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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
Dis
ease
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
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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