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Interstitial Lung Disease (ILD)• Large number of conditions that

may involve:⎻ Alveoli

⎻ Alveolar epithelium

⎻ Capillary endothelium

⎻ Spaces between structures

⎻ Perivascular and lymphatic tissues

• Share similar radiographic, physiologic, or pathologic manifestations

• Similar symptoms⎻ Cough

⎻ Dyspnea on exertion

⎻ Fatigue

King, T. Chapter 261. In: Harrisonʼs Principles of Internal Medicine;19th ed.https://homesecurity.press/quotes/histology-of-interstitial-lung-disease.html.

Diagnostic Challenges• Common differential

diagnosis⎻ Asthma⎻ COPD⎻ Bronchopulmonary infection

• Other potential diagnoses⎻ Upper airway cough

syndrome⎻ Gastroesophageal reflux

disease (GERD)⎻ ACE inhibitor⎻ Bronchiectasis⎻ Cardiac

Heart failure Angina

⎻ Anemia⎻ Obesity/deconditioning

Misdiagnosis is common!

Average time between emergence of symptoms and

diagnosis is 1-2 YEARS

Collard HR, et al. Respir Med. 2007;101(6):1350-1354.Jegal Y, et al. Am J Respir Crit Care Med. 2005;171(6):639-644.King TE Jr, et al. Am J Respir Crit Care Med. 2001;164(6):1025-1032. Ley B, et al. Am J Respir Crit Care Med. 2011;183(4):431-440.

Barriers to a Timely Diagnosis

Symptoms• Nonspecific

• Require investigation to determine etiology

• Insidious, prolongeddevelopment

Labs/Imaging• No specific lab test

• Chest imaging required

Exam• Crackles often missed

or misdiagnosed

Lack of certainty increases the risk for misdiagnosis and misclassification

When To Investigate for ILD

Key symptoms

Exertional dyspnea

Nonproductive cough

Objective findingsCrackles; Exertional

desaturation;

Spirometry (low FVC) or low DLCO;

Abnormal chest X-ray

Further evaluation

for ILD

Suspected ILD

HRCT

Potential cause/ associated condition?

Specific diagnosis:• CTD• HP

• Occupational• Familial ILD

Chest HRCT pattern

UIP • Probable UIP, • Indeterminate

• Alternative diagnosis

Multidisciplinary discussion

BALSurgical lung

biopsy

Multidisciplinary discussion

IPF

Yes

No

BAL, bronchoalveolar lavage; CTD, connective tissue disease; HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia.Modified from Raghu G, et al. Am J Respir Crit Care Med. 2018;198(5):e44-e68.

Diagnostic Algorithm

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Importance of Multidisciplinary Teams (MDTs)

MDTPulmonologist:

Detailed history & exam

Pulmonary function testing

Radiologist:

HRCT

Echocardiogram

Laboratory Specialist:

Serologic testing

Pathologist:

Surgical biopsy

MDTs allow for more accurate disease classification, diagnosis, and prognosis.

GOAL: Utilize communal 

knowledge to reach a consensus on  diagnosis and 

treatment approach

Challenges in ILD

• Term “ILD” comprises numerous, distinct disorders⎻Similar symptoms, physiology, radiology⎻Difficult nomenclature

• Poorly defined epidemiology⎻ Incidence and prevalence may be higher

than previously estimated

• Variable morbidity and mortality

• Limited, often toxic treatmentsRosas IO, et al. Ann Am Thorac Soc. 2014;11:S169-177.Coultas DB, et al. Am J Respir Crit Care Med. 1994;150:967-972.Global Burden of Disease Study 2013 Collaborators. Lancet. 2015;386(9995):743-800.

Interstitial Lung Diseases

ILD of known cause

or association

Medications Radiation

Vasculitis Pneumoconioses

Sarcoidosis IIPs

IPFNonspecific interstitial

pneumonia

Respiratory bronchiolitis – ILD

Desquamative interstitial

pneumonia

Cryptogenic organizing pneumonia

Acute interstitial pneumonia

Rare IIPs (LIP, IPPFE) Unclassifiable ILD

Other ILD

Pulmonary LCH LAM

Eosinophilic pneumonias

Alveolar proteinosis

Genetic syndromes

IIP = idiopathic interstitial pneumonia; IPF = Idiopathic pulmonary fibrosis; LIP = lymphoid interstitial pneumonia; IPPFE = idiopathic pleuroparenchymal fibroelastosis; LCH = Langerhans cell histiocytosis; LAM = lymphangioleiomyomatosis.Adapted from: ATS/ERS Guidelines for IIP. AJRCCM. 2002:165:277-304, and ATS/ERS Update on IIPs. AJRCCM. 2013;188:733-748. Modified from King TE Jr, et al. Lancet. 2011;378(9807):1949-1961.

Progressive phenotype describes…Acute exacerbations

AND/ORRapidly progressing disease course

Natural History of IPF

Like IPF, the course of most ILD is unpredictable

HRCT of Acute Exacerbation of IPF

From Collard HR, et al. Am J Respir Crit Care Med. 2007;176(7):636-643.

Acute Exacerbations in ILD(AE-ILD)

• Can occur at any time during the disease⎻ May be presenting

manifestation• Rapid worsening of

respiratory symptoms with increased dyspnea within a ≤1-month period

• May also include⎻ Cough⎻ Increased sputum⎻ Fever, flu-like symptoms

From Leuschner G, Behr J. Front Med (Lausanne). 2017;4:176.

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Question

Does every acute exacerbation of ILD lead to progression of disease?

AE-ILD vs Progressive ILD

Acute Event

• Infection• Micro-

aspiration• Mechanica

l stretch

ILDWidespread acute lung

injuryAE-ILD

Acceleration of underlying

chronic factors

contributing to fibrotic process

Pro-gressive ILD

• Unknown factors cause AE-ILD to lead to accelerated ILD

progression in some patients • Each ILD type likely expresses a

distinct immune response that leads down a common fibrotic

path

Collard HR, et al. Am J Respir Crit Care Med. 2016;194(3):265-275.

Case 1: Mr. Jones

• 68-year-old man developed dyspnea on exertion (DOE) upon climbing stairs 6 months ago

• Negative cardiology work up; CXR revealed interstitial changes

• CT scan consistent with UIP pattern• Negative evaluation for other etiologies (medications,

CTD, environmental triggers)• Oxygen saturation 96% at rest and 92% on his ETT• Several months later his 6MWT demonstrated 550

meters but desaturation to 86% on RA• FVC 64% of predicted and DLCO 43% of predicted

Case 1: Mr. Jones (cont’d.)

• No evidence of acute exacerbation by HRCT

• Negative repeat CT scan• Specific diagnosis unknown,

however…• Despite initially not appearing

ready for lung transplant, he was quickly worked up

• Because of rapid progression, patient reached top of the list within weeks and received lung transplant

Question

Did Mr. Jones have a rapidly progressing ILD phenotype?

Genetics

Exposure risk

Immune response

Determinants of disease course

Injury

Repair

Concept of a Rapid Progression Phenotype and Potential Lung

Molecular Pathophysiology

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Rapid Progression Concept in ILD Lung Tissue

• Early investigation using lung gene expression profiles

• Researchers identified a set of 102 RNA transcripts that were at least 5-fold up-regulated and a set of 89 RNA transcripts that were at least 5-fold down-regulated in the progressive ILD disease group (P=0.05)

• Genes and pathways included Surfactant Protein A and MAPK-EGR1-HSP70⎻ Both strongly implicated in pulmonary fibrosis

• In the future, there may be molecular signatures in lung tissue that can help to predict likelihood of disease progression

Boon K, et al. PLoS One. 2009;4(4):e5134.

Triggers of the Immune Response

• Subtype of DM-ILD with rapid progression

• Associated with upregulation of:⎻ TLR3 & TLR7

⎻ MDA5

⎻ RIG-I

⎻ INF-inducible genes

• Overproduction of INF-alpha linked with B-cell activating factor (BAFF)⎻ May be implicated in the

development of ILD

Zhang SH, et al. Br J Dermatol. 2018 Jun 27 [Epub ahead of print].

Examples in anti-melanoma differentiation-associated gene 5 (anti-MDA5) dermatomyositis (DM)-ILD

Rapid Progression Phenotypes• Likely a balance in immune response signaling• Recurrent injury framework

⎻ If you can’t remove the offending agent, it isn’t likely to slow down

• Genetic predispositions associated with disease progression:⎻ TLR3 polymorphisms ⎻ TOLLIP ⎻ MUC5B

• Immune system complexity ⎻ Likely very different for each disease state ⎻ Each share common feature of unresolvable inflammation

Normal or aberrant

Case 2: Mr. Smith

• 58-year-old man with rheumatoid arthritis reports worsening dyspnea and dry cough

• Exam: O2 sat 92% rest, crackles, clubbing, joint deformity with ulnar deviation at MCPs

• Labs: RF 35, CCP >250

Case 2: Mr. Smith (cont’d.)

PFTs 4/19/16 7/31/18

TLC (% predicted) 77 72

FVC (% predicted) 81 68

DLCO (% predicted) 58 48

Pulmonary Function Tests Over Time

Question

Is the rapid progression phenotype only found in IPF?

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ILDs with “Rapid Progression” Phenotypes

• Rapid progression phenotype found in many types of ILD⎻CTD or autoimmune-

featured ILD⎻Chronic hypersensitivity

pneumonitis⎻Unclassifiable ILD⎻ Fibrotic non-specific

interstitial pneumonia

• But don’t forget!⎻Environmental and

occupational exposures

⎻Smoking-related complications

⎻Medication toxicity (eg, RA meds)

⎻ Infection⎻Pulmonary embolism

Diagnosing ILD with a Progressive Phenotype

• High index of suspicion for ILD in at-risk patients, especially those with CTD or occupational exposures to dust⎻Consider differential diagnosis

• History and physical examination

• Laboratory studies

• PFTs

• Imaging (HRCT)

• Biopsy if indicated

Case 2: Mr. Smith (cont’d.)

• Multidisciplinary evaluation reveals progressive RA-ILD

Question

How should Mr. Smith’s RA-ILD be managed?

ILD Management• There is no universal treatment strategy for ILD;

approaches are tailored to ILD subtype and other factors • Numerous management decisions include:

– Whether to administer pharmacologic therapy

– How to best monitor the disease and assess indicators of stabilization improvement, and progression

– Whether to refer to ILD center

– Whether the patient should be referred for lung transplantation evaluation

– When to implement supportive, palliative care for patients with end-stage disease

• Guideline recommendations for some subsets of ILD rely on weak evidence

• Treatment of ILD remains a challenge

Assessing Disease Severity/Progression

• Pulmonary function testing

• Ambulatory oxygen saturation

• 6MWD

• Patient-reported symptoms

• Following signs/symptoms regularly over time⎻ Stable⎻ Slowly progressive⎻ Rapidly progressive

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Treatment Goals

• Decrease inflammation and prevent further lung scarring

• Remove triggers when possible

• Minimize and manage potential complications of ILD

• Improve or prevent deterioration in QOL

ILD Management Checklist

Pharmacotherapy

Consider pharmacotherapy

Age-appropriate vaccination

Patient Education

Smoking cessationWeight managementClinical trial enrollmentILD support groups

and educationAdvocacy group involvement

Supportive Care

Establish a follow-up plan• PFTs every 3-4 months

Supplemental oxygenHome SpO2 monitoringSleep study or nocturnal

oximetry

Rehabilitation

Pulmonary rehabilitation

Lung transplant evaluation

Comorbidity

• Address potential comorbidities/confounders (eg, PE, PH, CAD)

ILD TherapyPharmacotherapy

• Oral corticosteroids• Mycophenolate• Azathioprine• Cyclophosphamide• Pirfenidone• Nintedanib

Other Therapy

• Oxygen therapy⎻ Continuous vs situational

(ie, sleep, exercise)

• Pulmonary rehabilitation⎻ Exercise conditioning,

breathing techniques, respiratory therapy evaluation

• Lung transplant⎻ May be an option for

some patients

ILD and Comorbidities

• Comorbidities impair quality of life, impact respiratory status, and can lead to disease progression and death

• Early detection and accurate management of comorbidity are essential

• Common comorbidities:– Acute and chronic infection

– Gastroesophageal reflux disease

– Obstructive sleep apnea/sleep disorders

– Pulmonary hypertension

– Cardiovascular disease

Raghu G. Eur Respir Rev. 2017;26(145).

Therapy in Rapid Progressors

• No RCTs or FDA-approved therapies

• Approach based on case series, consensus, N of 1 trials

• Therapy is based on etiology of underlying ILD⎻ Hypersensitivity pneumonitis—eliminate triggering antigen

⎻ Drug induced ILD—discontinue medication

⎻ CTD-ILD—if infection not suspected, consider increasing immunosuppression

• Referral for lung transplant in appropriate patients

• Evaluation for O2 needs

• Re-assessment for comorbidities

Importance of a Shared Decision-Making

• Discuss safety/efficacy of available therapies

• Listen to patient’s preferences and concerns

• Focus on symptom control and management of comorbidities

• Set treatment expectations

• Discuss lung transplantation

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Palliative Care and Hospice: Integrate Early

Lanken PN, et al. Am J Respir Crit Care Med. 2008;177(8):912-927.

Palliative care and hospice should be integrated into ongoing patient care

Conclusion

• ILD describes different subtypes of lung disease that share similar symptoms and investigatory findings⎻ Can be diagnostically challenging⎻ Utilize MDT

• The course of ILD is unpredictable

• The progressive ILD phenotype includes⎻ Acute exacerbations⎻ Rapidly progressing disease course

• Tissue and blood studies have identified differences in RNA expression between slowly and rapidly progressing ILD⎻ Complexity of immune response represents ongoing

challenge

Conclusion (cont’d.)

• No universal management strategy for progressive ILD phenotype

• Combining different management strategies can improve outcomes and QOL⎻Pharmacotherapy

⎻Comorbidity management

⎻Supportive care

⎻Rehabilitation

⎻Patient education

⎻Palliative care and hospice

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