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0830 - Lee Restrictive Lung DZ

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RESTRICTIVE LUNG DISEASE
(A.K.A. ILD / DPLD)
Augustine Lee, MD
Mayo Clinic Florida
[email protected]

Diffuse parenchymal lung disease
(DPLD/ILD)
 Known causes/associations
 E.g. Asbestosis, Rheumatoid arthritis,
Hypersensitivity pneumonitis
 Granulomatous
 E.g. Sarcoidosis, (hypersensitivity pneumonitis)
 Other well defined
 E.g. Lymphangioleiyomyomatosis (LAM),
Pulmonary langerhans cell histiocytosis (PLCH),
Eosinophilic pneumonia
 Idiopathic interstitial pneumonias (IIP)

AJRCCM 2002, ATS/ERS statement
“ ILD’s “
 Inhaled Agents
 Inorganic: Silica, Asbestos,
Beryllium
 Organic: (HP), Animals,
Birds, Farm antigens
 Drug-Induced
 Antibiotics, Antiarrhythmics,
Anti-inflammatories,
Chemotherapeutics,
Antidepressants, Radiation,
Oxygen
 Connective Tissue Disease
 Scleroderma, PM/DM, SLE,
RA, MCTD, Ankylosing
spondylitis, Sjögren's,
Behçet's
 Infectious
 Atypical pneumonias, PCP,
TB, CVID
 Idiopathic
 Sarcoidosis, PCLH/EG/HX,
BOOP, LAM, UIP, NSIP, DIP,
RB-ILD, AIP, CEP
 Malignant
 Lymphangitic
carcinomatosis, BAC
 Others
 MPA, IPH
Adapted from: Flaherty, PCCU Vol 18, Lesson 3
(Chestnet.org)
Power of pathology in IIP
Bjoraker et al. (AJRCCM 1998)
Idiopathic Interstitial Pneumonias
 “Mostly” a histologic classification
 IPF: Idiopathic pulmonary fibrosis
 NSIP: Nonspecific interstitial pneumonia
 COP: Cryptogenic organizing pneumonia
 AIP: Acute interstitial pneumonia (AIP)
 RB-ILD: Respiratory bronchiolitis assoc. ILD
 DIP: Desquamative interstitial pneumonia
 LIP: Lymphocytic interstitial pneumonia
Clinical features
 Dyspnea on exertion
 Chronic cough, non-productive
 Bibasilar crackles (>85%)
 +/- Clubbing (>25%)
 +/- Signs of PAH/RHF
 Systemic disorders, extrapulmonary features?
 CTD (Scleroderma, RA, dermatomyositis), Neoplasm
 Exposures?
 Occupation (asbestos), drugs (antibiotics,
chemotherapy, antiarrhythmics, anti-rheumatics),
radiation, farm/ranch, birds/feathers, etc.
Physiologic Features: Restrictive

Radiologic features
High-Resolution CT chest
 Can be highly suggestive of diagnosis in:
 “Classic” UIP/IPF
 Sarcoidosis
 Asbestosis
 Hypersensitivity pneumonitis (subacute/chronic)
 Silicosis
 Pulmonary langerhans cell histiocytosis (PLCH)
 Lymphangioleiomyomatosis (LAM)
 Pulmonary alveolar proteinosis (PAP)
 Lymphangitic carcinomatosis
UIP Not-UIP
Differential by Distribution
 Mid-Upper lungs
 Histiocytosis X
 Sarcoidosis
 Hypersensitivity pneumonitis
 Eosinophilic pneumonia
 Tuberculosis
 Cystic fibrosis
 Pneumoconiosis (silica /
coal)
 Ankylosing spondylitis…
 Smoker’s emphysema
(cystic)
 Lower lungs
 IPF, Asbestosis, UIP
 Aspiration
 Collagen-vascular disease
associated ILD
 BOOP/COP (variable)
 Desquamative interstitial
pneumonia
 Non-specific interstitial
pneumonia
 Panlobular emphysema
(cystic)
Bronchoscopy
Leslie, Chest 2005
Surgical lung biopsy: VAT
IPF
 Prevalence 14-43 /100,000 (USA)
 Older age (75+ yo: 227/100,000)
 Male predominant, Smoking history
 Median survival still ~3-5 years
 Significant comorbidities
 PAH, cancer, depression, cardiovascular disease,
thromboembolism
 Supportive care important
 Education, oxygen, rehabilitation, comorbidities,
immunizations, end-of-life discussions
IPF: Diagnosis
 Biopsy
 Video assisted thoracoscopic (VAT) biopsy
 Histology: Usual interstitial pneumonia (UIP)
 HRCT: “UIP”
 Honeycombing (“Advanced scar”
 Reticulation/linear opacities (“Scar”)
 Subpleural, basilar predominant distribution
 +/- Traction bronchiectasis
 Minimal “ground glass”
 No consolidations/nodules
 Familial forms ~5%
 MUC5B, Surfactant protein A2/C, Telomerase

ATS/ERJ Statement 2002, 2011
Usual interstital pneumonia (UIP)
Poor prognostic markers
 Older age
 FVC decline ~10%
 DLCO decline ~15%
 HRCT pattern more UIP-ish
 Biopsy UIP (regardless of other NSIP)
 Fibrosis score on CT
 Fibroblast foci on biopsy
 Pulmonary hypertension

Natural history of IPF….
Statistics vs. Your patient
Symptoms
Diagnosis
D
i
s
e
a
s
e

D E A T H
Time
At the individual level…
Martinez AIM 2005)
Acute exacerbation of IPF
 ~23% of IPF, may be first presentation of IPF
 Presents with acute-subacute worsening
dyspnea, hypoxia, radiographic infiltrates
 No other apparent causes: ?Aspiration
 Resembles ARDS clinically & Biopsy: DAD (UIP)
 HRCT
 UIP in background, but superimposed ground glass
 Mortality >50%
 If require Mechanical ventilation ~90% death
 Therapy: steroids (in desperation)
IPF Therapies
 No drug proven to improve survival
 Exception: lung transplant
 Things that do not work:
 Interferon-gamma, Imatinib, Etanercept,
Bosentan, Sildenafil
 Things that may harm:
 Warfarin (ACE-IPF, Noth, AJRCCM 2012)
 Azathioprine, Prednisone, NAC (PANTHER,
NEJM2012)
 Ambrisentan (Raghu, AIM 2013)
PANTHER study, NEJM 2012
IPF Therapies
 Things that may work:
 Pirfenidone with possible FVC benefit (CAPACITY,
Lancet 2011)
 Thalidomide may help with cough in IPF (Horton,
AIM 2012)
 Notably pending:
 N-acetylcysteine (PANTHER), Pirfenidone
(ASCEND)
 Many others in the pipeline, including “biologics”
THE OTHER IIP
NSIP
 Younger than IPF, Some series more women
 HRCT: More ground glass
 Two histologic flavors:
 Cellular (better prognosis)
 Fibrotic (worse)
 Three main associations
 CTD: Scleroderma, dermatomyositis, RA
 Hypersensitivity like
 Drug-reactions (also familial, pediatric)
NSIP
 Treatment
 Identify and treat associated conditions
 Removing offending exposures
 Steroids & immunosuppressives
 Prognosis
 5 year survival up to 70%, but differs per histology

Travis WD. AJSP 2000; 24(1):19-33.
Travis WD. AJSP 2000; 24(1):19-33.
Cellular NSIP
Fibrotic NSIP
UIP
Cryptogenic Organizing Pneumonia
(a.k.a. BOOP)
 Associations
 Drug-induced, Infectious, CTD, Radiation, DAD/ARDS,
Hypersensitivity, Aspiration (foreign body reaction),
toxic fumes, IBD
 Peripheral consolidation or ground-glass
 Can have any manifestation: Alveolar (ground-glass
or consolidation), nodule (singly or multiple), mass,
interstitial, diffuse, focal
 Typically, restrictive physiology
 Surgical lung biopsy usually required
 Presentation: chronic to acute/fulminant
 May clinically present identical to pneumonia
 Often dramatic response to corticosteroids
Smoking related ILD’s
RB-ILD DIP
(Respiratory Bronchiolitis Assoc. ILD) (Desquamative Interstital Pneumonia)

 Surgical lung biopsy often required for diagnosis
 Findings of Respiratory Bronchiolitis on biopsy is not specific
 Compatible clinical picture
 Radiographic : Diffuse ground glass >>> reticular/reticulonodular
 Small cystic changes
 Prognosis
 Better prognosis than IPF/UIP
 CT abnormalities can persist even after smoking cessation
 Treatment
 Stop smoking, ? Steroids, Transplant
Other IIP
 LIP
 Associated with CTD (Sjogren’s), HIV, Primary biliary
cirrhosis, Castleman disease, SLE, Autoimmune
thyroiditis, ? low grade lymphomas
 Ground glass, centrilobular, cystic lesions
 AIP
 Original “Hamman-Rich” Syndrome
 Acute, fulminant presentation
 DAD with variable degrees of organizing pneumonia
on biopsy (seen with ARDS)
 Diagnosis of exclusion, Poor prognosis
MISCELLANEOUS ENTITIES
Pulmonary Langherans Cell Histiocytosis
 a.k.a. Eosinophilic granuloma, Histiocytosis X

 Young male smokers (20-50yo), Pneumothoraces
 Upper lobe, nodular, irregular cystic  Fibrosis
 Obstructive, Restrictive, or Mixed physiology
 Biopsy: aggregates of Langerhans cells, stellate
nodule formation, positive S100 & CD1a staining
 PAH, particularly ?PVOD
 Treatment: Smoking cessation, ?Steroids, Lung
transplant
Lymphangioleiomyomatosis (LAM)
 Young women, child bearing age
 Rare in men, and in post-menopausal
 Also seen in tuberous sclerosis (15-30%)
 Atypical proliferation of smooth muscle cells
(HMB45)
 Cystic lung disease, diffusely affected
 Pneumothorax (50%)
 Chylous effusion & ascites
 Angiomyolipoma: kidney, uterus, ovaries, lymph
 Elevated VEGF-D levels (correlates with FEV1)
 Sirolimus (Bissler, NEJM 2008, McCormack NEJM 2011)
 Hormonal manipulation, lung transplant
Well defined cysts, evenly distributed, extending to bases
Diffuse cystic lung diseases
 Pulmonary Langherhans Cell Histiocytosis
(PLCH)
 Lymphangioleiomyomatosis (LAM)
 Tuberous Sclerosis Complex (TSC)
 Lymphocytic interstitial pneumonia (LIP)
 Desquamative interstitial pneumonia (DIP)
 Birt-Hogg Dube syndrome
 Skin: fibrofolliculomas, Folliculin (FLCN) gene
 Amyloidosis, light-chain deposition disease
 Cystic metastatic disease (usu. Sarcoma)
 Follicular bronchiolitis

McCormack AJR 2011
ILD + CTD
 Systemic Sclerosis
 Polymyositis-dermatomyositis
 Systemic lupus erythematosus
 Rheumatoid arthritis
 Mixed connective tissue disease
 Ankylosing spondylitis
 ANCA associated vasculitis (Microscopic
polyangiitis)
ILD + Drugs
 Antibiotics
 nitrofurantoin,
sulfasalazine
 Antiarrhythmics
 amiodarone, tocainide,
propranolol
 Anti-inflammatories
 gold, penicillamine
 Anticonvulsants
 dilantin
 Chemotherapeutic
agents
 mitomycin C, bleomycin,
busulfan,
cyclophosphamide,
chlorambucil,
methotrexate,
azathioprine, BCNU
[carmustine],
procarbazine)
 Therapeutic radiation
 Oxygen toxicity
 Narcotics

PNEUMOTOX.COM
Occupational Lung Disease
 Silicosis
 Upper lung nodularities, Egg-shell calcification of lymph nodes,
Coalescence to fibrosis (PMF) or masses
 Increased risk for TB, cancers, and alveolar proteinosis
 Coal worker’s pneumoconiosis
 Coal “macules and nodules”, Coalescence to PMF, Diffuse fibrosis,
Chronic bronchitic symptoms, Rheumatoid nodules (Caplan’s
syndrome) , Coexisting issues also with smoking & silicosis
 Giant cell pneumonitis
 Hard metal pneumoconiosis: Tungsten carbide, but culprit is
cobalt  ? Hypersensitivity reaction
 Berrylliosis
 Clinically identical to sarcoidosis, Beryllium lymphocyte proliferation
test
Asbestos-related Lung Disease
 Asbestosis
 Fibrotic disease resembles IPF/UIP
 Only clues may be pleural plaques or history
 Cancers
 Bronchogenic cancers, Mesothelioma
 Smoking is multiplicative in increasing risk of cancer
 Benign Asbestos Related Pleura Effusion (BAPE)
 Shorter latency of <10-15 years, unlike most other asbestos related
conditions
 Can be symptomatic, exudative, hemorrhagic, +/- eosinophils
 Pleural plaques
 With or without calcification
 Diffuse pleural thickening
 Can cause “trapped lung” syndrome
 Worry about mesothelioma, especially if symptomatic
 Rounded atelectasis
 Peripheral rounded atelectasis with a “comet-tail”
Occupations with asbestos exposure
 Shipyards
 Plumbing, pipefitters
 Boilermakers
 Insulation workers
 Electricians
 Welders, cutters
 Asbestos mining/milling
 Secondary exposures
 Etc…
Asbestosis:
UIP, history +/- pleural plaques
Hypersensitivity Pneumonitis
 Hot-tub lung – mycobacterium avium-intracellulare complex
 Farmer’s lung – thermophilic actinomycetes
 Bird fancier’s lung – droppings, feathers, serum proteins
 Summer type pneumonitis – trichosporum in tatami mats
 Bagassosis – thermoactinomycetes from moldy sugar cane
 Laboratory worker’s lung – rodents
 Malt worker’s lung – aspergillus in moldy barley
 Byssinosis ? – cotton mill dust
 Numerous Others
 Humidfiers, Sauna, Lifegaurds, Tobacco growers, Mushroom
workers, Potato riddlers, Paprika slicers, Wine makers, Cheese
workers, Coffee workers, Tea growers, Pituitary snuff takers,
Thatched roof, Wood pulp workers, Wood dust pneumonitis,
Composters, Maple bark, etc…
Hypersensitivity Pneumonitis
 Acute, Subacute, Chronic
 Mid to upper lungs, sparing bases
 Centrilobular ground glass nodules
 Ground glass mosaicism (regional air-trapping)
 Fibrosis with UIP pattern
 Diagnosis
 Exposure history, +/- Serum precipitins,
 BAL: lymphocytic alveolitis (CD8>CD4)
 Biopsy: loosely formed non-caseating granulomas in a
peri-bronchial distribution
 Treatment
 Removal of offending agent, Protective devices
 Corticosteroid therapy
Eosinophilic Lung Diseases - 1
 Acute eosinophilic pneumonia
 Younger, more males, triggered by smoking or
exogenous exposure, Acute & severe, can lead to
respiratory failure (looks like ARDS)
 Rare blood eosinophils, BAL diagnostic (>25% eos.),
responds to steroids, infrequent relapse
 Chronic eosinophilic pneumonia
 Older, more women, h/o asthma/atopy, subacute to
chronic presentation, photonegative pulmonary
edema (patchy peripheral consolidations)
 Blood eosinophils common, BAL diagnostic,
responds to steroids, more common to relapse

Chronic eosinophilic pneumonia
Exogenous Lipoid pneumonia

 CT may suggest aspiration distribution of ground
glass or consolidation, Mosaicism, Fat density
Vcuthoracicimaging.com
Pulmonary alveolar proteinosis
 Pulmonary alveolar proteinosis, very rare
 Dysregulation in turnover of surfactant protein  Alveolar
accumulation of phospholipoproteins
 Deficiency or dysfunction of GM-CSF or its receptor
 Abnormalities in the surfactant protein
 Most idiopathic cases are now thought to be autoimmune
 Diagnosis
 HR-CT findings
 BAL: PAS+, “Mississippi mud”
 Biopsy
 Autoimmune = antibodies to GM-CSF
 Treatment
 Whole lung lavage
 GM-CSF (SQ or inhaled)
 Confirmed anti-GM-CSF autoantibodies, and no circulating GM-CSF
 Awaiting response
Crazy-paving
Summary
 Familiarize with the idiopathic interstitial pneumonias, the
most important of which is IPF/UIP
 No known drug therapy. Pirfenidone may become available.
 Know what drugs not to “try”, & discontinue if they are on them
currently.
 Always look for associated conditions or exposures to
remove
 Has direct management & prognostic implications
 Extrapulmonary symptoms & findings may be strong clues
 HRCT chest is an invaluable tool in the differential of
diffuse parenchymal lung diseases
 Combined with other tests, clinical features, may be diagnostic
 Some very rare diseases are easy to diagnose with unique
radiographic & clinical features
 Treatment options are available (e.g. PAP, LAM)
Bonus Slides
Eosinophilic Lung Diseases - 2
 Allergic bronchopulmonary aspergillosis (ABPA)
 Asthma, IgE, Blood eos., Serum precipitins, +/-
Central bronchiectasis with mucoid impaction
 Loffler Syndrome (simple pulm. eosinophilia)
 Self limited, fleeting, symptomatic infiltrates,
parasites (Ascaris, Dirofilaria) & drugs
 Churg-Strauss Syndrome (EGPA)
 Asthma, Tissue infiltration (sinus, skin, lung, GI,
kidney, heart, CNS), vasculitis (mononeuritis
multiplex, skin), rarely diffuse alveolar hemorrhage,
MPO-ANCA/P-ANCA
 Hypereosinophilic syndrome
 Multiorgan manifestation, r/o hematologic disorder,
consider CSS/EGPA
Sarcoidosis
 10-35/100,000 (USA)
 African-Americans, Scandinavians
 Asymptomatic ~50%
 Pulmonary /Lymphatics (>90%)
 Upper predominant, bronchovascular/ perilymphatic
nodularity/ consolidation, Adenopathy, Fibrosis/scar (UIP),
Conglomerate mass, Endobronchial, Pleural, …
 Cutaneous
 EN, Lupus pernio, Darrier-Roussy, Maculopapular,
Koebner phenomenon, Plaque,…
 Ocular (20%):
 Uveitis (7% of uveitis is due to sarcoid), Iritis,
Keratoconjunctivitis, Sicca

 Mid-upper lungs

 Peri-lymphatic
 Micronodules along pleura,
fissure, bronchovasculature

 Fibrosis
 Variable degrees
 Retraction, cystic
 Honeycombing

 Adenopathy

Sarcoidosis
 Cardiac (5%)
 Sudden death (ventricular arrhythmias, heart
blocks), Cardiomyopathies, Conduction,
Infarction, Aneurysm, Esp. Japanese/East Asian
descent
 Neurological (5-10%)
 Neuropathy (CN7, peripheral), peripheral
neuropathy (small-fiber sensory), Meningeal,
Encephalopathy, Hydrocephalus,
Myopathy/myositis, seizures
Sarcoidosis
 Renal
 Hypercalcemia (Vit D mediated)
 Renal failure, Nephrocalcinosis, Nephrolithiasis
 Endocrine:
 Pituitary, hypothalamus (DI)
 Gastrointestinal:
 Liver, spleen
 Other:
 Bone, ENT (sinus, partoid), Glands,Hematologic
Syndromes
 Lofgren syndrome

 Hilar lymphadenopathy
 Erythema nodosum
 Acute Arthritis
 Fever
 Uveoparotid fever
(Heerdfordt's)

 Fever
 Uveitis
 Parotitis
 +/- CN7 palsy (the most
common neurologic
finding in Sarcoidosis)

Sarcoidosis
 Histologic confirmation of non-caseating
granulomas
 Skin, bronchial, lung, lymphatics, eye
 Bronchoscopy (~90% yield)
 Treatment
 Observation (Spontaneous remission 50-60%)
 NSAID: hydroxychloroquine
 Steroids
 Immunosuppressives: Methotrexate, azathioprine,
infliximab, adalimumab
 Transplant
 Per individual organs: e.g AICD for heart
Pulmonary Alveolar Microlithiasis
 Idiopathic, Familial, Lungs diffusely affected by
microliths, Asymptomatic usually but can progress
 Abnormality of calcium phosphate homeostasis,
autosomal reccessive
NEJM 2003
NEJM 2003

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