Chronic Interstitial (Restrictive, Infiltrative) Lung Diseases Feb. 28. 2016 Ch. 12 p (459 – 512

Respiratory Pathology Outline Acute respiratory distress syndrome Obstructive lung diseases Restrictive lung diseases Vascular diseases 2

Restrictive Lung Disease Bilateral, patchy, and chronic involvement of the pulmonary C.T., mainly the alveolar walls. Bilateral, patchy, & chronic involvement of the pulmonary C.T., mainly the alveolar walls.

Chronic Interstitial Lung Diseases Diffuse interstitial fibrosis of the lung cause restrictive lung diseases reduced lung compliance, (stiff lung) FEV / FVC is normal. Caused by heterogeneous diseases Injury to the alveoli, activated macrophages release TGF-β. IPF; patchy fibrosis with cystic spaces (honeycomb lung). Also known as usual interstitial pneumonia (UIP).

Th1 Th2, Eosinophils, Mast cells Pathways of macrophage activation

Schematic representation of the pathogenesis IPF

Restrictive lung diseases REDUCED COMPLIANCE (stiff lung), reduced gas exchange Diffuse Honeycomb FIBROSING GRANULOMATOUS EOSINOPHILIC SMOKING RELATED PAP (Pulmonary Alveolar Proteinosis If you “squeezed” a lung with restrictive lung disease, you would note it wasn’t as “spongy” as a normal lung. This is the definition of reduced compliance. It simply will not “comply” when squeezed (or moved by respiratory motion either)! In contract to the “obstructive” lung diseases.

Major Categories of Chronic Interstitial Lung Disease Fibrosing Usual interstitial pneumonia (idiopathic pulmonary fibrosis) Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia Associated with collagen vascular disease Pneumoconiosis Associated with therapies (drugs (amiodarone, bleomycin, methotrexate) & radiation) Granulomatous Sarcoidosis Hypersensitivity pneumonia Eosinophilic Loeffler syndrome Drug allergy–related Idiopathic chronic eosinophilic pneumonia Smoking-Related Desquamative interstitial pneumonia Respiratory bronchiolitis

Idiopathic pulmonary fibrosis, (IPF; usual interstitial pneumonitis [UIP], honeycomb fibrosis) radiograph There are increased brighter interstitial markings marked in lower lung fields. Idiopathic pulmonary fibrosis, radiograph There are increased brighter interstitial markings in all lung fields as a consequence of idiopathic pulmonary fibrosis (IPF; usual interstitial pneumonitis [UIP]). Affected patients have continuing loss of lung volumes; pulmonary function studies show reduced forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV1). Because both are reduced, the FVC/FEV1 ratio generally remains unchanged. These reductions are typically proportional with restrictive lung diseases such as IPF. This disease is probably mediated by an inflammatory response to alveolar wall injury, but the inciting event in IPF is unknown. Patients may survive weeks to years, depending on the severity, with eventual end-stage honeycomb fibrosis.

Idiopathic pulmonary fibrosis, CT image This chest CT scan in lung window mode shows very prominent bright interstitial markings in the posterior lung bases. There are also smaller darker lucent areas that represent honeycomb change, a characteristic feature of usual interstitial pneumonitis, a descriptive term for an idiopathic and progressive restrictive lung disease that can affect middle-aged individuals with progressive dyspnea, hypoxemia, and cyanosis. Patients develop pulmonary hypertension and cor pulmonale as a result. Some familial forms of IPF are associated with telomerase gene defects. The term nonspecific interstitial pneumonia is reserved for cases with less severe restrictive disease and microscopic findings that include either more pronounced chronic inflammation or fibrosis at the same stage of development Idiopathic pulmonary fibrosis, CT image; Shows very prominent bright interstitial markings in the posterior lung bases. There are also smaller darker lucent areas that represent honeycomb change, a characteristic feature of usual interstitial pneumonitis.

L R A V Normal lung, CT image Normal lung, CT image This chest CT scan at soft-tissue density reveals the normal appearance of the right (* ) and left (X ) lungs—essentially black from air density—in a normal man. Contrast material in the bloodstream gives the right (R ) and left (L ) chambers of the heart and the aorta (A ) a bright appearance. Bone of the vertebral body (V) and ribs also appears bright. The AP diameter is normal. Normal lung, CT image

Honeycomb change, gross Regardless of the cause of restrictive lung diseases, many eventually lead to extensive pulmonary interstitial fibrosis. The gross appearance shown here in a patient with organizing DAD is known as “honeycomb lung” because of the appearance of the irregular residual small dilated airspaces between bands of dense fibrous interstitial connective tissue. The lung compliance is markedly diminished so that patients receiving mechanical ventilation require increasing positive end expiratory pressure (PEEP), predisposing them to airway rupture and development of interstitial emphysema. Honeycomb change, gross Regardless of the cause of restrictive lung diseases, many eventually lead to extensive pulmonary interstitial fibrosis. The gross appearance shown n a patient with organizing DAD is known as “honeycomb lung”

IPF; Honeycomb change; gross IPF; Patchy, progressive lung fibrosis Symptoms: gradual onset cough, dyspnea. Respiratory failure and cor pulmonale within about 3 years Radiologic and histologic term: “Usual Interstitial Pneumonia (UIP)” IPF; Honeycomb change; gross

Fibrosis Fluid L, Eosino, Mast Honeycomb change, microscopic There is dense fibrous connective tissue (Red square ) surrounding residual airspaces filled with pink proteinaceous fluid. These remaining airspaces have become dilated and lined with metaplastic bronchiolar epithelium. This produces marked diffusion block to gas exchange. Vital capacity as well as residual volume both become diminished with this restrictive, interstitial lung disease. The interstitial inflammation usually is patchy and consists of an alveolar septal infiltrate of mostly lymphocytes and occasional plasma cells, mast cells, and eosinophils. Idiopathic pulmonary fibrosis, (IPF; usual interstitial pneumonitis (UIP), honeycomb fibrosis), microscopic There is dense fibrous connective tissue ( ) surrounding residual airspaces filled with pink proteinaceous fluid The interstitial infiltrate; Lymphocytes, plasma cells, mast cells, and eosinophils

IPF: tons of fibrosis

Interstitial fibrosis, microscopic A trichrome stain highlights in blue the collagenous interstitial connective tissue of pulmonary fibrosis. The extent of the fibrosis determines the severity of disease, which is marked by progressively worsening dyspnea. The alveolitis that produces fibroblast proliferation and collagen deposition is progressive over time. If such patients are intubated and given mechanical ventilation, just as in the case of severe chronic obstructive pulmonary disease, it is unlikely that they can be extubated. It is crucial to determine patient advance directives for medical care. Interstitial fibrosis, microscopic A trichrome stain highlights in blue the collagenous interstitial connective tissue of pulmonary fibrosis

NON-SPECIFIC INTERSTITIAL PNEUMONIA (NSIP) a chronic bilateral interstitial lung disease of unknown etiology. it carries a much better prognosis than that for IPF. cellular and fibrosing patterns No honeycombing

CRYPTOGENIC ORGANIZING PNEUMONIA (COP) Some alveolar spaces are filled with balls of fibroblasts. Although compressed, adjacent alveoli are relatively normal Rx; Steroids

“COLLAGEN” VASCULAR DISEASES Rheumatoid Arthritis SLE (“Lupus”) Progressive Systemic Sclerosis (Scleroderma)

Pneumoconioses Coal bagasse Size matters (1-5 μm particles are worst) A group of chronic fibrosing diseases of the lung resulting from exposure to organic and inorganic particulates, most commonly mineral dust asbestos silica nodules Mining, & fabrication of materials, insulation Sandblasting, quarrying, mining, stone cutting, ceramics

Coal worker’s pneumoconiosis, microscopic Emphysema Coal dust–induced disease varies from asymptomatic anthracosis, to simple coal worker’s pneumoconiosis (coal macules or nodules, and centrilobular emphysema), to progressive massive fibrosis (PMF), manifested by increasing pulmonary dysfunction, pulmonary hypertension, & cor pulmonale Coal worker’s pneumoconiosis, microscopic Asymptomatic anthracosis, to simple coal worker’s pneumoconiosis (coal macules or nodules, and centrilobular emphysema), to progressive massive fibrosis (PMF) There is no increased risk for lung cancer.

Silicosis, microscopic; The most common pneumoconiosis. Silicosis, microscopic; A greater degree of exposure to silica and an increasing length of exposure determine the amount of silicotic nodule formation and the degree of restrictive lung disease, which is progressive and irreversible. The manifestations of silicosis can range from asymptomatic silicotic nodules to PMF; persons with silicosis also have an increased susceptibility to tuberculosis. The relationship between silica exposure and subsequent lung cancer is controversial.Silicosis increases the risk for lung carcinoma about twofold. Silicosis, microscopic; The most common pneumoconiosis. Silicotic nodules (arrow ) (bundles of collagen & a surrounding inflammatory reaction) Range from asymptomatic silicotic nodules to PMF +/- Calcification (egg shell calcification) There is anincrease risk for TB & lung cancer .

Asbestos fibers come in two forms; the stiff amphiboles have a greater fibrogenic and carcinogenic potential than the serpentine chrysotiles. • Asbestos exposure is linked with six disease processes: (1) parenchymal interstitial fibrosis (asbestosis); (2) localized fibrous plaques or, rarely, diffuse pleural fibrosis; (3) pleural effusions; (4) lung cancer; (5) malignant pleural and peritoneal mesotheliomas; and (6) laryngeal cancer. • Cigarette smoking increases the risk of lung cancer in the setting of asbestos exposure; moreover, even family members of workers exposed to asbestos are at increased risk for cancer. Asbestos fibers

Ferruginous bodies, microscopic The cause of interstitial lung disease could be asbestosis. The inhaled long, thin object known as an asbestos fiber becomes coated with iron and calcium, then is called a ferruginous body, several of which are seen here with a Prussian blue iron stain. Ingestion of these fibers by macrophages sets off a fibrogenic response through release of cytokine growth factors that promote continued collagen deposition by fibroblasts. Some houses, business locations, and ships still contain construction materials with asbestos, particularly insulation, so care must be taken to prevent inhalation of asbestos fibers during remodeling or reconstruction. Ferruginous bodies, microscopic; The long, thin asbestos fiber coated with iron and calcium, called a ferruginous body, several of which are seen here with a Prussian blue iron stain

QUIZ

Pleural fibrous plaques, gross; Seen here on the pleural aspects of the diaphragmatic leaves are several tan-white pleural plaques (arrow ) typical of pneumoconioses and of asbestosis in particular. Chronic inflammation induced by the inhaled dust particles results in fibrogenesis.

GRANULOMATOUS SARCOIDOSIS, i.e., Non-caseating granulomas (Idiopathic) HYPERSENSITIVITY (Dusts, bacteria, fungi, Farmer’s Lung, Pigeon Breeder’s Lung)

SARCOIDOSIS LN & Lung, but eye, skin or…. UNKNOWN ETIOLOGY Immune, Genetic factors YOUNG BLACK WOMEN fever, cough, dyspnea, night sweats, and weight loss can lead to restrictive lung disease Minimal pulmonary disease that resolves with corticosteroid Rx. Patients often have fever, nonproductive cough, dyspnea, chest pain, night sweats, and weight loss. More severe cases can lead to restrictive lung disease, with increasing dyspnea along with nonproductive cough. Multiple organs may eventually become involved, particularly eyes, skin, skeletal muscle, and bone marrow. CXR: hilar LN & pulmonary interstitial fibrosis

Sarcoidosis in mesenteric lymph node; Non-Caseating Granulomas are the RULE “Asteroid” bodies within these granulomas are virtually diagnostic

“Caseating” and a “non-caseating” granuloma The classical difference between a “caseating” and a “non-caseating” granuloma, is often the difference between TB and sarcoid. Which one might culture out acid-fast bacteria? Ans: The one on the LEFT (i.e., caseating) “Caseating” and a “non-caseating” granuloma