INTERSTITIAL ( RESTRICTIVE) LUNG DISEASES 1

1. INTERSTITIAL (RESTRICTIVE) LUNG DISEASES 1 GAIL FEINBERG, DO and LIISA A. RUSSELL, MD

2. Objectives • Define and classify interstitial lung diseases by • histopathology (inflammation and fibrosis vs. granulomatous) and by • etiology (known vs. unknown). • Distinguish epidemiologic aspects of ILDs • Recognize the clinical presentation of ILDs. • List the important components of evaluation of ILDs, including H&P, blood tests, imaging, special tests such as PFTs. • Describe therapeutic approaches and their efficacy for ILDs. • Discuss critical aspects of specific ILDs including • Pneumoconioses • Idiopathic pulmonary fibrosis • Acute cryptogenic interstitial pneumonitis • ILD associated with connective tissue disorders • ILD associated with medications/radiation • ILD resulting from acute lung injury • Hypersensitivity pneumonitis • Sarcoidosis

3. General Interstitial lung diseases are chronic, nonmalignant, noninfectious diseases that cause fibrosis and remodeling of the alveolar walls. They cause dyspnea and cough, show a reticular pattern of opacification on imaging and a restrictive defect on PFTs. About 60-70% of the time we can identify a cause: occupational exposures (silica, asbestos), connective tissue disease, medication reaction.

4. General, continued About 30-40% of the time we see ILD in people who have no known reason to develop them. These are the Idiopathic Interstitial Pneumonias and the nomenclature is confusing! The treatment is steroids then cytotoxics, but response isn’t always great. In fact, some ILDs have a very poor prognosis of either inexorable progression (asbestosis) or rapid compromise (IPF/UIP, AIP).

5. Terminology and Definitions ILD = interstitial lung disease ILDs = Diffuse Parenchymal Lung Diseases ILDs = a heterogeneous group of disorders that cause diffuse parenchymal lung damage, affecting the interstitium, alveolar epithelium, pulmonary capillary and lymphatic endothelium, basement membrane and perivascular and perilymphatic tissues. ILDs are grouped together because of • Clinical (= functional) similarity. • Radiographic similarity • Histologic similarity.

6. Classifying ILDs We can subdivide them according to whether the underlying cause is known or unknown • Known (60-70%) • Occupational and environmental exposures, e.g. pulmonary fibrosis in asbestosis, pulmonary alveolar proteinosis in acute massive silica exposure • Associated connective tissue disorder or other primary disease (chronic pulmonary edema, neurofibromatosis, lymphangioleiomyomatosis in tuberous sclerosis, vasculitides, chronic gastric aspiration

7. Classifying ILDs We can subdivide them according to whether the underlying cause is known or unknown • Unknown (30-40%) • Idiopathic interstitial pneumonias. • Idiopathic conditions that have distinct histology, clinical features and presentation and so are considered unique diseases • sarcoidosis, eosinophilic pulmonary diseases, pulmonary Langerhanscell histiocytosis, pulmonary alveolar proteinosis, lymphangioleiomyomatosis,.

8. WHY ALPHABET SOUP? American and British investigators have different names for the same condition. The same goes for clinicians and pathologists. • Usual interstitial pneumonia (UIP) aka the clinical condition of Idiopathic pulmonary fibrosis (IPF) • Nonspecific interstitial pneumonia (NIP or NSIP) • Bronchiolitis obliterans organizing pneumonia (BOOP)= cryptogenic organizing pneumonia (COP) • Respiratory bronchiolitis (RB) or respiratory bronchiolitis associated interstitial lung disease (RBIL) • Desquamative interstitial pneumonitis (DIP) • Acute respiratory distress syndrome (ARDS) = Diffuse Alveolar Damage (DAD) • Acute Interstitial Pneumonia (AIP), some call this idiopathic acute lung injury (ALI- DAD), some call this Hamman-Rich syndrome.

9. CLASSIFICATION OF CHRONIC INTERSTITIAL LUNG DISEASES BY PREDOMINANT MORPHOLOGIC FEATURES There are >200 different conditions and evolving nomenclature for them! We can subdivide them according to their underlying histopathology • Predominantly inflammation and fibrosis (the majority) • Predominantly granulomatous reactions (sarcoid, hypersensitivity pneumonitis)

10. MAJOR CATEGORIES OF INTERSTITIAL LUNG DISEASE BY MORPHOLOGIC FEATURES Alveolar wall damage resulting in interstitial fibrosis: • Pneumoconioses • Collagen vascular diseases associated lung diseases • Drug reactions • Radiation pneumonitis • Idiopathic pulmonary fibrosis (IFP) aka cryptogenic fibrosingalveolitis: histologic pattern of usual interstitial pneumonia (UIP) and exclusion of all other causes are required for the diagnosis of IPF • Cryptogenic organizing pneumonia (COP), aka bronchiolitis obliterans organizing pneumonia (BOOP) • Non-specific interstitial pneumonia (NSIP) • Acutelung injury ALI--DAD

11. MAJOR CATEGORIES OF INTERSTITIAL LUNG DISEASE BY MORPHOLOGIC FEATURES Granulomatous inflammation resulting in interstitial fibrosis: • Hypersensitivity pneumonitis • Sarcoidosis Eosinophilic: • Loeffler syndrome • Drug-allergy related • Idiopathic chronic eosinophilic pneumonia

12. CHRONIC NTERSTITIAL LUNG DISEASES BY ETIOLOGY • Post ALI-DAD • Occupational and environmental exposure - Asbestosis, silicosis, coal worker’s pneumoconiosis, hypersensitivity pneumonitis, etc. • Drug- or treatment related - Chemotherapeutic agents, radiation, oxygen • Smoking-related - Desquamative interstitial pneumonitis (DIP), respiratory bronchiolitsi(RB) • Immunologic lung disease - Sarcoidosis - Collagen vascular diseases - Necrotizing granulomatous polyangiitis - Goodpasturesyndrome - Allograft rejection • Idiopathic pulmonary fibroses • Other - Alveolar proteinosis

13. LUNG DISEASE ASSOCIATED WITH AIR POLLUTANTS Mineral dusts: • Coal dust, silica, asbestos, beryllium, iron oxide, zinc oxide, barium sulfate Organic dusts that induce hypersensitivity pneumonitis: • Moldy hay, bagasse, bird droppings Organic dusts that induce asthma: • Cotton, flax, hemp, red cedar dust Chemical fumes and vapors: • Nitrous oxide, sulfur dioxide, ammonia, benzene, insecticides Urban air

14. As a PCP, I am usually just distinguishing along the top tier! The further classifications will be handled by pulmonology, radiology and pathology. Why? To guide tx

15. Presentation of ILD • Respiratory symptoms • Progressive exertional dyspnea • Persistent, usually nonproductive cough • Hemoptysis, wheezing, chest pain less common • Incidental finding on CXR • Interstitial opacities in a reticular, nodular, or reticulonodular pattern • Hilar lymphadenopathy for early stage sarcoidosis

17. Relevant History • Age • Gender • Smoking history • Duration of illness • Prior medication use • Family history • Occupational history and environmental exposures

18. Physical Exam Findings • Crackles (velcro rales) – may hear even if normal CXR • Inspiratory squeaks • Corpulmonale – left parasternal systolic lift, loud S2 exaggerated in the pulmonic region • Cyanosis – late stage • Clubbing – late stage • Extrapulmonary findings

19. Extrapulmonary physical findings in the Interstitial Lung Diseases

20. Interstitial Lung Diseasework-up

21. Work up of ILDs • History and physical exam • Evaluate for known causes and coexisting dz • Functional Evaluation • PFTs • ABGs • Cardiopulmonary Exercise Testing • Imaging • CXR • HRCT • Tissue Diagnosis • Bronchoscopy with bronchoalveolarlavage or transbronchial biopsy • Lung biopsy

22. Bottom line: If you can identify an environmental exposure or systemic disease as the cause of the patient’s symptoms, then treat that. If not, you’ll need tissue to get your diagnosis.

24. Complete PFTs • Spirometry • Lung volumes • Diffusing capacity • Most forms of ILD produce a restrictive defect with reduced total lung capacity, functional residual capacity and residual volume. • Flow rates are decreased , but changes are in proportion to the decreased lung volumes; thus, the FEV1/FVC ratio is usually normal or increased. • Lung volumes decrease as lung stiffness worsens with disease progression.

25. ABGs • Resting arterial blood gas results may show • Normal • Hypoxemia • Alkalosis • CO2 retention at end stages of disease

26. Cardiopulmonary Exercise Testing • Sometimes patients with normal O2 sat at rest quickly desaturate with exertion (or with sleep). To detect this important condition, exercise testing with pulse-ox and ABGs can be performed. • This happens because the patient fails to decrease dead space appropriately with exercise (high VD/VT ratio).

27. Imaging ILDs • CXR • High-resolution CT • Distinguishes airspace from interstitial dz • Better assesses extent and distribution of disease • More likely to detect underlying or coexisting dz (occult mediastinal adenopathy, carcinoma, emphysema) • May help avoid biopsy if there is a diagnostic pattern

28. As many as 10% of patients with ILD will have a normal CXR! Especially those with hypersensitivity pneumonitis. If you suspect ILD, proceed with a complete eval. Likewise, if an asymptomatic patient has an abnormal CXR, proceed with complete eval. We want to treat before progressive dz causes irreversible damage.

29. The most common radiographic abnormality is a reticular pattern; however, nodular or mixed patterns are not unusual. These findings are due to alveolar filling and increased interstitial markings. Generally, the correlation between severity of the xray and clinical condition is poor. An exception is honeycombing, which does correlate with pathologic findings and a poor prognosis.

31. Indications for Tissue Diagnosis • Differential DX includes: infections, malignancy, multiple types of ILDs with multiple possible associated primary diagnoses • Definitive diagnosis helps assess disease activity, guide appropriate therapy, and avoid the confusion and anxiety of an inaccurate prognosis. • Transbronchialbiopsy via bronchoscopy may suffice (only, if the disease is evident in the peribronchial parenchyma as in sarcoidosis), but usually a surgical biopsy is needed (most often video-asistedthoracoscopic biopsy, less often open lung biopsy)

32. Pneumoconiosis Sarcoidosis Acute lung injury AIL-DAD (separate lecture on ARDS-DAD) Acute Interstitial Pneumonitis aka Hamman-Rich Idiopathic Pulmonary Fibrosis/UIP ILD associated with Connective Tissue Disorders Radiation-induced interstitial lung disease Specific ILDs we are going to look at:

33. GETTING BACK TO: Source: Interstitial Lung Diseases, Harrison's Principles of Internal Medicine, 19e Citation: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. Harrison's Principles of Internal Medicine, 19e; 2015

34. Alveolo-capillary membrane is central to the develolpment of ILD

35. WHATIZZIT?? ?? ?

36. INTERSTITIAL LUNG DISEASES Pathogenesis: • Alveolar injuryis the primary problem regardless of the type or specific cause of interstitial disease • In mild or self limiting injury healing is complete • Severe diffuse acute alveolar damage (DAD) or ongoing low-grade alveolar damage heals by fibrosis and leads to loss of functioning lung parenchyma and results in respiratory insufficiency • Activation of pulmonary macrophages is a key event in the development of pulmonary fibrosis

37. INTERSTITIAL LUNG DISEASES Pathogenesis, continued: • Chemoattractantsfrom activated macrophages activate and recruit PMNs (e.g. IL-8 and leukotriene B4 ) • Oxidants and proteases from macrophages and PMNs injure type I pneumocytes and degrade lung scleroproteins • Type II pneumocytesderived from alveolar epithelial stem cells proliferate and repair the epithelium • Secrete chemotactic and growth factors that attract more macrophages to alveoli • Stimulate fibroblast growth (platelet-derived growth factor, TGF-β, and others) • Produce gelatinases (members of the matrix metallo- proteinase family), which degrade basement membrane components

39. Case Study…

40. History • 60y/o male presents to the office complaining of chronic shoulder pain bilaterally with decreased work endurance. He has worked for Granite City for the past 40 years, cutting out the quartz and granite for countertops and helping to install when needed, and is having difficulty with production at work.

41. Past Medical History • Positive for very well controlled hypertension, otherwise negative. • Non smoker, occasional beer on weekends. • No surgeries • No daily meds (occasionally aspirin for shoulder pain which is really not helpful)

42. Physical • Other than decreased range of motion of the upper extremities bilaterally with some crepitace with ROM testing, the physical is benign. • …and you order xrays of both shoulders in your office (because you can), which show advanced degenerative arthritis….however….

43. xray

44. Differential (for lung)? • Pneumonia • COPD • Hypersensitivity pneumonitis • Miliary Tuberculosis • Silicosis • Coal workers pneumoconiosis • Asbestosis

45. Pneumoconiosis Occupational lung disease caused by dust inhalation • Anthracosis – carbon • Coalworkers – black lung • Silicosis – grinder’s dz • Bauxite fibrosis • Berylliosis • Siderosis – iron dust • Byssinosis – cotton • Silicosiderosis – mix of silica and iron • Labrador lung – miners exposed to iron, silica and anthophyllite dust (a type of asbestos) • Lunar lung – astronauts exposed to lunar dust

47. PNEUMOCONIOSES - GENERAL • Occupational lung diseases induced by inorganic and organic particulates and chemical fumes and vapors • The development of pneumoconiosis depends on: - The amount of dust retained in the airways and lung parenchyma - The size and shape of particles: The most dangerous particles measure 1-5μm, because they can reach the terminal airways and alveoli and get deposited there. Smaller particles stay in the air and get exhaled. Larger particles get stuck in the mucociliary blanket and get expectorated out. - Particle solubility and physiochemical reactivity - Additional effects of other irritants, such as tobacco smoke

48. “EGGSHELL” CALCIFICATIONS NOT SPECIFIC FOR SILICOSIS Ill-defined bilateral hila with multiple calcified lymph nodes. Blunted rightcostophrenicangle. Elongated aortic arch. Multiple lymph nodes with "eggshell" calcification along the mediastinum and bilateral pulmonary hila show particularly well in the retrocardiac space in the lateral film.

49. STUDY CASE SILICOSIS THICKENED FIBROTIC PLEURA SILICOTIC NODULES

50. SILICOTIC NODULES (CONSTRUCTION WORKER) COMPRESSED PA LUMEN FIBRINOID NECROSIS