Sheet: Restrictive Lung disease Done by: Yousef Qandeel

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1 Sheet: Restrictive Lung disease Done by: Yousef Qandeel

2 Restrictive lung diseases Restriction in lung expansion so we take less air volume mainly because of something in the interstitium of the lung, alveolar, etc and the diffusion is also affected the main symptoms in restrictive lung diseases : dyspnea, dry cough, with no wheezes, and we can see restrictive pattern on pulmonary function test (explained in the physiology lecture). مثل صوت قرقعة عند نهاية الشهيق clinically we hear end inspiratory crackles Restrictive lung diseases are of two types: 1- Chronic diffuse interstitial diseases (we will discuss this type) 2- Chest wall diseases : inability to expand the lung م سام للرئة تتوسع ى بمع ى ن الرئة بتكون سليمة ما فيها ا ي ش بس يف مر ا ا ي ش الجد ل مكتوب بالتلخيص تاع الدكتور احفظوا بس المرضيى smoking-related البا ي ف بس المش ح بالمحا ى ضة Autoimmune diseases (connective tissue diseases): these diseases come with fibrosing diseases. 1- SLE (systemic lupus erythematosis)

3 2- RA ( Rheumatoid arthritis) 3- Scleroderma (systemic sclerosis) Sarcoidosis is called histological diagnosis of exclusion because we must exclude other diseases that cause non-caseating granuloma such as TB and fungal infection (diseases that cause caseating granuloma may also cause non-caseating granuloma) and other diseases. pulmonary Langerhans cell histiocytosis also called eosinophilic granuloma Chronic diffuse interstitial diseases, introduction Chronic interstitial pulmonary diseases are a heterogeneous group of disorders characterized predominantly by inflammation and fibrosis of the pulmonary interstitium. Many of the entities are of unknown cause and pathogenesis, and some have an intra-alveolar (macrophages in the alveolar spaces like in Desquamative Interstitial Pneumonia or proteinaceous material like in Pulmonary alveolar proteinosis) as well as an interstitial component. There is frequent overlap in histologic features among the different conditions. End stage lung : when a dense fibrosis in most of the interstitium which distort the architecture of the alveoli and the remaining lung tissues appear as honeycomb, can be seen grossly, radiologically, and microscopically. This may happen due to the overlap. Chronic diffuse interstitial diseases (clinical, radiological and functional features) Features of restrictive disease: dyspnea, tachypnea, end-inspiratory crackles, and eventual cyanosis, without wheezing or other evidence of airway obstruction Features of restrictive disease: reductions in diffusion capacity, lung volume, and lung compliance Bilateral radiographic changes: small nodules, irregular lines, or groundglass shadows (indicates fibrosis), all corresponding to areas of interstitial fibrosis

4 Eventually, secondary pulmonary hypertension and cor pulmonale may result Although the entities can often be distinguished in the early stages, the advanced forms are hard to differentiate because all result in scarring and gross destruction of the lung, often referred to as end-stage lung or honeycomb lung Idiopathic pulmonary fibrosis(ipf) Unknown cause Other names: 1- Cryptogenic fibrosing alveolitis 2- Microscopically: Usual interstitial pneumonia this is a pattern that can be also seen due to connective tissue disease, chronic hypersensitivity pneumonia, asbestosis etc. Temporal heterogeneity can be seen in Usual interstitial pneumonia in which areas are mature dense fibrosis (pink in color) and areas with immature fibrosis (bluish in color) so the normal biopsy tru-cut is not useful to see this feature, instead we take wedge biopsy (larger cut) Pathogenesis : Repetitive damage and abnormal repair of alveolar epithelium The changes are especially seen in the lower lobes, the subpleural regions, and along the interlobular septa Factors: -Environmental most importantly smoking also metal, wood, stone, farming, hair-dressing, gastric reflux, etc. -Genetic: 1- TERT & TERC (components of telomerase) as a reminder telomerase add a repetitive sequence at the end of DNA to protect it

5 2- genes for components of surfactant abnormal protein with subsequent unfolded protein response in type II pneumocytes 3- Increased secretion of MUC5B mucin a common genetic variant in 1/3 patients with IPF -Age rarely appearing before the age of 50 years IPF, clinical course Clinical course. IPF begins insidiously with gradually increasing dyspnea on exertion and dry cough. Most patients are 55 to 75 years old at presentation. Hypoxemia, cyanosis, and clubbing occur late in the course. The progression in an individual patient is unpredictable. Usually there is a gradual deterioration in pulmonary status despite medical treatment with immunosuppressive drugs such as steroids, cyclophosphamide, or azathioprine. Other IPF patients have acute exacerbations of the underlying disease and follow a rapid downhill clinical course. The median survival is about 3 years after diagnosis. Lung transplantation is the only definitive therapy. Pneumoconioses

6 Anthracosis : black dye can be seen in lung biopsy or in lymph nodes (macrophages with phagocytized carbon) without accumulation of macrophages when accumulation of macrophages it s called macules or simple coal worker s pneumoconiosis these 2 come with little to no pulmonary dysfunction. Complicated form of coal worker s is progressive massive fibrosis (can be with asbestos and silica so not only coal dust ) Caplan syndrome : Rheumatoid arthritis involvement (with coal dust, asbestosis, or silicosis) The term pneumoconiosis was originally coined to describe the nonneoplastic lung reaction to inhalation of mineral dusts encountered in the workplace it now also includes diseases induced by organic as well as inorganic particulates and chemical fumes and vapors We will discuss the 3 most common mineral dust pneumoconioses: -due to coal dust -due to silica -due to asbestos Pneumoconioses, notes on pathogenesis Particles greater than 5 to 10 μm are unlikely to reach distal airways, whereas particles smaller than 0.5 μm move into and out of alveoli, often without substantial deposition and injury 1-5 μm are the most dangerous Coal dust is relatively inert, and large amounts must be deposited in the lungs before lung disease is clinically detectable silica & asbestos ما الها عالقة بالشطان الرئة عىل عكس ال Coal dust Asbestos can also cause Mesothelioma (pleural or peritoneal).

7 The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of inflammation, lung injury and fibrosis phagocytosis and inflammasome activation then IL-1 secretion Lymphatic drainage by macrophages or by the material itself accentuates the inflammatory response Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than other particles (synergic effect in asbestos with tobacco smoking to cause lung cancer and not Mesothelioma) Coal worker s pneumoconiosis A range of changes: ى *التدخي ما اله عالقة بال *mesothelioma -Asymptomatic anthracosis pigment deposits without cellular reaction -Simple coal worker s pneumoconiosis (CWP) macrophages accumulate with little to no pulmonary dysfunction coal macules & coal nodules especially the upper lobes and upper zones of the lower lobes -Complicated CWP or progressive massive fibrosis (PMF), in which fibrosis is extensive and lung function is compromised less than 10% of cases of simple CWP progress to PMF PMF can be a complication of any of the pneumoconioses Although coal is mainly carbon, coal mine dust contains a variety of trace metals, inorganic minerals, and crystalline silica Coal worker s pneumoconiosis, clinical features CWP usually is a benign disease that produces little decrement in lung function. In those in whom PMF develops, there is increasing pulmonary dysfunction, pulmonary hypertension and cor pulmonale. Progression from CWP to PMF has been linked to a variety of variables including higher coal dust exposure levels and total dust burden.

8 Unfortunately, once established PMF has a tendency to progress even in the absence of further exposure. After taking smoking-related risk into account, there is no increased frequency of lung carcinoma in local miners, a feature that distinguishes CWP from both silica and asbestos exposures. Silicosis The most prevalent chronic occupational disease in the world Workers involved in sandblasting and hard-rock mining are at particularly high risk Silica occurs in both crystalline and amorphous forms, but crystalline forms (including quartz, cristobalite, and tridymite) are by far the most toxic and fibrogenic The particles interact with epithelial cells and macrophages Activation of inflammasome, pro-inflammatory and fibrogenic cytokines When mixed with other minerals, the fibrogenic effect of quartz is reduced Silicotic nodules that may progress to PMF Upper zones more Silicosis, clinical features Usually incidentally on x-ray: fine nodularity in the upper zones of the lung Most patients do not develop shortness of breath until late in the course, after PMF is present with many of them developing cor pulmonale Silicosis is associated with an increased susceptibility to tuberculosis So sometimes we can see caseation in the nodules

9 depression of cell-mediated immunity, and crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteria بتأثر عىل عمل المناعة ضد TB ف تجمع كبي من TH1 ى بصي ي ف البداية ع TH1 ى بصي غي فعال ي phagocytes ما تخلصت من TB ف بتستد ي TB دليل عمل استجابة غي فعالة عىل granuloma بعملوا macrophages Increased risk of lung cancer Asbestosis & asbestos-related diseases Asbestos: crystalline hydrated silicates with a fibrous geometry Associated diseases (1) Parenchymal interstitial fibrosis (asbestosis) (2) Localized fibrous plaques(pleural plaques), or rarely, diffuse fibrosis in the pleura (3) Pleural effusions (4) Lung carcinoma (5) Malignant pleural and peritoneal mesothelioma (6) Laryngeal carcinoma Risk to family members And asbestos can cause cancers in other places like the stomach Pleural plaque is the most common asbestos-related disease which are asymptomatic (incidental finding) Asbestosis & asbestos-related diseases, pathogenesis Microscopically asbestos bodies have head, and peaded tail inside a macrophage covered by iron shell (from the macrophage) As with silica crystals, once phagocytosed by macrophages, asbestos fibers activate the inflammasome and damage phagolysosomal membranes, stimulating the release of proinflammatory factors and fibrogenic mediators

10 Initiator and promoter of malignancy Synergy between smoking and asbestos in causing lung cancer but not mesothelioma Diffuse pulmonary interstitial fibrosis with asbestos bodies Asbestosis begins in the lower lobes and subpleurally, spreading to the middle and upper lobes of the lungs as the fibrosis progresses Pleural plaques are the most common manifestation of asbestos exposure and are well-circumscribed plaques of dense collagen mostly anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm. Uncommonly, asbestos exposure induces pleural effusion or diffuse pleural fibrosis Asbestosis & asbestos-related diseases, clinical features Progressively worsening dyspnea appears 10 to 20 years after exposure may be static or progress to cor pulmonale Pleural plaques are usually asymptomatic and are detected on radiographs as circumscribed densities Lung or pleural cancer associated with asbestos exposure carries a particularly poor prognosis Sarcoidosis a multisystem disease unknown etiology non-caseating granulomatous inflammation in many tissues and organs Schaumann and asteroid bodies inside the granulomas Schaumann bodies are concentric calsifications can be seen in granulomas and it s neither specific or sensitive for Sarcoidosis.

11 Asteroid bodies are needle shaped crystals and it s also neither sensitive or specific some other diseases may also cause non-caseating granulomas (like we said before fungal infections and TB can also cause non-caseating) bilateral hilar lymphadenopathy or lung involvement (or both), visible on chest radiographs, is the major finding at presentation in most cases Bilateral hilar lymphadenopathy bilateral lung infiltrates and hilar lymphadenopathy lung infiltrates and most of the time it s self-limited disappear after a period of time with or without therapy. Eye and skin involvement each occurs in about 25% of cases, and either may occasionally be the presenting feature of the disease ن الرئة )النسبة م للحفظ( احيانا presenting feature بتكون المريض عنده المر ى بالعي ا الجلد بد Sarcoidosis, epidemiology and pathogenesis Epidemiology Sarcoidosis occurs throughout the world, affecting both genders (equally) and all races and age groups. There are, however, certain interesting epidemiologic trends: A consistent predilection for adults younger than 40 years of age. A high incidence in Danish and Swedish populations, and in the united States among African Americans (in whom the frequency is 10 times higher than in whiter). A higher prevalence among nonsmokers, an association that is virtually unique to Sarcoidosis among pulmonary diseases Several immunologic abnormalities in Sarcoidosis suggest the development of a cell-mediated response to an unidentified antigen. The process is driven by CD4+ helper T cells

12 Sarcoidosis, organs involved Lungs 90% of cases with tendency to localize in the connective tissue around bronchioles and pulmonary venules and in the pleura ( lymphangitic distribution) 5% to 15% of patients, the granulomas eventually are replaced by diffuse interstitial fibrosis, resulting in a so-called honeycomb lung Hilar and paratracheal lymph nodes are enlarged in 75% to 90% of patients, while one-third present with peripheral lymphadenopathy Skin lesions 25%...especially erythema nodosum Sarcoidal granulomas uncommon in these lesions Eye & lacrimal glands 1/5 to 1/2 of patients (iritis or iridocyclitis, unilateral or bilateral) also choroiditis, retinitis, optic nerve involvement suppression of lacrimation sicca syndrome (Sarcoidosis affecting lacrimal gland) xerophthalmia: dry eye Unilateral or bilateral parotitis with painful enlargement in<10%...xerostomia (no saliva in the mouth: dry mouth) Sjögren's syndrome is an autoimmune condition with xerostomia and xerophthalmia Combined uveoparotid involvement is designated Mikulicz syndrome Spleen, liver and bone marrow: commonly involved by microscopic granulomas but less commonly with clinical manifestations Hypercalcemia Why? Because macrophages in Sarcoid granulomas produce activated vitamin D so absorption of calcium increase

13 Sarcoidosis, clinical notes Many are asymptomatic incidentally on x-ray or autopsy: bilateral hilar lymphadenopathy Any organ of the previously mentioned may be the presenting one In 2/3s of symptomatic patients: respiratory (dyspnea, dry cough) or constitutional signs & symptoms (fever, weight loss, night sweats etc.) Night sweats associated with: TB, lymphoma, and Brucellosis also What is Löfgren syndrome? Acute presentation of Sarcoidosis ( hilar lymphadenopathy, erythema nodosum, and poly-arthralgia/ poly-arthritis) For diagnosis: Clinical, radiographic and biopsy findings after excluding other causes especially TB (may cause non-caseating granulomas) ACE is increased in the blood and in bronchoalveolar lavage (taking liquid from bronchi and alveoli by bronchoscopy) about 60% of cases CD4+ T cells are increased around the granulomas and in bronchoalveolar lavage (and even in biopsy) while there is peripheral T cytopenia Angiotensin Converting Enzyme (ACE) increase in blood and bronchoalveolar lavage (doesn t help with indicating progression of the disease but can be decreased after therapy) but T cells only increase around granuloma while in the blood there is T cytopenia.