I have no relevant conflicts of interest to disclose

I have no relevant conflicts of interest to disclose

Diffuse parenchymal lung disease (DPLD) and its associations Secondary lobular anatomy DPLD History, clinical findings, temporal evolution, and exposures HRCT Approach Pattern of Disease Location in the secondary lobule HRCT Approach Upper versus lower lung zone predominance Central versus peripheral predominance Idiopathic Interstitial Pneumonias NSIP, COP, RB-ILD, DIP, LIP, and AIP IPF Teaching Points

Common Clinical Problem Diffuse/widespread infiltrates on a chest radiograph Diffuse does not imply uniformity of involvement Diffuse infiltrates are non-specific radiographic findings that do not diagnose causation

Causes of Widespread/Diffuse Infiltrates on Chest Radiograph Edema (water) Pulmonary hemorrhage (blood) Infection (pus) Inflammation Fibrosis Neoplasm

Important Associations with DPLD Drug induced injury Environmental induced injury Occupational induced injury Relationship to other systemic illness (collagen vascular disease and/or autoimmune disease) Genetic relationships

Descriptive term for diffuse lung diseases that affect the interstitium or alveolar space There are shared physiologic, radiographic, and pathologic features

Understanding of lung anatomy is essential for approach to DPLD especially with the widespread use of HRCT The secondary lobule is the basic anatomic unit of pulmonary structure and function Interpretation of DPLD is based upon the type of involvement of the secondary lobule

Smallest lung unit surrounded by connective tissue septa Measures 1-2 cm and is made up of 5-15 pulmonary acini, that contain the alveoli for gas exchange Supplied by the terminal bronchiole in the center, that is paralleled by the centrilobular artery Pulmonary veins and lymphatics run in the periphery within the interlobular septa

Centrilobular Area Central part of the secondary lobule Site of diseases that enter the lungs through the airways Perilymphatic Area Peripheral part of the secondary lobule Site of diseases that are located in the lymphatics of the interlobular septa

DPLD of Known Cause (collagen vascular disease, drugs, infection, occupation) Idiopathic Interstitial Pneumonias Idiopathic Pulmonary Fibrosis Desquamative Interstitial Pneumonia, Respiratory Bronchiolitis Interstitial Lung Disease, Acute Interstitial Pneumonia, Cryptogenic Organizing Pneumonia, Nonspecific Interstitial Pneumonia, Lymphocytic Interstitial Pneumonia Granulomatous DPLP (Sarcoidosis) Other forms of DPLD (Lymphangioleiomyomatosis and Pulmonary Langerhans Cell Histiocytosis)

Pattern of Disease Reticular Nodular High-attenuation (groundglass, consolidation) Low-attenuation (emphysema, cystic) Location in the secondary lobule Centrilobular, perlymphatic, or random Upper versus lower lung zone predominance Central versus peripheral predominance Additional findings Pleural fluid Lymphadenopathy Cardiomegaly Esophageal dilation Traction bronchiectasis

Morphologic findings have to be combined with history of the patient and clinical findings Clinical presentation Demographics (age/gender/race) Pulmonary and extrapulmonary manifestations Temporal course Environmental exposure and occupational history Drug history Smoking history Past history of illnesses Family history

Acute Onset (1-14 days) Limited diagnoses considered in the differential Acute interstitial pneumonia, acute hypersensitivity pneumonitis, acute eosinophilic pneumonia, acute decompensated heart failure, acute infectious process Sub-acute to Chronic (Months to Years) More common presentation Less useful to narrow the differential diagnosis

Organic Antigens (bacteria, fungi, mycobacteria) Moldy hay, silage, grain Aerosolized hot tub water Stagnant humidifier water Organic Antigens (animal protein) Bird feathers and droppings Laboratory animal dander Inorganic Antigens Di-isocyanates (used in production of polyurethanes) Aerosolized machine lubricants

Inorganic Dusts Asbestos Silica Iron (siderosis) Mixed (coal worker) Complex (9/11 lung disease) Radiation Exposure

Complete past medication review Medications taken for prolonged periods Some medications have a long latency period (amiodarone) Over-the-Counter Medications Oily nose drops Herbal medications Illegal/Recreational Drugs Temporal relationship with current manifestations

Reticular Pattern Too many lines Coalescence of lines creates nodular appearance at intersection The result of thickening of the interlobular septa or as a result of fibrosis (honeycombing) Septal Thickening Thickening of the lung interstitium by fluid, fibrous tissue, or infiltration by cells Smooth: Usually seen in interstitial pulmonary edema but also seen in alveolar proteinosis and lymphangitic spread of carcinoma Nodular or Irregular: Lymphangitic spread of carcinoma or lymphoma, sarcoidosis and silicosis

Smooth Septal Thickening Alveolar Proteinosis (accumulation of PAS positive phospholipoprotein from surfactant) Crazy Paving (PJP, ARDS, NSIP, BAC, COP, sarcoidosis, and alveolar hemorrhage) Irregular Septal Thickening Focal irregular septal thickening in the right upper lobe due to lymphangitic carcinomatosis In sarcoidosis the findings would be more diffuse

Random Randomly distributed relative to the structures of the lung and secondary lobule Centrilobular Nodules spare the pleural surfaces Most peripheral nodules are centered 5-10 mm from fissues or the pleural surface Perilymphatic Seen in relation to pleural surfaces, interlobular septa, and peribronchovascular interstitium Almost always visible in subpleural location

Hematogenous metastases Miliary tuberculosis Miliary fungal infections Extensive sarcoidosis may mimic the pattern Pulmonary Langerhans Cell Histiocytosis (early nodular stage) Characterized by multiple cysts of varying size Early disease with nodules (later cavitate to form cysts) Smoking related (upper lung predominance)

Without tree-inbud opacities Ill-defined nodular ground-glass opacities removed from pleural and fissural surfaces Subacute Hypersensitivity Pneumonitis RB-ILD LIP

Ground-glass nodules with prominent tree-in-bud opacities Appearance of an irregular and often nodular branching structure, most easily identified in the lung periphery Represents dilated and impacted (mucous or pus filled) centrilobular bronchioles (bronchiolitis) Clustered: MTB/MAI, Fungal, Bacterial Infection Diffuse: Panbronchiolitis, viral infections, cystic fibrosis

Nodules visible along the pleural surface, the central bronchovascular interstitium, and along interlobular septa Sarcoidosis Silicosis Coal-Workers Pneumoconiosis

Ground-Glass Opacity Hazy increase in lung opacity without obscuration of underlying vessels Increase in lung density is due filling of alveolar spaces with pus, edema, hemorrhage, inflammation, or tumor cells Also secondary to thickening of the interstitium or alveolar walls below the spatial resolution of HRCT (as seen in fibrosis 60-80% of patient s with GGO on HRCT have active and potentially treatable lung disease

Acute Pulmonary Edema Heart failure ARDS Pulmonary Hemorrhage Pneumonia Acute Eosinophilic Pneumonia Chronic Hypersensitivity Pneumonitis Organizing Pneumonia Chronic Eosinophilic Pnuemonia Fibrosis UIP NSIP Bronchoalveolar Cell Carcinoma

Consolidation Hazy increase in lung opacity with obscuration of underlying vessels Pneumonia PJP, viral, bacterial, Mycoplasma Eosinophilic pneumonia Organizing pneumonia Edema: Heart failure, ARDS, AIP Fibrosis: UIP, NSIP, radiation Tumor: BAC and lymphoma Idiopathic: Sarcoidosis and Alveolar Proteinosis

Emphysema Areas of low attenuation without visible walls as a result of parenchymal destruction Honeycombing Presence of small cystic spaces with irregularly thickened walls composed of fibrous tissue Predominate in peripheral and subpleural lung regions Several contiguous layers IPF, connective-tissue disease, asbestosis, endstage HP, end-stage sarcoidosis

Bronchiectasis Localized bronchial dilation Bronchial wall thickening, lack of normal tapering with visibility of airways in the peripheral lung, mucous retention in the bronchial lumen Prior infection (focal bronchiectasis) Cystic fibrosis Cilia abnormalities (primary ciliary dyskinesia) Autoimmune disease (RA, Sjogren s) ABPA Inflammatory bowel disease Immune deficiency (immunoglobulin deficiency and HIV) Alpha-1 antitrypsin

Cysts and Cavities Cysts are radiolucent areas with a wall thickness < 4 mm Lymphangioleiomyomatosis Pulmonary Langerhans Cell Histiocytosis Lymphocytic Interstitial Pneumonia Cavities are radiolucent areas with a wall thickness > 4mm Staph aureus, fungal infection, TB, septic emboli, squamous cell cancer, Wegner s

Upper Lung Zone Inhaled particles (silica, coal) Smoking related diseases Centrilobular emphysema RB-ILD Pulmonary Langerhans Cell Histiocytosis Hypersensitivity Pneumonitis Sarcoidosis Lower Lung Zone UIP (IPF, collagen vascular disease) Asbestosis Aspiration Pulmonary edema Panlobular emphysema Affects the whole secondary lobule Alpha-1 antitrypsin deficiency

Central Zone Sarcoidosis Cardiogenic pulmonary edema Pulmonary alveolar proteinosis Peripheral Zone UIP (IPF, collagen vascular disease) Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Asbestosis Hematogenous metastases

One of the most common histologic findings in patients with IIP s Need to distinguish from UIP given the improved survival and responsiveness to corticosteroids Typical age is 40-50 years Gradually worsening dyspnea over several months, cough, fatigue, weight loss No gender predilection Need to rule out secondary causes Collagen vascular disease, hypersensitivity pneumonitis, druginduced pneumonitis, HIV infection

Histologic Features Temporally and spatially homogenous lung involvement Cellular NSIP: thickening of alveolar septa is caused by inflammatory cells Fibrosing NSIP: interstitial fibrosis is seen in addition to mild inflammation Imaging Features (HRCT) Subpleural and symmetric distribution of lung abnormalities Patchy ground-glass opacities combined with irregular linear or reticular opacities and scattered micronodules

Typical age is 55 years Women and men are equally affected Mild dyspnea, cough, and fever developing over a few weeks Need to exclude known causes of organizing pneumonia Infection, drug-induced, collagen vascular disease PFT s show restriction and diffusion impairment Minority with airways obstruction Typical complete recovery with oral corticosteroids High rate of relapse within 1-3 months of stopping treatment Prolonged treatment for at least 6 months initially to avoid relapse

Histologic Features Patchy process characterized primarily by organizing pneumonia involving alveolar ducts and alveoli with our without bronchiolar intraluminal polyps Connective tissue of all the same age Changes centered on small airways Imaging Features (HRCT) Findings are more extensive than expected from review of plain radiograph Peripheral or peribronchial distribution with lower lung zone predominance Opacities vary from ground-glass to consolidation Opacities migrate (changing size and location)

Respiratory bronchiolitis Histopathologic lesion found in cigarette smokers Pigmented intraluminal macrophages in the 1 st and 2 nd order respiratory bronchioles Rarely symptomatic but can rarely present as an ILD Current smokers typically age 30-40 years 30 pack year history Men affected twice as often as women Present with mild dyspnea and cough Symptoms are not disabling Mild to moderate reduction in DLCO Treatment is smoking cessation

Histologic Features Intraluminal accumulation of pigmented macrophages centered around the respiratory bronchioles Mild peribronchiolar inflammation Imaging Features (HRCT) Plain chest radiograph insensitive for detection Centrilobular nodules in combination with ground-glass opacities and bronchial wall thickening Ground-glass opacities correlate with macrophage accumulation in alveolar ducts and alveolar spaces Pigmented alveolar macrophages in a terminal bronchiole and the adjacent alveoli (arrows). Moderate peribronchiolar inflammation and fibrosis are present (arrowhead).

Considered by many to represent the end of a spectrum of RB-ILD Typical age is 40-50 years Current or former smokers Rarely occurs in nonsmokers who have had environmental inhalation exposures Men affected twice as often as women Insidious onset of dyspnea and dry cough over weeks to months Progression to respiratory failure and death can occur Treatment is smoking cessation Oral corticosteroids can be trialed

Histologic Features Accumulation of pigmented macrophages and a few desquamated alveolar epithelial cells in the alveoli Lung involvement is more diffuse and uniform in DIP opposed to RB-ILD Imaging Features (HRCT) Diffuse ground-glass opacities Correlates histologically with the spatially homogenous intraalveolar accumulation of macrophages and thickening of alveolar septa Peripheral and lower lung zone predominance Irregular linear opacities and a reticular pattern are frequent

Typical age is fifth decade of life Present with slowly progressive dyspnea and cough (over a period of 3 or more years) Fever, night sweats, weight loss, chest pain, arthralgia Very rare Need to evaluate for secondary causes Sjogrens, RA, primary biliary cirrhosis, autoimmune hemolytic anemia, chronic active hepatitis, hypogammaglobulinemia, severe combined immunodeficiency, AIDS More common in women Corticosteroids are used for treatment Response is unpredictable

Histologic Features Diffuse infiltration of the interstitium by lymphocytes, plasma cells, and histiocytes Reactive lymphoid follicles distributed along the peribronchiolar regions Imaging Features (HRCT) Diffuse bilateral abnormalities with a lower lung predominance Ground-glass attenuation (diffuse interstitial inflammation) Thin-walled perivascular cysts (usually within the lung parenchyma throughout the mid lung zones) Widening of alveolar septa by lymphoid infiltrates (arrow) (inset), which consist of mature lymphocytes, plasma cells, and histiocytes.

Mean age of 50 years Men and women are equally affected Prior illness suggestive of a viral upper respiratory infection Myalgias, arthralgias, fever, chills, malaise Median time from 1 st symptom to time of presentation is less than 3 weeks Hypoxemia develops early and progresses rapidly to respiratory failure Need to distinguish from: Diffuse alveolar damage (DAD) superimposed on UIP, DAD with collagen vascular disease, ARDS (DAD of known cause), infection (PJP, CMV), druginduced pneumonitis, acute hypersensitivity pneumonitis, and acute eosinophilic pneumonia No proven treatment Corticosteroids may be effective in early phase of disease Poor prognosis with nearly 50% mortality rate

Histologic Features (Diffuse Alveolar Damage) Early exudative phase Interstitial and intraalveolar edema, formation of hyaline membranes, and diffuse alveolar infiltration by inflammatory cells Organizing phase (end of first week of lung injury) Formation of granulation tissue resulting in alveolar wall thickening Fibrotic changes in AIPD are uniform and characterized by numerous fibroblasts but relatively little collagen deposition Imaging Features (HRCT) Early exudative phase Ground-glass opacities (alveolar septal edema and hyaline membranes) Areas of consolidation (less extensive and limited to the dependent area of the lung) Intraalveolar edema and hemorrhage Organizing phase Consolidations present (intraalveolar fibrosis) Late phase Architecularal distortion, traction bronchiectasis, and honecombing

The most common entity of the IIPS 50 years old or older Progressively worsening dyspnea and nonproductive cough No obvious gender predilection Incidence in men age 55 or greater is greater than women of the same age Estimated mean survival of 2-5 years from the time of diagnosis Two new treatment options recently FDA approved Pirfenidone (Esbriet) Nintedanib (Ofev)

Histologic Features Hallmark of usual interstitial pneumonia (UIP) is presence of scattered fibroblastic foci Lung involvement is heterogenous and areas of normal lung alternate with interstitial inflammation and honeycombing Discordant histologic patterns may be present UIP pattern in one biopsy specimen is associated with a worse prognosis

UIP Pattern Requires All Four Features Subpleural, basal predominance Reticular abnormality Honeycombing with or without traction bronchiectasis Absence of features listed as inconsistent with UIP pattern Inconsistent with UIP Pattern Upper or mid-lung predominance Peribronchovascular predominance Extensive ground-glass abnormality Profuse micronodules Discrete cysts Diffuse mosaic attenuation/airtrapping Consolidation in bronchopulmonary segments

May provide a specific diagnosis in a limited number of cases of DPLD Lymphocentric Disorders Sarcoidosis, carcinoma, infection Specific Histopathology Eosinophilic pneumonia, alveolar proteinosis Insufficient to diagnose histopathologic patterns that require establishment of an architectural patent (most IIPs)

1. Granulomatous diseases 2. Malignant tumors/lymphangitic 3. DAD (any cause) 4. Certain infections 5. Alveolar proteinosis 6. Eosinophilic pneumonia 7. Vasculitis 8. Amyloidosis 9. EG/HX/PLCH 10. LAM 11. RB/RBILD/DIP 12. UIP/NSIP/LIP COP 13. Small airways disease 14. PHT and PVOD Transbronchial Biopsy Often Sometimes Never Surgical Biopsy

IIPs are rare but are considered prototypes of the much more common secondary interstitial pneumonias that can be encountered in frequent disorders (sarcoidosis, vasculitis, and collagen vascular disease) The classification of IIPs is based on histologic criteria, but those histologic patterns are closely associated with imaging patterns that correlate well with histologic findings Establishing the final diagnosis of IIPs requires close communication and interaction between clinicians, radiologists, and pathologists Diagnosis of IIPs is a dynamic process, and preliminary diagnostic assumptions may need to be revised during the diagnostic work-up. High-resolution CT is indicated in virtually all patients suspected to have IIPs

It is key to identify patients with UIP and differentiate them from patients with other IIPs, because UIP has a substantially poorer prognosis than other IIPs In all patients suspected to have IIPs who do not show the typical clinical and radiologic features of UIP, surgical lung biopsy should be performed Biopsy specimens should always be obtained from more than one lobe, and high-resolution CT should serve as a guiding tool for determining the appropriate anatomic location of the biopsy site