Interstitial Lung Diseases

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updates in IPF 2015

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By Dr. Riham Hazem Raafat Lecturer of Chest Diseases Ainshams University Interstitial Lung Diseases

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Lung Interstitial Pulmonary Fibrosis (IPF): 1ry (Idiopathic) Occupational Collagenic Granulomatous Irradiation Resection Drug induced (Bleomycin, Methotrexate, Cyclophosphamide) Pleura Pleural effusion Pneumothorax Pleural fibrosis Pleural tumours Pleural thickening Chest Wall Trauma Kyphoscoliosis Ankylosing Spondylitis Neuromuscular Disease (Myasthenia/Guillain Barre) Morbid obesity Scleroderma Abdomen Severe Distension Restrictive Lung Diseases Extra- Parenchymal Parenchymal

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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

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

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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:

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:

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.

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* 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:

Clinical-Radiologic-Pathologic Approach to ILD

When Should I Suspect ILD?:

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

ILD Features:

ILD Features Similarities 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 :

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:

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:

Pleuroparenchymal Fibroelastosis Pleural thickening Traction bronchiectasis & Fibrotic changes Elastotic tissue intra-alveolar

Idiopathic Pulmonary Fibrosis:

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)

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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)

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Risk 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:

Clinical-Radiologic-Pathologic Approach to ILD

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Diagnostic criteria of IPF in immunocompetent adult in In the absence of a surgical lung biopsy (ATS/ERS 2000) Major Criteria Exclusion of known causes. Abnormal pulmonary function tests with evidence of restriction and impaired gas exchange. Bibasilar reticular abnormalities with minimal or no ground glass opacities on HRCT scans. Transbronchial biopsy or bronchoalveolar lavage showing no features to support an alternative diagnosis. Minor Criteria Age older than 50 years Insidious onset of otherwise unexplained dyspnea on exertion Duration of illness more than 3 months 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:

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 IPF IPF Not IPF No Possible UIP Inconsistent w/ UIP UIP Probable UIP Non-classifiable fibrosis

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Raghu G, et al . Am J Respir Crit Care Med . 2011;183:788-824. 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 OR Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP AND

HRCT Criteria for UIP:

HRCT Criteria for UIP UIP Pattern Possible UIP Pattern Subpleural, basal predominance + + Reticular abnormality + + Honeycombing (+/- traction bronchiectasis) + - Absence of “inconsistent ” features + + Raghu G, et al . Am J Respir Crit Care Med . 2011;183:788-824.

Idiopathic Pulmonary Fibrosis:

Idiopathic Pulmonary Fibrosis Normal Lungs Usual Interstitial Pneumonia

UIP Pattern:

UIP Pattern

Possible UIP Pattern:

Possible UIP Pattern traction bronchiectasis

HRCT features inconsistent with IPF:

HRCT features inconsistent with IPF Inconsistent 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:

Inconsistent With UIP distinct lobular pattern

Before You Biopsy…:

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:

Diagnosis of IPF by Lung Biopsy Raghu G, et al . Am J Respir Crit Care Med . 2011;183:788-824. 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 Radiologic Pattern

Idiopathic Pulmonary Fibrosis:

Idiopathic Pulmonary Fibrosis Normal Lung Usual Interstitial Pneumonia

Idiopathic Pulmonary Fibrosis:

Idiopathic Pulmonary Fibrosis Normal Lung Fibroblastic focus in Usual Interstitial Pneumonia

Management:

Management

2011 Guidelines on Management of IPF:

2011 Guidelines on Management of IPF Treatment Strong For Weak For 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:

Three Recent IPF Clinical Trials American Thoracic Society 2014 PANTHER N-acetylcysteine (NAC) ASCEND pirfenidone INPULSIS nintedanib (BIBF1120)

PANTHER N-acetylcysteine (NAC):

PANTHER N-acetylcysteine (NAC)

Possible NAC Mechanisms of Action:

Possible NAC Mechanisms of Action Increase glutathione  a ntioxidation Downregulate lysyl oxidase (LOX) activity, (essential for collagen deposition)

PANTHER 2012 Adverse Events:

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. Percentage ATS 2011 2011-2013 2014 Pre-2011

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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

ASCEND Pirfenidone:

ASCEND Pirfenidone

Possible Mechanisms of Pirfenidone Action:

Possible Mechanisms of Pirfenidone Action TNF- α IL-6 Pirfenidone TGF- β IL-6 MMPs Collagenases ROIs Collagen Antifibrotic Molecular target unclear Active in several animal models of fibrosis (lung, liver, kidney)

CAPACITY 2011:

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 2014 Pre-2011

CAPACITY Endpoints:

CAPACITY Endpoints Endpoint CAPACITY-2 CAPACITY-1 FVC  X Overall survival X X Progression-free survival  X Six-minute walk distance X  DL CO X X Dyspnea X X Exertional desaturation X X

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ASCEND 2014 ATS 2011 2011-2013 Pre-2011 2014

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Endpoints 1 0 : Δ FVC or death 2 0 : 6-MWD PFS Dyspnea Death 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% DL CO pred FEV 1 /FVC ≥ 0.80 6-MWD ≥ 150 m 555 Patients

ASCEND Summary:

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

ASCEND Conclusions:

66 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

FDA Approval of Pirfenidone (Esbriet):

67 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 Precautions Temporary dosage reductions or discontinuations may be required:

Pirfenidone Warnings and Precautions Temporary 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.

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Adverse Effects, Cautions Caution Adverse Effect Taken after food to  these upsets (though food significantly  its absorption) GI Upset (N, V, dyspepsia) Avoid exposure to sunlight, use sunscreen. Photosensitivity Check at baseline, monthly for 6 M, then every 3 M  Transaminases Avoid before driving vehicles Dizziness Monitor weight,  caloric intake if needed. Weight Loss

Pirfenidone: Other Considerations:

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.

INPULSIS Nintedanib:

INPULSIS Nintedanib

Possible Mechanisms of Nintedanib Action:

Possible Mechanisms of Nintedanib Action Triple kinase inhibitor Phosphatase activator Antiangiogenic, antitumor activity VEGF Nintedanib PDGF FGF SHP-1 Pleiotropic Effects

Nintedanib Showed Promise for FVC Endpoint:

Richeldi L, et al. N Engl J Med. 2011:365;1079-1089. Nintedanib Showed Promise for FVC Endpoint ATS 2011 2011-2013 2014 Pre-2011

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INPULSIS 2014 ATS 2011 2011-2013 Pre-2011 2014

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Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082. INPULSIS-1 and INPULSIS-2 Study Design Endpoints 1 0 : Δ FVC 2 0 : Time to first AE Δ SGRQ Inclusion Criteria Age > 40 IPF ≤ 5y ≥ 50% FVC pred 30 - 79% DL CO pred HRCT within 1y Nintedanib 300 mg Daily Placebo 52 Weeks 3 2 1066 Patients AE – Acute Exacerbation SGRQ – St. George’s Respiratory Questionnaire

INPULSIS Summary:

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:

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

FDA Approval of Nintedanib (Ofev):

79 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)

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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 90 Diarrhea (%) 62 19 63 18 Nausea(%) 23 6 26 7

Nintedanib Warnings and Precautions:

81 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:

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 82

Current Phase 2 Trials for IPF Next Generation Therapy?:

Current Phase 2 Trials for IPF Next 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 :

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:

Oxygen Therapy

Pulmonary Rehabilitation:

Pulmonary Rehabilitation

Risk Factor Reduction:

Risk Factor Reduction

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Lung Transplantation for IPF: 2014 Referral Guidelines Histopathologic or radiographic evidence of usual interstitial pneumonitis (UIP) Abnormal lung function: FVC < 80% predicted or DL CO < 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:

Other Therapies Stem Cell Therapy Proteolytic Enzymes ??

Acute Exacerbation of IPF:

Acute Exacerbation of IPF Diagnostic Criteria Previous 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

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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:

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

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Diagnosis of IPF IF increased risk of mortality Evaluate and list for lung transplantation at time of diagnosis

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Thank you!

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