Interstitial lung diseases Martina Doubková I P F RTG Definition Diffuse parenchymal lung diseases (DPLDs), also called interstitial lung diseases (ILDs), are a large (comprise 200 entities) and heterogeneous group of acute and chronic lung disorders. ILDs are characterized by a variable degrees of inflammatory and fibrotic changes affecting the interstitial spaces, airspaces, and alveolar walls. Classification of DPLDs according to histology üGranulomatous process (reverzible process): sarcoidosis, silicosis, collagen – vascular/connective tissue diseases, hypersensitivity pneumonitis üProcess with the terminal lung fibrosis (nonreverzible process): idiopathic pulmonary fibrosis, collagen vascular disease üProcess with the presence of granuloma and fibrosis: hypersensitivity pneumonitis Classification of DPLDs by etiology ILDs of known cause ülung infections (bacterial, fungal, viral, protozoal) üpostirradiation damage (external irradiation) üinhalation causes (occupational exposure, organic and inorganic dusts) ühaemodynamic causes (congestive heart failure, uremia) üneoplasia (lymfangitis carcinomatosis) üinheredited cause (neurofibromatosis, tuberous sclerosis) üdrug causes (busulfan, amiodaron…) www.pneumotox.com ümetabolic causes (m. Gaucher, m. Crohn...) ILDs of unknown cause (idiopathic pulmonary fibrosis, sarcoidosis, collagen vascular disease) Classification of DPLDs by frequency of occurrence Øfrequent ILDs (IPF, sarcoidosis) Øless frequent ILDs (drug damage, hypersensitivity pneumonitis) Ørare ILDs (lymphangioleiomyomatosis, pulmonary Langerhans´s cell histiocytosis) Classification of ILDs Group Clinical entitis Idiopathic interstitial pneumonias IPF - UIP, NSIP, BOOP, DIP, AIP, LIP, RBILD DPLD of known cause Pneumoconiosis Hypersensitivity pneumonitis Granulomatous DPLD Sarcoidosis Histiocytosis X Vasculitis Other forms of DPLD Lymphangioleiomyomatosis Alveolar proteinosis Diagnosis of DPLD History – searching for etiology, symptoms, duration of symptoms Physical examination – dyspnea, cough, fatigue, end-inspiratory fine crackles on auskultation, clubbing, skin lesions, cyanosis.. Blood tests and other tests - antibody, angiotensin-converting enzyme,.. Imaging – chest radiography (X-ray), high-resolution computed tomography (HRCT) + other imaging methods Pulmonary function tests – restrictive picture, obstructive or a combination, reduced gas transfer Bronchoscopy with bronchoalveolar lavage (BAL) – a physician takes samples from inside the lungs: biopsies, fluid (BAL) or endobronchial brushing. Lung biopsy – transbronchial lung biopsy, open thoracotomy or preferentially by video-assisted thoracoscopy Sarcoidosis Definition Descriptive definition: Sarcoidosis is a multisystem disorder of unknown cause(s). It commonly affects young and middle-aged adults and frequently presents with bilateral hilar lymphadenopathy, pulmonary infiltration, and ocular and skin lesions. The liver, spleen, lymph nodes, salivary glands, heart, nervous system, muscles, bones, and other organs may also be involved. Definition The definition by morfology: The characteristic lesion of sarcoidosis is a discrete, compact, noncaseating epithelioid cell granuloma. The epithelioid cell granulomas consist of highly differentiated mononuclear phagocytes (epithelioid cells and giant cells) and lymphocytes. Sarcoid granulomas may develop fibrotic changes. Epidemiology and etiology of sarcoidosis Epidemiology: prevalence in the CR 63,1/100 000 incidence in the CR 3,7/100 000 rate women:men 2:1 Etiology: infection (viruses, mycobacteria, other infectious agens), hypersensitivity, immunity, an exposure to an antigen – inorganic materials in a genetically predisposed, susceptible host. Sarcoidosis is a polygenetic disorder. Several alleles were associated with susceptibility (HLA DR2, 11, 12, 14, 15, 17) or protective effects (HLA DR1, DR4) for sarcoidosis. A genetic predisposition may explain the heterogeneity in disease presentation and severity among different ethnic and racial groups. Immunopathogenesis of sarcoidosis Imunopatogeneze sarkoidózy Immunopathogenesis: immunological abnormalities are characterized by the accumulation of actived CD 4+ T cells of the Th 1 type and macrophages at sites of ongoing inflammation. Cytokines and other mediators produced by these cells contribute to granuloma formation. Immunopathogenesis of sarcoidosis Clinical presentation of sarcoidosis Acute sarcoidosis üLofgren's syndrome – bilateral hilar adenopathy on X-ray, erythema nodosum, fever, arthralgia or arthritis, negativ tuberculin skin test. üHeerfordt's Waldensröm syndrome: fever, uveitis, parotid enlargement, and facial nerve palsy. üsarcoid infiltration of scars Chronic sarcoidosis üSarcoidosis lasting at least 2 years üRespiratory involvement and other organs is graver üChronic or progressive course is observed 10% - 30% of patients üProgressive sarcoidosis can lead to death in 1 – 5% of cases Clinical presentation of sarcoidosis. Pulmonary sarcoidosis üInvolvement of intrathoracic organs, i. e. lymph nodes, lung parenchyma or pleura occurs in 90% of all cases ü üDyspnea, cough, chest pain similar to cardiac angina occur most frequently Clinical presentation of sarcoidosis. Extrapulmonary sarcoidosis üSarcoidosis of lymph nodes and spleen üSarcoidosis of eyes – iridocyclitis, conjunctivitis, uveitis üSarcoidosis of skin – erythema nodosum, lupus pernio üMusculoskeletal sarcoidosis – arthritis, arthralgias, myalgias, myopathy üNeurosarcoidosis – CNS or PNS üSarcoidosis of heart üSarcoidosis of other organs Diagnosis of sarcoidosis üHistory, physical examination - exposure, symptoms üLaboratory and immunological tests – whole blood count, metabolic panel (electrolytes, calcium, liver enzymes, creatinine, blood urea nitrogen), urinalysis, angiotensin-converting enzyme, sIL-2r, neopterin, hypercalcemia, hypercalciuria üRadiology, imaging – chest X-ray: bilateral hilar adenopathy, upper lobe infiltrates, HRCT scan: peribronchial thickening, gallium scan: uptake in mediastinum and parotids üPulmonary function tests – spirometry and diffusion capacity for carbonmonooxide (DLCO) üBronchoscopy with BAL – lymphocytic alveolitis with a CD4/CD8 – ratio > 3.5 – 10, TNF alfa üExamination of impairment organs - eye (ophthalmological examination), heart (electrocardiography) üBiopsy – lung biopsy (endobronchial, transbronchial, videothoracoscopy) and other biopsy sites (lymph nodes, skin) Diagnosis of sarcoidosis üThe need for biopsy: If sarcoidosis is suspected the diagnosis should be made with biopsy whenever possible – except for the cases of typical presentation of a Lofgren's syndrome Chest radiograph stages of sarcoidosis 0 … Normal chest radiograph I … Bilateral hilar lymphadenopathy (BHL) II … BHL + diffuse pulmonary infiltration III ...Difuse pulmonary infiltration, but without hilar lymphadenopathy IV … Pulmonary fibrosis ü Differential diagnosis of sarcoidosis üAutoimmune diseases – Churg - Strauss syndrom, Wegener’s granulomatosis üExposures – aluminium, beryllium, talc, titanium, zirconium üInfections - brucellosis, coccidioidomycosis, histoplasmosis, mycobacterial infection, syphyllis, toxoplasmosis üMalignancy - lymphoma üOther – hypersensitivity pneumonitis, methotrexate toxicity Overview of therapy for pulmonary sarcoidosis üA large number of patients undergo spontaneous remission or have a benign clinical course üThere is no easy way to assess disease activity and severity, so that predicting the course and prognosis of the disease is difficult. üThe marked variability in presentation and clinical course make it difficult to develop treatment guidelines. üThe cause of the disease is unknown; consequently, no specific treatment exists. Absolute Relative Neurologic Symptomatic pulmonary disease Cardiac Arthritis Hypercalcemia Hepatic Ocular – when topical therapy has failed Other life – or organ – threatening disease Indication for systemic therapy SIRS: systemic inflammatory response system Substance (mechanism) Proposed use in sarcoidosis Side effects Corticosteroids: Prednisone 0.5 mg/kg/day, prednisolone (IL-2, TNF α) Use for all forms of sarcoidosis, topical application, inhalation Osteoporosis, DM, hypertension, insomnia Chloroquine, hydroxychloroquine Skin disease, neuro-, steroid-sparing, hypercalcaemia Ocular toxicity, nausea Methotrexate (IL-2,TNF α) Acute, chronic sarcoidosis, steroid-sparing Nausea, neutropenia, hepatotoxicity, pulmonary fibrosis Azathioprine (IL-2, TNF α) Few data for chronic sarc., steroid-sparing Nausea, neutropenia Current pharmacological treatment options for sarcoidosis Pentoxifylline (influence on lymphocytes, TNF α) Efficacy for acute (mild-moderate) disease Gastrointestinal intolerance Thalidomide (IL-12, TNF α) Useful for chronic skin disease, no effect on pulmonary disease, anti-angiogenic Somnolence, teratogenic, constipation, peripheral neuropathy Cyclophosphamide Because of toxicity only for refractory cases Neutropenia, nausea, cystitis, carcinogenic Cyclosporine (IL – 2, T-cell activation) Possible effect for neurosarcoidosis, no clinical improvement, no steroid-sparing effect Renal failure, hypertension, can cause lymphoma TNFα antagonists: infliximab (monoclonal antibody), etanercept Limited data about effectiveness and dosage, possible use for refractory disease. No good evidence for effect Increased rate of tuberculosis, allergic reaction, possibly carcinogenic Current pharmacological treatment options for sarcoidosis Current pharmacological treatment options for sarcoidosis Chest radiograph stratification (Scadding scale) Stage Description Rate of spontaneous resolution Stage 0 Normal radiograph ? Stage 1 BHL 60% - 90% Stage 2 Difuse pulmonary infiltrates and BHL 50% - 60% Stage 3 Diffuse infiltrates only < 30% Stage 4 Fibrotic lundg disease 0% Stages do not represent sequential steps in disease course and are based only on the posterior –anterior chest radiograph Idiopathic pulmonary fibrosis (IPF, KFA) Idiopathic pulmonary fibrosis (IPF, KFA) üIPF, known in Europe as cryptogenic fibrosing alveolitis, is a clinical term that describes a chronic fibrosing interstitial pneumonia with no known cause. üIPF is a progressive and lethal pulmonary fibrotic lung disease. IPF is the most common of the idiopathic interstitial pneumonias (IIP) and the one that is unresponsive to treatment. Epidemiology and etiology of IPF Epidemiology: incidence 7 – 11 cases per 100 000 prevalence 13 – 20 cases per 100 000 more males 1.4 : 1, between 40 and 70 years of age median survival from the diagnosis of IPF: 2 – 4 years Etiopathogenesis: the etiological agent(s) in IPF has not been elucidated, two key features, alveolar epithelial cell injury and dysregulation of fibroblasts appear to be pivotal in the pathogenesis of UIP/IPF. Risk factors are associated with IPF: cigarette smoking, exposure to commonly prescribed drugs, chronic aspiration, environmental factors (metal dust, wood dust), infectious agents (EBV), genetic predisposition (familial IPF – 0,5 – 3 per cent of cases of IPF) Diagnosis of IPF ü History - symptoms, duration of symptoms, … Physical examination – shortness of breath (dyspnea), cough, fatigue, on auskultation there are end-inspiratory crackles and are most prevalent in the lung bases, clubbing, cyanosis, cor pulmonale Clinical symptoms üa progressive shortness of breath, or dyspnoea: 90% üchronic nonproductive cough: 74% üend-inspiratory crackles : 80% üclubbing: 50 - 60% ü Laboratory and serological tests are nonspecific Chest radiograph, High resolution CT scanning + others imaging Pulmonary function tests – restrictive lung volumes and capacities, reduced the carbon monooxide transfer factor (DLCO), hypoxemia with widened alveolar-arterial oxygen gradient that increases with exercise Bronchoscopy with BAL – differential diagnosis of fibrosing interstitial pneumonias but is not diagnostic of IPF Lung biopsy – open thoracotomy or preferentially by video-assisted thoracoscopy Diagnosis of IPF Radiographic findings of IPF Conventional chest radiograph – diffuse bilateral interstitial or reticulonodular infiltrates with a predilection for basilar and peripheral (subpleural) regions High resolution thin section CT scan – reticular densities (interlobular and intralobular septal lines), traction bronchiectasis, honeycomb change, minimal or no ground glass opacities; predilection for peripheral (subpleural) and basilar regions Treatment of IPF üThis disease progress slowly or rapid to respiratory failure. ü üSpecific idiopathic pulmonary fibrosis treatment options include: antifibrotic agent pirfenidone or nintedanib ü üOther medications: oxygen therapy, pulmonary rehabilitation, lung transplantation. üLung transplantation (LTx) may be considered for patients with end-stage pulmonary fibrosis (who are not benefiting from medicines, and who have no other serious medical problems). Two-year survival following SLT ranges from 60 to 80 per cent, 5-year survival is 40-60 per cent. Treatment of IPF Thank you for your attention.