By Prof. Ramadan Nafae Professor and Head of Chest Department Zagazig, Faulty of Medicine.

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

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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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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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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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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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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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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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.

By Prof. Ramadan Nafae Professor and Head of Chest Department Zagazig, Faulty of Medicine.

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Transcript of By Prof. Ramadan Nafae Professor and Head of Chest Department Zagazig, Faulty of Medicine.