october 13, 2014 - namcp sussman.pdf · october 13, 2014 do you intend to ... . patient with...
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Novel Diagnostic and Treatment Strategies in the Management of Idiopathic Pulmonary Fibrosis
Novel Diagnostic and Treatment Strategies in the Management of Idiopathic Pulmonary Fibrosis
Robert Sussman, MD
Overlook Medical Center
Atlantic Health System
October 13, 2014
Do you intend to discuss any off-label or investigational drugs or devices in your presentation?
“All drugs for this disease are investigational”
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October 15, 2014
The Food and Drug Administration on October 15 approved two new oral medications for idiopathic pulmonary fibrosis, nintedanib (Ofev) and pirfenidone (Esbriet) ………
Case #1Case #1
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71-year-old male with progressive dyspnea on exertion for 2 years.
He was previously able to walk > 2 miles; over the past 2 years it decreased to 1/2 mile.
Currently, he has difficulty with activities such as dancing and mowing the lawn.
Case 1Case 1
PFT 18 months prior revealed mild obstructive airways disease, but the patient used bronchodilators without much relief of symptoms.
One year prior, he developed “pneumonia” with fever, chills, and a nonproductive cough. The CXR at that time was read as mildly prominent interstitial markings.
Case 1Case 1
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• Smoked 20 pack years
• Denies occupational exposures
• No exposure to birds or mold
• No use of hot tubs
Case 1Case 1
Physical Exam: BP: 130/80 Heart rate: 70Respiratory rate: 22Temperature: 96.9Oximetry: 93% on room airLungs: Bibasilar rales
Case 1Case 1
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• Vital capacity = 55%.
• FEV-1/FVC = 80%
• Diffusing capacity (DLCO) = 37%
• ABG: pH=7.41, PCO2 =41, PAO2 = 79 (RA)
Case 1Case 1
6-minute walk test:
Oximetry: 96% at rest on RA
Oximetry dropped to 83% walking on RA
Case 1Case 1
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CT ImagesCT Images
CT ImagesCT Images
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CT ImagesCT Images
CT ImagesCT Images
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CT ImagesCT Images
Is the clinical presentation and CAT scan sufficient for a diagnosis?1. Yes
2. No
3. Uncertain
Case 1Case 1
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VATS BiopsyVATS Biopsy
VATS BiopsyVATS Biopsy
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What is your diagnosis?1. COP
2. IPF
3. NSIP–cellular
4. NSIP–fibrotic
5. HP
6. AIP
7. Other
Case 1Case 1
Diagnosis:Diagnosis:
?
Case 1Case 1
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Diagnosis:Diagnosis:
UIP / IPF
Case 1Case 1
What would your management approach be?1. No treatment
2. Prednisone
3. Prednisone + a cytotoxic
4. NAC
5. Interferon-gamma
6. Pirfenidone
7. Nintedinab
8. Refer for clinical trial
Case 1Case 1
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CXR ReportCXR Report
“Chronic increased interstitial markings”
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ILD: Differential DiagnosisILD: Differential Diagnosis
• Idiopathic
• Nonidiopathic– Occupational
– Granulomatous (sarcoid, HP)
– Drug induced
– CTD
– Inherited
– PAP
– COP
– Malignancy
– CHF
Modified from Ryu JH, et al. Mayo Clin Proc. 1998;73:1085-1101.ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
Idiopathic ILD: Evolving ClassificationIdiopathic ILD: Evolving Classification
1970s 2011IPF
(a heterogeneousgroup that included
a number ofdiseases)
IPF/UIP
NSIP
DIPRB-ILD
AIP
Cellular
Fibrotic
IIP
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Approach to the Diagnosis of IPF
Clinical• History• Physical• Laboratory• PFTs
Primary carephysicians
Pulmonologists Radiologists Pathologists
Multidimensional and multidisciplinary
Radiology
• Chest X-ray• HRCT
Pathology
• Surgical lung biopsy
Approach to the ILD Patient
Martinez F, Flaherty K. Available at: http://www.chestnet.org/education/online/pccu/vol18/lessons03_04/lesson03.php.
Patient with Suspected ILD
Hx, PE, CXR, PFT, Labs
STOPHRCT
Hx and HRCT consistentwith IPF
Hx and HRCT Dx of other
ILD
Suspected other ILD
Atypical clinical or CT features of IPF
STOP STOP
STOPVATS
UIP Non IIPLIPOPDADDIPNSIP RBILD
Yes
No
Yes
No
Dx likely by bronch?
Is bronch diagnostic?
Dx likely by bronch?
Is bronch diagnostic?
Yes
Yes
No
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IPF: Evolving DefinitionIPF: Evolving Definition
• Definition highlights– Chronic, progressive illness
– Gold standard is not an isolated feature but rather a constellation of clinicoradiographic and pathologic characteristics
– Absence of a defined etiologic agent
– Consensus requirements for definition
Current Definition of IPFCurrent Definition of IPF
“...Specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with the histologic appearance of usual interstitial pneumonia (UIP)...”
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
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IPF DefinitionIPF Definition
NOT all UIP patterns are IPF, but all IPF has UIP.• UIP: usual interstitial pneumonia (pattern) is a
histopathologic term
• IPF : is a clinical entity with UIP on biopsy
• IPF is the most common form of IIP
Diagnosis of IPFDiagnosis of IPF
1. Clinical evaluation
2. Radiographic evaluation
3. Pathologic evaluation
Adapted from ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
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HistoryHistory
• DOE – slowly progressive
• Cough – usually nonproductive
• Occupational and drug history
• Joint and rash history
• Exposure history (birds, molds)
DemographicsDemographics
• Patients with IPF
– Above 50 years of age
– No racial predilection
– Male predominance (1.5:1 to 1.7:1)
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Risk Factors for IPFRisk Factors for IPF
• Familial risk (genetic)
• Smoking
• Environmental factors (eg, wood dust, metal dust)
• Chronic aspiration associated with GERD
• Infectious agents
Adapted from ATS/ERS. Am J Respir Crit Care Med 2000;161:646-664.
Risk FactorsRisk Factors
Smoking
• Former smokers OR: 1.9 (95% CI: 1.3 to 2.9)• Smokers (21- 40 pack-years) OR: 2.3
(95% CI: 1.3 to 3.8)• Risk increased with pack-years of smoking
Baumgartner KB, et al. Am J Respir Crit Care Med. 1997;155:242-248.Enomoto et al. Chest 2003;123:2007-2011
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Epidemiology of IPFEpidemiology of IPF
Estimated 83,000 currentpatients in the United States
Prevalence
Weycker D, et al. Prevalence, Incidence, and Economic Costs of Idiopathic Pulmonary Fibrosis. Paper presented at: CHEST 2002; November 2-7, 2002; San Diego, Calif.
Estimated 31,000 newpatients per year in the United States
Incidence
0
50
100
150
200
250
300
45-54 55-64 65-74 75+
Male
Female
0
20
40
60
80
100
120
45-54 55-64 65-74 75+
Male
Female
Age Age
Per
100
,000
Physical ExamPhysical Exam
• Velcro rales
• Clubbing
• Signs of CTD
• May be normal
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Clinical EvaluationClinical Evaluation
• Pulmonary function (Findings are characteristic but not specific for IPF)
– Restrictive ventilatory defect• Reduced TLC, FVC
• Normal or increased FEV1/FVC ratio
– Impaired gas exchange• Decreased PaO2, DLCO
• Desaturation on exercise oximetry
• Increased A-a gradient
Adapted from ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
Physiologic Patterns in ILDPhysiologic Parameters Direction of Change
FVC
FEV1/FVC
DLco
TLC
Exercise P(A-a)O2 difference Typical Findings in IPF:• Restrictive picture with impaired gas exchange
• Normal resting PFTs do not exclude IPF
• Desaturation on 6-Minute Walk Test
Alhamed EH, et al. Clin Chest Med. 2001;22:715-750.Lama VN, et al. Am J Respir Crit Care Med. 2003;168:1084-1090.
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Clinical EvaluationClinical Evaluation
• Serologic testingESR
ANA
RF
HP panel
ANCA
CK & aldolase
ACE
Jo-1 antibody and Scl-70
Adapted from ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
Diagnosis of IPFDiagnosis of IPF
1. Clinical evaluation
2. Radiographic evaluation
3. Pathologic evaluation
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HRCTExpected Findings for IPF
• Irregular reticular abnormalities • Subpleural, posterior, lower-lobe
predominance• Subpleural honeycombing• Minimal ground-glass opacities• Traction bronchiectasis (late)• Mild lymph node enlargement
Consider Alternate Diagnosis
• Pleural effusion• Pleural thickening• Moderate ground-glass densities• Large mediastinal/hilar nodes• Central lobular nodules and cysts
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:646-664.
Prone scans are often best for showing early abnormalities
Early HRCT Findings in IPFEarly HRCT Findings in IPF
Slide courtesy of Kevin O. Leslie, MD
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Courtesy of W. Richard Webb, MD.
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HRCT and IPFHRCT and IPF
• Think of another diagnosis in the presence of:– Pleural thickening
– Moderate ground-glass densities
– Mediastinal / hilar adenopathy
– Upper lobe predominant disease
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Diagnosis of IPFDiagnosis of IPF
1. Clinical evaluation
2. Radiographic evaluation
3. Pathologic evaluation
Lung Biopsy and ILD/IPFLung Biopsy and ILD/IPF
• Indications
– Establish a specific diagnosis when HRCT
and /or clinical features are atypical
– Major purpose of histologic examination is to distinguish UIP from other histologic subsets of IIP which may be more treatable
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Lung Biopsy and ILD/IPFLung Biopsy and ILD/IPF
• Fiberoptic bronchoscopy with transbronchiallung biopsy (+/- BAL)– Rarely done
– Excludes other diagnosis
– Incapable of establishing diagnosis of IPF/UIP
• VATS biopsy
Lung Biopsy and ILD/IPFLung Biopsy and ILD/IPF
• Is lung biopsy always needed for diagnosis of IPF?
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Surgical Lung Biopsy and IPFSurgical Lung Biopsy and IPF
• Atypical clinical features or course
• Lack of HRCT “confident” diagnosis of IPF
• Absence of contraindications
The Histopathology of IPF• UIP is the histologic lesion essential for IPF
diagnosis–Cardinal features
Temporal heterogeneity• Dense fibrosisnormal lung
Predilection for peripheral (subpleural) and basilar region
Fibroblastic foci (aggregates of proliferating fibroblasts and myofibroblasts)
Microscopic honeycomb cysts
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2000;161:646-664. Kaminski N, et al. Am J Respir Cell Mol Biol. 2003;29:S1-S105.
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UIP: Subpleural FibrosisUIP: Subpleural Fibrosis
UIP: Transition from Normal to FibroticUIP: Transition from Normal to Fibrotic
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UIP: Fibroblast FociUIP: Fibroblast Foci
Treatment of IPF – Pre October 2014 Treatment of IPF – Pre October 2014
• Refer to clinical trial if possible:– Interferon Gamma
– Bosentan
– Ambrisentan
– Sildenafil
– NAC
– Pirfenidone
– Nintedanib
– Anti-LOXL2
– Anti-IL12
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Treatment of IPF – Post October 2014 Treatment of IPF – Post October 2014
Pirfenidone (Esbriet)
Nintedanib (OFEV)
Clinical Trial
PirfenidonePirfenidone
• FDA approved October 2014
• Mechanism of action unknown
• Oral medication
• TID dosing with meals
• Slows progression of disease
• Side effects: GI, fatigue, LFT abnormalities, photosensitivity
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PirfenidonePirfenidone
PirfenidonePirfenidone
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PirfenidonePirfenidone
NintedanibNintedanib
• FDA approved October 2014
• Mechanism of action: Tyrosine kinaseinhibitor
• Oral medication
• BID dosing
• Slows progression of disease
• Side effects: diarrhea (62%), nausea, LFT abnormalities
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NintedanibNintedanib
NintedanibNintedanib
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Treatment of IPFTreatment of IPF
• Supplemental oxygen
• Pulmonary rehab
• Refer for lung transplant if eligible
• End of life planning
IPF: Co-morbiditiesIPF: Co-morbidities
– Pulmonary hypertension– GERD– Osteoporosis– Deconditioning– Obstructive sleep apnea
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Cause of DeathCause of Death
IPF[N=543]
1-7 years follow-up
60% died[N=326]
Respiratory failure39%
Lung cancer
10%
Pulmonaryembolism
3%
Pulmonary infection
3%
Cardiovasculardisease
27%
Other18%
Panos RJ, et al. Am J Med. 1990;88:396-404.
Progression of IPF:Acute Exacerbation vs Slow DeclineProgression of IPF:Acute Exacerbation vs Slow Decline
50%
Years
Res
pir
ato
ryfu
nct
ion
/sym
pto
ms
1 2 3 4
FV
C
Traditional view of UIP/IPF progression
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50%
Years
Res
pir
ato
ryfu
nct
ion
/sym
pto
ms
1 2 3 4
FV
C
Progression of IPF:Acute Exacerbation vs Slow DeclineProgression of IPF:Acute Exacerbation vs Slow Decline
Acute exacerbation
Step theory of UIP/IPF progression
Acute Exacerbations of IPFAcute Exacerbations of IPF
• Acute worsening of dyspnea and PFTs
• HRCT with new ground glass infiltrates
• Infectious etiologies ruled out
• Mortality very high
• Trial of high dose steroids and cytoxanindicated
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Differential Diagnosis of IPFDifferential Diagnosis of IPF
• Some of the other IIPs do respond to treatment (Steroids +/- cytotoxics) so important to differentiate– NSIP
– COP
– HSP
Cryptogenic Organizing Pneumonia (COP)Cryptogenic Organizing Pneumonia (COP)
• Granulation tissue plugs within alveolar ducts, which consist of loose edematous connective tissue
• May be idiopathic, secondary, or even associated with another specific histologic entity
• Synonym: bronchiolitis obliterans organizing pneumonia (BOOP)
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COPCOP
COPCOP
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Histologic Features of Nonspecific Interstitial Pneumonia (NSIP)Histologic Features of Nonspecific Interstitial Pneumonia (NSIP)
• Mild to moderate interstitial mononuclear infiltrate
• +/- Diffuse interstitial fibrosis with preserved architecture on elastic tissue stain
• Fibroblast foci or organizing pneumonia not prominent, especially in cases with paraseptal/subpleural involvement
NSIP/F UIP
Different Patterns of FibrosisDifferent Patterns of Fibrosis
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IPF: SummaryIPF: Summary
IPF a progressive, irreversible, and lethal disease
“Everyone will get worse, you just don’t know when or how fast.”
New and future treatments finally offer hope
Review of Case #1
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71-year-old male with progressive dyspnea on exertion for 2 years.
He was previously able to walk > 2 miles; over the past 2 years it decreased to 1/2 mile.
Currently, he has difficulty with activities such as dancing and mowing the lawn.
Case 1Case 1
PFT 18 months prior revealed mild obstructive airways disease, but the patient used bronchodilators without much relief of symptoms.
One year prior, he developed “pneumonia” with fever, chills, and a nonproductive cough. The CXR at that time was read as mildly prominent interstitial markings.
The patient has no bird or mold exposure, smoked 20 pack years, drinks socially, and denies occupational exposures.
Case 1Case 1
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Physical Exam: BP: 130/80 Heart rate: 70Respiratory rate: 22Temperature: 96.9Oximetry: 93% on room airLungs: Bibasilar rales
Case 1Case 1
Vital capacity = 55%.
Diffusing capacity (DLCO) = 37%
Blood gases: pH is 7.41, PCO2 of 41, PAO2 of 79;
on room air.
Case 1Case 1
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CT ImagesCT Images
Is the clinical presentation and CAT scan sufficient for a diagnosis?1. Yes
2. No
3. Uncertain
Case 1Case 1
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VATS BiopsyVATS Biopsy
VATS BiopsyVATS Biopsy
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What is your diagnosis?1. COP
2. IPF
3. NSIP–cellular
4. NSIP–fibrotic
5. HP
6. Other
Case 1Case 1
What would your management approach be?1. No treatment
2. Prednisone
3. Prednisone + a cytotoxic
4. NAC
5. Interferon gamma
6. Pirfenidone
7. Nintedanib
8. Refer for clinical trial
Case 1Case 1
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Questions?Questions?