View
4
Download
0
Category
Preview:
Citation preview
1
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
1 2
3 4
5 6
2
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.
7 8
9 10
11 12
3
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
13 14
15 16
17 18
4
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?
19 20
21 22
23 24
5
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
25 26
27 28
29 30
6
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
31 32
33 34
35 36
7
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
37 38
39
Recommended