CLI Week 5 Flashcards
(45 cards)
Asthma
- Atopic asthma is caused by a TH2 and IgE response to environmental allergens in genetically predisposed individuals à airway inflammation à release of mediators + remodelling of airway à airway dysfunction
- As the disease becomes more severe there is increased secretion of growth factors à mucous gland hypertrophy, smooth muscle proliferation, angiogenesis, fibrosis and nerve proliferation.
- Hypersensitivity with immediate and late-phase reaction
- Non-atopic asthma has the same pathogenesis but without the TH2 + B cell involvement
- As the disease becomes more severe and chronic and loses its sensitivity to corticosteroids, there is greater evidence of a Th1 response with release of mediators such as TNF-α and associated tissue damage, mucous metaplasia and aberrant epithelial and mesenchymal repair.
Acute Phase:
- Allergen (re-exposure) transported by dendritic cell through mucosal lining à presented to TH2 cell which secretes IL-4, IL-5 à Stimulates B cells to produce IgE à IgE binds to Fc receptor on mast cells à release of granule contents + production of cytokines (IL-5 – recruits eosinophils) and other mediators
- When eosinophils that are recruited are activated they also release granules and mediators exacerbating the reaction
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Leads to bronchoconstriction, increased mucous production, variable degrees of vasodilation + increased vascular permeability
- Bronchoconstriction is triggered by direct stimulation of sub epithelial vagal receptors through central and local reflexes triggered by mediators produced by mast cells and other cells in the reaction.
- Antigen directly stimulates vagal afferent nerve (central)
- Mast cell mediators stimulate vagal efferent nerve (local)
- Bronchoconstriction is triggered by direct stimulation of sub epithelial vagal receptors through central and local reflexes triggered by mediators produced by mast cells and other cells in the reaction.
Late phase:
- Dominated by recruitment of leukocytes, notably eosinophils, neutrophils, and more T cells à release additional mediators
- Several factors released from eosinophils also cause damage to epithelium
- TH2 predominant type of T cell but TH17 also contributes and they recruit neutrophils
Inflammatory mediators and cytokines:
- IL-3 – Activation of mast cells, eosinophils
- IL-4 – Stimulates production of IgE
- IL-5 – Activates locally recruited eosinophils
- IL-9 – Activation of mast cells
- IL-13 – Stimulates mucous secretion from bronchial submucosal glands and also promotes IgE production by B cells
- Leukotrienes C4, D4 and E4 – Prolonged bronchoconstriction + increased vascular permeability + increased mucous secretion
- Acetylcholine – Released from intrapulmonary parasympathetic nerves à airway smooth muscle constriction via stimulation of muscarinic receptors
- Histamine – Bronchoconstriction
- Prostaglandin D2 – Bronchoconstriction + vasodilation
- Platelet activating factor – Aggregation of platelets and release of serotonin from their granules
Idiopathic pulmonary fibrosis
- Pulmonary disorder of unknown aetiology
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Characteristics = patchy, progressive bilateral interstitial fibrosis
- Can result in severe hypoxaemia and cyanosis in severe cases
- More common in males over 60yo (according to Robbins)
- Pathologic changes are known as usual interstitial pneumonia – seen in many diseases such as asbestosis etc. therefore IPF is when there is no known cause
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Pathogenesis:
- Repeated cycles of epithelial activation/injury by some unidentified agent
- Inflammation and induction of TH2 type T cell response w/ eosinophils, mast cells, Il-4 and IL-13 in lesions
- Abnormal epithelial repair at site of damage and inflammation Ú fibroblastic proliferation
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TGF-beta1 might be causing abnormal repair – release from injured type I pneumocytes
- Transformation of fibroblasts into myofibroblasts
- Therefore excessive deposition of collagen and ECM
- Histological hallmark = patchy interstitial fibrosis worsening with time
- Dense fibrosis causes collapse of alveolar walls and formation of cystic spaces lined with hyperplastic type II pneumocytes resulting in honeycomb fibrosis
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Clinical features:
- Gradual onset of non-productive cough and progressive dyspnoea
- Velcro-like crackles during inspiration
- Late stages: cyanosis, cor pulmonale, peripheral oedema
Pneumoconiosis
Pneumoconiosis = non-neoplastic lung reaction to inhalation of organic and inorganic particulates (may also include chemical fume and vapour-induced)
- Usually mineral dust – coal dust, silica and asbestos
- Usually by particles 1-5μm in diameter because lodged at bifurcation of distal airways
- Pulmonary alveolar macrophages play central role in pathogenesis of lung injury by promoting inflammation and producing reactive oxygen species and fibrogenic cytokines
Coal Worker’s Pneumoconiosis
CWP stages
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Asymptomatic anthracosis (pigment without perceptible cellular reaction)
- Carbon pigment accumulated in CT, lymphatics or in lymph nodes
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Simple CWP (accumulation of macrophages with little to no dysfunction)
- Characterised by coal macules and nodules scattered throughout the lungs
- Coal macules = dust-laden macrophages
- Coal nodule = coal macules + small amounts of collagen fibres arrayed in delicate network
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Complicated CWP/PMF (extensive fibrosis and lung function compromised)
- Background of simple CWP by coalescence of coal nodules and generally requires many years to develop
- Characterised by: multiple, intensely blackened scars larger than 2cm that consist of dense collagen and pigment
Note: less than 10% of simple CWP progress to PMF
CWP Clinical Features
- In PMF – increasing pulmonary dysfunction, cor pulmonale
Silicosis
- Silicosis = inhalation of crystalline silica which interact with epithelial cells and macrophages, causing activation and release of mediators incl. IL-1, TNF, fibronectin, fibrogenic cytokines etc.
- Most prevalent chronic occupational disease in the world
- Characterised by silicotic nodules (concentrically-arranged hyalinised collagen fibres) with a silica particle in the centre of the nodules
- These nodules coalesce into collagenous scars which progress to PMF
- Clinical features:
- Pulmonary function either normal or only moderately affected
- Most don’t have SOB until later, after PMF is present
Asbestosis
- Asbestos = crystalline hydrated silicates
- Causes fibrosis by process involving interaction of particulates with lung macrophages
- Asbestos is also a tumour initiator and promotor – oncogenic on the mesothelium mediated by reactive free radicals generated by asbestos fibres themselves
- Can’t distinguish asbestosis from UIP morphologically except for presence of asbestos bodies = asbestos fibres coated with iron-containing proteinaceous material which are formed when macrophages attempt to phagocytose asbestos fibres
- Iron from phagocyte ferritin
- Pleural plaques are most common manifestation of asbestos exposure (plaques of dense collagen containing calcium)
- Clinical features:
- Same as other chronic interstitial lung diseases
Airway obstruction
Can be incomplete or complete
- Complete obstruction of the upper airway occurs when there is inability to talk, cough or breath. Apnea and cyanosis are present and paradoxical respirations may be noted.
- Incomplete obstruction occurs when there is partial upper airway obstruction and ability to breath is maintained. Inspiratory stridor and increased work of breathing are the hallmarks.
Upper airway obstruction can be due to the following factors:
- luminal (e.g. foreign body)
- intramural (e.g. tumour, neuromuscular diseases)
- extramural (e.g. thyroid mass)
Acute bronchitis
It is usually viral but can be complicated with bacterial infection, particularly in smokers and in patients with chronic airflow limitation. Symptoms include cough, retrosternal discomfort, chest tightness, and wheezing. This usually resolves spontaneously over 4-8 days.
Acute laryngotracheobronchitis or croup
Usually a result of infection with one fo the parainfluenzae viruses or measles virus. Symptoms are most severe in children under 3 years of age. Inflammatory oedema involving the larynx causes a hoarse voice, barking cough (croup) and stridor. Tracheitis produces a burning retrosternal pain. Treatment is oxygen and inhaled steam, tracheostomy is needed in severe cases
Epiglottitis
Epiglottitis is an acute inflammation in the supraglottic region of the oropharynx with inflammation of the epiglottis, vallecula, arytenoids, and aryepiglottic folds. In adults, the most common organisms that cause acute epiglottitis are Haemophilus influenzae (25%), followed by H parainfluenzae, Streptococcus pneumoniae, and group A streptococci.
In spite of acute epiglottitis generally having a good prognosis, the risk of death for persons is high due to sudden airway obstruction and difficulty intubating patients with extensive swelling of supraglottic structures.
Cystic fibrosis
An autosomal recessive condition occurring in 1:2000 live births. It is caused by mutations in a single gene on the long arm of chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations in the CFTR gene result in the production of a defective transmembrane protein which is involved in chloride transportation across epithelial cell membranes in the pancreas, respiratory, GI and reproductive tracts. The decreased chloride transport is accompanied by decreased transport of sodium and water, resulting in dehydrated viscous secretions that are associated with luminal obstruction and destruction and scarring of exocrine glands.
Neonates may present with meconium ileus or, rarely, with other features such as anasarca. Patients younger than 1 year may present with wheezing, coughing, and/or recurring respiratory infections and pneumonia. GI tract presentation in early infancy may be in the form of steatorrhea, failure to thrive, or both.
Patients diagnosed later in childhood or in adulthood are more likely to have pancreatic sufficiency and often present with chronic cough and sputum production. Approximately 10% of patients with cystic fibrosis remain pancreatic sufficient; these patients tend to have a milder course.
Acute Respiratory Distress Syndrome
Acute Respiratory Distress Syndrome
- ARDS is a clinical syndrome of progressive respiratory insufficiency caused by diffuse alveolar damage in the setting of sepsis, severe trauma or diffuse pulmonary infection
- Damage to the endothelial and alveolar epithelial cells with inflammation, are the key initiating events and the basis of lung damage
- The characteristic histologic picture is that of hyaline membranes lining alveolar walls. Edema, scattered neutrophils and macrophages and epithelial necrosis are also present.
Acute lung injury
Also called non-cardiogenic pulmonary oedema and is characterized by the abrupt onset of significant hypoxemia and bilateral pulmonary infiltrates in the absence of cardiac failure. ARDS is a manifestation of severe ALI.
Severe Acute respiratory syndrome (SARS)
A viral respiratory disease of zoonotic origin caused by the SARS coronavirus (SARS-CoV).- first appeared in November 2002 in china and subsequently spread to hong kong, taiwan, Singapore, Vietnam and Toronto where large outbreaks occurred. The main way that SARS seems to spread is by close person-to-person contact. The virus that causes SARS is thought to be transmitted most readily by respiratory droplets (droplet spread) produced when an infected person coughs or sneezes.
In general, SARS begins with a high fever (temperature greater than 100.4°F [>38.0°C]). Other symptoms may include headache, an overall feeling of discomfort, and body aches. Some people also have mild respiratory symptoms at the outset. About 10 percent to 20 percent of patients have diarrhea. After 2 to 7 days, SARS patients may develop a dry cough. Most patients develop pneumonia.
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP)
Idiopathic pulmonary fibrosis portends a poor prognosis, and, to date, no proven effective therapies are available for the treatment of idiopathic pulmonary fibrosis beyond lung transplantation.
Pathophysiology:
it is currently believed that idiopathic pulmonary fibrosis (IPF) is an epithelial-fibroblastic disease, in which unknown endogenous or environmental stimuli disrupt the homeostasis of alveolar epithelial cells, resulting in diffuse epithelial cell activation and aberrant epithelial cell repair.
In the current hypothesis regarding the pathogenesis of idiopathic pulmonary fibrosis, exposure to an inciting agent (eg, smoke, environmental pollutants, environmental dust, viral infections, gastroesophageal reflux disease, chronic aspiration) in a susceptible host may lead to the initial alveolar epithelial damage. Reestablishing an intact epithelium following injury is a key component of normal wound healing. In idiopathic pulmonary fibrosis, it is believed that after injury, aberrant activation of alveolar epithelial cells provokes the migration, proliferation, and activation of mesenchymal cells with the formation of fibroblastic/myofibroblastic foci, leading to the exaggerated accumulation of extracellular matrix with the irreversible destruction of the lung parenchyma.
Sarcoidosis
Sarcoidosis
A multisystem granulomatous disorder of unknown aetiology that commonly affects young adults and usually presents with bilateral hilar lymphadenopathy (BHL), pulmonary infiltration and skin or eye lesions. The diagnostic histopathological feature is the presence of non-caseating granulomas in various tissues. Immunological abnormalities include high levels of CD4+ T cells in the lung that secrete Th1 dependent cytokines such as IFN-gamma and IL-2 locally.
Clinical manifestations include lymph node enlargement, eye involvement, skin lesions (erythema nodosum, painless subcut nodules), and visceral (liver, marrow) involvement. Lung involvement occurs in 90% of cases with formation of granulomas and interstitial fibrosis.
Anatomy of Airways:
Upper Airway – nose to trachea
Trachea:
- Starts at C6 ends at T4 when the Primary Bronchi start
- Has C shaped cartilage rings – no cartilage posteriorly
- 1.8cm diameter, 12-14cm long
- Respiratory Mucosa: pseudostratified ciliated columnar epithelia with goblet cells
- In smokers transforms to stratified squamous to protect from toxins – but lose cilia ability
Primary Bronchi:
- Left is more horizontal than right – hence right gets blocked more when ya inhale the peanut
- Bifurcation is called carina
- Secondary Bronchi – one for each lung lobe, 3 on right, 2 on left, then Tertiary Bronchi then Bronchioles
Lower Airway – bronchi to alveoli
Conduction Zone:
- Filters, warms, moistens air – nose, nasal cavity
- Bronchi have cartilage plates for support
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Bronchioles – no cartilage – so this is where collapse can happen in emphysema
- Less than 1mm diametre
Respiratory Zone:
- Gas exchange – alveoli
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Pulmonary Acinus:
- Respiratory Bronchioles
- Alveolar Ducts
- Alveolar Sacs
Alveoli:
- Made of Pneumocytes
- Type 1: simple squamous epithelium – the lining
- Type 2: cuboidal – secrete surfactant – fewer than Type 1
- Also have Alveolar Macrophages to munch the bad things – both fixed and free macrophages
Control of Breathing:
- Central Controller – Pons, Medulla
- Sensor – chemoreceptors in brain, aorta, carotid bodies
- Mechanoreceptors in lung
- Effectors: Respiratory muscles – diaphragm, intercostals, abdominal muscles
Medulla:
- Dorsal Respiratory Group – Inspiration
- Input from CN 9 and 10
- Receives information from peripheral chemoreceptors, baroreceptors and pulmonary stretch receptors
- Pulmonary stretch receptors feed back via the Vagus Nerve
- Sends information back to Phrenic and Intercostal Nerves – activates diaphragm and intercostals
- Ventral Respiratory Group – active inspiration and expiration
- Mostly inactive in normal quiet breathing
- Contribute extra respiratory drive during increased demand
Pons:
- Pontine Respiratory Group – contains the pneumotaxic (limits inspiration) and apneustic (prolongs inspiration)centres
Chemical Control: Important bit
- Arterial CO2 – acts indirectly on medulla respiratory centres
- Arterial H+ - acts on peripheral chemoreceptors and indirectly (via CO2 changes) on the medulla respiratory centres
- Arterial O2 – acts on peripheral chemoreceptors in carotid and aortic bodies
- IMPORTANT: increased PaCO2 has a potent acute effect on respiratory drive but only a weak chronic effect after a few days
- SO PATIENTS WITH COPD RELYING ON THEIR HYPOXIC DRIVE TA-DA!
Peripheral Chemoreceptors:
- Carotid bodies and Aortic arch – most sensitive to changes in PaO2
- Carotid input to medulla via Glossopharyngeal nerve
- Aortic input to medulla via Vagus nerve
Hypoxia, Respiratory Drive in health and Disease.
- Respiratory drive refers to the process by which detected changes in the body’s pH and PCO2 levels are responded to by the central nervous system’s corrective stimulation of the rhythm, effort and rate of breathing. The control and response of the respiratory system takes place within the medulla of the brain stem. The spinal cord serves as the conduit through which the appropriate neural signals are converyed to the muscles of respiration.
- It is affected by the levels of CO2 in the blood. Level changes are detected by central chemoreceptors in the medulla and by peripheral chemoreceptors in the carotid artery and aorta. The feedback loop and resulting neural signals cause breathing patterns to change accordingly and the body is able to maintain the correct acid-to-base and O2 to CO2 ratios.
- Hypoxic drive is when the body uses oxygen chemoreceptors instead of carbon dioxide receptors to regulate the respiratory cycle.
- In the case such as COPD ® when there are chronically high levels of CO2 in the blood, the body will begin to rely on the O2 receptors and less on the CO2 receptors. So if there is an increase in oxygen levels the body will decrease the rate of respiration.
Pathophysiology of Shortness of Breath in Asthma and COPD.
- Damage to the air sacs in the lungs causes them to become large which leads to breathing difficulties as well as inflammation and irritation in the lining of the lungs.
- Not as much oxygen exchange across the damaged alveoli.
Pulmonary Function tests.
- Spirometry measures airflow. By measuring how much you exhale, and how quickly you exhale, spirometry can evaluate a broad range of lung diseases. In a spirometry tst, while you are sitting, you breathe into a mouthpiece that is connected to an instrument called a spirometer. This records the amount and the rate of air that you breathe in and out over a period fo time.
- In COPD, emphysema, asthma, chronic bronchitis and infections ® the lungs contain too much air and take longer to empy ® obstructive lung disorders
- To interpret a PFT ®
- Determine if the FEV1/FVC is low ® if low ® obstructive, if normal ® restrictive
- Determine if the FVC is low
- Confirm the restrictive pattern
- Grade the severity fo the abnormality
- Determine reversibility of the abnormality
Clinical assessment and definition/diagnosis of Asthma:
- Paroxysmal recurrent attacks of wheezing (or in childhood of cough) due to airways narrowing, which changes in severity over short periods of time
- Airflow limitation
- Airway hyperresponsiveness
- Bronchial inflammation
- The principal symptoms of asthma are wheezing attacks and episodic shortness of breath. Symptoms are usually worst during the night, especially in uncontrolled disease. Cough is a frequent symptom that sometimes predominates, especially in children in whom nocturnal cough can be a presenting feature. Attacks vary greatly in frequency and duration. Some patients only have one or two attacks a year that last for a few hours, while others have attacks lasting for weeks. Some patients have chronic persistent symptoms, on top of which there are fluctuations.
- In chronic asthma, inflammation may be accompanied by irreversible airflow limitation as a result of airway wall remodelling that may involve large and small airways and mucus impaction.
- Extrinsic asthma occurs most frequently in atopic individuals: i.e. those with positive skin-prick reactions to common inhalant allergens such as dust mite, animal danders, pollens and fungi; 90% of children and 70% of adults with persistent asthma have positive skin- prick tests to inhalant allergens. Childhood asthma is often accompanied by eczema. Sensitization to chemicals or biological products in the workplace is a frequently overlooked cause of late-onset asthma in adults.
- Intrinsic asthma often starts in middle age. Nevertheless, many patients with adult-onset asthma show positive allergen skin tests and on close questioning some of these will give a history of childhood respiratory symptoms suggesting they have extrinsic asthma.
- Non-atopic individuals may develop asthma in middle age from extrinsic causes such as sensitization to occupational agents such as toluene diisocyanate, intolerance to non- steroidal anti-inflammatory drugs such as aspirin or because they were given β-adrenoceptor-blocking agents for concur- rent hypertension or angina that block the protective effect of endogenous adrenergic agonists. Extrinsic causes must be considered in all cases of asthma and, where possible, avoided.
Triggers of asthma- Atopy:
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Occupational sensitisers (increased in smokers)
- Low molecular weight compounds, e.g. reactive chemicals such as isocyanates and acid anhydrides that bond chemically to epithelial cells to activate them as well as provide haptens recognized by T cells.
- High molecular weight compounds, e.g. flour, organic dusts and other large protein molecules involving specific IgE antibodies
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Non-specific factors
- Cold air and exercise
- Exercise-induced wheeze is driven by release of histamine, prostaglandins (PGs) and leukotrienes (LTs) from mast cells as well as stimulation of neural reflexes when the epithelial lining fluid of the bronchi becomes hyperosmolar owing to drying and cooling during exercise.
- Atmospheric pollution, irritant dusts, vapour and fumes
- Diet
- Intake of fresh fruit and vegetables shown to be protective (possibly due to antioxidants in them)
- Emotion
- May influence acutely and chronically
- Understandably anxious patients at risks of life-threatening attacks
- Drugs
- NSAIDs (other than COX-2 alone)
- NSAIDs inhibit arachidonic acid metabolism via the cyclooxygenase (COX) pathway, pre- venting the synthesis of certain prostaglandins. In aspirin- intolerant asthma there is reduced production of PGE2 which, in a sub-proportion of genetically susceptible subjects, induces the overproduction of cysteinyl leukotrienes by eosinophils, mast cells and macrophages.
- Beta-blockers
- There is no direct sympathetic innervation of the smooth muscle of the bronchi, and antagonism of parasympathetically induced bronchoconstriction is critically dependent upon circulating epinephrine (adrenaline) acting through β2-receptors on the surface of smooth muscle cells. Inhibition of this effect by β-adrenoceptor-blocking drugs such as propranolol leads to bronchoconstriction and airflow limitation, but only in asthmatic subjects. Selective β1-adrenergic-blocking drugs such as atenolol may still induce attacks of asthma; ideally alternative drugs should be used to treat hypertension or angina in asthmatic patients.
- NSAIDs (other than COX-2 alone)
- Allergen – as seen in major pathology issues
- Cold air and exercise