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RESTRICTIVE LUNG DISEASE

(A.K.A. ILD / DPLD)


Augustine Lee, MD
Mayo Clinic Florida
Lee.augustine@mayo.edu

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
ILDs
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, Sjgren's,
Behet'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
Smokers 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
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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 ILDs
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 (Sjogrens), 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 workers pneumoconiosis
Coal macules and nodules, Coalescence to PMF, Diffuse fibrosis,
Chronic bronchitic symptoms, Rheumatoid nodules (Caplans
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
Farmers lung thermophilic actinomycetes
Bird fanciers lung droppings, feathers, serum proteins
Summer type pneumonitis trichosporum in tatami mats
Bagassosis thermoactinomycetes from moldy sugar cane
Laboratory workers lung rodents
Malt workers 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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