Diseases With Restrictive Pattern PDF

Interstitial (restrictive) diseases with fibrosing (restrictive) pattern and a few others Eric Harp, DO 1 Learning objectives 1. Describe general principles of restrictive lung disease and chronic interstitial disease and the resultant pulmonary function testing pattern, imaging and gross findings (...

Interstitial (restrictive) diseases with fibrosing (restrictive) pattern and a few others Eric Harp, DO 1 Learning objectives 1. Describe general principles of restrictive lung disease and chronic interstitial disease and the resultant pulmonary function testing pattern, imaging and gross findings (if applicable) 2. Describe examples of extrapulmonary causes of a restrictive pulmonary function pattern 3. Describe pathophysiology, clinical, histopathologic and radiologic features of usual interstitial pneumonia/idiopathic pulmonary fibrosis (IPF) 4. Describe pathophysiology, clinical features of, and associations with Nonspecific interstitial pneumonia 5. Describe the term organizing pneumonia and the pathophysiology and clinical features of Cryptogenic organizing pneumonia 6. Describe pathophysiology and clinical features of hypersensitivity pneumonitis 7. Describe pathophysiology and clinical features of radiation-induced lung injury 8. Describe pathophysiology and clinical features of pulmonary eosinophilia 9. Describe pathophysiology and clinical features of desquamative interstitial pneumonitis 10. Describe pathology and clinical features of respiratory bronchiolitis-associated interstitial lung disease(s) 11. Describe osteopathic considerations in patients with extrinsic and intrinsic restriction to lung function 2 Restrictive disorders Characterized by reduced total lung capacity Contributors Chest wall disorders Acute/chronic interstitial disorders Fibrosing Granulomatous Eosinophilic Smoking-related Pulmonary alveolar proteinosis 3 www.clevelandclinicmeded.com Restrictive disorders Chest wall disorders kyphoscoliosis neuromuscular disease myasthenia gravis amyotrophic lateral sclerosis Guillain-Barre (post-viral inflammatory demyelinating neuropathy) polio abdominal adiposity (obesity) These extrinsic causes of restriction will have a normal alveolar-arterial (A-a) gradient (in absence of other lung disease) www.radiopaedia.com Spineuniverse.com 4 Interstitial disorders-overall frequency Pneumoconiosis 25% (occupational) Sarcoidosis 25% (granulomatous) Idiopathic pulmonary fibrosis 15% Collagen vascular/autoimmune 10% Remaining 25% >100 causes Some of these diseases actually have an intra-alveolar (air space) component in addition to an interstitial component Hypersensitivity pneumonitis Radiation-induced Drug toxicity (bleomycin, busulfan, amiodarone, methotrexate) Granulomatosis with polyangiitis (vascular) 5 Restrictive disorders “restrictive” is a functional designation Diseases are classified by histologic and clinical features FEV1 FVC 3 3 Decreased lung volume decreased FVC FEV1/FVC: >80% 6 Chronic interstitial diseases Also known as diffuse parenchymal diseases Often involve a maladaptive or suboptimal response to injury Characterized by Inflammation fibrosis 7 http://library.med.utah.edu/WebPath/LUNGHTML/LUNG097.html Chronic interstitial diseases Chronic lung fibrosis can ensue Eventually, secondary pulmonary hypertension and right-sided heart failure associated may result with time 8 http://library.med.utah.edu/WebPath/LUNGHTML/LUNG097.html Seidel's Guide to Physical Examination. Tenth Edition. 2023 Chronic interstitial diseases Clinical features Dyspnea Tachypnea often short, shallow breaths End-expiratory crackles Eventual cyanosis Not wheezing-these are not really airway problems like asthma, chronic bronchitis, bronchiectasis Imaging features Bilateral Small nodules Interstitial irregular lines Ground glass shadows Robbins and Cotran. Pathologic Basis of Disease. Tenth Edition. 2021 9 Restrictive diseases with a fibrosing pattern Idiopathic pulmonary fibrosis (IPF) Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia 10 Restrictive diseases with a fibrosing pattern Idiopathic pulmonary fibrosis (IPF) specific form of chronic, fibrosing interstitial lung disease (ILD) of unknown cause associated with histologic and radiological features of usual interstitial pneumonia (UIP) Progressive pulmonary fibrosis (PPF) is a relatively new clinical term describes patient with interstitial lung disease other than IPF with worsening clinical course (worsening symptoms, radiological progression and physiological progression) 11 Idiopathic pulmonary fibrosis Pathogenesis-unknown Probably mediated by an abnormal inflammatory response to alveolar wall injury Possible contributors include: Repeated cycles of Environmental lung injury and Smoking Metal fumes, wood dust, stone polishing, hair-dressing Genetic healing with collagen deposition Germline mutations in TERT and TERC (telomerase genes), surfactant and mucin genes (variants lead to increased susceptibility to injury) http://healthsciences.utah.edu/utah-genome-project/projects-list/idioipathic-pulmonary-fibrosis Age >50 Telomerase effect? 12 Idiopathic pulmonary fibrosis Damage of alveolar epithelium (type 1 pneumocytes) is a key event Aberrant Wnt pathway may be related to abnormal remodeling Increased activity likely has role in abnormal fibrosis Danger signals from damaged epithelial cells activate fibroblasts collagen 13 Robbins and Cotran. Pathologic Basis of Disease. Tenth Edition. Figure 15-13 Idiopathic pulmonary fibrosis Evolution and progression Begins as patchy dense fibrosis involving peripheral and perivenular areas mild architectural destruction is mild fibroblastic focus (green dots) located between fibrotic area and normal lung later, structural remodeling occurs due to wider fibrosis which causes shrinkage honeycomb cysts develop in association with traction bronchiolectasia 14 Hashisako M, Fukuoka J. Pathology of Idiopathic Interstitial Pneumonias. Clin Med Insights Circ Respir Pulm Med. 2016 Feb 29;9(Suppl 1):123-33. doi: 10.4137/CCRPM.S23320. PMID: 26949346; PMCID: PMC4772910. Idiopathic pulmonary fibrosis > 50 years 55-75 years Males more commonly affected Associated with cigarette smoking Clinical features: Not present for many years Insidious, gradual onset of dyspnea Dry cough Fatigue Hypoxemia, cyanosis, and clubbing occur late Pulmonary hypertension Median survival 3 years Poor steroid response Transplant only definitive management Tyrosine kinase inhibitors TGF both been shown to slow disease progression 15 www.radiopaedia.com Idiopathic pulmonary fibrosis Definitive diagnosis is based on combination of imaging (CT) and histology Histology – usual interstitial pneumonia (UIP) Fibroblastic foci, subpleural fibrosis Characteristic computed tomography (CT) pattern (but not entirely specific for idiopathic pulmonary fibrosis) www.radiopaedia.com 16 Idiopathic pulmonary fibrosis A. Areas of fibrosis (thicker, darker pink) mainly located in peripheral zones of lobules B. Patchy dense fibrosis affects peripheral area inside lobule and perivenular area (arrowhead) C. Subpleural fibroblastic focus consists of fibroblasts and myofibroblasts D. Microscopic honeycomb cysts often covered by columnar ciliated epithelium E. Elastic stain highlights architectural destruction seen as thick fragmented elastic fibers F. Elastic fibers accumulate in peripheral areas 17 Hashisako M, Fukuoka J. Pathology of Idiopathic Interstitial Pneumonias. Clin Med Insights Circ Respir Pulm Med. 2016 Feb 29;9(Suppl 1):123-33. doi: 10.4137/CCRPM.S23320. PMID: 26949346; PMCID: PMC4772910. Idiopathic pulmonary fibrosis Fibroblastic foci Subpleural fibrosis Usual interstitial pneumonia pattern corresponds to honeycombing seen on gross and imaging involves interlobular septa Robbins and Cotran. Pathologic Basis of Disease. Tenth Edition. Figures 15-14,15 18 Idiopathic pulmonary fibrosis-imaging Prominent bright interstitial markings most evident in posterior lung bases Typically, bibasilar patchy fibrosis Smaller darker, round lucent areas represent honeycomb change 19 Robbins and Cotran Atlas of Pathology. Fourth Edition. 2021. Figure 5.38 Idiopathic pulmonary fibrosis-imaging Increased brighter interstitial markings bilateral May appear patchy Affected patients have continuing loss of lung volumes Pulmonary function studies may show reduced forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV 1 ) FEV 1/ FVC ratio may remain unchanged Patients may survive weeks to years, depending on the severity, with eventual end-stage “honeycomb” fibrosis 20 Robbins and Cotran Atlas of Pathology. Fourth Edition. 2021. Figure 5.38 Idiopathic pulmonary fibrosis Gross description Fibrotic changes in lower lobes Shrunken lung with hobnailed pleura due to scarring Elastic hard consistency Diffuse (relatively subpleural dominant) destruction of lung mesenchyme Multiple air cysts due to honeycomb change Traction bronchiectasis can be seen, pulling open airways creating “honeycomb” cystic areas Honeycomb lung is not specific to idiopathic pulmonary fibrosis; however, it is idiopathic pulmonary fibrosis (IPF) with which it is most associated Honeycomb lung 21 Robbins and Cotran Atlas of Pathology. Fourth Edition. 2021. Figure 5.40 Idiopathic pulmonary fibrosis Honeycomb changes are also referred to as traction bronchiectasis 22 commons.wikimedia.org, radiopaedia.org Idiopathic pulmonary fibrosis Septal thickening and replacement by fibroblasts (and collagen) 23 Corrin B, Nicholson AG, Burke M, Rice A: Pathology of the Lungs, 3rd ed, St. Louis, Churchill Livingstone Elsevier, 2011, p 148, Fig. 4.25 Forbes CD, Jackson WF: Color Atlas and Text of Clinical Medicine, 3rd ed, St. Louis, Mosby, 2003 p 186, Fig. 4.140. Idiopathic pulmonary fibrosis Trichrome stain-collagen fibrosis http://library.med.utah.edu/WebPath/LUNGHTML/LUNG028.html 24 Corrin B, Nicholson AG, Burke M, Rice A: Pathology of the Lungs, 3rd ed, St. Louis, Churchill Livingstone Elsevier, 2011, p 268. Fig. 6.1.4 Idiopathic pulmonary fibrosis- summary Dense fibrous connective tissue ( ) surrounding residual airspaces that have become dilated Extent of fibrosis determines severity of disease Example of a maladaptive repair process Injured lung produces fibroblast proliferation and collagen deposition Leads to a marked diffusion block to gas exchange Robbins and Cotran Atlas of Pathology. Fourth Edition. 2021. Figure 5.41 25 Nonspecific interstitial pneumonia A “fibrosing” lung disease with a restrictive pattern 2nd most common type of interstitial pneumonia Much better prognosis than usual interstitial pneumonia May be primary or associated with connective tissue disease (collagen vascular disease), also HIV Involves bilateral lower lobes Affects younger patients (50–60) Younger than usual interstitial pneumonia Affects female non-smokers no clear association with cigarette smoking 26 Nonspecific interstitial pneumonia Pathophysiology: a type of epithelial injury and dysregulated repair fibrosis involves the alveolar septa uniformly and diffusely In later phase, cystic changes can occur due to traction mild distortion of the lung architecture may occur 27 Hashisako M, Fukuoka J. Pathology of Idiopathic Interstitial Pneumonias. Clin Med Insights Circ Respir Pulm Med. 2016 Feb 29;9(Suppl 1):123-33. doi: 10.4137/CCRPM.S23320. PMID: 26949346; PMCID: PMC4772910. Nonspecific interstitial pneumonia Pathophysiology: a type of epithelial injury and dysregulated repair Imaging Temporal and spatial homogeneity different from patchy findings of usual interstitial pneumonia Uniform involvement May see subpleural sparing Histology-two patterns: Cellular: lymphocytes and plasma cells (less common) Fibrosing: diffuse or patchy infiltrates in same stage of development Looser fibrosis Fewer and less prominent fibroblastic foci Absent –honeycombing, granulomas, hyaline membranes 28 Yoshikawa A. Nonspecific interstitial pneumonia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumornonspecificintpneumo.html. Accessed February 7th, 2024 Nonspecific interstitial pneumonia Clinical features Insidious onset Dyspnea Dry cough Fatigue weight loss Restrictive pattern on pulmonary function testing Decreased forced vital capacity (FVC) Decreased diffusing capacity of lung for carbon monoxide (DLCO) 29 www.radiopaedia.com Nonspecific interstitial pneumonia Treatment no standard treatment for idiopathic NSIP Up to 80% improved with glucocorticoids (steroids) with / without other immunosuppressive drugs (azathioprine and cyclophosphamide) Treat background diseases (e.g., autoimmune diseases) 30 Yoshikawa A. Nonspecific interstitial pneumonia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumornonspecificintpneumo.html. Accessed February 7th, 2024 “Cryptogenic” organizing pneumonia Organizing pneumonia represents a group of lung lesions associated with a variety of diseases, including infections and systemic illnesses pattern commonly seen Cryptogenic organizing pneumonia relatively rare but important consideration due to its clinical, radiological and histologic manifestations diagnosis not made by a pathologist; rather, a diagnosis of exclusion made by the multidisciplinary care team Histologically, both cryptogenic organizing pneumonia and “organizing pneumonia” (could call secondary) are characterized by: polypoid fibroblastic aggregations plug alveolar sacs, ducts and bronchioles 31 “Cryptogenic” organizing pneumonia No gender predominance No smoking association Most patients previously healthy Affects 50-60 years Histologically, both cryptogenic organizing pneumonia and secondary organizing pneumonia are characterized by polypoid fibroblastic aggregations which plug alveolar sacs, ducts and bronchioles correspond to alveolar or airspace opacities seen on imaging at one time referred to as bronchiolitis obliterans organizing pneumonia (BOOP) Not really an airway disease (but is an airspace disease) Robbins and Cotran. Pathologic Basis of Disease. Tenth Edition. Figure 15-16 32 Cryptogenic organizing pneumonia Pathophysiology: Organizing pneumonia is a repair process (wound healing) in response to preceding alveolar injury Injury to capillary endothelial cells and alveolar epithelial cells results in leakage of plasma protein, especially coagulation factors Intra-alveolar coagulation of proteins and coagulation factors generate fibrin clotting on alveolar surfaces Fibroblasts / myofibroblasts migrate into damaged area, proliferate and generate loose fibrosis in the form of a small ball Intra-alveolar “fibrosis” is seen as response to injury or infection (virus), drugs, inhaled toxins, graft vs host) 33 Robbins and Cotran. Pathologic Basis of Disease. Tenth Edition. Figure 15-16 Cryptogenic organizing pneumonia Clinicopathologic syndrome Can be associated with different diseases rheumatoid arthritis, can be a medication adverse effect (amiodarone) Clinical features: dyspnea and cough Imaging: patchy subpleural, peribronchial airspace consolidation (alveolar opacities) Histology: polypoid plugs of loose connective tissue (Masson bodies, balls of fibroblasts) Diagnosis: clinical, pathology, lab, imaging correlation biopsy (shown); negative cultures (discount an infectious pneumonia); restrictive pattern (may not be present) Treatment: oral corticosteroids (good response, some resolve without) may relapse treat underlying condition 34 Robbins and Cotran. Pathologic Basis of Disease. Tenth Edition. Figure 15-16 Cryptogenic organizing pneumonia Histology: polypoid plugs of loose connective tissue (Masson bodies, balls of fibroblasts*) May appear as buds of granulation tissue Composed of fibroblasts and myofibroblasts in a loose matrix NO interstitial fibrosis or honeycomb lung Fibroblasts are IN the airspaces (alveolar ducts, alveoli) Robbins and Cotran. Atlas of Pathology. Fourth Edition. 2021. eFigure 5.12 35 Autoimmune diseases Systemic lupus erythematosis (SLE) Rheumatoid arthritis Rheumatoid nodules Pulmonary hypertension Systemic sclerosis Dermatomyositis Can show Nonspecific interstitial pneumonia Usual interstitial pneumonia Organizing pneumonia Bronchiolitis Pleuritis, effusions 36 Interstitial/restrictive lung disease-key points Idiopathic pulmonary fibrosis Histologic pattern is usual interstitial pneumonia (UIP) Fibrosis is patchy, different stages of evolution Repeated cycles of lung injury with collagen deposition by fibroblasts Involves TGF- activation of interstitial fibroblasts Nonspecific interstitial pneumonia Can be secondary to SLE (lupus), HIV or primary Fibrosis in same stage Better prognosis, younger patients 37 Interstitial lung disease-key points Cryptogenic organizing pneumonia Balls of fibroblasts within alveoli No interstitial fibrosis or honeycombing Good prognosis but may relapse 38 Robbins and Cotran, Pathologic Basis of Disease, Tenth Edition. Figure 15.16 Hypersensitivity pneumonitis Extrinsic allergic alveolitis from a known inhaled antigen Can involve alveolar walls (differentiate from asthma) Immune reaction to organic dust containing an antigen or a microorganism antigen Induces a Type III or Type IV hypersensitivity (mixed) Non-caseating granulomas (2/3 of cases) supports it to be at least partly a T cell mediated disease Chronic exposure can lead to: irreversible fibrosis (includes granulomas) septal thickening traction bronchiectasis more elegant description of honeycombing seen on imaging 39 Hypersensitivity pneumonitis Initiation may be antibody or cell mediated Key involved cells are lymphocytes and macrophages Not IgE related No peripheral eosinophilia Symptoms should improve with removal of offending agent Clinical presentation/features: Acute: Fever, dyspnea, dry cough, chest tightness, headache Chronic: Hypoxemia, cyanosis 40 Goljan Rapid Review. Fifth Edition. From Damjanov, MD, PhD: Pathology for the Health Professions, 4th ed, Philadelphia, Saunders Elsevier, 2012, p 180, Fig. 8-18 Hypersensitivity pneumonitis Farmer lung Hay and spores of Saccharopolyspora rectivirgula (thermophilic actinomycetes) Silo filler lung Inhaled nitrogen gas from plant material Pigeon breeder lung (bird fancier) Humidifier/air-conditioner lung https://en.wikipedia.org/wiki/Rock_dove Thermophillic bacteria 41 http://library.med.utah.edu/WebPath/LUNGHTML/LUNG098.html Hypersensitivity pneumonitis Interstitial disease loosely formed granulomas (below) chronic inflammation often centered around bronchioles 42 Robbins and Cotran, Pathologic Basis of Disease, Tenth Edition. Figure 15.23 Hypersensitivity pneumonitis loosely formed granulomas http://library.med.utah.edu/WebPath/LUNGHTML/LUNG091.html 43 Radiation-induced lung injury Pathophysiology: related to proinflammatory cytokine release from radiation treatment (cell damage) TNF-alpha, IL-l, IL-6 Clinical: may not show symptoms Dry cough Dyspnea Low grade fever Acute radiation pneumonitis: 3-12 weeks after treatment involves exudative phase-type inflammation symptoms due to effects of neutrophils and fluid, edema Chronic: symptoms after 6-12 months may be due to fibrosis 44 Pulmonary eosinophilia Uncommon Acute eosinophilic pneumonia Diagnosis of exclusion Lung disease associated with eosinophils in alveolar and interstitial spaces usually with peripheral eosinophilia but not Langerhans cell histiocytosis must exclude: drug reactions (antibiotics, cytotoxic or antiinflammatory drugs) immune disorders (Churg-Strauss syndrome, collagen vascular disease, asthma, hypereosinophilic syndrome, chronic eosinophilic leukemia, myeloid and lymphoid neoplasms with eosinophilia and rheumatoid arthritis) infections (bacteria, Aspergillus, HIV, parasites helminths, Dirofiliaria and filarial) tobacco or nicotine products (flavors) 45 Image courtesy of pathologyoutlines.com. Accessed 01/31/2023 Pulmonary eosinophilia Acute eosinophilic pneumonia Group of diseases with common histology: Mixed septal inflammatory infiltrate Eosinophils within alveolar spaces (shown) Rapid onset of fever, hypoxemia, dyspnea Idiopathic chronic eosinophilic pneumonia Loeffler syndrome self-limited eosinophilic pneumonia with peripheral blood eosinophilia 46 Image courtesy of pathologyoutlines.com. Accessed 01/31/2023 Smoking-related interstitial diseases Obstructive diseases chronic obstructive pulmonary disease (COPD) Restrictive disease Usual interstitial pneumonia/IPF? Smoking likely leads to fibrosis in some patients Desquamative interstitial pneumonitis Respiratory bronchiolitis-associated interstitial lung disease http://helpforsmoking.com/smokers-lungs Both contain smokers’ macrophages -abundant cytoplasm with dusty brown pigment 47 http://www.cam.ac.uk/research/news/clogged-up-immune-cells-help-explain-smoking-risk-for-tb Credit: Kevin Takaki and drawn by Paul Margiotta Smoking-related interstitial diseases Desquamative interstitial pneumonitis Uncommon but peculiar Male more commonly affected Age 40-60 years Bilateral alveolar septa (interstitium) thickened by sparse inflammatory infiltrate of lymphocytes, plasma cells, and occasional eosinophils Characterized by macrophages filling alveolar spaces resemble fallen off “squamous” cells Desquamative interstitial pneumonia 48 Robbins and Cotran, Pathologic Basis of Disease, Tenth Edition. Figure 15-24 Smoking-related interstitial diseases Desquamative interstitial pneumonitis Pathophysiology: smoking thought to induce GM-CSF and other insults activate macrophages Clinical features: Dyspnea, dry cough, weeks or months Clubbing of digits Spirometry and function testing mild restrictive abnormality moderate reduction of diffusing capacity Treatment/management excellent response to steroid therapy smoking cessation Robbins and Cotran. Atlas of Pathology. Fourth Edition. 2021. eFigure 5.13 Macrophages fill alveolar spaces in a current or recent former smoker Desquamative interstitial pneumonitis 49 Respiratory bronchiolitis-associated interstitial lung disease Respiratory bronchiolitis present in virtually all smokers chronic inflammation and mild peribronchiolar fibrosis Common histologic lesion in cigarette smokers (>30 pack years) Reserved for those smokers with significant pulmonary symptoms, abnormal pulmonary function, and imaging abnormalities Symptoms are usually mild and improve with smoking cessation Other smoking related changes are often present Take home: respiratory bronchiolitis is often present in smokers with symptoms and/or imaging findings 50 Respiratory bronchiolitis-associated interstitial lung disease Respiratory bronchiolitis accumulation of macrophages within terminal airways and peribronchiolar airspaces 51 Respiratory bronchiolitis-associated interstitial lung disease Respiratory bronchiolitis Smoker macrophages contain yellow, finely granular pigment Smoker pigment is positive on iron stain (blue stain, right) does not represent hemosiderin 52 Perry W, Konopka K. Respiratory bronchiolitis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumorrespbronchiolitis.html. Accessed February 9th, 2024 Restrictive disorders Osteopathic considerations Somatic dysfunction as a representation of respiratory difficulty T2-T7, C2-C3 viscerosomatic reflexes Goal is to optimize and move to normalize balance imbalance may increase work of breathing Extrinsic restrictions more addressable than intrinsic (interstitial) restrictions Diaphragm excursion abdominal adiposity Improve spinal mobility Associated counterstrain tenderpoints Anterior Rib 1-10 Posterior Rib 1-10 Anterior Thoracic 1-6 Posterior Thoracic 1-12 53