Transcript ILD 2012

By
Prof. Ramadan Nafae
Professor and Head of Chest Department
Zagazig , Faulty of Medicine
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
 HAMMAN and RICH were the first to describe (in
1935 and 1944) four patients who died of rapidly
progressive lung disease characterized by diffuse
interstitial pneumonia and fibrosis.
Interstitium
 Refers to the microscopic anatomic space bounded
by the basement membrane of epithelial and
endothelial cells.
 Within this interstitial space, fibroblast like cells
(mesenchymal and connective tissue cells) and
extracellular matrix components (interstitial
collagens, elastin, proteoglycans) are present
 It is clear that the disease is not restricted to
the interstitium as it involves epithelial,
endothelial
and
mesenchymal
cells,
macrophages and recruited inflammatory
cells, secreted proteins, and aberration of
matrix component within the alveolar space.
In addition, the disease process extends into
the alveolar space, acini, bronchiolar lumen
and bronchioles.
ILD is a heterogeneous syndrome with the following
common clinical features:
1. Exertional dyspnea
2. Bilateral diffuse infiltrates on chest radiographs
3. Physiological abnormalities with a restrictive lung defect,
decreased diffusing capacity (DLco) and abnormal alveolararterial oxygen gradient (PAO2 – PaO2) at rest or with
exertion.
4. Absence of pulmonary infection and neoplasm.
5. Histopathology
with varing degrees of fibrosis and
inflammation with or without evidence of granulomatous or
secondary vascular changes in the pulmonary parenchyma.
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
Epidemiology
 It is more frequent than previously recognized.
 Incidence ranges from 3 to 26 per 100.000 per year.
 The prevalence of preclinical and undiagnosed ILD in
the community is 10 times that of clinically
recognized.
 Among these, IPF is the most common,
representing at least 30% of the incident cases.
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
Diffuse Parenchymal Lung Disease (DPLD)
DPLD of known cause, eg,
drugs or association, eg,
collagen vascular disease
Idiopathic
interstitial
pneumonias
Idiopathic
pulmonary
fibrosis
Granulomatous
DPLD, eg,
sarcoidosis
Other forms of
DPLD, eg, LAM,
HX, etc
IIP other than idiopathic
pulmonary fibrosis
Desquamative interstitial
pneumonia
Respiratory bronchiolitis
interstitial lung disease
Acute interstitial pneumonia
Cryptogenic organizing
pneumonia
Nonspecific interstitial
pneumonia (provisional)
Lymphocytic interstitial
pneumonia
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:277-304.
ATS/ERS Classification of Idiopathic
Interstitial Pneumonias
Histologic Pattern
Clinical/Radiologic/Pathologic
Diagnosis
Usual interstitial pneumonia
Idiopathic pulmonary fibrosis/cryptogenic
fibrosing alveolitis
Nonspecific interstitial
pneumonia
Nonspecific interstitial pneumonia
Organizing pneumonia
Cryptogenic organizing pneumonia
Diffuse alveolar damage
Acute interstitial pneumonia
Respiratory bronchiolitis
Respiratory bronchiolitis interstitial lung
disease
Desquamative interstitial
pneumonia
Desquamative interstitial pneumonia
Lymphoid interstitial
pneumonia
Lymphoid interstitial pneumonia
IIP Classification
Diagnosis
Radiology
Distribution
Pathology
IPF/UIP
Fibrosis, HC
Basilar, peripheral
Temporal heterog., FF,
fibrotic and normal lung,
microscopic HC
NSIP
GGO +/- fibrosis
Basilar, peripheral
Diffuse interstitial inflammation
+/- fibrosis
COP
GGO, nodules,
consolidation
Patchy upper lungs,
small airways, alveolar
Granulation tissue plugs in
alveolar ducts and alveoli
AIP
GGO,
consolidation
Diffuse, random
Hyaline membranes, immature
fibroblasts in alveolar spaces
and interstitium to variable
degree
RB-ILD
Bronchiectasis,
GGO
Upper lungs,
bronchocentric
Respiratory bronchiolitis
surrounded by Ms in alveoli
DIP
GGO,
consolidation
Basilar, peripheral,
alveolar
Alveolar Ms in air spaces
diffusely in the biopsy
LIP
GGO, nodules,
cysts
Patchy
Lymphoid hyperplasia
HC, honeycombing; GGO, ground glass opacity; FF, fibrotic foci; M, macrophage
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
Four proposed mechanisms and potential variations in lung
responses
to inhaled agents
Inhaled
environmental
agents
(fumes, dust, smoke)
Genetic
predisposition
Delivery
&
persistence
Alveolar epithelial cell injury
Biochemical
Wound healing (inflammation,
coagulation, epithelial/endothelial
repair)
Chronic airflow
obstruction
Normal
Immunologic
Fibrotic
Pulmonary
fibrosis
Recent Hypothesis:
 Inflammatory hypothesis
 Epithelial Cell Apoptosis
 Angiogenesis
 Abnormal Matrix Turnover
 Th1 versus Th2 Cytokines
 Growth Factor Production
 Altered Fibroblast Phenotypes
 Myofibroblast Recruitment and Maintenance
LUNG INJURY
AGE
GENETIC FACTORS
ENVIRONMENTAL FACTORS
NATURE OF INJURY
– Etiologic agent
– Recurrent vs single
– Endothelial vs epithelial
Histopathologic Pattern
DIP
RB-ILD
Inflammation
LIP
COP
NSIP
AIP
UIP
Fibrosis
Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
Approach to the Diagnosis of
ILD
Clinical
• History
• Physical
• Laboratory
• PFTs
Primary care
physicians
Radiology
• Chest X-ray
• HRCT
Pulmonologists
Pathology
• Surgical lung biopsy
Radiologists
Pathologists
Multidimensional and multidisciplinary
ILD presents a clinical conundrum as;
 1st at least 150 clinical entities and situation are
associated with ILD.
 2nd difficulty to determine the best specific diagnostic
approach.
 3rd a conclusive cause cannot be ascertained (even after
lung biopsy) in a significant portion of patients.
 Finally even when a specific diagnosis is made, an
effective therapeutic regimen is not available for many
patients with ILD.
Diagnosis
History
The patient's age, cigarette-smoking status and
sex may provide useful clues.
Thorough medical history that must include a
review of environmental factors, occupations,
exposures, medication, and drug usage and
family medical history.
Age:
 Infancy and childhood:
• Follicular bronchiolitis
• Cellular interstitial pneumonia
• Acute idiopathic pulmonary hemorrhage of infancy
Age (cont.):
 Before age 40:
 Familial idiopathic pulmonary fibrosis
 Metabolic storage disorders
 Hermansky pudalic syndrome
 Other inherited interstitial lung diseases
 Collagen vascular disease- associated ILD
 LAM
 Pulmonary Langerhans’cell granulomatosis
 Sarcoidosis
 After age 50: IPF 1 in 500 people over the age of 75
yrs.
Race:
 Sarcoidosis occurs 10-12 folds among
blacks.
Gender :
 Gender clearly affects the way patients present with
pulmonary fibrosis: Men tend to present later in the
disease, whereas women tend to present earlier.
 Women :
 Collagen vascular disease- associated ILD
 LAM
 Tuberous sclerosis
 Men:
 Pneumoconiosis
History (cont.)
Smoking – related ILD :
1. Desquamative interstitial pneumonia.
2. RBILD.
3. Pulmonary Langerhans’ cell histiocytosis.
4. IPF.
5. Rheumatoid arthritis associated ILD.
6. Acute eosinophilic pneumonia.
Smoking (cont.)
 Cigarette smoking is associated with a 1.6- to 2.3-
fold excess risk of pulmonary fibrosis.
 The recognition that theses diseases are related to
smoking is not just a matter of cinematic the
cornerstone of therapy for theses patients is
smoking
cessation,
in
absence
of
which,
immunosuppressive therapy may have no effect
whatsoever.
ILD by onset and duration:
 Acute onset (days to weeks):
 AIP
 Acute pneumonitis from collagen vascular disease





(especially SLE)
COP
Drugs
DAH
Eosinophilic lung disease
Hypersensitivity pneumonitis
ILD by onset and duration (cont.):
 Subacute (weeks to months):
 Collagen vascular disease- associated ILD
 COP
 Drugs
 Subacute hypersensitivity pneumonitis
 Chronic (months to years):
 Chronic hypersensitivity pneumonitis
 Collagen vascular diseaes- associated ILD
 IPF and NSIP
 Occupation – related lung diseases.
History (cont.)
 Farming or exposure to known causes of
hypersensitivity pneumonitis including birds,
drugs, humidifiers.
 History of aspiration, dysphagia, arthritis,
recurrent sinusitis, pneumothorax, muscle
and skin symptoms, dry and gritty eyes, dry
mouth and hemoptysis.
Physical examination
Physical examination of the respiratory system is
rarely helpful in the diagnostic evaluation of
interstitial lung diseases.
The classical “Velcro rales” or inspiratory
crackles, occur not only in most patients with
IPF but also in many other interstitial lung
diseases.
Clubbing :
 Eighty percent of patients with clubbing have a
respiratory disorder.
 Among patients with ILD clubbing is found in 25-
50% of patients with IPF and 50% of patients with
DIP and 75% of patients with ILD from rheumatoid
arthritis.
Physical examination (cont.)
Extrathoracic findings can be insightful e.g.
 Skin abnormalities, peripheral lymphadenopathy
and hepatosplenomegally are commonly associated
with sarcoidosis.
 Iridocyclitis, uveitis or conjunctivitis may be
associated with sarcoidosis.
Physical examination
 Characteristic skin rashes and lesions occur in collagen
vascular diseases, disseminated histocytosis-X, tuberous
sclerosis and neurofibromatosis.
 Signs of arthritis may be associated with sarcoidosis or
collagen vascular diseases
 Sclerdactyly, Raynaud's phenomenon and telangiectatic
lesions are characteristics features of scleroderma and
CREST syndrome.
 Epilepsy, mental retardation in tuberous sclerosis.
 Diabetes insipidus in Langerhans cell granulomatosis
Chest Radiographic pattern
 First review previous chest radiographs as this
allows the clinician to ascertain the onset,
progression, chronicity and stability of patient's
disease.
 A rare patient with ILD will present with a normal
chest radiograph.
 When radiographic abnormalities are noted,
their distribution and appearance are useful in
narrowing the differential diagnosis of ILD.
Radiographic Clues (cont.)
 Mid/upper
lung
field
disease:
sarcoidosis,
silicosis, ankylosing spondylitis, histiocytosis X.
 Lower lung field predominance: asbestosis,
idiopathic pulmonary fibrosis, collagen vascular
disease.
 Kerley
B
lines:
congestive
heart
lymphangitic carcinoma, LAM.
 Pleural plaques/ thickening: asbestosis.
failure,
Radiographic Clues (cont.)
 Pleural effusion: congestive heart failure, lupus,
rheumatoid arthritis, LAM, drug induced.
 Hilar
adenopathy:
sarcoidosis
(bilateral
and
symmetrical), lymphangitic carcinoma (unilateral).
 Preserved lung volumes: sarcoidosis, histiocytosis
X, LAM.
 Thin walled cysts (better seen on HRCT):
histiocytosis X, LAM.
Radiographic Clues (cont.)
Photographic
negative
of
pulmonary
edema: Chronic eosinophilic pneumonia.
Recurrent pneumothorax:
Langerhans’ cell granulomatosis.
LAM
Tuberous sclerosis.
Neurofibromatosis.
Computed tomography and high-resolution CT images
 CT and HRCT scans are more sensitive and have a greater
ability to detect anatomic abnormalities than do chest radiograph.
 Its impressive sensitivity help both in ruling out a diagnosis of
ILD and in defining the parenchymal, pleural and mediastinal
abnormalities in these disorders.
 It helps the surgeon to identify areas of non-fibrotic, active
disease and relatively unaffected areas to guide appropriate site
selection for biopsy.
HRCT (Cont.)
 HRCT helps in identifying "active and reversible
inflammation" (ground
irreversible
fibrotic
glass attenuation) and
manifestations
(traction
bronchiectasis, bronchiolectasis and honeycombing).
 Extensive fibrotic changes suggest end or advanced
stage disease with limited potential for both
invasive diagnostic and therapeutic approaches
which could be toxic.
Computed tomography and high-resolution CT images
 HRCT has the potential for differentiating sarcoidosis,
lymphangitic carcinomatosis and bronchiolitis.
 The presence of cystic images within the parenchyma
raises the possibilities of three major cystic ILD;
 LAM,
Tuberous
sclerosis
and
Langerhans
cell
granulomatosis

In LAM and Tuberous sclerosis, the cysts are numerous, thin
walled, typically less than 2 mm in diameter and distributed
throughout the pulmonary parenchyma.

In Langerhans cell granulomatosis cysts are bizar shaped and
distributed predominantly in the upper lobes.
Computed tomography and high-resolution CT images
 In acute hypersensitivity pneumonitis HRCT
show multifocal diffuse ground glass
attenuation despite a normal chest
radiograph.
 Smokers with symptomatic RBILD typically
have patchy ground glass attenuation on
HRCT.
 IPF is characterized by patchy subpleural and
basilar fibrosis.
 A normal HRCT does not exclude the presence
of microscopic ILD in a patient with a high
pretest probability of the disorder.
Pulmonary physiology testing
 Regardless of the cause, a restrictive lung defect
and decreased diffusing capacity (DLco) are the
predominant physiological abnormalities seen in
ILD.
 Decreased FEV1, FVC, TLC
 The (PAO2 – PaO2) difference, at rest or with
exercise may be normal or increased.
Differential diagnosis by function:
 When there is a decrease in MVV out of
proportion to the decrease in FEV1 and a
decrease in maximal inspiratory pressures,
diseases such as polymyositis, scleroderma and
SLE should come to mind.
 A mixed pattern of obstructive and restrictive
abnormalities may be present when ILD coexists
with COPD or Asthma.
Differential diagnosis by function (cont.):
 ILD associated with asthma or recurrent bronchospasm
include; Churg-Strauss syndrome, ABPA, Sarcoidosis
(endobronchial) and tropical pulmonary
interstitial
eosinophilia.
 Resting pulmonary function tests:
Document the existence, gauge the severity and provide
clues that are useful in the differential diagnosis of ILD.
Also they are useful in the monitoring of clinical
progression of the disease or response to therapy.
 Exercise affords the most sensitive diagnostic
and physiological test for ILD. The degree of
arterial hypoxemia induced by exercise and the
alveolar-arterial difference in P02 (PAO2 –
PaO2 gradient) correlate well with the degree
of pulmonary fibrosis.
Routine laboratory tests
Include:
 Complete blood count, leucocytic differential
 ESR
 Chemistry
profile
(calcium,
liver
function
tests,
electrolytes, renal function tests)
 Screening for collagen vascular diseases and urine analysis.
 When appropriate, creatinine kinase, aldolase, and
angiotensin converting enzyme levels should be measured.
Bronchoscopy with transbronchial biopsy
 Provide additional information, especially when tissue
abnormalities tend to be distributed in peribronchiovascular
areas e.g. Sarcoidosis, LAM and Lymphangitic carcinomatosis.
 It may disclose certain distinctive abnormalities e.g.
Tight, uniform, well formed non caseating granulomas of
sarcoidosis.
Smooth muscle proliferation of LAM.
Lymphatic metastasis of malignant cells.
Giant cell granulomas are suggestive of hard metal
pneumoconiosis.
 It is diagnostic if an infectious agent or malignancy is
detected.
"Bronchoalveolar lavage"
Surgical lung biopsy: Thoracoscopy-Guided and
open lung biopsy
 Surgical lung biopsy remains the “gold standard”
for diagnosis. It is, however, by no means always
definitive: the size of specimens, site of biopsy,
expertise of pathologists and interobserver
differences among pathologists are factors that may
preclude a conclusive diagnosis.
 The site of the biopsy should be chosen on the basis
of HRCT findings and ideally be at the interface of
involved and less involved lung tissue.
 A biopsy of more than one site in the lung is more
helpful.
Surgical lung biopsy: ThoracoscopyGuided and open lung biopsy
 TGLB or open lung biopsies merit consideration
as the final diagnostic step.
 Which patient are suitable candidates for these
procedures?
 Unexplained dyspnea on exertion or abnormal
results on pulmonary function testing favor such
interventions (normal chest radiographs or HRCT
scans do not negate the need for tissue
diagnosis).
 On the other hand, not all patients with typical
clinical features compatible with IPF require
surgical lung biopsy for definitive diagnosis.
Diagnostic approach to suspected ILD
American Journal of Respiratory Cell and Molecular Biology VOL.29,
2003
Diagnostic Criteria for IPF in the Absence of a
Surgical Lung Biopsy
Major Criteria
Minor Criteria
Exclusion of other known causes of ILD
Age > 50 years
Evidence of restriction and/or impaired
gas exchange
Insidious onset of otherwise
unexplained dyspnea on exertion
HRCT: bibasilar reticular abnormalities
with minimal ground glass opacities
Duration of illness > 3 months
TBB or BAL that does not support an
alternative diagnosis
Bibasilar, inspiratory, Velcro®
crackles
All major criteria and at least 3 minor criteria must be present
to increase the likelihood of an IPF diagnosis
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
Treatment
 The therapeutic regimen used for patients with ILD
needs to be tailored to the patient and the disease
process (disease-specific intervention).
 Avoidance of the offending agent or its
environment.
 The use of corticosteroids, alone or in combination
with
immunosuppressives
(azathioprine,
cyclophosphamide) is currently recommended for
most patients with chronic fibrotic lung disorders.
 However the clinical response is variable and
unpredictable, some ILDs generally have a better
prognosis and response more favorably than do
others.
Novel therapies in IPF
 A number of agents that interfere with collagen
synthesis have been tested:
 Pirfenidone (A pyridone molecule)
 IFN--1b (A glycoprotein) cost > 50.000$ per patient per year in
USA.







IFN-ß-1a.
Colchicine
D-Penicillamine (A chelating agent).
N-acetylcysteine (Antioxidant).
Captopril (ACE inhibitor).
Bosentan (Endothelin-1 receptor antagonist).
Imatinib mesylate (A protein-tyrosine kinase inhibitor).
Novel therapies in Sarcoidosis
 Hydroxychloroquine: is effective for control of
cutaneous sarcoid and has been successfully used
to treat sarcoid-associated hypercalcemia, arthritis,
neurological disease, and pulmonary disease.
 Infliximab and etanercept (TNF-alpha inhibitor).
 Pentoxifyllin and Thalidomide (TNF-alpha
antagonists).
 Methotrexate (10-25mg / week).
Novel therapies in ILD associated
with CT disease
 Infliximab.
 Bosentan.
Novel therapies in ILD due to
pulmonary alveolar proteinosis
 Granulocyte Macrophage Colony Stimulating
Factor (GM-CSF):
A cytokine that stimulates the granulocytes,
macrophages, dendritic cells, and bone marrow
precursors of platelets. Administered by either S.C
injection or aerosolized form. It has recently been
demonstrated to effectively control disease course
and provide a very useful alternative to traditional
therapy of whole lung lavage
Treatment of LAM
 Estrogen-containing medications should be
discontinued.
 Oophorectomy, progesterone, Tamoxifen and
luteinizing
hormone-releasing
hormone
analogs have been used with limited success.
 Lung transplantation offers the only hope for
cure despite reports of recurrent disease in the
transplanted lung.
Management of pulmonary
hypertension complicating ILD
 Beraprost sodium: prostacyclin analogue.
 Sildenafil : phosphodiestrase inhibitor.
 Bosentan: endothelin-1 antagonist.
 Theses medications may have beneficial
effects that extend beyond vasodilatation,
including anti-fibrotic and anti-inflammatory
effects
Other measures
 Plasmapheresis is indicated in intractable and severe cases of
alveolar hemorrhage syndrome resistant to corticosteroids and
immunosuppressives.
 Supplemental oxygen is indicated to maintain adequate oxygen
saturation.
 Unless contraindicated, all patients should receive pneumococcal
and periodic influenza vaccinations.
 Other supportive measures such as rehabilitation are indicated in
appropriate patients.
 Lung transplantation is a viable surgical option for selected
patients who don't respond to currently available therapeutic
regimens .
Items:
 Definition
 Epidemiology
 Classification
 Pathogenesis
 Diagnosis
 Treatment
 Final comments
Final Comments
 The interstitial lung diseases are a fascinating collection
of lung diseases that occur at any age group and may
develop as a consequence of an extraordinarily broad
collection of systemic diseases.
 The importance of a careful history and physical
examination cannot be overstated, and may obviate
many expensive diagnostic tests.
 The diagnosis and management of interstitial lung
diseases often requires active discussion and
collaboration between the clinician, surgeon, pathologist
and radiologist.
Final Comments
 Recent studies challenge the dogma that lung
biopsy is the gold standard for diagnosing
interstitial lung disease. Rather than the lung
biopsy per se, the new gold standard for the
diagnosis is the combined input from the
diagnostic studies (radiology, pathology, and
functional testing) and clinical evaluation that
allows
a
situations.
confident
diagnosis
in
many