Postgraduate Course 17 Lung fibrosis and sarcoidosis · Postgraduate Course 17 Lung fibrosis and...

ERS International Congress Amsterdam 2630 September 2015

Postgraduate Course 17 Lung fibrosis and sarcoidosis

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Postgraduate Course 17 Lung fibrosis and sarcoidosis

AIMS: To describe the different diagnostic approaches and treatment modalities in adult and paediatric patients with interstitial lung diseases. TARGET AUDIENCE: Paediatric and adult pulmonologists, epidemiologists, health professionals, public health physicians, and scientists interested in the aetiology and prevention of lung disease. CHAIRS: J. Muller-Quernheim (Freiburg, Germany), V. Poletti (Forli, Italy) COURSE PROGRAMME PAGE

14:00 The pathomechanism of lung fibrosis and sarcoidosis 5 M. Funke-Chambour (Bern, Switzerland)

14:45 The diagnostic and therapeutic standard 48 K. Antoniou (Heraklion, Greece)

15:30 Break

16:00 Chronic interstitial lung in children: diagnosis and treatment 147 A. Clement (Paris, France)

16:45 Lung transplantation: the pros and cons 225 G. Verleden (Leuven, Belgium)

Additional course resources 276

Faculty disclosures 277

Faculty contact information 278

Answers to evaluation questions 279

To help you provide advice to your patients, ELF produces factsheets on lung health and disease. These are informed by patient and professional interviews and written in language that is easy to understand.

You can download an electronic version of all the factsheets from the ELF website. There are over 30 titles, covering a range of topics, in more than 8 different languages.

www.europeanlung.org

Recent factsheets:

Exercise and air quality: 10 top tips

Vaccination and lung disease

Chronic cough

Smoking when you have a lung condition

Primary spontaneous pneumothorax

E-cigarettes

Work-related lung conditions

Severe and difficult-to-treat asthma

EUROPEANLUNGFOUNDATION

Bringing together patients and the public with respiratory professionals

The pathomechanism of lung fibrosis and sarcoidosis

Dr Manueal Funke-Chambour Inselspital

Universittsklinik fr Pneumologie Freiburgstrasse 4

3010 Bern SWITZERLAND

[email protected]

AIMS

Understanding the pathomechanism of IPF Apprehend the change of paragdigm if IPF pathogenesis from predominant inflammation

to impaired wound repair in IPF Understanding the pathomechanism of granulomatous disease potentially leading to

fibrosis SUMMARY Idiopathic pulmonary fibrosis (IPF) was considered longtime a defect in immune response. Over years patients were treated with triple immunosuppression. A model of impaired wound repair has replaced this paradigm. More importantly, the PANTHER study comparing azathioprine, prednisone and N-acetylcysteine against placebo revealed that mortality under this treatment was increased. Understanding the exact pathomechanism of disease is crucial in order to develop treatment strategies. Tremendous progress has been made in understanding the mechanisms of pathogenesis of IPF. On the microscopic level a distinct histopathological pattern is observed in IPF. The typical heterogeneous distribution of fibrotic areas with fibroblast accumulation (so-called fibroblats foci) is called usual interstitial pneumonia (UIP), which is not exclusively found in IPF, but also other fibrotic lung diseases (e.g. rheumatoid arthritis). On the cellular level, initial injury by undetermined agents (so-called hit e.g. by gastric reflux, environmental substances, smoking, infection) induces epithelial cell apoptosis. Apoptosis of epithelial cells leads to interrupted alveolar structures and prompt vascular leak. Fibrin is released and accumulates in the alveolar space. The coagulation cascades are activated. Released cytokines and activated coagulation induce further wound repair mechanisms, which are exaggerated in lungs of IPF patients possibly due to genetic differences and/or multiple hits. Fibroblasts are main player of wound repair, covering the epithelial defect. Fibroblasts transform into myofibroblasts and group into so-called fibroblast foci, the hallmark of UIP pattern. Myofibroblasts produce extracellular matrix, which further stimulates fibrosis progression. They are also resistant towards apoptosis in contrast to epithelial cells undergoing apoptosis. This phenomena has been called apoptosis paradox. These and other mechanisms lead to accumulation of fibrotic tissue instead of alveolar structure and can ultimately end in respiratory failure due to impaired gas exchange possibilities. Understanding the underlying mechanisms has lead to the development of different anti-fibrotic medications, which are now being recognized as effective treatment for this devastating disease.

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Other pulmonary lung diseases can lead to pulmonary fibrosis. Granulomatous disease like sarcoidosis may ultimately present with advanced lung fibrosis. Histopathological hallmark of sarcoidosis are non-caseating granuloma, which can infiltrate multiple organs. On the mechanistic level, impaired T cell response is involved in sarcoidosis development. Continuous production of cytokines is responsible for an exaggerated activation of the immune system. Treatment of sarcoidosis differs from fibrotic disease like IPF, as suppression of the immune system remains the main approach for sarcoidosis patients. If end stage fibrosis in sarcoidosis responds to antifibrotic treatments needs to be determined. REFERENCES 1. ATS/ERS/JRS/ALAT. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary

fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824

2. The idiopathic pulmonary fibrosis clinical research network. Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis. N Engl J Med 2012; 366:1968-1977.

3. Thannikal VJ, Horovitz JC. Evolving concepts of apoptosis in IPF. Proc Am Thorac Soc 2006; 3:350-356.

4. Bagnato G and Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev 2015; 24:102-114.

5. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999 Aug; 160(2):736-55.

6. Baughman RP et al. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med 2011 Mar 1; 183(5):573-81.

7. Iannuzzi MC et al. Sarcoidosis. N Engl J Med 2007 Nov 22; 357(21):2153-65. EVALUATION

1. Apoptosis paradox in IPF involves (mark all that apply)

a. Epithelial cells and endothelial cells b. Macrophages and fibroblasts c. Myofibroblasts and epithelial cells d. Epithelial cells and macrophages

2. Extracellular matrix in the fibrotic lung (mark all that apply) a. induces fibrosis b. reduces fibrosis c. is produced during fibrosis d. is produced during the phase of resolution during wound healing

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3. Origin of myofibroblasts can be (mark all that apply) a. resident fibroblasts b. epithelial cells c. circulating bone marrow derived cells d. blood vessels

4. Sarcoidoisis (mark all that apply) a. Has typically necrotizing granulomata b. Leads always to lung fibrosis if untreated c. Lung fibrosis in sarcoidosis shares the same pathomechanisms with IPF d. Can be treated with anti-fibrotics e. None of above

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The pathomechanism of lung fibrosis and sarcoidosis

Manuela Funke-Chambour MD

Pulmonary DepartmentUniversity Hospital

Inselspital Bern, Schweiz26.09.2015

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Conflict of interest disclosure

I have no, real or perceived, direct or indirect conflicts of interest that relate to this presentation.

Affiliation / financial interest Nature of conflict / commercial company name

Grants/research support (to myself, my institution or department):

Boehringer Ingelheim, Intermune, Roche, GSK

Honoraria or consultation fees: Boehringer Ingelheim, Intermune, Actelion

This event is accredited for CME credits by EBAP and speakers are required to disclose their potential conflict of interest going back 3 years prior to this presentation. The intent of this disclosure is not to prevent a speaker with a conflict of interest (any significant financial relationship a speaker has with manufacturers or providers of any commercial products or services relevant to the talk) from making a presentation, but rather to provide listeners with information on which they can make their own judgment. It remains for audience members to determine whether the speakers interests or relationships may influence the presentation.Drug or device advertisement is strictly forbidden.

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Aims

Aim 1: Apprehend the change of paradigm of IPF pathogenesis from predominant inflammation to impaired wound repair

Aim 2: Understanding the pathomechanisms for inflammatory disease potentially leading to fibrosis (example sarcoidosis)

Aim 3: Understanding the importance to distinguish different pathomechanism of lung fibrosis for treatment decisions

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Interstitial lung disease (ILD)

Alveolarepithelcells

capillary

Interstitial lung disease

Widening of interstitial space by:

Influx of inflammatory cells

Migration of fibroblasts

Accumulation of extracellular matrix

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Clinical symptomes and findings of ILD

Progressive exertional dyspnea Dry cough Weight loss

Unspecific clinical findings

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Interstitial lung diseases

American Thoracic Society/European Respiratory Society International Multidisciplinary ConsensusClassification of the Idiopathic Interstitial Pneumonias. Am. J. Respir. Crit. Care Med. January 15, 2002vol. 165 no. 2 277-304

Pulmonary Fibrosis - example IPF

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An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733748, Sep 15, 2013.

Major idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis Idiopathic nonspecific interstitial pneumonia Respiratory bronchiolitisinterstitial lung disease Desquamative interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia

Rare idiopathic interstitial pneumonias Idiopathic lymphoid interstitial pneumonia Idiopathic pleuroparenchymal fibroelastosis

Unclassifiable idiopathic interstitial pneumonias

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Idiopathic pulmonary fibrosis

Fatal lung disease with unpredictable decline of lung function due to fibrosis1,2

Prognosis is extremely poor, no cure available

Specific histopathologic and radiologic criteria (usual interstitial pneumonia - UIP)1

The cause is not known1,2

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An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med Vol 183. pp 788824, 2011

Funke M, Geiser T. Idiopathic pulmonary fibrosis: The turning point is now. Swiss Med Wkly. 2015 May 29;145.

An Official ATS/ERS/JRS/ALAT Clinical Practice Guidelines: Treatment of Idiopathic Pulmonary Fibrosis: Executive Summary An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med Vol 192. No 2, pp 238-248, 2015

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UIP/IPF radiological features

Hansell D M et al. Radiology 2008;246:697-722

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Histopathology


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Histopathology

Honey combing

Fibroblast focus

Katzenstein AL, Myers JL. State of the Art: Idiopathic pulmonary fibrosis: Clinical Relevance of pathological classification. AJRCCM Vol 157. pp 1301-1315, 1998.

Usual Interstitial Pneumonia- UIP

Idiopathic pulmonary fibrosis Connective tissue disease Chronic Hypersensitivity Pneumonitis Asbestosis


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Risk factors

Smoking

Environmental pollution

Viral or bacterial infection

Reflux


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Risk factors: Genetics


Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA. A Mutation in the Surfactant Protein CGene Associated With Interstitial Lung Disease. N Engl J Med 2001;344:573-79.

SPC

Seibold MA et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011 Apr 21;364(16):1503-12.

MUC5B

Armanios MY et al. Telomerase Mutations in Families with Idiopathic Pulmonary Fibrosis. N Engl J Med 2007, Mar 29;356(13):1317-26.

Telomerase associated genes (TERT, TERC)

In familial pulmonary fibrosis and sporadic forms of IPF

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FROM INFLAMMATION TO IMPAIRED WOUND HEALING

Stimulus

Chronic inflammation

Injury

Fibrosis

Repetitive Stimuli

Sequential Injury

Aberrant wound healing

Fibrosis

Genetic factors

Other risk factors

Modified from Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med, Vol. 345, No. 7 August 16, 2001 21

Epithelial cell-Apoptosis

- Fibroblast apoptosis- Collagen reabsorption- Re-epithelialisation

insult

Coagulation(Fribrin)

Phase of Resolution

Alveolarepithel Capillary

ExtracellularMatrix

Fibroblasts

Wound healing

Vaskular Leak with extravascular Coagulation

Fibroblast Recruitment, proliferation and matrix

deposition

IPF model of impaired wound healing


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insult


Phase of Resolution


ExtracellularMatrix

Fibroblasts

Wound healing



deposition


Dysregulation of any of these phases can contribute to fibrosis


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ALVEOLAR EPITHELIAL CELLS

Alveolar type I cell

epithelium

basal membrane

endothelium

Alveolar type II cell

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Damage of alveolar epithelial cells - apoptosis -

Type II pneumocytes undergo apoptosis in IPF/UIPBarbas-Filho JV et al. Evidence of type II pneumocyte apoptosis in the pathogenesis of IPF/UIP. J Clin Pathol 2001;54:132-138.

Funke M. et al. The Lysophosphatidic acid Receptor LPA1 promotes epithelial cell apoptosis after lung injury. AJRCMB Mar;46(3):355-64.

WT LPA1 KO

Figure 1

0

WTLPA1 KO

2

4

TUNEL (+) cells / hpf

p21(+) cells / hpf 0

1

2

3

A B C

D E F

G H

TUNEL

p21

p53

J

WTLPA1 KO

time after challenge (d)0 1 3 5

time after challenge (d)0 3


0

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D3

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insult


Phase of Resolution


ExtracellularMatrix

Fibroblasts

Wound healing



deposition



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Fibroblast

The myofibroblasts

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Myofibroblast

SMA

Funke M, Geiser T. Idiopathic pulmonary fibrosis: The turning point is now. Swiss Med Wkly. 2015 May 29;145.

Fibroblast foci

ECM production

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Origin of the myofibroblast

1. Resident fibroblasts differentiate into myofibroblasts

1. Epithelial-mesenchymal transition

2. Circulating fibrocytes or bone marrow-derived progenitors are recruited to sites of injury

Bagnato G and Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. Eur Respir Rev 2015;24:102-114.


Hinz B et al. The myofibroblast- one function, multiple origins. Am J Pathol 2007Jun;170(6):1807-16..

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ALVEOLAR EPITHELIAL INTERACT WITH MESENCHYMAL CELLS

Wolters PJ et al. Pathogenesis of IPF. Annu Rev Pathol 2014;9:157-179.

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Epithelial mesenchymal crosstalk

Alveolar epithelial cells Increased apoptosis Dysregulated proliferation Impaired wound healing

Fibroblasts/Myofibroblasts Myofibroblasts differentiation Resistance to apoptosis Increased proliferation Increased migration Enhanced ECM production

Modified from Thannickal ARM 2004

PDGF TGF- 6 integrin

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Apoptosis paradox in IPF

Thannikal VJ, Horovitz JC. Evolving concepts of apoptosis in IPF. Proc Am Thorac Soc 2006; 3:350-356.

Epithelial cells undergo apoptosis

Fibroblasts become resistant to apoptosis

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Apoptosis paradox in lung fibrosis- regulatory role for LPA1

Epithelium

Lung Injury

Fibrin Clot

Re-epithelialization

ExtracellularMatrix

FibroblastsFibroblast Recruitment

Proliferation and Matrix Deposition

Vascular leak andExtravascular Coagulation

Capillary

TGF- LPAPG E2

Epithelial Cell Death Fibroblast

Apoptosis

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Pulmonary Fibrosis - example IPFBleomycin-induced fibrosis is dependent on LPA1

Wild type LPA1 KO

14d post bleomycin, H&E stain, 100x

14d post bleomycin, Massons trichrome stain, 400xAndrew M Tager et al. Nature Med 2008 Jan; 14 (1):45-54

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AEC apoptosis is decreased in LPA1 KO- TUNEL -

WT LPA1 KO

Figure 1

0

WTLPA1 KO

2

4



1

2

3

A B C

D E F

G H

TUNEL

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p53

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WT LPA1 KO

TUNEL

p53

p21

Supplemental Figure E1

A B

C D

E F

Figure E1. Minimal apoptosis was present in the lungs of WT and LPA1 KO mice at baseline. Representative (A, B) TUNEL/peroxidase-stained, (C, D) p53/peroxidase-stained, and (E, F) p21/peroxidase-stained sections of WT and LPA1 KO mouse lungs at baseline prior to bleomycin challenge (day 0). Scale bars = 50 m.

D0

D3

B

D

A

C

Funke M. et al. The Lysophosphatidic acid Receptor LPA1 promotes epithelial cell apoptosis after lung injury. AJRCMB 2011 Mar;46(3):355-64.

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AEC apoptosis is decreased in LPA1 KO- TUNEL -

WT LPA1 KO

Figure 1

0

WTLPA1 KO

2

4



1

2

3

A B C

D E F

G H

TUNEL

p21

p53

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0

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set

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**

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#

WT LPA1 KO

TUNEL

p53

p21

Supplemental Figure E1

A B

C D

E F

Figure E1. Minimal apoptosis was present in the lungs of WT and LPA1 KO mice at baseline. Representative (A, B) TUNEL/peroxidase-stained, (C, D) p53/peroxidase-stained, and (E, F) p21/peroxidase-stained sections of WT and LPA1 KO mouse lungs at baseline prior to bleomycin challenge (day 0). Scale bars = 50 m.

D0

D3

B

D

A

C

WT LPA1 KO

Figure 1

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WTLPA1 KO

2

4



1

2

3

A B C

D E F

G H

TUNEL

p21

p53

J

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0

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set

1

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5


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0.4

0.8

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**

**

**

#

WT LPA1 KO

Figure 1

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WTLPA1 KO

2

4



1

2

3

A B C

D E F

G H

TUNEL

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Pulmonary Fibrosis - example IPFAEC apoptosis is dependent on cells adhesion


0

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Figure 5

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% spread

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serum serum serum

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Anti-apoptotic effects of LPA in primary fibroblasts

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Extracellular matrix

IPF ECM: cellular Fibronectin (FN-EDA), Collagen I and III, proteoglycan, hyaluronan

Thannikal VJ et al. Matrix Biology of IPF. A Workshop Report of the National Heart, Lung, and Blood Institute. Am J Pathol 2014, 184:1643-1651.


38

MECHANICS (STIFFNESS)

Liu F et al. Feedback amplification of fibrosis through matrix stiffening and COX-2 supression. J Cell Biol 2010 Aug 23;190(4):693-706

39


American Thoracic Society/European Respiratory Society International Multidisciplinary ConsensusClassification of the Idiopathic Interstitial Pneumonias. Am. J. Respir. Crit. Care Med. January 15, 2002vol. 165 no. 2 277-304


An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med Vol 188, Iss. 6, pp 733748, Sep 15, 2013.

40


Sarcoidosis

inflammatory disease

non-caseating granulomata

affecting multiple organs Skin Heart Eye Nervous system Bone, joints, muscle Endocrine and exocrine dysfunction Gastro-, genitourinary involvement Hematological, immunological involvement

41


Risk factors

Environmental - World trade center collapseIzbicki G et al. World trade center sarcoid like granulomatous pulmonary disease in NYC Fire department rescue workers. Chest 2007; 131:1414.

InfectiousMycobacteriapropionibacteria

T cells dysfunction

Genetic predisposition

42

SARCOIDOSISRADIOLOGICAL CLASSIFICATION

Patterson KC et al. Pulmonary Fibrosis in Sarcoidosis. Ann AmThorac Soc Vol 10, No 4, pp 362-370.

Sarcoidosis - fibrotic pulmonary disease

43


Sarcoidosis

Courtesy from Dr. Sabina Berezowska, Pathology Department University of Berne, Switzerland

Noncaseating granulomata

bronchocentric

T cell mediated disease

44

IANNUZZI MC ET AL. SARCOIDOSIS. N ENGL J MED 2007;357:2153-2165.

45

NECESSITY TO DISTIGUISH ORIGIN OF FIBROSIS

If diagnosis can not be determined management is challenging diverging treatment approaches for IPF and non-IPF ILD PANTHER study with negative effects of immunosuppression in IPF

patients INPULSIS trial (Nintedanib) included possible IPF

Skolnik K, Ryerson CJ. Unclassifiable interstitial lung disease: A review. Respirology. 2015 Jun 9.

Diagnostic consens should be achieved whenever possible

46


Conclusion

Different mechanism, e.g. impaired wound repair or chronic inflammation, can lead to end stage lung fibrosis

Various pathways, specifically TGF-, VEGF, LPA or extracellular matrix production are involved and targeted in current treatment approaches for IPF. Immunosuppression might be indicated if inflammation is predominant.

Separating impaired wound healing from inflammatory disease is crucial to select adapted therapies.

47

The diagnostic and therapeutic standard

Dr Katerina Antoniou Assistant Professor of Thoracic Medicine

ERS ILD Group Chair Medical School, University of Crete

71003 Heraklion GREECE

[email protected] SUMMARY Advanced Pulmonary Sarcoidosis (APS) is characterized by significant fibrocystic pulmonary lesions at CT and pathology. There are two main patterns of APS, one with predominant central bronchovascular distortion, often associated with airflow limitation, and the other with predominant honeycombing with a different location than in UIP with severe restrictive impairment and very low diffusion capacity of the lung for carbon monoxide. APS may be burnt out but is most often still active as evidenced by several findings, including on 18F-fluorodeoxyglucose-PET.There is an increased mortality and morbidity with chronic respiratory insufficiency, pulmonary hypertension stemming from multiple mechanisms, chronic pulmonary aspergillosis and extra infections. Acute worsening episodes are frequent. Serial spirometry, particularly forced vital capacity, is the most reliable tool for monitoring evolution. A new elegant algorithm based on pulmonary function and CT may predict survival. Despite important stakes, there is still a lack of therapeutic recommendations. The treatment options for pulmonary sarcoidosis have increased over the past 10 years. As new treatments have been introduced, the best way to assess and compare treatments remains unknown. The goal of this presentation is to discuss the standard treatments for pulmonary sarcoidosis, including glucocorticoids, and cytotoxic agents, such as methotrexate, azathioprine and leflunomide, and compare them to the newer biological agents, such as infliximab and adalimumab. We also discuss some novel treatments which are currently being evaluated. To compare these different regimens, we look at the measures used to assess response. These include pulmonary function, chest imaging, steroid sparing potential and, more recently, improvements in quality of life measures. While there is, as yet, no standard assessment for response, there is a growing consensus that response to treatment may include improvement of one or more of the following: forced vital capacity, chest imaging and steroid sparing. Several drugs used for pulmonary sarcoidosis have demonstrated improvement in one or more of these measures. However, the use of antisarcoidosis treatment is most often required at least as a temporary trial. Finally, the effect of pulmonary hypertension treatment has recently been the object of further evaluation. REFERENCES 1. Valeyre D, Nunes H, Bernaudin JF., Advanced pulmonary sarcoidosis, Curr Opin Pulm

Med. 2014 Sep;20(5):488-9 2. Baughman RP, Medical therapy of sarcoidosis, .Lower EE.Semin Respir Crit Care Med.

2014 Jun; 35(3):391-406. doi: > 10.1055/s-0034-1376401. Epub 2014 Jul 9. 3. Baughman RP, Grutters JC, New treatment strategies for pulmonary sarcoidosis:

antimetabolites, biological drugs, and other treatment approaches, Lancet Respir Med. 2015 Jul 20. pii: S2213-2600(15)00199-X. doi: 10.1016/S2213-2600(15)00199-X. [Epub ahead of print]

48

4. Baughman RP, Lower EE., Treatment of Sarcoidosis, Clin. Rev Allergy Immunol. 2015 Aug; 49(1):79-92. doi: > 10.1007/s12016-015-8492-9

EVALUATION 1. Which of the following drugs is the first choice as steroid sparing agent in sarcoidosis?

a. leflunomide b. infliximab c. mycophenolate d. methotrexate e. azathioprine

2. Which of the following is not an indication for the use of biological TNFa inhibitors?

a. unsucceful treatment with prednisolone and antimetabolites b. pulmonary disease with increased lymphocytes in BAL c. debilitation by lupus pernio d. neurosarcoidosis in persistent disease activity e. cardiac sarcoidosis in persistent disease activity

3. Fibrotic sarcoidosis has been associated with increased mortality from:

a. acute worsening events b. infections c. pulmonary hypertension d. respiratory insufficiency e. all of the above

49

The diagnostic and therapeutic standard

Dr Katerina Antoniou, MD, PhD

Assistant Professor of Thoracic Medicine ERS ILD Group Chair

Medical School, University of CreteHeraklion, Crete

50

Disclosures

None to declare

Some material is provided by Prof Baughman and Prof Wells

51

Outline of the talk

Introduction

Main issues

Diagnosis

Monitoring

Treatment

52

Introduction

Pulmonary fibrosis occurs a significant proportion of pulmonary sarcoidosis patients

It is associated with morbidity and some mortality

However not all patients with fibrosis are impaired by their disease

Treatment options are unclear

53

Increasing mortality from sarcoidosis

Swigris JJ, et al. Am J Respir Crit Care Med 2011; 183(11):1524-1530.54

Increasing mortality from sarcoidosis

Swigris JJ, et al. Am J Respir Crit Care Med 2011; 183(11):1524-1530.55

Respiratory Failure in Sarcoidosis

Seven year study at one institution

479 patients followed for at least 1 year 22 (4.6%) died

13 died of respiratory failure

2 died from causes unrelated to sarcoidosis

Chest X-ray Stage

All Patients

Died of Respira-tory Failure

0 27 0

1 101 0

2 92 0

3 41 0

4 62 13 (21%)

Baughman RP, et al. Sarcoidosis 1997;14:154-15856

Respiratory Failure in Sarcoidosis

Vital Capacity,

l

LowestVC

Highest VC after Therapy

2.5 352 381

Baughman RP, et al. Sarcoidosis 1997;14:154-15857

Mortality for fibrotic SarcoidosisStudy Total

number of patients

Number with Stage 4 disease

Duration of follow up, median or mean(years)

Overall mortality

Mortality of stage 4

Nardi 142 142 (100%) 7 11% 11%

Baughman 479 62 (13%) 7 4.6% 21%

Walsh 503 503 (100%) 4.2 21% 21%

Nardi A, et al. Eur Respir J 2011; 38(6):1368-1373.Baughman RP, et al. Sarcoidosis 1997; 14:154-158.Walsh SL, et al. Lancet Respir Med 2014; 2(2):123-130.

58

Survival of Stage 4 sarcoidosis

Nardi A, et al. Eur Respir J 2011; 38(6):1368-1373.59

Survival of Fibrotic SarcoidosisBromptom Experience

Walsh SL, et al. Lancet Respir Med 2014; 2(2):123-30.

Original Confirmation

60

IPF versus Sarcoidosis Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis

Most patients die from progressive fibrosis

Honeycombing in basilar and subpleural regions

Anti-inflammatory therapy has very limited role

Acute exacerbations have a high morbidity and mortality

Pulmonary hypertension is seen in some patients

Sarcoidosis Pulmonary Fibrosis

Only a small percentage have progressive fibrosis

Traction bronchiectasis in upper lobes

Anti-inflammatory therapy is useful in most patients

Acute events occur frequently and usually are self limited

Pulmonary hypertension is a common complication

61

Initial evaluation

Determine whether the reason to treat is symptomatic or is driven by objective measures of disease severity

If the latter, do not try to measure reversibility with precision. Focus on disease severity

The evaluation of severity is multi-dsicplinary: PFT >chest radiography, sx

62

If dyspnoea is disproportionate

Exclude cardiac involvement

Exclude pulmonary hypertension

Consider the multiplicity of alternative causes of dyspnoea: sarcoid-related and others

Quantify exercise tolerance objectively: 6MWD, is limitation due to hypoxia

63

Not all stage 4 patients are dyspneic

Yeager H, et al. Sarcoidosis Vasc Diffuse Lung Dis 2005; 22(2):147-153.64

Fibrosis patient with no symptoms2009 2012

FVC 2.47 2.42

FVC % predicted

99% 100%

FEV-1 1.80 1.63

FEV1/FVC 73% 68%

DLCO 9.39 10.46

DLCO % predicted

52% 59%

65

Accurate monitoring

66

Goals of monitoring

Detection of progression Complications of treatment

Need for oxygen therapy

Detection of complications such as aspergilloma, pulmonary hypertension

Optimal timing of referral for transplantation

67

Historical detection of progression

Symptoms, chest radiography, pulmonary function tests

PFT traditionally viewed as cardinal

Consensus statement that serial chest radiography and spirometry should be used

ATS/ERS/WASOG statement on sarcoidosis. AJRCCM 1999; 160:736-755

68

Key issues

Do we now have alternatives to traditional monitoring modalities?

Why there is not a best stand-alone test to detect change

How best should we integrate data in identifying change?

69

Candidate modalities

BAL or exhaled breath markers

Serum markers: IL2, serum ACE, Ca, Calciferol and others

None of these have a validated role in routine monitoring although some may alert the clinician to a higher likelihood of change

Imaging modalities other than chest radiography ..

70

Imaging modalities

Gallium scanning: .obscolescence

HRCT scanning: .frustration

FDG PET: .promise but uncertainty

71

FDG PET scanning

More sensitive than gallium scanning in detecting active pulmonary disease

Not clear that adds usefully to baseline staging

Useful in monitoring selected patients?

From Chowdhury FU et al, 200972

Change in FDG PET

Reductions in abnormal signal following steroid therapy

In a study of infliximab in refractory sarcoid, there was complete or partial regression of signal in 11/12 patients.

Keijsers RGM. Sarcoidosis VDLD 2008; 25:143-50

Teirstein AS et al. Chest 2007; 132:1949-53

From Chowdhury FU et al, 2009 73

HRCT

Surely ideal for the detection of change!

Current studies that validate serial HRCT .74

HRCT: the problems (1)

Validation.What exactly is the gold standard for

change?

Is HRCT sometimes too sensitive?

76

HRCT: the problems:

What constitutes important change?

Change in morphology? - definiteChange in extent? - uncertain

77

HRCT: the problems

How should change in extent be scored?

What constitutes a significant change?

Is significant change scored reproducibly?

Radiation

78

The Potchen precept

The only utility of a (diagnostic)

test is to reduce uncertainty

EJ Potchen

79

Serial HRCT

Should not be performed by protocol

Useful to diagnose aspergilloma

May be useful when other tests are confusing, and therefore a baseline HRCT justifiable in pulmonary sarcoidosis.

80

So we are left with what we have always had

Pulmonary function tests:

- which test?

- what constitutes significant change?

Chest radiography

- how to score it?

- how to integrate it?

Symptoms81

In clinical practice, the detection of change is multidisciplinary

There is no single clinical variable or primary end-point that applies equally to all patients

82

Pulmonary function tests

Major heterogeneity in patterns of functional impairment

Obstruction, restriction, disproportionate reduction in measures of gas transfer

FVC may, on average, be the single most reliable serial variable

But a cardinal variable should sought in each patient

83

Pulmonary function end-points

Measurement variation an increasing confounder in less progressive disease (Bayes theorem). False positive changes of 10-15% in FEV1 and FVC a key problem.

Therefore, a need to examine trends in separately measured variables (DLco!) to confirm consistency in trends

84

PFT changes in Fibrotic Sarcoidosis

Nardi Baughman Walsh (Group A)

Number 142 129 251

FVC % predicted

71.6+22.4 * 78.4+20.4 82.4+24.2

FEV-1% predicted

63.9+20.7 57.2+18.0 72.9 +25.7

FEV1/FVC % 73.4+14.0 72.4+13.4 N.R.

DLCO % predicted

56.2+17.8 75.2+23.8 58.5+21.4

Nardi A, et al. Eur Respir J 2011; 38(6):1368-1373.Baughman RP and Lower EE, University of Cincinnati clinic.Walsh SL, et al. Lancet Respir Med 2014; 2(2):123-130. 85

Detection of pulmonary hypertension

Amongst sarcoidosis patients with chronic exercise intolerance, up to 50% have pulmonary hypertension

This is a further reason to monitor DLco routinely in more advanced pulmonary disease.

Isolated change in DLco at two to four years in 15-20%

Baughman RP et al: Sarcoidosis VDLD 2006; 28:103-116

Zappala CJ et al: Sarcoidosis VDLD 2011; 28:81-160 86

How should chest radiographs be scored?

Historically, change has been quantified as change in morphologic components or, more simply, as change in stage.

We run the risk of asking too much of the chest radiograph

It is a blunt instrument, we need a blunt scoring system

87

Change in pattern versus simple change in extent

Comparison of Muers system and a simple system in a cohort of 135 patients

Simple five-point scale for global change

FVC trends correlated better with gobal change (R = 0.35, p

A three-point serial CXR scale(better/no change/worse)

A more sensitive measure than change in stage (p

For clinical trials

Although FVC the best primary end-point, it has the twin problems of insensitivity and the possibility of false positive changes of 10-15%. Therefore, a composite end-point is recommended

EITHER a change in FVC>15% OR a change in FVC of 5-15% in association with a definite change on chest radiography

90

In clinical practice

Rationalise PFT trends.

Integrate with side by side chest radiography and symptomatic change. Do not view PFT as definitive unless the amplitude of change is definitive or trends are supported by other data

If still in doubt, consider HRCT

91

CPI

CPI >40 CPI > 40

MPAD/AAD > 1

or

Extent of fibrosis on HRCT >20%

Yes

High risk/poor prognosis

No

Low risk/good prognosis

CPI=91.0-(0.65*percent predicted DLCO)-(0.53*percent predicted FVC)+(0.34*percent predicted FEV-1)

Walsh SL, et al. Lancet Respir Med 2014; 2(2):123-30. 92

HRCT in sarcoidosis: Major Features

Three main CT patterns Bronchial distortion,

Honeycombing

Linear opacities.

Other patterns Endobronchial granulomatous lesions

Aspergilloma colonization

Bronchiectasis

Air trapping

Naccache JM, et al J Comput Assist Tomogr 2008;32:905-912.Hennebicque AS,et al Eur Radiol 2005;15:23-30. 93

Pathology of fibrotic sarcoidosis Prospectively evaluated histologic sections from 9

lung explants with end-stage sarcoid lung disease 7 women and 2 men.

Four lungs showed active granulomatous disease, with nonfibrotic nodular granulomas in the interstitium;

Five were predominantly fibrotic, of which 3 had areas of honeycombing (cysts lined by respiratory epithelium with surrounding scar). Patients in the fibrotic phase were significantly older (P=0.016).

Xu L, Kligerman S, Burke A. Am J Surg Pathol 2013; 37(4):593-600.

94

Pathology of fibrotic sarcoidosis

Granulomas were present in a lymphatic distribution (along bronchi, the lobular septa, and the pleura)

Granulomas were not identified in 2 lungs in the fibrotic phase.

In contrast to the honeycombing of UIP, the honeycombing was predominantly central, with prominent bronchiectasis.

These end-stage sarcoid lungs were characterized by a fibrotic and active granulomatous pattern, both of which are very distinct from that seen in UIP.

Xu L, Kligerman S, Burke A. Am J Surg Pathol 2013; 37(4):593-600.95

End stage pulmonary sarcoidosis:Features of explanted lung of 7 pts

Radiographic findingsInterstitial fibrosis

Other findings

Upper lobe bullous emphysema with hilar adenopathy

Mild None

Fibronodular changes, focal emphysematous blebs with hilar and mediastinal adenopathy

Moderate None

BHL with fibronodular disease Severe None

Hilar adenopathy with hilar retraction SevereSevere IP with occasional fibroblastic foci

Upper lobe honeycombing with mediastinal adenopathy and sparing of lung bases

MildSevere IP with superimposed DAD

Upper lobe disease with mediastinal and hilar adenopathy

Severe Honeycomb with UIP pattern

Upper lobe disease with ground-glass opacities in the left lower lobe

Severe Honeycomb with UIP pattern

Shigemitsu H, et al. Eur Respir J 2010;35:695-697 96

End stage sarcoidosis with usual interstitial pneumonitis pattern

Fibroblastic foci

Shigemitsu H, et al. Eur Respir J 2010;35:695-69797

Treatment issues

98

For individual patients, evaluation is focused on indications for treatment

In medical texts, indications for therapy often provided as confusing and lengthy lists of individual indications

Even respiratory indications can be drawn up as a list of scenarios, based on individual tests

There are two broad reasons to treat pulmonary sarcoidosis and our evaluation should focus on these

99

Baseline evaluation with regard to treatment indications

Is there unacceptable loss of quality of life?

Is there danger of long-term disability?

The two often overlap but are definitely NOT synonymous

Clarity on which treatment goal applies influences both management and monitoring profoundly

100

Evaluation of loss of QOL

Is there a symptom package which requires

treatment, even though organ involvement is only mild?

Tabulate pulmonary (cough, dyspnoea and chest pain) and associated non-pulmonary (arthralgia, eye symptoms, fatigue et alia) symptoms

If treatment not required for danger reasons,

patient-driven QOL-based treatment decisions are appropriate

101

The evaluation of whether treatment is needed for danger

reasons

102

Patterns of disease behaviour

Self limited inflammation Stable burnt out fibrosis

Major inflammation (with or without fibrosis) Progressive fibrotic disease, driven by occult

inflammation in which stabilisation is a realistic goal

Inexorably progressive fibrotic disease despite best treatment: rare in sarcoidosis

103

The essential pulmonary goal with regard to dangerous disease

To protect the lungs from progressive fibrotic damage as long as disease remains active, whilst identifying the minimum dose that meets this aim

This applies equally to predominantly inflammatory and fibrotic disease.

104

The real problem is distinguishing between stable and progressive

fibrosis The issue is the long term prevention of

disease progression

We need a measure of disease activity in fibrotic disease which identifies progressiveness

105

Measures of disease activity that

fail or have not been evaluated Imaging: Gallium signal, HRCT patterns. I

will return to a possible exception.

Bronchoalveolar lavage

Serum measures: inflammatory markers, ACE, IL2, cholicalciferol

Breath markers106

If assessing disease activity fails

us... Fall back on first principles

More severe disease has a track record of repeated

progression and is therefore more likely to progressive in future. In more severe disease, further irreversible damage has more devastating consequences

Disease duration matters

Plainly, observed stability and progression matter 107

Staging severity

Primary variables FEV1, FVC, DLco

No absolute threshold for all patients. Confounding effect of the normal range.

Uneasy about observation if DLco

Treatment issues The greatest difficulties in pulmonary

sarcoidosis are the most frequent difficulties

Clarity of indications for treatment - danger versus QOL is the basis of acceptance of management by patients

Do not overuse second line treatments

Treat irreversible sarcoidosis to slow decline when disease is severe or progressive

109

Second line agents? Toxiicity of treatments can be ranked

broadly into three groups

The nastiest is prolonged high dose steroid

The nicest is low dose steroid (10mg Pred)

The steroid-sparing agents are somewhere in between

Therefore the key question is. 110

Are the long-term needs of the patient, vis a vis either danger or quality of life, met by Prednisolone 10mg daily?

111

Efficacy and safety profile in Sarcoidosis

Its efficacy and toxicity profile: compared withmethotrexate in a large retrospective cohort

similar efficacy, more infections in patients treated with azathioprine

Baughman et al. : half of the patients who failed to respond to methotrexate had a positive response when they switched to azathioprine.

It was not described whether patients were irresponsive or had to quit due to side effects.

Improvement of lung function and steroid dose was not quantified in these reports.Vorselaars, A. D.; et al. Chest, 2013, 144, 825-812

Baughman, R. P.; et al. Sarcoidosis Vasc. Diffuse Lung Dis.,1997112

D.M. Vorselaars, et al. Inflammation & Allergy - Drug Targets, 2013 115

Second-line therapyMTX/AZA/LEF/HCQ

116

Vorselaars AD, Wuyts WA, Vorselaars VM, et al. Chest 2013117

http://www.ncbi.nlm.nih.gov/pubmed?term=Vorselaars AD[Author]&cauthor=true&cauthor_uid=23538719http://www.ncbi.nlm.nih.gov/pubmed?term=Wuyts WA[Author]&cauthor=true&cauthor_uid=23538719http://www.ncbi.nlm.nih.gov/pubmed?term=Vorselaars VM[Author]&cauthor=true&cauthor_uid=23538719

Results

200 patients were included: 145 received methotrexate and 55 azathioprine.

Of all patients completing one year of therapy, 70% had a reduction in daily prednisone dose of at least 10 mg.

FEV1 showed a mean increase of 52 ml/year (p=0.006) and VC of 95 ml/year (p=0.001) in both treatment groups.

There were more patients with infections in the azathioprine group (34.6 vs 18.1% p=0.01), but no differences regarding other side effects.

119

Side Effects

INFECTIONS

121

Side effects Respiratory infections requiring antibiotics comprised the

majority (30 patients);

4 patients experienced varicella zoster virus (all in methotrexate group).

One case of empyema and two cases of sepsis (all in azathioprinegroup) occurred.

GI problems were reported by 37 patients (19.0%) patients and were the most common reason for patients to quit treatment because of nausea, stomachache, and diarrhea.

Severe hepatic function decline requiring alteration or discontinuation of treatment was found in 14 patients (7.2%);

Liver function recovered in all patients after discontinuation of treatment.

Other repeatedly reported side effects were headache (4.1%) and malaise (7.7%). 122

Treat the InflammationThree months of Infliximab

PRE POST123

Survival of Stage 4 sarcoidosis


Treatment of Stage 4 sarcoidosis

95 (67.4%) patients had their sarcoidosis therapy significantly intensified after inclusion. Corticosteroids

Initiation or reintroduction in 39 cases

Increase dosage in 19 cases

Other drugs Methotrexate in 19 cases

Hydroxychloroquine in 11 cases

Azathioprine in 5 cases

Thalidomide in 1 case

Mycophenolate in 1 case


Treatment of Stage 4 sarcoidosis

Evaluation of PFTs within 312 months of therapy was available in 57 patients. HRCT (51 patients), SACE (52 patients) and BAL (25 patients) were performed before the initiation of therapy.

The recorded outcomes were: Improvement (36.8%),

Stability (50.9%)

Worsening (12.3%).


Acute worsening of sarcoidosis

Progression of pulmonary

disease

Progression of other organ systems

Cardiac

Pulmonary hypertension

Muscle disease

Neurologic disease

Complications of damaged lung parenchyma

Bronchospasm

Bacterial infections

Chronic pulmonary aspergillosis

Know associations to sarcoidosis or treatment

Pulmonary embolism

Diabetes

Coronary artery disease

Unknown associations to sarcoidosis

Judson MA and Baughman RP Current Opin Resp Dis 2014 127



disease


Cardiac


Muscle disease

Neurologic disease


Bronchospasm




Pulmonary embolism

Diabetes



Judson MA and Baughman RP Current Opin Resp Dis 2014 in press 128

Outcome of FEV-1/FVC with Corticosteroid Therapy

Chambellan A et al. Chest 2005;127:472-481

2005 by American College of Chest Physicians

Early treatment

Late treatment

129



disease


Cardiac


Muscle disease

Neurologic disease


Bronchospasm




Pulmonary embolism

Diabetes



Judson MA and Baughman RP Current Opin Resp Dis 2014 in press 130

Acute exacerbations in IPF are associated with significant short term mortality

Abe S, et al. Intern Med 2012; 51:1487-91131

Mycetoma as a consequence of Sarcoidosis

132

Aspergillosis in Sarcoidosis

Represents a major health care burden of the disease Denning DW, et al. Eur Respir J 2013;

41(3):621-626.

In series from Detroit, occurred in 2% of all patients seen in their clinic Pena TA, et al. Lung 2011;189:167-172

May respond to anti-fungal therapy Kravitz JN, et al. Chest 2013; 143(5):1414-

1421.133

Prevalence of sarcoidosis associated pulmonary hypertension (SAPH)

Echo alone Right Heart Cath

All patients attending clinic

Patients referred for evaluation of dyspnea

Patients listed for transplant

134

Pulmonary Hypertension associated with Stage 4 disease

Baughman RP, et al. Chest 2010;138:1078-1085.Sulica R, et al. Chest 2005;128:1483-1489.Barnett CF, et al. Chest 2009;135:1455-1461.

135

6 Minute walk 1.8Normal right

ventricle

Watch

Desat 2.5

TAPSE < 1.8Evidence of right ventricular dysfunction

Echo indeterminateMean PA/ascending aorta>1

Right heart catheterization

Screening for Sarcoidosis Associated Pulmonary Hypertension

136

Survival from time of cath

Patients with SAPAH had significantly shorter predicted survival compared to other two groups (P

Characteristics of patients:Mild/moderate versus severe PAH

Pam< 40 mm Hg Pam> 40 mm Hg P value

Number 71 31

Mean SD Mean SD

AgePHDx 53.164 8.6718 53.100 9.6930 0.9742

PA m 30.925 4.8668 50.086 6.4256

Time until first serious event defined as death, lung transplant, or hospitalization

Difference between groups, p=0.0225

PA m< 40 mm Hg

Pam> 40 mm Hg

139

Treatment for SAPH

Class/Drug Evidence ResultsEndothelin receptor antagonistBosentan DBPC45

CS40-42

DBPC45

Significantly improved hemodynamics at after 16 weeks versus placebo

Ambrisentan PCS64 PCS64

Trend for improvement in HRQoL

DBPC: double blind, placebo controlled; PCS: prospective case series; CS: case series 140

Treatment for SAPHClass/Drug Evidence ResultsProstacyclinsEpoprostenol CS60, CR58 CS60

Clinical improvementIloprostenol PCS61 PCS61

Improved hemodynamics in 6/15

Improved HRQoL

DBPC: double blind, placebo controlled; PCS: prospective case series; CS: case series

141

Treatment for SAPH

Class/Drug Evidence ResultsPhosphodiesterase inhibitorSildenafil CS39;41;42 CS39

Improvement in hemodynamics but not 6MW distance

Multiple drug therapy

CS 40-42

DBPC: double blind, placebo controlled; PCS: prospective case series; CS: case series 142

Bosentan for sarcoidosis associated pulmonary arterial hypertension

(BoSAPAH): a double-blind, placebo controlled study

Robert P. Baughman, University Cincinnati

Dan A Culver, Cleveland Clinic Foundation

Francis Cordova, Temple University

Maria Padilla, Mount Sinai New York

Kevin Gibson, University of Pittsburgh

Elyse E Lower, University of Cincinnati

Peter J Engel, Ohio Heart and CardiovascularBaughman RP et al Chest 2014: 145: 810-817. 143

Study Outcome at 16 weeks43 patients

All with RHC and 6MWT

Bosentan

25 pts

16 weeks

23 had 6MWT

16 weeks

21 had RHC

2 stopped drug before week 8

Placebo

14 pts

16 weeks

11 had 6MWT

16 weeks

9 had RHC

2 stopped drug before week 8

2 screen failures

2 withdrew consent

RHC: right heart catheterization; 6MWT: 6 minute walk test144

PA Mean pressure before and after 16 weeks of therapy

145

Conclusion

Pulmonary fibrosis is a significant problem in pulmonary sarcoidosis

Not all patients with pulmonary fibrosis are dyspneic

For the dyspneic patient, there is significant mortality

Treatment may helpful in the dyspneic patient

146

Chronic interstitial lung diseases in children: Diagnosis and treatment

Prof. Annick Clement Department of Paediatric Pulmonology

National Reference Center for Rare Lung Diseases University Pierre et Marie Curie

Trousseau Hospital 26 Av. Dr. A. Netter

75571 Paris FRANCE

[email protected] AIMS

To describe the spectrum of diffuse parenchymal lung diseases/interstitial lung diseases in the postnatal period and during childhood

To describe the diagnostic approaches To describe the treatment strategies

SUMMARY

Interstitial lung diseases (ILD) in children represent a heterogeneous group of respiratory disorders that affect the lung parenchyma. ILD is an umbrella term for a number of pathological conditions characterized by inflammation and/or remodeling of the various anatomical components, which include the alveolar structure (i.e. the alveolar epithelium, the interstitium, and the pulmonary capillary endothelium) as well as the terminal bronchioles. In most situations, these diffuse lung disorders are chronic, with high morbidity and mortality. ILD are rare and cover a large spectrum of diseases. Their causes remain undetermined in many situations. In addition, in children, disease expressions are dynamically influenced by the ongoing process of lung growth and maturation. Consequently, epidemiology of the various forms of pediatric ILD is difficult to establish. Extrapolation from small studies has suggested an approximate incidence of 0.8 case per 100.000 population. However, this estimation is certainly under-estimated due to the lack of standardized definitions, the absence of organized reporting systems, and the variety of pathological conditions. In addition, clinical presentation is nonspecific, contributing to a poor recognition of the disorders that may be confused with other diseases. Classical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can contribute to progressive lung damage and ILD. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The presentation reviews ILD in infants and children, with emphasis on current concepts of pathophysiological mechanisms and etiology. Pediatric ILD diagnosis requires a structured evaluation paying attention to patient and family history, exposures and systemic diseases Based on this clinical approach, the main groups of pediatric ILD include : 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic strategies are mainly based on anti-inflammatory, immunosuppressive and/or anti-fibrotic drugs. An overall favorable response to corticosteroid therapy is observed in around 50% of cases. Respiratory sequelae include limited exercise tolerance and/or a need for long-term oxygen therapy. The outcome is highly variable with a mortality rate around 15 %.

147

http://en.wikipedia.org/wiki/Pulmonary_alveolushttp://en.wikipedia.org/wiki/Epitheliumhttp://en.wikipedia.org/wiki/Capillaryhttp://en.wikipedia.org/wiki/Endothelium

REFERENCES

1. Clement A, Nathan N, Epaud R, Fauroux B and Corvol H. Interstitial lung diseases in children. Orphanet J Rare Dis. 2010 Aug 20; 5:22.

2. Deterding RR, Brody AS, Hagood JS, Young LR. Children's Interstitial Lung Disease. .Pediatr Allergy Immunol Pulmonol. 2010 Mar; 23(1):91-96.

3. Nathan N, Abou Taam R, Epaud R, Delacourt C, Deschildre A, Reix P, Chiron R, de Pontbriand U, Brouard J, Fayon M, Dubus JC, Giovannini-Chami L, Bremont F, Bessaci K, Schweitzer C, Dalphin ML, Marguet C, Houdouin V, Troussier F, Sardet A, Hullo E, Gibertini I, Mahloul M, Michon D, Galeron L, Vibert JF, Thouvenin G, Corvol H, de Blic J, Clement A, For The French Respirare Group FT. A national internet-linked based database for pediatric interstitial lung diseases: the French network. Orphanet J Rare Dis. 2012 Jun 15; 7(1):40.

4. Kurland G, Deterding RR, Hagood JS, Young LR, Brody AS, Castile RG, Dell S, Fan LL, Hamvas A, Hilman BC, Langston C, Nogge LM, Redding GJ. An official American Thoracic Society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Am J Respir Crit Care Med. 2013, 188(3): 376- 394.

5. Taytard J, Nathan N, de Blic J, Fayon M, Epaud R, Deschildre A, Troussier F, Lubrano M, Chiron R, Reix P, Cros P, Mahloul M, Michon D, Clement A, Corvol H; French RespiRare group. New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort. Orphanet J Rare Dis. 2013 Oct 14; 8(1):161-8.

6. Bush A, Anthony G, Barbato A, Cunningham S, Clement A, Epaud R, Gilbert C, Goldbeck L, Kronfeld K, Nicholson AG, Schwerk N, Griese M; ch-ILD collaborators. Research in progress: put the orphanage out of business. Thorax. 2013 Oct;68(10):971-3

7. Kuo CS, Young LR. Interstitial lung disease in children. Curr Opin Pediatr. 2014 Jun; 26(3):320-7.

8. Nathan N, Marcelo P, Houdouin V, Epaud R, de Blic J, Valeyre D, Houzel A, Busson PF, Corvol H, Deschildre A, Clement A; RespiRare and the French Sarcoidosis groups. Lung sarcoidosis in children: update on disease expression and management. Thorax. 2015 Jun; 70(6):537-42.

9. Nathan N, Corvol H, Amselem S, Clement A. Biomarkers in Interstitial lung diseases. Paediatr Respir Rev. 2015 May. pii: S1526-0542(15)00035-4.

10. Bush A, Cunningham S, de Blic J, Barbato A, Clement A, Epaud R, Hengst M, Kiper N, Nicholson AG, Wetzke M, Snijders D, Schwerk N, Griese M; chILD-EU collaboration. European protocols for the diagnosis and initial treatment of interstitial lung disease in children. Thorax. 2015 Jul. pii: thoraxjnl-2015-207349.

EVALUATION

1. Which of the following is the LESS FREQUENT cause of surfactant disorders after the neonatal period?

a. SFTPB defect b. SPTPC defect c. ABCA3 defect d. Nkx2.1 defect

2. Which of the following is an UNLIKELY diagnosis in infants with ILD?

a. Neuroendocrine cell hyperplasia b. Pulmonary glycogenosis c. Idiopathic pulmonary fibrosis d. Pulmonary proteinosis

3. Which of the following is the LESS FREQUENT ILD diagnosis in young children?

a. Hemosiderosis b. Surfactant disorder c. Connective disorder d. Granulomatous disease

148

http://www.ncbi.nlm.nih.gov/pubmed/22332034http://www.ncbi.nlm.nih.gov/pubmed/24125570http://www.ncbi.nlm.nih.gov/pubmed/24125570http://www.ncbi.nlm.nih.gov/pubmed/23429832http://www.ncbi.nlm.nih.gov/pubmed/23429832http://www.ncbi.nlm.nih.gov/pubmed/24752172http://www.ncbi.nlm.nih.gov/pubmed/25855608http://www.ncbi.nlm.nih.gov/pubmed/25855608http://www.ncbi.nlm.nih.gov/pubmed/26027849http://www.ncbi.nlm.nih.gov/pubmed/?term=Bush%20A%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Cunningham%20S%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=de%20Blic%20J%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Barbato%20A%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Clement%20A%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Epaud%20R%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Hengst%20M%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Kiper%20N%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Nicholson%20AG%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Nicholson%20AG%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Wetzke%20M%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Snijders%20D%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Schwerk%20N%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=Griese%20M%5BAuthor%5D&cauthor=true&cauthor_uid=26135832http://www.ncbi.nlm.nih.gov/pubmed/?term=chILD-EU%20collaboration%5BCorporate%20Author%5Dhttp://www.ncbi.nlm.nih.gov/pubmed/26135832

Annick Clement

Department of Pediatric PulmonologyNational Reference Center for Rare Lung DiseasesUniversity Pierre et Marie Curie, Trousseau Hospital, Paris, Fr

Chronic interstitial lung diseases in children:

Diagnosis and treatment

ERS INTERNATIONAL CONGRESS 2015

AMSTERDAM, Netherlands, 26-30 september

149

Presenter disclosure

Annick Clement

No conflicts of interest to declare in relation to this presentation

150

Diffuse Parenchymal Lung diseases (DPLD)

Interstitial Lung Diseases (ILD)

and

DPLD: a larger group of clinical conditions than ILD

ILD DPLD

151

DPLD: Diseases of the lung parenchyma

The lung parenchyma: the respiratory zone

Composed of respiratory bronchioles, alveolar ducts, alveolar sacs

152

DPLD vs ILD

More adapted to the various clinical situations

Larger group of pathologic conditions

Physiopathology: additional cellular partners and pathways, also implicated in the processes of lung growth and development

DPLD

153

Pediatric DPLD/ILD and age particularities

Pseudoglandular Canalicular Saccular Alveolar

154

Diffuse developmental disordersAcinar dysplasiaCongenital alveolar dysplasiaAlveolar capillary dysplasia with misalignementof pulmonary veins

Growth abnormalities reflecting deficient alveolarizationPulmonary hypoplasiaChronic neonatal lung diseaseBronchopulmonary dysplasia

Specific conditions of undefined etiologyNeuroendocrine cell hyperplasia of infancyPulmonary glycogenosis

Surfactant dysfunction disordersSFTPB mutationsSPTPC mutationsABCA3 mutationsPulmonary proteinosis

Disorders more prevalent in infancy Other disorders

Disorders related to systemic disease processesCollagen vascular disordersSarcoidosisStorage diseaseLangerhans cell histiocytosis

Disorders of the normal host-presumed immune intact Infectious/post-infectious processesAspiration syndromeRelated to environmental agents

Hypersensitivity pneumonitisToxic inhalation

Eosinophilic pneumonia

Disorders of the immune compromised hostOpportunistic infectionsRelated to therapeutic interventionRelated to transplantation and rejection

Disorders masquerading as ILDLymphatic disordersRelated to cardiac dysfuntionArterial hypertensive vasculopathy

Study cohort: 165 patientsAll diagnostic lung biopsies in children < 2 yrs

DPLD/ILD: Classification in infants

Kurland G et al. Am J Respir Crit Care Med 2013

155













156













157

Rare conditions

Physiopathology Disrupted structural or functional developmentGenetic contributors

DiagnosisUsually diagnosed by lung biopsy or autopsy

Mortality approaches 100%

Diffuse developmental disorders


158


Growth abnormalities reflecting deficient alveolarizationPulmonary hyoplasiaChronic neonatal lung diseaseBronchopulmonary dysplasia











159

Term newborn, uncomplicated pregnancy Rapidly developing respiratory distress Tachypnea, cyanosis Profound hypoxemia Severe pulmonary hypertension Unresponsiveness to usual intervention

Diffuse Alveolar Capillary Dysplasia

Diagnosis: Lung biopsy or autopsy Extra-pulmonary abnormalities (50-80 %)

Gastrointestinal, genitourinary cardiovascular

Lethal Some familial forms

Patient case

160

Diagnosis: Histology

Thickened alveolar septae with decreased number of dilated pulmonary capillaries located away from the alveolar epithelium, and absence of the usual alveolar-capillary barrier

Malposition of congested pulmonary veins, adjacent to pulmonary artery branches in the same adventitial sheath

Medial hypertrophy of small pulmonary arteries and muscularization of distal arterioles

Lymphangiectasis (30% cases)


Abnormal vascular development and deficient alveolarization

161

Stankiewicz P et al. Am J Med Genet 2009

Member of the FOX (Forkhead box) family of transcription factors characterized by a distinct forkhead DNA binding domain

Role in:Epithelium-mesenchyme signaling, as a downstream target of Sonic hedgehog Cell migration during embryonic and fetal development

Among causes: FOXF1 dysfunction


Dharmadhikari AV et al. Current Genomics 2015

3.9 kb gene, 2 exons, located on chromosome 16q24.1 Complex expression of FOXF1, with the maternal copy being predominantly

expressed

~ 40% patients with Diffuse Alveolar Capillary DysplasiaDeletions of the FOX gene cluster ( FOXF1, FOXC2, FOXL1) Inactivating mutations of FOXF1

10% familial forms (recessive)

FOXF1

FOXF1

162













163













164

Pediatric DPLD and bronchopulmonary dysplasia (BPD)

Term or preterm infants, with early postnatal lung injury Presenting with severe pulmonary symptoms

Variable alveolar enlargement

Clinical condition

Histology

BPD: current description Histology: fewer airway abnormalities and more parenchymal changes CT scan: parenchymal infiltrates and ground glass in almost 50%

Tonson La Tour A et al. Pediatr Pulmonol 2013

165













166

Neuroendocrine cell hyperplasia of infancy

3 month old term infant Parent concern: permanent fast breathing Happy despite tachypnea (60-80/min) Poor weight gain SaO2: 93-95%

Patient case

Chest X-ray: hyperinflation

Bronchoscopy: No structural abnormalities Normal cytology and No infection

Echocardiogram normal

167

Neuroendocrine cell hyperplasia of infancy

Young LR et al. Chest 2013

Increased numbers of bombesine-immunopositivepulmonary neuroendocrine cells

No ev

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