interstitial lung diseases

By

Dr. Riham Hazem RaafatLecturer of Chest Diseases

Ainshams University

Lung

Interstitial PulmonaryInterstitial Pulmonary Fibrosis (IPF):Fibrosis (IPF):

• 1ry (Idiopathic)

• Occupational

• Collagenic

• Granulomatous

• Irradiation

• Resection

• Drug induced(Bleomycin, Methotrexate, Cyclophosphamide)

Pleura

• Pleural effusion

• Pneumothorax

• Pleural fibrosis

• Pleural tumours

• Pleural thickeningChest Wall

• Trauma

• Kyphoscoliosis

• Ankylosing Spondylitis

• Neuromuscular Disease (Myasthenia/Guillain Barre)

• Morbid obesity

• Scleroderma

Abdomen

Severe Distension

Restrictive Lung DiseasesRestrictive Lung DiseasesExtra-ParenchymalParenchymal

Parenchymal RLD Extraparenchymal RLD

FVC Decreased Decreased

MVV Normal Decreased

DLCO Decreased Normal

FVC: Forced Vital Capacity

MVV: Maximum Voluntary Ventilation

DLCO: Carbon Monoxide Diffusion

Adapted from: ATS/ERS Guidelines for IIP. AJRCCM. 2002;165:277-304.

Diffuse Parenchymal Lung Disease (DPLD)

DPLD of known cause, eg, drugs or association, eg, collagen vascular disease

Idiopathic interstitial

pneumonias

Granulomatous DPLD, eg,

sarcoidosis

Other forms of DPLD, eg, LAM,

HX, etc

Idiopathic pulmonary

fibrosis

IIP other than idiopathic

pulmonary fibrosis

Desquamative interstitial pneumonia

Acute interstitial pneumonia

Nonspecific interstitial pneumonia (provisional)

Respiratory bronchiolitis interstitial lung disease

Cryptogenic organizing pneumonia

Lymphocytic interstitial pneumonia

Pleuroparenchymal fibroelastosis

Travis WD, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748.

Major Idiopathic Interstitial Pneumonias

Category

Clinical-Radiologic-Pathologic Diagnosis

Associated Radiographic and/or Pathologic pattern

Chronic fibrosing

IPF UIP

Idiopathic nonspecific interstitial Pneumonia (iNSIP) NSIP

Smoking-related

Respiratory bronchiolitis-ILD (RB-ILD) Respiratory bronchiolitis

Desquamative interstitial pneumonia (DIP) Desquamative interstitial pneumonia

Acute/ subacute

Cryptogenic organizing pneumonia (COP) Organizing pneumonia

Acute interstitial pneumonia (AIP) Diffuse alveolar damage

Travis et al. Am J Respir Crit Care Med. 2013;188:733-748.

Other Idiopathic Interstitial Pneumonias

Category Clinical-Radiologic-Pathologic Diagnosis

Associated Radiographic and/or Pathologic pattern

Rare

Idiopathic lymphoid interstitial pneumonia (iLIP)

Lymphoid interstitial pneumonia

Idiopathic pleuroparenchymal fibroelastosis (IPPFE)

Pleuroparenchymal fibroelastosis

Unclassifiable Unclassifiable IIP Many

Travis et al. Am J Respir Crit Care Med. 2013;188:733-748.

*Causes of unclassifiable IIP: (1) Inadequate clinical, radiologic, or pathologic data (2) Major discordance between clinical, radiologic, and

pathologic findings that may occur in the following situations:

(a) Previous therapy resulting in substantial alteration of radiologic or histologic findings (e.g., biopsy of DIP after steroid therapy, which shows only residual NSIP)

(b) New entity, or unusual variant of recognized entity, not adequately characterized by the current ATS/ERS classification (e.g., variant of organizing pneumonia with supervening fibrosis); and

(c) Multiple HRCT and/or pathologic patterns that may be encountered in patients with IIP.

Clinical-Radiologic-Pathologic Approach to ILD

When Should I Suspect ILD?One from Column A and one from Column B

“ACES”

ILD FeaturesSimilarities Differences

• Dyspnea– Progressive– Exertional

• Cough– Non-productive

• Bibasilar crackles• Restrictive ventilatory

defect• Exertional desaturation• ILD on HRCT

• Prior/current exposures• Extrapulmonary findings

– Sarcoidosis– Connective tissue disease– Joint involvement

• Serologies• HRCT

– Honeycombing– Ground glass – Distribution of abnormalities

• Histopathology

Known Causes of ILD: History & Physical Exam

• Drugs– eg, Amiodarone, bleomycin,

nitrofurantoin

• Radiation‒ External beam radiation therapy to

thorax

• Connective Tissue Diseases– Rheumatoid arthritis– Systemic sclerosis (scleroderma)– Idiopathic inflammatory

myopathies– Vasculitis

• Occupational/Environmental– Inorganic antigens

(Pneumoconioses)• Asbestosis• Coal worker’s

pneumoconiosis• Silicosis

– Organic antigens (Hypersensitivity Pneumonitis)

• Birds• Mold

Serological Evaluation

• Minimum: ANA, RF, CCP (ATS/ERS guidelines)• Based on history & physical exam, consider:

– Extractable nuclear antigen (ENA) autoantibody panel– Anti-centromere antibody– ESR & CRP– MPO/PR3 (ANCA) antibodies– Anti-cardiolipin antibodies, lupus anticoagulant– Creatine kinase, aldolase– Hypersensitivity pneumonitis panel

• Should be performed before a biopsy

Pleuroparenchymal Fibroelastosis

•Pleural thickening•Traction bronchiectasis &

Fibrotic changes

Elastotic tissue intra-alveolar

Idiopathic Pulmonary Fibrosis• Peripheral lobular fibrosis of unknown cause• Clinical impact

– Exertional dyspnea– Cough– Functional and exercise limitation– Impaired quality-of-life– Risk for acute respiratory failure and death

• Median survival time of 3-5 years• Two new drugs approved by the FDA in October 2014

‒ Nintedanib (Ofev)‒ Pirfenidone (Esbriet, Pirfenex)

IPF is defined as a specific form of chronic,

fibrosing interstitial pneumonia of unknown

cause, typically affecting adults over 50 years,

limited to the lungs, and associated with the

histopathologic and/or radiologic pattern of usual

interstitial pneumonia (UIP)

Risk Factors for IPFRisk Factors for IPF

Hereditary Acquired

* Gene Mutations • Smoking (> 20 packs.year).

• Pneumoconiosis.

• GERD: microaspiration.

• Viral infections (HCV, Herpes)

• Autoimmunity.

Clinical-Radiologic-Pathologic Approach to ILD

Major CriteriaA.Exclusion of known causes.B.Abnormal pulmonary function tests with evidence of restriction and impaired gas exchange.C.Bibasilar reticular abnormalities with minimal or no ground glass opacities on HRCT scans.D.Transbronchial biopsy or bronchoalveolar lavage showing no features to support an alternative diagnosis.

Minor CriteriaA. Age older than 50 yearsB. Insidious onset of otherwise unexplained dyspnea on exertionC. Duration of illness more than 3 monthsD. Bibasilar inspiratory crackles on chest auscultation

The presence of all of the major diagnostic criteria, as well as at least three of the four minor criteria, increases the likelihood of a correct clinical diagnosis.

Diagnostic Algorithm for IPF

Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.

Suspected IPF

Identifiable causes for ILD?

HRCT

Surgical Lung Biopsy

MDD

IPF/Not IPFIPF Not IPF

No

Possible UIPInconsistent w/ UIP

UIPProbable UIPNon-classifiable fibrosis


2011 ATS/ERS Diagnostic Criteria for IPF

*also known as diffuse parenchymal lung disease, DPLD

Exclusion of known causes of ILD*

UIP pattern on HRCT without surgical biopsy

ORDefinite/possible UIP pattern on HRCT with a surgical lung

biopsy showing definite/probable UIP

AND

HRCT Criteria for UIP

UIP Pattern

Possible UIP

PatternSubpleural, basal predominance + +Reticular abnormality + +Honeycombing (+/- traction bronchiectasis) + -Absence of “inconsistent” features + +


Idiopathic Pulmonary Fibrosis

Normal Lungs Usual Interstitial Pneumonia

UIP Pattern

Possible UIP Pattern

traction bronchiectasis

HRCT features inconsistent with IPFInconsistent Features

Upper lobe predominant

Peribronchovascular predominance

Ground-glass > extent of reticular abnormality

Profuse micronodules

Discrete cysts

Diffuse mosaic attenuation/gas-trapping

Consolidation

Inconsistent With UIP

distinctlobular pattern

Before You Biopsy…

• Can you confirm the diagnosis without a biopsy?• Is it safe?

– Extensive honeycombing– Pulmonary hypertension– High oxygen requirements– Progressive disease

• Avoid a “diagnostic trial” of steroids if possible

Diagnosis of IPF by Lung Biopsy


UIP Probable UIP

Possible UIP Not UIP Not

performed

UIP IPF IPF IPF Not IPF IPF

Possible UIP IPF IPF +/- IPF Not IPF Not IPF

Inconsistent with UIP +/- IPF Not IPF Not IPF Not IPF Not IPF

Histopathologic Pattern

Radi

olog

ic P

atter

n


Normal Lung Usual Interstitial Pneumonia


Normal Lung Fibroblastic focus inUsual Interstitial Pneumonia

Management

2011 Guidelines on Management of IPF

Treatment Strong For

WeakFor

Weak Against

Strong Against

Corticosteroid X

Colchicine X

Cyclosporine A X

Interferon γ 1b X

Bosentan X

Etanercept X

NAC/Azathioprine/Prednisone X

NAC X

Anticoagulation X

Pirfenidone X

Mechanical ventilation X

Pulmonary rehab X

Long-term oxygen X

Lung transplantation X

Three Recent IPF Clinical Trials American Thoracic Society 2014

• PANTHER N-acetylcysteine (NAC)• ASCEND pirfenidone• INPULSIS nintedanib (BIBF1120)

PANTHERN-acetylcysteine (NAC)

Possible NAC Mechanisms of Action

• Increase glutathione antioxidation • Downregulate lysyl oxidase (LOX) activity,

(essential for collagen deposition)

PANTHER 2012 Adverse Events

• Triple therapy has higher incidence of adverse events than placebo

P-value for each comparison < 0.05

IPFNet writing committee. N Engl J Med 2012;366;1968-77.

P-values < 0.05

Raghu G, et al. N Engl J Med. 2012;366:1968-1977.

Perc

enta

ge

ATS 2011

2011-2013 2014Pre-2011

PANTHER Adverse Effects 2014:NAC Does Not Reduce FVC Decline

Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.

Conclusion: NAC offered no significant benefit with respect to the preservation of FVC in patients with IPF with mild-to-moderate impairment in lung function

ASCENDPirfenidone

Possible Mechanisms of Pirfenidone Action

TNF-αIL-6

Pirfenidone

TGF-βIL-6

MMPsCollagenases

ROIs

Collagen

• Antifibrotic• Molecular target

unclear• Active in several

animal models of fibrosis (lung,

liver, kidney)

CAPACITY 2011

CAPACITY-2 CAPACITY-1

• One pirfenidone trial was positive, one was negative• CAPACITY-1 placebo group FVC declined more slowly than expected

ATS 2011

2011-2013 2014Pre-2011

CAPACITY Endpoints

Endpoint CAPACITY-2 CAPACITY-1FVC XX

Overall survival XX XX

Progression-free survival XX

Six-minute walk distance XX DLCO XX XX

Dyspnea XX XX

Exertional desaturation XX XX

ASCEND 2014ATS

20112011-2013Pre-2011 2014

Endpoints

10: Δ FVC or death

20: 6-MWDPFSDyspneaDeath

ASCEND Study Design

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

Oral Pirfenidone 2403 mg Daily

Placebo

52 Weeks

PFS - Progression-free survival

Inclusion Criteria

•Age 40-80•Confirmed IPF•50 - 90% FVC pred •30 - 90% DLCO pred •FEV1/FVC ≥ 0.80 •6-MWD ≥ 150 m

555 Patients

ASCEND Summary

• Treatment with pirfenidone for 52 weeks significantly reduced disease progression, as measured by – Changes in % predicted FVC (P < 0.001) – Changes in 6-minute walk distance (P = 0.04)– Progression-free survival (P < 0.001)

• Treatment with pirfenidone reduced all-cause mortality and treatment emergent IPF-related mortality in pooled analyses at week 52

• Pirfenidone was generally safe and well tolerated

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• Pirfenidone, as compared with placebo, reduced disease progression in patients with IPF

• Treatment was generally safe, had an acceptable side effect profile, and was associated with fewer deaths

ASCEND Conclusions

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• Approved October 15, 2014• Indicated for the treatment of IPF• Dosage and administration

– 801 mg (three 267 mg capsules) three times daily with food – Doses should be taken at the same time each day– Initiate with titration

• Days 1 through 7: 1 capsule 3x per day• Days 8 through 14: 2 capsules 3x per day• Days 15 onward: 3 capsules 3x per day

– Consider temporary dosage reduction, treatment interruption, or discontinuation for management of adverse reactions.

• Prior to treatment, conduct liver function tests.

*Pirfenex is the indian form (200mg, 30 cap, 195 L.E)

FDA Approval of Pirfenidone (Esbriet)

Pirfenidone Warnings and PrecautionsTemporary dosage reductions or discontinuations may be required

• Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with pirfenidone. Monitor ALT, AST, and bilirubin before and during treatment.

• Photosensitivity and rash: Photosensitivity and rash have been noted with pirfenidone. Avoid exposure to sunlight and sunlamps. Wear sunscreen and protective clothing daily.

• Gastrointestinal disorders: Nausea, vomiting, diarrhea, dyspepsia, gastro-esophageal reflux disease, and abdominal pain have occurred with pirfenidone.

Adverse Effects, CautionsAdverse Effects, Cautions

Adverse EffectAdverse Effect CautionCaution

GI Upset (N, V, dyspepsia) Taken after food to these upsets (though food significantly its absorption)

Photosensitivity Avoid exposure to sunlight, use sunscreen.

Transaminases Check at baseline, monthly for 6 M, then every 3 M

Dizziness Avoid before driving vehicles

Weight Loss Monitor weight, caloric intake if needed.

Pirfenidone: Other Considerations• Post-marketing experience (reactions of unknown frequency)

– Agranulocytosis – Angioedema – Bilirubin increased in combination with increases of ALT and

AST• Drug interactions

– Metabolized primarily via CYP1A2– Activators and inhibitors of CYP1A2 should be used with

caution with pirfenidone• Use with caution with mild/moderate hepatic impairment, not

recommended for patients with severe impairment• Use with caution with mild/moderate/severe renal impairment,

not recommended for patients with ESRD requiring dialysis• Smoking causes decreased exposure to pirfenidone. Instruct

patients to stop smoking prior to treatment with pirfenidone and to avoid smoking when using pirfenidone.

INPULSISNintedanib

Possible Mechanisms of Nintedanib Action

• Triple kinase inhibitor• Phosphatase activator• Antiangiogenic,

antitumor activity VEGF

Nintedanib

PDGF FGF SHP-1

Pleiotropic Effects

Richeldi L, et al. N Engl J Med.2011:365;1079-1089.

Nintedanib Showed Promise for FVC Endpoint

ATS 2011

2011-2013 2014Pre-2011

INPULSIS 2014ATS

20112011-2013Pre-2011 2014

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

INPULSIS-1 and INPULSIS-2 Study Design

Endpoints

10: ΔFVC

20: Time to first AE Δ SGRQ

Inclusion Criteria

•Age > 40•IPF ≤ 5y•≥ 50% FVC pred •30 - 79% DLCO pred •HRCT within 1y

Nintedanib 300 mg Daily

Placebo

52 Weeks

3

2

1066 Patients

AE – Acute ExacerbationSGRQ – St. George’s Respiratory Questionnaire

INPULSIS Summary

• Nintedanib had significant benefit in adjusted annual rate of change in FVC • INPULSIS-1 Δ = 125.3 ml P < 0.001• INPULSIS-2 Δ = 93.7 ml P < 0.001

• Nintedanib had significant benefit in time to the first acute exacerbation in INPULSIS-2• INPULSIS-1 HR = 1.15 P = 0.67• INPULSIS-2 HR = 0.38 P = 0.005

• Significant difference in favor of nintedanib for the change from baseline in the total SGRQ score in INPULSIS-2 but not INPULSIS-1

INPULSIS Conclusions

• Nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression

• Nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients

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• Approved October 15, 2014• Indicated for the treatment of IPF• Dosage and administration

– 150 mg twice daily approximately 12 hours apart taken with food– Consider temporary dose reduction to 100 mg, temporary

interruption, or discontinuation for management of adverse reactions.

– Prior to treatment, conduct liver function tests.

FDA Approval of Nintedanib (Ofev)

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Common Nintedanib Adverse Events

Event INPULSIS-1 INPULSIS-2

Nintedanib (n = 309)

Placebo (n = 204)

Nintedanib (n = 329)

Placebo (n = 219)

Any (%) 96 89 94 90Diarrhea (%) 62 19 63 18

Nausea(%) 23 6 26 7

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• Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with nintedanib. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required.

• GI disorders: Diarrhea, nausea, and vomiting have occurred with nintedanib. Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue nintedanib if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment.

• Embryofetal toxicity: Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

• Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known CAD.

• Bleeding events have been reported. Use nintedanib in patients with known bleeding risk only if anticipated benefit outweighs the potential risk.

• GI perforation has been reported. Use nintedanib with caution when treating patients with recent abdominal surgery. Discontinue nintedanib in patients who develop GI perforation. Only use nintedanib in patients with known risk of GI perforation if the anticipated benefit outweighs the potential risk.

Nintedanib Warnings and Precautions

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014.

Nintedanib: Other Considerations• Drug interactions

– Nintedanib is a substrate of P-glycoprotein (P-gp) and CYP3A4– Concomitant use of P-gp and CYP3A4 inducers with nintedanib should

be avoided– Patients treated with P-gp and CYP3A4 inhibitors and nintedanib

should be monitored closely for adverse reactions • Nintedanib is a VEGFR inhibitor, and may increase the risk of

bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.

• Nintedanib not recommended for patients with moderate or severe hepatic impairment

• < 1% excreted via the kidney; no data on patients with severe renal impairment and ESRD

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Current Phase 2 Trials for IPFNext Generation Therapy?

Trial Target N Primary Endpoint

Co-trimoxazole (Ph 3) Pneumocystis jiroveci 56 Change in FVC or respir. Hospital’n

FG-3019 Anti-CTGF 90 Change in FVC from baseline

Rituximab CD-20 58 Titers of anti-HEp-2 autoantibodies

Simtuzumab Anti-LOXL2 500 PFS

GC-1008 TGF- 25 Safety, tolerability, PK

QAX576 Anti-IL-13 40 Safety, tolerability, FVC

Tralokinumab Anti-IL-13 302 Change in FVC from baseline

STX-100 αvβ6 32 Adverse events

BMS-986020 LPA Receptor 300 Rate of change in FVC

Clinical Trial Conclusions • 2014 is a watershed year in IPF

– NAC did not show efficacy (PANTHER)– Pirfenidone (ASCEND) and nintedanib (INPULSIS) showed

efficacy in mild/moderate IPF– Pirfenidone and nintedanib approved 10/15/14 for the

treatment of IPF– Still need data on advanced disease, combination therapy,

long-term safety, adherence• Implications of having approved drug(s)

– Need early and accurate diagnosis– Role of IPF and ILD Centers of Excellence is evolving

Oxygen Therapy

Pulmonary Rehabilitation

Risk Factor Reduction

Lung Transplantation for IPF:2014 Referral Guidelines

• Histopathologic or radiographic evidence of usual interstitial pneumonitis (UIP)

• Abnormal lung function: FVC < 80% predicted or DLCO < 40% predicted

• Any dyspnea or functional limitation attributable to lung disease

• Any oxygen requirement, even if only during exertion

Weill D, et al. J Heart Lung Transplant.2014 Jun 26. [Epub ahead of print].

Other Therapies

• Stem Cell Therapy• Proteolytic Enzymes ??

Acute Exacerbation of IPFAcute Exacerbation of IPF

Diagnostic CriteriaPrevious or concurrent diagnosis of idiopathic pulmonary fibrosis.

• Unexplained worsening or development of dyspnea within 30 days.

• HRCT with new bilateral ground-glass abnormality and/or consolidation superimposed on background reticular or honeycomb pattern consistent with UIP.

• Exclusion of alternative causes: Infection Left heart failure Pulmonary embolism

It’s an acute, clinically significant deterioration of unidentifiable cause and proposed four diagnostic criteria

Baseline IPF Exacerbation

Reducing the risk of exacerbations

*Steroids up to pulse dose +/- Immunosuppresives +/- PMX Bimobilized

Fiber Column Hemoperfusion & Tacrolimus showed response acc. to HRCT pattern*Sildenafil, Imatinib, Bosentan & Triple therapy were tried with no reported improvement. *Pirfenidone has shown inconsistent effects on AEx-IPF.

*Nintedanib reported a lower incidence of AEx-IPF in patients treated with nintedanib 300 mg/day than placebo(It is interesting that nintedanib may have an effect on AEx-IPF whereas the tyrosine kinase inhibitor imatinib, which inhibits the platelet-derived growth factor receptor (PDGFR), did not . Nintedanib is an inhibitor of PDGFR, vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor (FGFR) and this specificity of inhibition may be key to its effects on AEx-IPF)

*Antacid might decrease frequency

Diagnosis of IPF

IF increased risk of mortality

Evaluate and list for lung transplantation at time of diagnosis

interstitial lung diseases

Education