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Interstitial lung disease: A clinical overview and general approach. 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

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interstitial lung disease a clinical overview and general approach

Interstitial lung disease: A clinical overview and general approach


Prof. Ramadan Nafae

Professor and Head of Chest Department

Zagazig , Faulty of Medicine

  • Definition
  • Epidemiology
  • Classification
  • Pathogenesis
  • Diagnosis
  • Treatment
  • Final comments
  • Definition
  • Epidemiology
  • Classification
  • Pathogenesis
  • Diagnosis
  • Treatment
  • Final comments

HAMMAN and RICHwere the first to describe (in 1935 and 1944) four patients who died of rapidly progressive lung disease characterized by diffuse interstitial pneumonia and fibrosis.


  • 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:

  • Exertionaldyspnea
  • Bilateral diffuse infiltrates on chest radiographs
  • Physiological abnormalities with a restrictive lung defect, decreased diffusing capacity (DLco) and abnormal alveolar-arterial oxygen gradient (PAO2 – PaO2) at rest or with exertion.
  • Absence of pulmonary infection and neoplasm.
  • Histopathology with varing degrees of fibrosis and inflammation with or without evidence of granulomatous or secondary vascular changes in the pulmonary parenchyma.
  • Definition
  • Epidemiology
  • Classification
  • Pathogenesis
  • Diagnosis
  • Treatment
  • Final comments
  • 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.
  • Definition
  • Epidemiology
  • Classification
  • Pathogenesis
  • Diagnosis
  • Treatment
  • Final comments

Diffuse Parenchymal Lung Disease (DPLD)

Idiopathic interstitial pneumonias

Other forms of DPLD, eg, LAM, HX, etc

DPLD of known cause, eg, drugs or association, eg, collagen vascular disease

Granulomatous DPLD, eg, sarcoidosis

Idiopathic pulmonary fibrosis

IIP other than idiopathic pulmonary fibrosis

Respiratory bronchiolitis interstitial lung disease

Desquamative interstitial pneumonia

Cryptogenic organizing pneumonia

Acute interstitial pneumonia

Lymphocytic interstitial pneumonia

Nonspecific interstitial pneumonia (provisional)

ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:277-304.

iip classification
IIP Classification

HC, honeycombing; GGO, ground glass opacity; FF, fibrotic foci; M, macrophage

  • 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)






Alveolar epithelial cell injury


Wound healing (inflammation,

coagulation, epithelial/endothelial




Chronic airflow





recent hypothesis
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
etiologic agent recurrent vs single endothelial vs epithelial


– Etiologic agent

– Recurrent vs single

– Endothelial vs epithelial

Histopathologic Pattern











Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.

  • Definition
  • Epidemiology
  • Classification
  • Pathogenesis
  • Diagnosis
  • Treatment
  • Final comments
approach to the diagnosis of ild
Approach to the Diagnosis of ILD
  • Clinical
  • History
  • Physical
  • Laboratory
  • PFTs
  • Radiology
  • Chest X-ray
  • HRCT
  • Pathology
  • Surgical lung biopsy

Primary care





Multidimensional and multidisciplinary


ILD presents a clinical conundrum as;

  • 1st at least 150clinical 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.


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.

  • Infancy and childhood:
    • Follicular bronchiolitis
    • Cellular interstitial pneumonia
    • Acute idiopathic pulmonary hemorrhage of infancy
age cont
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.
  • 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
History (cont.)

Smoking – related ILD :

  • Desquamative interstitial pneumonia.
  • RBILD.
  • Pulmonary Langerhans’ cell histiocytosis.
  • IPF.
  • Rheumatoid arthritis associated ILD.
  • Acute eosinophilic pneumonia.
smoking cont
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
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
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

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
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 examination1
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
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
Radiographic Clues (cont.)
  • Mid/upper lung field disease: sarcoidosis, silicosis, ankylosingspondylitis, histiocytosis X.
  • 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 cont1
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 cont2
Radiographic Clues (cont.)
  • Photographic negative of pulmonary edema: Chronic eosinophilic pneumonia.
  • Recurrent pneumothorax:

Langerhans’ cell granulomatosis.


Tuberous sclerosis.


computed tomography and high resolution ct images
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 (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.

Computed tomography and high-resolution CT images

  • HRCT has the potential for differentiating sarcoidosis, lymphangiticcarcinomatosis 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 images1
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
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
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
Routine laboratory tests


  • 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
Bronchoscopy with transbronchial biopsy
  • Provide additional information, especially when tissue abnormalities tend to be distributed in peribronchiovascular areas e.g. Sarcoidosis, LAM and Lymphangiticcarcinomatosis.
  • It may disclose certain distinctive abnormalities e.g.
    • Tight, uniform, well formed non caseatinggranulomas 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.
surgical lung biopsy thoracoscopy guided and open lung biopsy
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 biopsy1
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 criteria for ipf in the absence of a surgical lung biopsy
Diagnostic Criteria for IPF in the Absence of a Surgical Lung Biopsy

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.

  • Definition
  • Epidemiology
  • Classification
  • Pathogenesis
  • Diagnosis
  • Treatment
  • Final comments
  • 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
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
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 due to pulmonary alveolar proteinosis
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
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
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.
  • Definition
  • Epidemiology
  • Classification
  • Pathogenesis
  • Diagnosis
  • Treatment
  • Final comments
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 comments1
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.