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NAVIGATING the NEW ERA in IPF:
Comorbidities and Complications
FACULTY
Title
Affiliation
Learning Objectives
• Identify approaches to IPF management that
are covered in current guidelines, taking into
account the strength of relevant
recommendations
• Formulate a plan, based on available data and
expert consensus, for addressing acute
exacerbations of IPF
• Explain the impact and treatment of common
comorbidities of IPF
Common Complications and
Comorbidities of IPF
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•
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•
GERD
Pulmonary hypertension
Emphysema
Acute exacerbation
OSA
CVD and Thromboembolism
Depression
IPF and GERD
Lee JS, et al. Am J Med. 2010;123(4):304-311.
Gastroesophageal Reflux Disease (GERD)
• Definition: Symptoms or complications resulting
•
•
•
•
•
from the reflux of gastric contents into the
esophagus or beyond, into the oral cavity
(including larynx) or lung
Risk factor for IPF
Common in patients with IPF
– Clinically silent in the majority of cases
May have nonacid components (alkaline GERD)
Etiology unknown
Contribution to IPF pathology unknown
Katz PO, et al. Am J Gastroenterol. 2013;108(3):308-328.
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
GERD
• Diagnosis
– Barium swallow
– Esophageal manometry
– 24 hour pH probe
• Treatment
– PPI’s
– Nissen fundoplication
• WRAP-IPF trial
• ClinicalTrials.gov: NCT01982968
Raghu G, et al. Eur Respir J. 2006;27:136-142.
GERD Prevalence
•
•
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•
1.
2.
3.
4.
Normal: 10-20%1
IPF: 90%2
COPD: 60%3
Cystic Fibrosis: 35 to 81%4
Katz PO, et al. Am J Gastroenterol. 2013;108(3):308-328
Raghu G, et al. Eur Respir J. 2006;27,136-142.
Kempainen RR, et al. Chest. 2007; 131:1666-1671.
Robinson NB, et al. Ann Am Thorac Soc. 2014;11(6):964-968.
GERD
Distal % Reflux Time ln
• Acid GERD prevalent in IPF (87%)
• 47% experience classic GERD symptoms
• GERD and IPF severities not correlated:
DLCO
FVC
% Predicted
% Predicted
Raghu G, et al. Eur Respir J. 2006;27:136-142.
GERD Treatment and Survival
Survival
Taking GERD
medications
Not taking
GERD
medications
Time to Event (days)
Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):1390-1394.
ATS/ERS Recommendation
• The recommendation for the treatment of
asymptomatic GER in patients with IPF is weak
• Asymptomatic GER should be treated in the
majority of patients with IPF, but not treating
asymptomatic GER may be a reasonable choice
in a minority ()*.
* () = GRADE quality of evidence very low
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
IPF With Severe PH
mPAP = 61 mmHg
Prevalence of PH in IPF
Hamada (2007)
Raghu (2010)
Patel (2007)
Song (2009)
Nathan (2007)
Zisman (2007)
Shorr (2007)
Minai (2009)
Nadrous (2005)
Nathan (2008)
RHC
Echo
at evaluation
at transplantation
Estimate of PH Prevalence, %
Nathan SD, Cottin V. Eur Respir Monogr. 2012;57:148–160.
Distribution of mPAPs in IPF Patients
25
Frequency
20
15
10
5
0
10.00
20.00
30.00
40.00
50.00
mPAP
Lettieri et al. Chest 2006. 129:746-752
PAH: mPAP > 25 mm Hg
Mean Pulmonary Artery Pressure:
Prognostic Value in IPF
Cumulative Probability to Survival
1.0
n = 54
No (mPap ≤ 25 mm Hg)
0.8
n = 25
0.6
Yes (mPap > 25 mm Hg)
0.4
0.2
0.0
P < 0.001
0
1
Lettieri CJ, et al. Chest. 2006;129:746-752.
2
3
4
Years to Event
5
6
7
PH in IPF: Impact on 6MWT
mPAP < 25 mm Hg
(N=24)
mPAP > 25 mm Hg
(N=10)
P value
366 ± 82
144 ± 66
< 0.001
88 ± 4
80 ± 4
< 0.001
mPAP ≤ 25 mm Hg
(N=27)
mPAP > 25 mm Hg
with normal PCWP
(N=7)
P value
402 ± 25
210 ± 50
0.002
6MWD (m)
SpO2 nadir (%)
Lettieri CJ, et al. Chest. 2006;129:746-752.
6MWD (m, adjusted for
FVC%)*
Patel NM, et al. Chest. 2007;132(3):998-1006.
When to Suspect PH in IPF
• PFTs
– DLCO <40%
• 6MWT
– SpO2 ≤ 88%
– Heart rate recovery at 1 minute < 13 bpm
• BNP
• Echocardiography
Echocardiography Does Not Accurately
Predict PH in Patients With IPF
50
48%
40%
Patients (%)
40
30
20
12%
10
0
Under
Estimation
Over
Estimation
Accurate
N=110, idiopathic pulmonary fibrosis patients with both echo and RHC
Comparison of RVSP by echo to PASP by RHC
Nathan SD, et al. Respir Med. 2008;102:1305–1310.
Treatment With an Endothelin-1 Antagonist
• ARTEMIS study
• Patients
– IPF aged 40 to 80 years
– Minimal or no
honeycombing on HRCT
– Not selected for PH
• Treatment
– Ambrisentan, 10 mg/d or
– Placebo
• Terminated for lack of efficacy
at interim analysis
Raghu G, et al. Ann Intern Med. 2013;158(9):641-649.
P = 0.010
Treat IPF Patients for PH?
• Ambrisentan, bosentan, and macitentan have been
•
•
found non-efficacious or harmful
IPF patients should NOT be routinely treated for
PH
ABIM's Choosing Wisely:
– "Don’t routinely offer pharmacologic treatment with
advanced vasoactive agents approved only for the
management of pulmonary arterial hypertension to
patients with pulmonary hypertension resulting from
left-sided heart disease or hypoxemic lung diseases
(groups II or III pulmonary hypertension)."
http://www.choosingwisely.org. Accessed August 2014.
STEP-IPF
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Sildenafil (PDE-5 inhibitor) acts as pulmonary vasodilator
20 mg three times daily vs placebo
12 weeks + 12 week extension
N = 180 patients with IPF
Sildenafil
(N = 89)
Placebo
(N = 91)
P-value
9/89 (10%)
6/91 (7%)
0.39
ΔDLCO (%)
−0.33
−1.87
0.04
ΔPPO2 (mm Hg)
−0.63
−3.64
0.02
ΔSOB Questionairre
0.22
6.81
0.006
ΔSGRQ (QOL)
−1.64
2.45
0.01
Endpoint
6MWD improvement ≥ 20%
(Primary)
Zisman DA, et al. N Engl J Med. 2010;363(7):620-628.
STEP-IPF Subgroup Analysis
• 19% of subjects had RVSD
• Subjects with RVSD treated with sildenafil (vs
placebo)
– Less decrement in 6MWD (P = 0.01)
– Greater improvement in SGRQ (P = 0.005) and
– Greater improvement in EuroQol visual analog
scores (P = 0.04)
Han MK, et al. Chest. 2013;143(6):1699-1708.
ATS/ERS Recommendation
• PH should not be treated in the majority of patients
with IPF, but treatment may be a reasonable choice in
a minority (weak recommendation, very low-quality
evidence). ()*
• In patients with moderate to severe PH (mPAP > 35
mm Hg) documented by right heart catheterization, a
trial of vasomodulatory therapy may be indicated
• It is not clear if IPF with PH represents a distinct clinical
phenotype (IPF–PH)
* () = GRADE quality of evidence very low
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
Combined Pulmonary Fibrosis and
Emphysema Syndrome (CPFE)
CPFE
• Upper lobe emphysema and lower lobe fibrosis
• Most often observed in males
– Mean age 65 years
– Tobacco smokers or ex-smokers of > 40 pack-years
• May comprise up to 35% of patients with IPF
• Symptoms and morbidity largely attributable to severe
precapillary PH
– Risk of PH ~50%
Cottin V. Eur Respir Rev. 2013;22(128):153-157.
Features of CPFE
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Severe dyspnea
Unexpected subnormal spirometry findings
Severely impaired DLCO
Hypoxemia with exercise
Characteristic imaging features
– High HRCT fibrotic score
• Basal crackles
Cottin V. Eur Respir Rev. 2013;22(128):153-157.
CPFE Outcomes in 2 IPF Cohorts
• 365 patients with IPF
– 29 (8%) had CPFE
• Patients with CPFE had
– Less fibrosis on HRCT scans
– Higher FVC
– Greater oxygen requirements
• No difference in mortality with IPF +/- emphysema
(HR, 1.14; 95% CI, 0.61-2.13; P = 0.69)
Ryerson CJ, et al. Chest. 2013;144(1):234-240.
Management of Patients With Combined
Pulmonary Fibrosis and Emphysema (CPFE)
• No specific treatment for CPFE
– Absence of specific trials or prospective data
– IPF trials not adequate
• Smoking cessation; bronchodilators;
supportive care; oxygen supplementation;
lung transplant
• Discuss corticosteroids +/- azathioprine if NSIP
considered
Adapted from ERS/ESC guidelines, Galiè N et al. Eur Respir J. 2009;34:1219.
Acute Exacerbations Punctuate
Slow Decline
(5-10% of patients per year)
King TE Jr, et al. Lancet. 2011;378(9807):1949-1961.
Acute Exacerbations of IPF
• Incidence 5-10% per year
• Diagnostic criteria
1.
2.
Diagnosis of IPF
Unexplained worsening or development of dyspnea within
30 days
3. HRCT with new bilateral ground-glass abnormality and/or
consolidation superimposed on a background reticular or
honeycomb pattern consistent with UIP
4. No evidence of pulmonary infection by endotracheal
aspirate or bronchoalveolar lavage
5. Exclusion of alternative causes, including
• Left heart failure
• Pulmonary embolism
• Identifiable cause of acute lung injury
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
Collard HR, et al. Am J Respir Crit Care Med 2007;176:636–643.
Management of Patients With
Acute Exacerbations
• Exclude other causes
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–
–
–
Infection
CHF
Pulmonary embolism
Ischemic heart disease
• HRCT
• Bronchoscopy (if permitted by medical status)
• Patients usually treated with broad-spectrum
antibiotics and corticosteroids (unproven efficacy)
Walter N, et al. Proc Am Thorac Soc. 2006;3:330-338.
ATS/ERS Recommendation
• The majority of patients with acute
exacerbation of IPF should be treated with
corticosteroids, but corticosteroids may not be
reasonable in a minority (weak
recommendation, very low-quality evidence).
Raghu G, et al. Am J Respir Crit Care Med. 2011;183(6):788-824.
Sleep Disruption is Common in IPF
• Impaired physical and social functioning1
• Sleep quality should be a primary therapeutic goal
• Nocturnal hypoxemia is common
– Associated with
• significant sleep disruption,1
• decreased energy levels
• impaired physical functioning2
– Daytime SpO2 is a strong predictor of nocturnal SpO23,4
– Daytime spirometric measures are poor predictors of
nocturnal hypoxia
– Clinical trial of supplemental oxygen is recruiting
(clinicaltrials.gov NCT01961362)
1. Mermigkis C, et al. Med Princ Pract. 2009;18:10-15.
2. Clark M, et al. Thorax. 2001;56:482-486.
3. Douglas NJ, et al. Am Rev Respir Dis. 1990;141:1055-1070.
4. Cormick W, et al. Thorax. 1986;41:846-854.
Is OSA Common in IPF?
• 55 subjects with IPF
• Sleep apnea evaluation
– Epworth Sleepiness Scale (ESS)
– Sleep Apnea Scale of Sleep Disorders (SA-SDQ)
– Nocturnal polysomnography (NPSG)
• Other measures
– Spirometry (FEV1, FVC)
– Total lung capacity
– DLCO
– BMI
Lancaster LH, et al. Chest. 2009;136:772-778.
OSA Is Common in IPF
• Findings that did not correlate with OSA
– Spirometry
– Lung volume
– DLCO
– ESS
• Findings that did correlate
with OSA
– SA-SDQ: r = 0.45, P = 0.01
– BMI: r = 0.30, P = 0.05
No OSA
AHI  5/h
12%
20%
68%
Mild
AHI 5–15/h
Moderate/Severe
AHI > 15 events/h
AHI: apnea-hypopnea index
Lancaster LH, et al. Chest. 2009;136:772-778.
Sleep in IPF Patients
OSA-hypopnea syndrome (OSAHS)
34 newly diagnosed IPF patients, therapy naive
Overnight polysomnography
An abnormal total AHI (> 5) in 59% of the included subjects
TLC might predispose IPF patients in sleep disordered breathing
TLC, % Predicted
•
•
•
•
Mermigkis C, et al. Sleep Breath. 2010;14(4):387-390.
P = 0.03, r = -0.38
REM AHI
Managing Sleep
• Caregiver should observe patient
• Oxygen desaturation common with ILD, independent
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of OSA
Frequent awakening
Arrhythmia
MI more common during sleep
GERD: don’t eat just before sleep
ATS/ERS
– There are no data on which to make recommendations for
treatment of OSA in the setting of IPF.
Cardiovascular Disease in IPF
• Prevalence: 20% of IPF patients have comorbid CVD
• CVD diagnosed during follow-up significantly
•
•
increased mortality (HR 4.7)
Increased incidence of
• ACS
• Angina
• DVT
• CAD
CHF and CAD account for 1/3 deaths in IPF
Hyldgaard C, et al. Respir Med. 2014;108(4):647-653.
Hubbard RB, et al. Am J Respir Crit Care Med 2008; 178:1257-1261.
Izbicki G, et al. Respir Med. 2009; 103(9):1346-1349
Odds Ratios for Risk Factors of CVD for
Incident Cases of IPF
• UK database: The Health Improvement Network (THIN)
Risk factor
Cases
Controls
(n=3211) (n=12,307)
(%)
(%)
Odds Ratio
(95% CI)
Pvalue*
Hypertension
25.6
21.3
1.31 (1.19-1.44)
<0.001
Diabetes
14.0
12.0
1.20 (1.07-1.34)
0.003
Ex-smoker
38.7
26.3
2.20 (1.99-2.43)
Current smoker
13.54
13.45
1.44 (1.27-1.65)
<0.001
BMI > 31
15.1
13.3
1.16 (1.02-1.32)
<0.001
* Likelihood ratio test
http://journal.publications.chestnet.org/. Accessed August 2014.
Rate Ratios for Ischemic Heart Disease
and Stroke
IPF vs Control Subjects
#
events
in cases
Crude
rate in
cases
(per 1000
pyrs)
#
events
in
controls
Crude
rate in
controls
(per 1000
pyrs)
Rate
Ratio
Pvalue*
IHD
135
17.6
474
9.9
2.32
< 0.001
Stroke
87
11.3
523
10.3
1.25
0.09
Outcome
* Likelihood ratio test
http://journal.publications.chestnet.org/. Accessed August 2014.
Cumulative Incidence of IHD is Higher
With IPF
http://journal.publications.chestnet.org/. Accessed August 2014.
Percent survival
100
Significant CAD
Mild or no CAD
N=52
75
P=0.003
50
N=21
25
0
0
250 500 750 1000 1250 1500 1750 2000
Days
Nathan SN, et al. Respir Med. 2010:104:1035-1041.
VTE is Elevated in Patients With IPF
• National Center for Health
patients with IPF
• Data suggest a link between
a pro-fibrotic and a procoagulant state
Sprunger DB, et al. Eur Respir J. 2012;39(1):125-132.
Background
population
1.31%
COPD
1.22%
Lung Cancer
1.14%
2.0%
• Increased risk of IPF 
• VTE decreased life span of
1.74%
1.0%
with VTE
IPF
0.0%
Statistics, 1988–2007
• 46,450,489 total records
– 218,991 patients with IPF
– 3815 (1.74%) also diagnosed
Prevalence of VTE
VTE is Associated with ILD
• Danish registry study,
ILD Hazard Ratios
1980-2007 records
• 7.4 million individuals
VTE
• Conclusion: In the general
population, everdiagnosed VTE was
associated with ILD,
particularly among those
never treated with
anticoagulants
1.8
Pulmonary
Embolism
2.4
DVT Only
1.3
Control Subjects
Sode BF, et al. Am J Respir Crit Care Med. 2010;181(10):1085-1092.
1
0
1
2
3
Depression in IPF
• Observed in ~25% of patients with IPF
– 9.8% in a general population of elderly subjects
– 26% in patients with COPD
• Correlated strongly and independently with
– dyspnea
– pain
– sleep quality
– FVC
• Baseline depression score was the strongest
predictor of depression score at 6 months (r = 0.59,
P < 0.00005)
Ryerson CJ, et al. Respirology. 2012 ;17(3):525-32.
Correlation of Dyspnea with Depression
UCSD SOBQ Score
(increasing dyspnea)
All patients
Patients with IPF
● Non-IPF
o IPF
Depression Score
Ryerson CJ, et al. Chest. 2011;139(3):609-616.
(N = 52, r = 0.50; P = 0.0002)
(n = 20, r = 0.57; P = 0.009)
Proposed Study: CaNoPy
• UK mixed-methods cross-sectional study of care
• Interviews
– Interpretative Phenomenological Analysis
• Validated patient questionnaires
– Quality of life (EQ-5D)
– Depression (Hospital Anxiety and Depression Scale)
– Breathlessness (Borg dyspnea scale)
– Cough (Leicester Cough Questionnaire, Cough
Symptom Score)
Byrne A, et al.BMJ Open. 2013 Aug 7;3(8). pii: e003537.
Conclusions
• Comorbidities associated with IPF such as GERD,
CPFE, CVD, sleep apnea, and depression should be
treated
• Clinical trials testing drugs approved for pulmonary
hypertension in patients with IPF and PH have been
negative on IPF endpoints
– Other endpoints have been positive
– Guidelines recommend against treating IPF patients for PH
• Acute exacerbation is a serious complication of IPF