Interstitial Lung Disease (ILD) Pharmacotherapy Consider pharmacotherapy Age-appropriate vaccination

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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.

    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, prolonged development

    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 findings Crackles; Exertional

    desaturation; Spirometry (low FVC)

    or low DLCO; Abnormal chest X-ray

    Further evaluation

    for ILD

    Suspected ILD


    Potential cause/ associated condition?

    Specific diagnosis: • CTD • HP

    • Occupational • Familial ILD

    Chest HRCT pattern

    UIP • Probable UIP, • Indeterminate

    • Alternative diagnosis

    Multidisciplinary discussion

    BAL Surgical lung biopsy

    Multidisciplinary discussion




    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)

    MDT Pulmonologist:

    Detailed history & exam

    Pulmonary function testing

    Radiologist: HRCT


    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 treatments

    Rosas 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

    IPF Nonspecific interstitial


    Respiratory bronchiolitis – ILD

    Desquamative interstitial


    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/OR Rapidly 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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    Does every acute exacerbation of ILD lead to progression of disease?

    AE-ILD vs Progressive ILD

    Acute Event • Infection • Micro-

    aspiration • Mechanica

    l stretch

    ILD Widespread acute lung

    injury AE-ILD

    Acceleration of underlying

    chronic factors

    contributing to fibrotic process

    Pro- gressi ve 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


    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


    Did Mr. Jones have a rapidly progressing ILD phenotype?


    Exposure risk

    Immune response

    Determinants  of disease  course



    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


    Is the rapid progressi