November 22, 2011 Lung diseases Respiration system - pathophysiology - Disease can be divided into 3 groups: —Ventilation —Difussion —Perfusion - They can be manifested along or in combinations — obr12.jpg Defect of ventilation Defect of diffusion Defect of perfusion Defect in regulation of breathing Obstructive diseases Restrictive diseases Defect in oxygene transport oLung Diseases are primarily placed into two categories n1. Obstructive Lung Diseases pAsthma pCOPD nEmphysema nChronic Bronchitis n2. Restrictive Lung Diseases pAsbestosis pPulmonary Fibrosis p n n Obstructive lung diseases oThey are characterized by airway obstruction that is worse with expiration. oEither more force (i.e., use of accessory muscles of expiration) is required to expire a given volume of air or emptying of the lungs is slowed or both. oThe unifying symptom of obstructive disease is dyspnea, the unifying sign is wheezing. o oThe most common obstructive diseases are asthma, chronic bronchitis and emphysema. oBecause many individuals have both bronchitis and emphysema, they are often called COPD o Airway obstruction caused by emphysema, chronic bronchitis, and asthma obr7a obr7b Normal lung Emphysema obr7c Bronchitis obr7d Asthma Asthma bronchiale (GINA 2006) ØAsthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. Ø ØThe chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. Ø ØThese episodes are usually associated with widespread but variable airway obstruction that is often reversible either spontaneously or with treatment. Factors that contribute to airflow limitation in asthma obr6 C:\Dokumenty\Obrázky\hayfevera.jpg The hyper-responsive airways in asthma respond to a wide-range of provoking factors Proportions of asthmatic children sensitised to the common allergens Types of asthma Allergic asthma Non-allergic asthma IgE-mediated asthma IgE non-mediated asthma Pathogenesis of allergic asthma Fig7 Asthma response Early phase Late phase Pathogenesis of ASA (non atopic asthma) Paradigma of asthma pathogenesis Polygenic nature of asthma Common precipitants of asthma exacerbations • Respiratory virus infections • • Allergens • • Air pollution • • Excercise and hyperventilation • • Changes in wheather • • Occupational factors • • Foods, additives, drugs • • Endocrine factors • • Stress Asthma – clinical manifestations q During full remision nIndividuals are asymptomatic and pulmonary function tests are normal. q During partial remision There are no clinical symptoms but pulmonary function tests are abnormal q During attacks nIndividuals are dyspneic and respiratory effort is marked nBreath sounds are decreased except for considerable wheezing, dyspnea, non-productive coughing, tachycardia and tachypnea occur oSpirometry shows decreases in expiratory flow rate, forced expiratory volume (FEV), and forced vital capacity (FVC) o oFRC and total lung capacity (TLC) are increased. o oBlood gas analysis shows hypoxemia with early respiratory alkalosis or late respiratory acidosis. Asthma - pulmonary function Classification of Asthma Severity: Clinical Features Before Treatment Days with Nights with PEF % of personal symptoms symptoms best peak flow Step 4 Severe persistent Continual Frequent <= 60% Step 3 Moderate Daily >= 5 times per month >60% - < 80% persistent Step 2 Mild persistent 3-6 times per 3-4 times per month >= 80% week Step 1 Mild intermittent <= 2 times per <= 2 times per month >= 80% week Treatments Goals: §To reverse of acute attacks §To control recurrent attacks §To reduce bronchial inflammation and the associated hyperreactivity §+ elimination of allergens (if it is possible) Drugs: §Allergen´s immunotherapy §Bronchodilator (Beta agonists, Anticholinergic agents, Theophylline) §Immunosuppressant (corticosteroids) §Others (Leukotriene modifiers, antihistamine, e.g.) Allergen-specific immunotherapy oSpecific immunotherapy (SIT) using allergen extracts has been administered in many countries for the treatment of allergic diseases. oMechanisms of action: - Although the mechanisms of action of SIT have not been fully defined, some studies suggest that SIT may shift the immune system´s balance from Th2 to Th1 cells, with increased production of interleukin (IL-12) and interferon gamma (IFN-gamma). SIT also increases the anti-inflammatory cytokine IL-10. Bronchodilator Beta2 agonists - selective b2 agonists oalbuterol (short acting) o osalmeterol, formoterol (long lasting) obr4 Anticholinergic agents jgh10004f2 obr5 oInhibits phosphodiesterase and therefore increase cAMP oReduce intracellular calcium oCause membrane hyperpolarisation to prevent activity of smooth muscle oDecrease of infiltration of eosinophils into epithelium Methylxanthine theo Eg. Theophylline (similar to caffeine) Corticosteroids oInhibit the attraction of inflammatory cells to the site of allergic reaction o oBlock leukotriene synthesis oInhibit cytokine production and adhesion protein activation oReverse b2 receptor down-regulation The mechanisms of action of corticosteroids Krejsek et al., 2004 obr26 Leukotriene mediators - Inhibitors of 5-lipoxygenázy - Antagonists of cysteinyl LT receptors SINGULAIR® eg. SINGULAIR® (montelukast sodium): leukotriene D4 receptor antagonist singulair_diagram2 Anti- IgE and others…. Image Chronic obstructive pulmonary disease (COPD) oCOPD is defined as pathologic lung changes consistent with emphysema or chronic bronchitis. oIt is syndrome characterized by abnormal tests of expiratory airflow that do not change markedly over time, and without a reversible response to pharmacological agents. o o5-20% of adult population oMost frequently in men oThe fifth leading cause of death JAMA_LungHealth_ChronicOb_lev20_COPD_JPP_01 obr2 The complex, heterogenous overlapping of the three primary diagnoses include under diseases of air flow limitation is present on the next picture: 1. Chronic bronchitis Chronic bronchitis is defined as hypersecretion of mucus and chronic productive cough that continues for at least 3 months of years for at least 2 consecutive years. Incidence is increased in smokers (up to twentyfold) and even more so in workers exposed to air pollution. It is a major health problem for the elderly population. Repeated infections are common. bronchitis-and-normal-condition-in-tertiary-bronchus Chronic bronchitis - etiology oIt is primarily caused by cigarette smoke, both active and passive smoking have been implicated o oOther risk factors: - profesional exposition - air pollution - repeated infections of airways - genetics o o1 Chronic bronchitis - morphology oInspired irritants not only increase mucus production but also increase the size and number of mucous glands and goblet cells in airway epithelium oThe mucus produced is thicker and more tenacious than normal. This sticky mucus coating makes it much more likely that bacteria, such as H. influenze and S. pneumoniae, will become embedded in the airway secretions, there they reproduce rapidly. oCiliary function is impaired, reducing mucus clearance further. The lung´s defense mechanisms are tehrefore compromised, increasing susceptibility to pulmonary infection and injury. oThe bronchial walls become inflamed and thickened from edema and accumulation of inflammatory cells. o oInitially chronic bronchitis affects only the larger bronchi, but eventually all airways are involved. oThe thick mucus and hypertrophied bronchial smooth muscle obstruct the airways and lead to closure, particularly during expiration, when the airways are narrowed. oThe airways collapse early in expiration, trapping gas in the distal portions of the lung. oObstruction eventually leads to ventilation-perfusion mismatch, hypoventilation (increased PaCO2) and hypoxemia. obr1b Chronic bronchitis – clinical manifestations oIndividuals usually have a productive cough („smoker´s cough“) and evidence of airway obstruction is shown by spirometry oBronchitis patients are often described as „blue bloaters“ due to their tendency to exhibit both hypoxemia/hypercapnia and right heart failure with peripheral edema in spite of only moderate obstructive changes on pulmonary functional tests. o o Acute episodes (e.g. after infection) result in marked hypoxemia that leads to polycytemia and cyanosis (blueness) associated with an increase in pulmonary artery pressure, impairing right ventricular function, and significant jugular venous distension and ankle edema (bloated) o o oDiagnosis is made on the basis of physical examination, chest radiograph, pulmonary function tests and blood gas analyses. oThe best „treatment“ is prevention, because pathological changes are not reversible. oIf the individuals stops smoking, disease progression can be halted oTherapy: - bronchodilators o - expectorans o - chest physical therapy o - steroids o - antibiotics Chronic bronchitis – evaluation and treatment Chronic bronchitis: low-flow oxygen therapy oIt is administered with care to individuals with severe hypoxemia and CO2 retention oBecause of the chronic elevation of PaCO2, the central chemoreceptors no longer act as the primary stimulus for breathing. oThis role is taken over by the peripheral chemoreceptors, which are sensitive to changes in PaO2. oPeripheral chemoreceptors do not stimulate breathing if the PaO2 is much more than 60 mmHg. oTherefore, if oxygen therapy causes PaO2 to exceed 60 mmHg, the stimulus to breathe is lost, PaCO2 increases, and apnea results. oIf inadequate oxygenation cannot be achieved without resulting in respiratory depression, the individual must be mechanically ventilated) o nIt is abnormal permanent enlargement of gas-exchange airways (acini) accompanied by destruction of alveolar walls and without obvious fibrosis. n nIn emphysema, obstruction results from changes in lung tissues, rather than mucus production and inflammation, as in chronic bronchitis. n nThe major mechanism of airflow limitation is loss of elastic recoil. 2. Emphysema emphysema C:\vyuka\MCK 5\disketa\plice2a.jpg Healthy lung Emphysema lung Types of emphysema oThree distinctive types of alveolar destruction have been described, according to the portion of the acinus first involved with disease: 1) Centrilobular (centriacinar): - septal destruction occurs in the respiratory bronchioles and alveolar ducts, usually in the upper lobes of the lung. The alveolar sac (alveoli distal to the respiratory bronchiole) remains intact. It tends to occur in smokers with chronic bronchitis. 2) Panacinar (panlobular): - It involves the entire acinus with damage more randomly distributed and involving the lower lobes of the lung. It tends to occur in patients with a1-antitrypsin deficiency. 3) Distal acinar (subpleural): - It is typically seen in a young adult with a history of a spontaneous pneumothorax. obr3 oPrimary emphysema: o - it is commonly linked to an inherited deficiency of the enzyme a1-antitrypsin that is a major component of a1-globulin, a plasma protein. o - Normally it inhibits the action of many proteolytic o enzymes. o - Individuals with deficiency of this enzyme (AR) have an increased likelihood of developing emphysema because proteolysis in lung tissues is not inhibited. o oSecondary emphysema: o - It is also caused by an inability of the body to inhibit proteolytic enzymes in the lung. It results from an insult to the lungs from inhaled toxins, such as cigarette smoke and air pollution. Types of emphysema Pathophysiology of emphysema oEmphysema begins with destruction of alveolar septa o oIt is postulated that inhaled oxidants, such as those in cigarette smoke and air pollution, tip the normal balance of elastases (proteolytic enzymes) and antielastases (such as a1-antitrypsin) such that elastin is destroyed at an increased rate oExpiration becomes difficult because loss of elastic recoil reduces the volume of air that can be expired passively. oHyperinflation of alveoli causes large air spaces (bullae) and air spaces adjacent to pleura (blebs) to develop. oThe combination of increased RV in the alveoli and diminished caliber of the bronchioles causes part of each inspiration to be trapped in the acinus. Mechanisms of air trapping in emphysema oDamaged or destroyed alveolar walls no longer support and hold open the airways, and alveoli lose their property of passive elastic recoil. oBoth of the se factors contribute to collapse during expiration. obr5 oPatients with emphysema are able to maintain a higher alveolar minute ventilation than those with chronic bronchitis. Thus they tend to have a higher PaO2 and lower PaCO2 and have classically been referred to as „pink puffers“ o oPhysical examination often reveals a thin, tachypneic patient using accessory muscles and pursed lips to facilitate respiration. The thorax is barrel-shaped due to hyperinflation. o oThere is little cough and very little sputum production (in „pure“ emphysema) Emphysema – clinical manifestations o oPulmonary function tests: o o - indicate obstruction to gas flow during expiration o - airway collapse and air trapping lead to a decrease in FVC and FEV1 and an increase in FRC, RV, and TLC. o - diffusing capacity is decreased because destruction of the alveolocapillary membrane o oArterial blood gas measurements are usually normal until latge in the disease o Emphysema – evaluation Emphysema – approach to therapy oSmoking cessation is the most important intervention oInhaled anticholinergic agets ob2-adrenergic agonists oSteroids oLow-flow oxygen therapy in selected individuals oLung transplant can be considered obr1a o2 Cystic fibrosis (mucoviscidosis) oIt is AR inherited disorder that results from defective epithelial ion transport oOn simplistic level, CF is associated with abnormal secretions Cl- that may cause obstructive problems within the respiratory, digestive and reproductive tracts. oThe CF gene has been localized on chromosome 7 ß its mutation result in the abnormal expression of the protein cystic fibrosis transmembrane regulator (CFTR) = chloride channel present on the surface of many cells (airways, bile ducts, pancreas, sweat ducts, vas deferens) Pathogenesis of cystic fibrosis lung diseases obr6 o3 oThe most common manifestations are respiratory and gastrointestinal. o oRespiratory symptoms include: o persistent cough or wheeze and recurrent or severe pneumonia o Physical signs include barrel chest and digital clubbing. oGastrointestinal manifestations include: o meconium ileus at birth, failure to thrive, and malabsorptive symptoms, such as frequent loose and oily stools oMale with CF are typically infertile (98%) oMay be liver disease or diabetes mellitus Cystic fibrosis – clinical manifestations oThe standard method of diagnosis is the sweat test, which will reveal sweat chloride concentration in excess of 60 mEql/L. oGenotyping for CFTR mutation (above 800 variations) o oTreatment: o - chest physical therapy o - bronchodilators o - antibiotics o - pancreatic enzymes, vitamins o Cystic fibrosis – evaluation and treatment Restrictive lung diseases The lung volumes are reduced either because of: 1. Alteration in lung parenchyma. • 2. Diseases of the pleura, chest wall or neuromuscular apparatus. Physiologically restrictive lung diseases are defined by reduced total lung capacity, vital capacity and functional residual capacity, but with preserved air flow. Restrictive lung diseases may be divided into the following groups: oIntrinsic lung diseases (diseases of the lung parenchyma) o oExtrinsic disorders (extra-parenchymal diseases) Intrinsic Lung Diseases oThese diseases cause either: oInflammation and/or scarring of lung tissue (interstitial lung disease) o or oFill the air spaces with exudate and debris (pneumonitis). o oThese diseases are classified further according to the etiological factor. Extrinsic Disorders oThe chest wall, pleura and respiratory muscles are the components of respiratory pump. o oDisorders of these structures will cause lung restriction and impair ventilatory function. o oThese are grouped as: oNon-muscular diseases of the chest wall. oNeuromuscular disorders. Interstitial lung diseases oThere are a large number of diseases that affect the interstitium of the lung ß it is connective tissue present between the alveolar epithelium and capillary endothelium oSome of these diseases have known etiology, e.g. occupational diseases o oOthers are diseases of unknown etiology - most frequent of these are idiopatic pulmonary fibrosis (diffuse interstitial fibrosis), pulmonary fibrosis associated with collagen-vascular diseases, and sarcoidosis. Granulomatous Lung Diseases oInfections oSarcoidosis oHypersensitivity pneumonitis (EAA) o oWegener’s granulomatosis (WG) oReaction to tumours oForeign body oPneumoconiosis (Berrylium, Aluminium, Cobalt) oDrug reactions oDrug abusers oNecrotising sarcoidal granulomatosis (NSG) oEosinophilic pneumonia oBronchocentric granulomatosis (BCG) oChurg Strauss syndrome oLymphoid interstitial pneumonia (LIP) oSjogren’s disease oAmyloidosis oIncidental What is a granuloma? “a compact (organised) collection of mature mononuclear phagocytes (macrophages and/or epithelioid cells) which may or may not be accompanied by accessory features such as necrosis or infiltration of inflammatory leucocytes” Adams, 1983 Key features. A granuloma is: Discrete Avascular Comprises epithelioid histiocytes EJ Mark, 2004 Granulomas and granulomatous inflammation: synonymous or different? oGranuloma is well defined (sarcoidal or tuberculoid type) o oGranulomatous inflammation nDiffuse process, ill-defined nPalisading histiocytes in zones n The granulomas oNecrotising or non-necrotising? oIs the necrosis nCaseous nAbscess-like nDegeneration / fibrinoid necrosis o‘Distinct and compact’ or o ‘Soft and diffuse’? Necrotising granulomas oCaseous necrosis o oTB o oHistoplasmosis oCoccidioidomycosis oPneumocystis oFungi nCandida nAspergillus nPhycomycosis nBlastomycosis nCrypococcosis n oBacteria nNocardia, Actinomyces n oViruses o o Abscess-like necrosis Non-necrotising granulomas (mostly in the context of diffuse disease) oIs there associated interstitial pneumonitis? oNature of the granulomas? oDistribution of disease? Non-necrotising granulomas: Interstitial inflammation ABSENT oIf there are oTight well formed granulomas oEvidence of multisystem disease o‘Lymphatic’ distribution o oConsider oSarcoidosis oBerylliosis oAluminium oIf not oRandom distribution? Airways? Vessels? oTry viewing under polarised light oHistory of inhalation or injection? oFood, dust, haemosiderin, amyloid, Non-necrotising granulomas: Interstitial inflammation PRESENT oIf there are oInflammation and granulomas centriacinar oGranulomas often ‘soft’ oFoamy macrophages, cholesterol clefts, COP-like features o oConsider oHypersensitivity Pneumonitis (EAA) oIf not oRandom distribution? oCheck history oOther pathological features o oDrug reaction oAspiration pneumonia oForeign material? oEosinophilic pneumonia Diffuse Interstitial Pulmonary Fibrosis oSynonyms: idiopathic pulmonary fibrosis, interstitial pneumonia, cryptogenic fibrosing alveolitis. o oPathology oThickening of interstitium. oInitially, infiltration with lymphocytes and plasma cells. oLater fibroblasts lay down thick collagen bundles. oThese changes occur irregularly within the lung. oEventually alveolar architecture is destroyed – honeycomb lung oEtiology o oUnknown, may be immunological reaction. o oClinical Features oUncommon disease, affects adults in late middle age. oProgressive exertional dyspnea, later at rest. oNon-productive cough. oPhysical examination shows finger clubbing, fine inspiratory crackles throughout both lungs. oPatient may develop respiratory failure terminally. oThe disease progresses insidiously, median survival 4-6 years. Pulmonary Function oSpirometry reveals a restrictive pattern. FVC is reduced, but FEV1/FVC supernormal. oAll lung volumes – TLC, FRC, RV – are reduced. oPressure volume curve of the lung is displaced downward and flattened. A:\2012PFT1_JPEG_Conv.jpg oArterial PaO2 and PaCO2 are reduced, pH normal. oOn exercise PaO2 decreases dramatically. oPhysiologic dead space and physiologic shunt and VQ mismatch are increased. oDiffuse impairment contributes to hypoxemia on exercise. oThere is marked reduction in diffusing capacity due to thickening of blood gas barrier and VQ mismatch. Sarcoidosis oA disease characterized by the presence of granulomatous tissue. oThis is a systemic disease which involves eyes, brain, heart, lungs, bones and kidneys, skin, liver and spleen. oOn pathology a non-caseating granuloma composed of histiocytes, giant cells and lymphocytes. oIn advanced lung disease fibrotic changes are seen. Etiology oUnknown, likely immunological basis. o oClinical Fetures oFour stages are identified: oStage 0: No obvious intrathoracic involvement oStage 1: Bilateral hilar lymphadenopathy, often accompanied by arthritis, uveitis and erythema nodosum. oStage 2: Pulmonary parenchyma is also involved, changes in mid and upper zones. oStage 3: Pulmonary infiltrates and fibrosis without adenopathy. A:\s15.jpg o Pulmonary Function o oNo impairment occurs in stages 0 and 1. oIn stages 2 and 3 restrictive changes are seen. oTreatment and Prognosis o85% of these patients improve spontaneously, but 15% may develop progressive fibrosis and respiratory failure. oTreatment is other observation, but in symptomatic patients or deteriorating PFT’s – treatment recommended. oPrednisone 0.5- 1 mg/kg initially, then tapered and continued for 6 months to 1 year. Therapy oIt depends on etiology (if it is known) o oStopping the occupational exposure oAntibiotics oDiseases of unknown etiology (sarcoidosis, idiop. pulmonary fibrosis) corticosteroids oOxygen therapy Pulmonary edema It is excess water (fluid) in the lung oThe normal lung contains very little water or fluid. It is kept dry by lymphatic drainage and a balance among capillary hydrostatic pressure, capillary oncotic pressure, and capillary permeability o oIn addition, surfactant lining the alveoli repels water, keeping fluid from entering the alveoli. Pulmonary edema - pathogenesis obr9 Classification of pulmonary edema 1)High pressure (hydrostatic, cardiogenic) edema - It is associated with elevated capillary hydrostatic pressure 2)Low pressure (high permeability, noncardiogenic) edema - It refer to conditions in which hydraulic filtration coefficint is elevated and osmotic reflection coefficient is reduced interstitial edema x alveolar edema Effects of pulmonary edema oPulmonary vascular pressure and volume o In cardiogenic edema the increase in left atrial pressure is reflected passively in a retrograde direction to the pulmonary veins, capillaries, and arteries. This increase in pulmonary vascular pressure produces an increase in pulmonary blood volume. o o In permeability edema the passive increase in vascular volume is absent but the fundamental process of lung injury releases substances which may produce pulmonary vasoconstriction leadint to increased pulmonary artery pressure despite normal left atrial pressure. oPulmonary blood flow redistribution Cardiogenic edema is associated with a redistribution of blood flow in the lungs such that the lung bases, which normally receive the highest blood flow, experience a decrease in blood flow while the apices, which normally receive hte least amount of flow, experience an increase in blood flow. Perfusion redistribution becomes relevant in gas exchange. Perfusion of the pulmonary capillaries in an edema-filled alveolus has the effect of a right-to-left shunt since venous blood which is not exposed to alveolar air is admixed with oxygenated blood from nonedematous alveoli. Vasodilator therapy for congestive heart failure, while improving cardiac function, usually increases the severity of hypoxemia by reversing pulmonary blood flow redistribution. oLung compliance Interstitial edema produces a reduction in lung compliance which increases the elastic work the muscles must do to achieve a given tidal volume. Furthermore, even small amounts of edema fluid interfere with surfactant function, leading to increased surface tension, alveolar instability, and alveolar collapse. In cardiogenic edema the increase in pulmonary blood volume causes a further increase in lung stiffness. oAirway resistance (AR) There are several factors increasing airway resistance: 1)A reduction in lung volume produces an increase in airway resistance 2)Edema in the bronchovascular sheath produces compression of small airways 3)Fluid in the airways combined with edema of the bronchial mucosa narrows the lumen and increase AR. 4)Reflex bronchospasm which occurs in some patients with congestive heart failure – „cardiac asthma“ oOxygenation Alveolar edema produces a right-to-left shunt, which has the same effect on arterial PO2 as an anatomic shunt. oAcid-base balance o -mild forms of pulmonary edema stimulate interstitial „J“ receptors in the lung, leading to hyperventilation and respiratory alkalosis. -More severe forms increasing the work of breathing lead to relative hypoventilation and respiratory acidosis. -In cardiogenic edema while the metabolism of the respiratory muscles is increased, cardiac dysfunction leads to decreased blood flow, resulting in reduced tissue PO2, anaerobic metabolism, and metabolic acidosis. oThe treatment is based on pathophysiologic consequences and on pathogenic mechanisms: o oOxygen and respiratory support o oAcid-base balance o oReduce pulmonary capillary pressure o (increase plasma oncotic pressure) o Therapy