INTERSTITIAL LUNG DISEASE: A CLINICAL OVERVIEW AND GENERAL APPROACH Tasaduk Khan. MD.FRCP(UK).FCCP(USA). Senior Consultant pulmonologist. Security forces hospital, Riyadh.

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

Items:  Definition  Epidemiology  Classification  Pathogenesis  Diagnosis  Treatment  Final comments

Epidemiology  It is more frequent than previously recognized.  Incidence ranges from 3 to 26 per 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 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:

Items:  Definition  Epidemiology  Classification  Pathogenesis  Diagnosis  Treatment  Final 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 lung responses 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: AGE GENETIC FACTORS ENVIRONMENTAL FACTORS NATURE OF INJURY – Etiologic agent – Recurrent vs single – Endothelial vs epithelial Histopathologic Pattern DIPRB-ILDLIPCOPNSIPAIPUIP Inflammation Fibrosis LUNG INJURY

Items:  Definition  Epidemiology  Classification  Pathogenesis  Diagnosis  Treatment  Final comments

Approach to the Diagnosis of ILD Clinical History Physical Laboratory PFTs Primary care physicians PulmonologistsRadiologistsPathologists Multidimensional and multidisciplinary Radiology Chest X-ray HRCT Pathology Surgical lung biopsy

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 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  IPF

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.

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.

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 % of patients with IPF and 50% of patients with DIP and 75% of patients with ILD from rheumatoid arthritis.

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  Mid/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.)  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 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.

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.

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.

Diagnostic approach to suspected ILD

American Journal of Respiratory Cell and Molecular Biology VOL.29, 2003

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.

 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

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.

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