Interstitial lung disease: A clinical overview and general approach

1. Interstitial lung disease: A clinical overview and general approach By Prof. Ramadan Nafae Professor and Head of Chest Department Zagazig , Faulty of Medicine

2. Items: • Definition • Epidemiology • Classification • Pathogenesis • Diagnosis • Treatment • Final comments

3. Items: • Definition • Epidemiology • Classification • Pathogenesis • Diagnosis • Treatment • Final comments

4. 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. 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

5. 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.

6. 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.

7. Items: • Definition • Epidemiology • Classification • Pathogenesis • Diagnosis • Treatment • Final comments

8. 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.

9. Items: • Definition • Epidemiology • Classification • Pathogenesis • Diagnosis • Treatment • Final comments

10. 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.

11. ATS/ERS Classification of Idiopathic Interstitial Pneumonias

12. IIP Classification HC, honeycombing; GGO, ground glass opacity; FF, fibrotic foci; M, macrophage

13. Items: • Definition • Epidemiology • Classification • Pathogenesis • Diagnosis • Treatment • Final comments

14. Four proposed mechanisms and potential variations in lung responses to inhaled agents Inhaled environmental agents (fumes, dust, smoke) Delivery & persistence Genetic predisposition Alveolar epithelial cell injury Biochemical Wound healing (inflammation, coagulation, epithelial/endothelial repair) Immunologic Fibrotic Chronic airflow obstruction Normal Pulmonary fibrosis

15. 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

16. LUNG INJURY – Etiologic agent – Recurrent vs single – Endothelial vs epithelial Histopathologic Pattern AGEGENETIC FACTORSENVIRONMENTAL FACTORSNATURE OF INJURY DIP RB-ILD LIP COP NSIP AIP UIP Inflammation Fibrosis Thannickal VJ, et al. Annu Rev Med. 2004;55:395-417.

17. Items: • Definition • Epidemiology • Classification • Pathogenesis • Diagnosis • Treatment • Final comments

18. Approach to the Diagnosis of ILD • Clinical • History • Physical • Laboratory • PFTs • Radiology • Chest X-ray • HRCT • Pathology • Surgical lung biopsy Primary care physicians Pulmonologists Radiologists Pathologists Multidimensional and multidisciplinary

19. 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.

20. 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.

21. Age: • Infancy and childhood: • Follicular bronchiolitis • Cellular interstitial pneumonia • Acute idiopathic pulmonary hemorrhage of infancy

22. 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.

23. Race: • Sarcoidosis occurs 10-12 folds among blacks.

24. 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

25. History (cont.) Smoking – related ILD : • Desquamative interstitial pneumonia. • RBILD. • Pulmonary Langerhans’ cell histiocytosis. • IPF. • Rheumatoid arthritis associated ILD. • Acute eosinophilic pneumonia.

26. 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.

27. 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

28. 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.

30. 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.

31. 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.

32. 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.

33. 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.

34. 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

35. 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.

36. 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.

37. 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.

38. Radiographic Clues (cont.) • Photographic negative of pulmonary edema: Chronic eosinophilic pneumonia. • Recurrent pneumothorax: Langerhans’ cell granulomatosis. LAM Tuberous sclerosis. Neurofibromatosis.

42. 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.

43. 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.

44. 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.

45. 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.

49. 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.

50. 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.