by prof. ramadan nafae professor and head of chest department zagazig, faulty of medicine
TRANSCRIPT
By
Prof. Ramadan NafaeProf. Ramadan NafaeProfessor and Head of Chest Professor and Head of Chest
DepartmentDepartmentZagazig , Faulty of MedicineZagazig , Faulty of Medicine
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal comments
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal 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 alveolar-arterial 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.
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal 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.
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal comments
Diffuse Parenchymal Lung Disease (DPLD)
DPLD of known cause, eg, drugs or association, eg, collagen vascular disease
Idiopathic interstitial
pneumonias
Granulomatous DPLD, eg, sarcoidosis
Other forms of DPLD, eg, LAM,
HX, etc
Idiopathic pulmonary
fibrosis
IIP other than idiopathic pulmonary fibrosis
Desquamative interstitial pneumonia
Acute interstitial pneumonia
Nonspecific interstitial pneumonia (provisional)
Respiratory bronchiolitis interstitial lung disease
Cryptogenic organizing pneumonia
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 PatternHistologic PatternClinical/Radiologic/Pathologic Clinical/Radiologic/Pathologic DiagnosisDiagnosis
Usual interstitial Usual interstitial pneumoniapneumonia
Idiopathic pulmonary Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitisfibrosis/cryptogenic fibrosing alveolitis
Nonspecific interstitial Nonspecific interstitial pneumoniapneumoniaNonspecific interstitial pneumoniaNonspecific interstitial pneumonia
Organizing pneumoniaOrganizing pneumoniaCryptogenic organizing pneumoniaCryptogenic organizing pneumonia
Diffuse alveolar damageDiffuse alveolar damageAcute interstitial pneumoniaAcute interstitial pneumonia
Respiratory bronchiolitisRespiratory bronchiolitisRespiratory bronchiolitis interstitial lung Respiratory bronchiolitis interstitial lung diseasedisease
Desquamative interstitial Desquamative interstitial pneumoniapneumoniaDesquamative interstitial pneumoniaDesquamative interstitial pneumonia
Lymphoid interstitial Lymphoid interstitial pneumoniapneumoniaLymphoid interstitial pneumoniaLymphoid interstitial pneumonia
IIP ClassificationDiagnosisRadiologyDistributionPathology
IPF/UIPFibrosis, HCBasilar, peripheralTemporal heterog., FF, fibrotic and normal lung, microscopic HC
NSIPNSIPGGO +/- GGO +/- fibrosisfibrosisBasilar, peripheralBasilar, peripheral
Diffuse interstitial Diffuse interstitial inflammation inflammation +/- fibrosis+/- fibrosis
COPCOPGGO, nodules, GGO, nodules, consolidationconsolidation
Patchy upper lungs, Patchy upper lungs, small airways, small airways, alveolaralveolar
Granulation tissue plugs in Granulation tissue plugs in alveolar ducts and alveolialveolar ducts and alveoli
AIPAIPGGO, GGO, consolidationconsolidationDiffuse, randomDiffuse, random
Hyaline membranes, Hyaline membranes, immature fibroblasts in immature fibroblasts in alveolar spaces and alveolar spaces and interstitium to variable interstitium to variable degreedegree
RB-ILDRB-ILDBronchiectasisBronchiectasis, GGO, GGO
Upper lungs, Upper lungs, bronchocentricbronchocentric
Respiratory bronchiolitis Respiratory bronchiolitis surrounded by Msurrounded by Ms in s in alveolialveoli
DIPDIPGGO, GGO, consolidationconsolidation
Basilar, peripheral, Basilar, peripheral, alveolaralveolar
Alveolar MAlveolar Ms in air spaces s in air spaces diffusely in the biopsydiffusely in the biopsy
LIPLIPGGO, nodules, GGO, nodules, cystscystsPatchy Patchy Lymphoid hyperplasiaLymphoid hyperplasia
HC, honeycombing; GGO, ground glass opacity; FF, fibrotic foci; M, macrophage
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal comments
Inhaled environmental agents)fumes, dust, smoke(
Alveolar epithelial cell injury
Wound healing (inflammation ,coagulation, epithelial/endothelial
repair(
Pulmonary fibrosis
Normal Chronic airflow
obstruction
Genetic predisposition
Delivery &
persistence
Biochemical
Immunologic Fibrotic
Four proposed mechanisms and potential variations in lungresponses to inhaled agents
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
Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.
AGEAGEGENETIC FACTORSGENETIC FACTORSENVIRONMENTAL FACTORSENVIRONMENTAL FACTORSNATURE OF INJURYNATURE OF INJURY
– –Etiologic agentEtiologic agent – –Recurrent vs singleRecurrent vs single
– –Endothelial vs epithelialEndothelial vs epithelial
Histopathologic PatternHistopathologic Pattern
DIPDIP RB-ILDRB-ILD LIPLIP COPCOP NSIPNSIP AIPAIP UIPUIP
InflammatioInflammationn FibrosisFibrosis
LUNG INJURYLUNG INJURY
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal comments
Approach to the Diagnosis of ILD
Clinical• History• Physical• Laboratory• PFTs
Primary care physicians
Pulmonologists Radiologists Pathologists
Multidimensional and multidisciplinary
Radiology
• Chest X-ray• HRCT
Pathology
• Surgical lung biopsy
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.
DiagnosisHistory
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.
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.
History (cont.)
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.
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.
Clubbing :
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 diseaseMid/upper lung field disease: sarcoidosis,
silicosis, ankylosing spondylitis, histiocytosis
X.
Lower lung field predominance: Lower lung field predominance:
asbestosis, idiopathic pulmonary fibrosis,
collagen vascular disease.
Kerley B lines: congestive heart failure,
lymphangitic carcinoma, LAM.
Pleural plaques/ thickening: asbestosis.
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 glass attenuation) and
irreversible fibrotic 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.
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
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: Thoracoscopy-Guided 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 CriteriaMajor Criteria
Exclusion of other known causes of Exclusion of other known causes of ILDILD
Evidence of restriction and/or Evidence of restriction and/or impairedimpairedgas exchangegas exchange
HRCT: bibasilar reticular HRCT: bibasilar reticular abnormalitiesabnormalitieswith minimal ground glass with minimal ground glass opacitiesopacities
TBB or BAL that does not support TBB or BAL that does not support an alternative diagnosisan alternative diagnosis
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
All major criteria and at least 3 minor criteria must be present to increase the likelihood of an IPF diagnosis
Minor CriteriaMinor Criteria
Age > 50 yearsAge > 50 years
Insidious onset of otherwise Insidious onset of otherwise unexplained dyspnea on unexplained dyspnea on exertionexertion
Duration of illness > 3 Duration of illness > 3 monthsmonths
Bibasilar, inspiratory, VelcroBibasilar, inspiratory, Velcro®® cracklescrackles
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal 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
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.
Other measures
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DefinitionDefinition EpidemiologyEpidemiology ClassificationClassification PathogenesisPathogenesis DiagnosisDiagnosis TreatmentTreatment Final commentsFinal 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 confident diagnosis in many situations.