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