

Age (years)

11

Deaths due to IPF according to age

1.8 7.1

30.6

82.7

138

0

20

40

60

80

100

120

140

160

45-54 55-64 65-74 75-84 85+

de

ath

s/1

00,0

00

Olson, AJRCCM 2007:176;277

USA (1992-2003)

Age (years)

IPF: incidence and Prevalence > 65 years

93.7 93.7

202

495

0

100

200

300

400

500

2001 2011

incidence

prevalenceper

100,000

Raghu, Lancet Respir Med 2014:2;566

Medicare (5%), USA (2001-2011)

Median age newly diagnosed IPF was 79.4 years

Risk Factors for IPF

Age (predominantly elderly)

More common in males

Genetic (familial)

Chu, Semin Respir Crit Care Med 2016:37;321

12


Familial IPF

0.5 to 10% of cases of IPF

No clear genetic mutation

Isolated mutations in kindreds

Familial IPF: Mutations

Surfactant protein C and A

Mucin genes (MUC5B)

Telomerase (hTERT and hTR)


Risk Factors for IPF

Smoking

Occupational (dusts, metals, sand)

Gastroesophageal reflux (?)


13

IPF: Histology

• Usual Interstitial Pneumonia

(UIP pattern)

Usual Interstitial Pneumonia (UIP)

• Heterogeneity

• Fibroblastic foci

• Honeycombing

14

Transition to uninvolved lung present in the biopsy

Pathology of UIP/IPF

Fibroblastic focus-high power

15

• Distinguishing IPF from

NSIP and other ILDs

important since prognosis

and treatment differ

Chronic Interstitial Lung Disease

5

106

28

5

22

-10

10

30

50

70

90

110

IPF fibrotic NSIP cellular NSIP RBILD/DIP HP

Flaherty, Eur Respir J 2002:19;276

(U of Michigan) Surgical Lung Bx (n=169) 1989-2000

#

Prognosis of IPF/UIP and Other ILDs

Surgical biopsies n=169 (U Mich, 1989-2000)

Histological UIP most important feature determining mortality

UIP/IPF RR mortality 28.5 compared to other ILDs (p < 0.001)

Flaherty, Eur Respir J 2012:19;276

16

• Surgical (VATS) lung biopsy

is required to diagnose NSIP

Nonspecific interstitial pneumonia

Histological criteria for NSIP:

Temporal homogeneity

(lesions of same age)

Lacks features of other IIPs

(UIP, AIP, DIP/RBILD)


Cellular and fibrotic types

Fibrotic worse prognosis

17

Honeycombing

18

Can CT distinguish

IPF from NSIP?

UIP/IPF: HRCT Features

Patchy, heterogeneous

Lower lobes, subpleural

Reticular (linear) lines

Honeycomb cysts

Ground glass minimal or absent

19

Honeycomb cysts (UIP)

CT criteria (IPF vs NSIP)

Key discriminatory elements:

Honeycombing

Ground glass opacities

“Typical” CT (i.e., with

honeycombing) is specific

for UIP/IPF and eliminates

need for surgical lung biopsy

20

HRCT appearance vs survival

Su

rviv

al

(%)

Time from presentation (years)

Daniil, AJRCCM 1999;160:899

CT “atypical” of IPF

CT “typical” of IPF

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6 7

Honeycombing reflects:

more advanced disease

worse prognosis

Honeycomb change in any

lobe (CT-fib > 2) associated

with higher mortality

168 cases IIP (U Mich)

Flaherty, Eur Resp J 2002:19;276

21

CT fib > 2 worse survival

All lobes < 2

At least one lobe > 2

Flaherty Eur Respir J 2002:19;275

168 cases IIP (U Mich)

Honeycombing

No honeycombing

NSIP and IPF Overlapping Features

Distinguishing fibrotic NSIP

from IPF is difficult

Treatment differs (NSIP vs IPF)

Nonspecific Interstitial Pneumonia (NSIP)

• Immunosuppressive therapy and/or prednisone may be effective, particularly in cellular variants of NSIP

22


• Immunosuppressive therapy or prednisone not effective for IPF and may be harmful


• Median survival ~ 4 yrs

• Medical therapy (anti-fibrotic agents) marginally effective

• ? survival advantage

23

CT criteria (IPF vs NSIP)

Ground glass opacities

strongly favor NSIP


24

HRCT scan: NSIP vs IPF

IPF NSIP

Honeycombing +++ +/-

Ground glass +/- +++

IPF and NSIP

Discriminatory features

• Age

HRCT (GGO vs HC)

25

IPF and NSIP

Discriminatory features

• Older age favors IPF

Honeycombing (IPF)

Discriminating IPF from other ILDs

UIP (n=97); other ILD (n=38) (1995-2006)

No honeycombing on HRCT

No connective tissue disease

All had surgical lung biopsy

Fell, AJRCCM 2010:181;832

Discriminating IPF from other ILDs

Age and extent CT interstitial

score most predictive of IPF

Gender, desaturation, distance

walked on 6MWT, PFTs did not

discriminate IPF from other ILD


26

Age Powerful Predictor of IPF

Age > 70 yrs, > 95% had IPF

Age > 75 yrs, 100% had IPF


“Atypical” CT patterns are

non-specific; could represent

IPF or NSIP or other ILDs

• Need surgical lung biopsy

Surgical Lung Biopsy

22,000 SLB in USA for ILD (2000-2011)

Mortality (in-hospital):

1.7% (elective)

16.0% (non-elective)

Hutchinson, AJRCCM 2016 (May 15);1161

27

Surgical (VATS) Lung Biopsy

Risk excessive if advanced

age or unstable or high 02

requirements


•Clinical course

•Prognostic factors

•Best parameters to follow


• Median survival ~ 4 yrs

• Medical therapy (anti-fibrotic agents) marginally effective

• ? survival advantage

28


• immunosuppressive agents

or steroids are not beneficial

• Lung Transplant Best Option

Therapy for IPF

Early referral for lung transplant

May lose “window for transplant”

29

•IPF: course highly variable

and unpredictable

IPF: Pulmonary Function Tests

Serial PFTs 3-4 months

Spirometry, DLCO

6-minute walk tests

Course may be fulminant even

after initial indolent progression

PFTs may be stable for prolonged

periods

Acute exacerbations may be fatal

30

Increased Mortality if:

• Older age

Severe impairment PFTs

Hypoxemia

Honeycombing on CT

Pulmonary hypertension

PFTs in IPF: Prognostic Significance

• Not surprisingly, severe

impairment or decline in FVC,

DLCO, oxygenation, or 6MWD

predicts worse mortality

Changes in FVC at 6 months

IPF (n=80); NSIP (n=29) (U Mich)

> 10% decline FVC at 6 months

independent predictor mortality

(HR 2.47)

Flaherty, AJRCCM 2003:168;543

31

Serial PFTs Predict Prognosis

IPF (n=81) (Denver)

> 10% decline FVC at 6 or 12 mo

assoc with higher mortality

Collard, AJRCCM 2003:168;538

Serial PFTs Predict Prognosis

IPF (n=131); NSIP (n=48) (Korea)

> 10% decline FVC at 6 mo

best predictor of mortality

Jegal, AJRCCM 2005:171;169

• Declining FVC warrants

consideration for lung transplant

• However, fatalities can occur

even with prolonged stability

32

0

10

20

30

40

50

60

70

80

90

100

Jan-

06

May

-06

Sep-0

6

Jan-

07

May

-07

Sep-0

7

Jan-

08

May

-08

Sep-0

8

Jan-

09

May

-09

Sep-0

9

Jan-1

0

May

-10

FVC % pred

FEV1 % pred

DLCO % pred

SLT

68 m MK

Complications of IPF

•Acute exacerbations of IPF

•Pulmonary Hypertension

•Lung cancer (5-15%)

Acute Exacerbations of IPF

Incidence 19-35% < 2 years

Resembles ARDS

Diffuse lung damage (DAD)

Ground glass opacities (CT)

33

Risk Factors for AE-IPF

More severe disease

Prednisone or IS therapy

Winter months

Pulmonary hypertension

Thoracic surgery (VATS)

34

? Cause for AE-IPF

? Infection (viral)

AE- IPF: Treatment

Optimal treatment not clear

Randomized trials lacking

? value of steroid therapy

Song, Eur Respir J 2011:39;357

Prognosis of AE-IPF

56.2

18.510

0

10

20

30

40

50

60

70

80

90

100

1-year 5-year

surv

iva

l (%

)

all

requiring MV

AE-IPF, Korea (n=163)

Song, ERJ 2011:39;357

35

Severe AE-IPF

Prognosis if require MV

poor (> 90% mortality)

Unless on lung transplant

list, consider DNI/DNR

IPF-associated PAH

Pulmonary Hypertension

• PAH in 28-84% of patients with advanced IPF

• PAH markedly worsens survival

36

Pulmonary hypertension in IPF

• 2-D echo to assess sPAP

• ? If treatment of PAH affects

outcome

• Anecdotal responses to PAH-

specific agents but RCT lacking

PAH due to lung disease

• PAH-specific therapy may

have role in patients with

severe PAH as a bridge to

lung transplantation

Shino, Semin Respir Crit Care Med (Oct 2013)


•Medical Treatment

•Lung Transplant

37


• Course and “pace” of disease

highly variable

• Lung transplant 1st line but only

for selected patients

• Who should receive novel agents?

Treatment of IPF

• High dose prednisone was

standard of care for > 40 years

despite no evidence for benefit


• Despite lack of randomized,

placebo-controlled trials,

prednisone + azathioprine used

for more than 3 decades

38

Azathioprine for IPF

PANTHER Study (IPFnet)

terminated early (Oct 2011) due to

higher mortality and morbidity in

AZA + prednisone + NAC arm

N Engl J Med (May 24, 2012):366:1968

PANTHER STUDY: IPF

8

23

5

1

7

00

5

10

15

20

25

Mortality Hospitalizations AE

#

AZ + pred + NAC (n=77)

placebo (n=78)

N Engl J Med 2012:366:1968

39

Therapy of IPF

Other immunosuppressive agents unlikely to be efficacious

e.g., mycophenolate mofetil

IPF: which target?

• Multiple “targets” (cells,

cytokines, inflammation, fibrosis)

• Mechanisms of injury and fibrosis

overlap and redundant

• Pirfenidone (Esbriet)

• Nintedanib (Ofev)

FDA Approved Oct 15, 2014

40

Treatment of IPF

• In clinical trials, pirfenidone

and nintedanib slow rate of

decline but differences small

(DFVC 2-4%) at 1 yr

Pirfenidone for IPF

CAPACITY I (006) (n=344)

• pirfenidone (oral) vs placebo

CAPACITY II (004) (n=435)

Noble, Lancet 2011:377:1760

Pirfenidone for IPF

• No difference survival, DLCO,

6MWT, D02 sat

• Less decline FVC at 72 weeks

[Capacity II (004); not Capacity I (006)]

41

CAPACITY (004 + 006): DFVC 72 wks

-9-8

-8.5-9.6

-12.4

-11

-14

-12

-10

-8

-6

-4

-2

0

DF

VC

(%

) at

72

wee

ks

pirfenidone

placebo

Noble, Lancet 2011:377;1760

006 (n=344) 004 (n= 435) Pooled pirfen 2403

Pirfenidone for IPF

ASCEND Trial (52 wks):

Primary end-point:

disease progression

(D FVC > 10% or death)

King, N Engl J Med May 29, 2014

Pirfenidone for IPF

Pirfenidone 2403 mg/day (n=278)

Placebo (n=277)

King, N Engl J Med 2014:370;2083

42

Pirfenidone (ASCEND) Study

16.5

4

31.8

7.2

0

5

10

15

20

25

30

35

Decline FVC > 10% Death

%

pirfenidone(n=278)

placebo(n=277)

King, N Engl J Med 2014:370;2083

p = 0.1

p < 0.001

52 weeks

Pirfenidone Trials (IPF)

2023

16.5

35

27

31.8

0

5

10

15

20

25

30

35

40

pirfen 004 (72 wk) pirfen 006 (72 wk) NEJM 2014 (1 yr)

DF

VC

(%

) pirfenidone

placebo

> 10% decline FVC

Pirfenidone for IPF

• Slows rate of progression

• Impact on mortality uncertain

43

• Nintedanib (Ofev)

• Tyrosine kinase inhibitor

Nintedanib for IPF

Nintedanib 150 mg bid or placebo

52 weeks; change FVC

IMPULSIS-1 (n=511)

IMPULSIS-2 (n=544)

Richeldi, N Engl J Med 2014:370:2072

44

Nintedanib for IPF

Primary endpoint:

• D FVC at 52 weeks

Richeldi, N Engl J Med, May 29, 2014

Nintedanib: DFVC 52 wks

-2.8-3.1

-6 -6.2-7

-6

-5

-4

-3

-2

-1

0

DF

VC

(%

) at

52

wee

ks

nintedanib

placebo

Richeldi, N Engl J Med 2014:370;2072

Impulsis-1 Impulsis-2

Nintedanib: DFVC 52 wks

29.4 30.4

43.1

36.1

0

5

10

15

20

25

30

35

40

45

50

DF

VC

(>

10%

dec

lin

e)

nintedanib

placebo


Impulsis-1Impulsis-2

45

Nintedanib: Mortality 52 wks

5.5

7.8

0

1

2

3

4

5

6

7

8

9

mor

tali

ty %

nintedanib

placebo


p=0.14

Impulsis-1 + 2

RJ

46

Lung transplant for IPF

• Survival post-LT worse

in IPF compared to

other diagnoses

(may reflect age, comorbidities)

Yusen, J Heart Lung Transplant Oct 2013 :32(10)

Survival by Diagnosis (Jan 1990-June 2011)

47

Single or Bilateral Transplant?

• Bilateral lung transplant for IPF,

but not COPD, confers modest

improvement in survival


USA, LT (adults) May 2005-Dec 31, 2012:

• IPF (n=4,134) (SLT in 49%)

• COPD (n=3,174) (SLT in 41%)

Schaffer, JAMA 2015:313;936


After controlling for confounders,

BLT better survival than SLT in IPF

but not in COPD

Schaffer, JAMA 2015:313;936

48

Single or Bilateral LT?

50.4

6465.2 67.7

0

10

20

30

40

50

60

70

IPF COPD

surv

ival (

month

s)

SLT BLT

Schaffer, JAMA 2015;313;936

USA, 5/05 -12/31/12p=0.23p < 0.001

Lung Transplant for Elderly

ISHLT Guidelines (2006)

• Age > 65 “relative

contraindication” to LT

Orens, JHLT 2006:25;745

Survival by LT Recipient Age (Adults)

J Heart Lung Transplant Oct 2013

Jan 1990-June 2011

49

Lung Transplant for Elderly

UNOS, 1999-2006

8,363 adult LT recipients

Mortality (30 d, 90 d, 1-yr)

Weiss J Am Coll Surg 2009:208;400

Lung Transplantation

9.5 9.5 8.9 9.3

27

17.2 17.2 18.721.4

42

0

5

10

15

20

25

30

35

40

45

18-45y 46-55 y 56-60 y 61-69 y 70+

% m

ort

alit

y

90-day

1-year

Weiss, J Am Coll Surg 2009;208;400

Age as predictor of mortality

idiopathic pulmonary fibrosis (ipf) - … · 2 idiopathic pulmonary fibrosis (ipf) most common...

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