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Semester 2 Case 3: Turning Blue
* What are the dangers of smoking?
General effects: Lung cancer, COPD, carcinoma of the oesophagus, ischaemic heart disease, peripheral vascular disease, bladder cancer, an increase in abnormal spermatozoa, and memory problems. Maternal smoking: A decrease in birth weight of the infant, an increase in foetal and neonatal mortality, and an increase in asthma. Passive smoking: Risk of asthma, pneumonia and bronchitis in infants of smokers, an increase in cough and breathlessness in smokers and non-smokers with COPD and asthma, and increased cancer risk.
* What are the effects of smoking on the respiratory system?
Cigarette smoke contains polycyclic aromatic hydrocarbons & nitrosamines, which are potent carcinogens & mutagens in animals. It causes release of proteolytic enzymes from neutrophils granulocytes & macrophages. This attracts leukocytes, which release proteases, including elastase, which destroys elastin, and leads to lung damage. This process is usually inhibited by a1-antitrypsin, but this itself is inhibited by oxygen radicals released by leukocytes. Pulmonary epithelial permeability increases & correlates with the concentration of carboxyhaemoglobin in the blood. This increased permeability possibly allows easier access to carcinogens. A low-grade systemic inflammatory response is evident in smokers, involving mediators such as; elevated levels of C-reactive protein (CRP), fibrinogen, IL-6, & increased counts of WBC. There is also a reduction in endogenous nitric oxide production, which plays a role in regulation of pulmonary vasomotor tone. NO causes increased levels of cGMP in lung smooth muscle, which controls K+ and Ca2+ channels, controlling vasodilation. Effects on mouth, larynx, & pharynx These areas suffer continual irritation from smoking, & tobacco users my develop hoarseness, coughing & wheezing due to inflammation. Smoking is linked to cancers of the mouth, larynx, & pharynx. Effects on bronchi The smoke acts on the cilia & damages them so that they no longer function. Excess mucus
& foreign matter build up in the bronchial space. Symptoms of chronic bronchitis arise to compensate for this. A frequent cough & expulsion of phlegm indicate this first stage of COPD. Effects on lungs The alveoli suffer from cigarette smoking, eventually breaking down & losing their effectiveness in gas exchange. It causes apoptosis of alveolar epithelial cells, which may be due to an interaction between aldehydes &
oxidants present in cigarette smoke or formed in cigarette smoke-exposed cells. Cigarette smoke also suppresses proliferation, attenuates attachment and augments detachment of the alveolar epithelial cells. It can also suppress surfactant secretion & collagen production. Effects on pulmonary blood vessels Tobacco use causes atherosclerosis. When the pulmonary vessels are affected, high blood pressure results, which causes pulmonary hypertension. This can lead to arrhythmia, heart failure, DVT, and pulmonary embolism.
[1, 2, 3, 4]
* What is COPD?
[1, 2] Chronic
obstructive pulmonary disease is the occurrence of chronic bronchitis &
emphysema in the same patient, who is almost always a smoker. Prior to 1979, patients with these conditions were often classified by: symptoms (e.g. chronic bronchitis, chronic asthma), pathological changes (e.g. emphysema), and physiological correlates (pink puffers
& blue bloaters). Body Size Chest Hyperinflation Predominant Disease Post-mortem Finding Cor Pulmonale Secondary Polycythaemia Cyanose Blood Gases
Pink Puffers Thin Marked Emphysema Panacinar emphysema Absent Absent Absent Low PaCO2
Blue Bloaters Obese Present Chronic bronchitis Centrilobular emphysema Present Present Centrally Raised PaCO2
This presents 2 ends of a spectrum of illness & most patients fall between the two. It was a recognition that emphysema & chronic bronchitis overlapped & often coincided which led to the need for the new term 'COPD'. COPD is a disease state characterised by airflow limitation that isn't fully reversible. Airflow limitation is usually both progressive &
associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Epidemiology & Aetiology It is caused by long-term exposure to toxic particles & gases. >90% of cases are caused by cigarette smoking in developed countries. However, only 10-20% of heavy smokers ([?]30 cigarettes per day) develop COPD - some individuals are more susceptible. The risk to someone who smokes 30-a-day is 20 times that of a non-smoker. Climate & air pollution are less important. However, there's a great increase in COPD mortality during periods of heavy atmospheric pollution. Urbanisation, social class, & occupation may also play a part in aetiology, but are difficult to separate from effects of smoking. In the UK, COPD causes about 18million lost working days for men & about 2.1million lost working days for women per year. It accounts for 7% of sickness absences. According to WHO, 65million people have moderate to severe COPD. >3million people died of COPD in 2005. It accounted for about 5% of all deaths globally. It is estimated that by 2020 it'll become the 3rd most common cause of death. Pathophysiology Bronchitis Characteristics: The most consistent finding is hypertrophy & increase in number of mucus-secreting goblet cells of the bronchial tree, evenly distributed throughout the lung but mainly seen in larger bronchi. Initially in disease before development of breathlessness, small airways are particularly affected. The initial inflammation is reversible. In more advanced cases, the bronchi become obviously inflamed, and there is pus in the lumen. In severe disease, acute & chronic inflammatory cells & lymphoid follicles infiltrate on the walls of the bronchi & bronchioles. However, it is predominantly CD8+ cells, unlike in asthma. Mucus becomes more acidic, making it more viscous. Ulcers appear in the epithelial layer, which cause squamous epithelium to replace columnar cells on healing (AKA: squamous cell metaplasia). Fibrosis of bronchial walls also occurs. These changes cause airflow limitation, so there is low arterial oxygenation, high CO2, and low pH. In later stages of bronchitis, inflammation continues even after smoking cessation.
Thickened walls & airway narrowing
Emphysema Characteristics: Dilatation & destruction of the lung tissue distal to the terminal bronchiole, caused by elastase that's released by inflammatory mediators. Therefore, lung elasticity increases, and air can get in more easily and Total Lung Capacity increases. However, the loss of alveolar elastic recoil means it is more difficult to exhale. Small airways & alveoli collapse. The loss of alveoli results in decreased gas transfer. There are fewer but larger alveoli. Emphysema is classified according to the site of damage: Centri-acinar emphysema: This is extremely common. It is concentrated around respiratory bronchioles. More distal alveolar ducts & alveoli tend to be well-preserved. Modest cases aren't associated with disability. Severe centri-acinar emphysema causes substantial airflow limitation. Pon-acinar emphysema: This is less common. It involves the whole of the acinus, and in its extreme form, the lung becomes a mass of bullae. (Bullae are large cavities left by alveolar septal ruptures.) Severe airflow limitation &
V / Q
(ventilation/perfusion) mismatch occur. This can occur in a1-trypsin deficiency. Irregular emphysema: Scarring & damage affecting lung parenchyma patchily without particular regard for acinar structure. This picture shows the pathological changes to the airways in chronic bronchitis & emphysema. Ventilation/perfusion mismatch occurs in COPD, partly due to damage & mucus plugging of smaller airways from chronic inflammation, and partly because of rapid expiratory closure of smaller airways owing to loss of elastic recoil from emphysema. This causes a fall in PaCO2 & increase in work of respiration because ventilation isn't sufficient enough to saturate the perfusion. CO2 exertion isn't impaired to the same extent. Many patients (pink puffers) show normal PaCO2, as they seek to maintain blood gases by increasing respiratory effort. Other patients (blue bloaters) fail to do this, and their PaCO2 increases. Hypercapnia A short-term | PaCO2: Stimulates respiration. A long-term | PaCO2: Become insensitive to CO2 & reply on hypoxaemia to drive their ventilation. These patients appear less breathless & due to low PaO2 values start to retain fluid & stimulate production of erythrocyte (RBCs). This is polycythaemia. As a consequence, they become bloated, plethoric (containing excessive blood), and cyanosed. Administering oxygen to these 'blue bloaters' can worsen the situation by decreasing respiratory drive in patients who rely on hypoxia. This can result in an increase in PaCO2 by decreasing the respiratory drive, worsening respiratory failure. Fletcher & Peto studies show that a loss of 50ml/year in FEV1 in COPD, compared to 20ml/year in healthy people. In summary: Limitation of airflow in small airways (airways that are <2mm in diameter), leading to hyperinflation of lungs & breathlessness, is thought to be caused by 3 mechanisms: 1) Loss of elastic fibres & alveolar attachments of airways due to emphysema ?
Reduces elastic recoil & airways collapse during expiration. 2) Inflammation & scarring cause small airways to narrow.
3) Mucus secretion blocks airways. Pathogenesis
* Cigarette smoking - Smokers have neutrophil granulocytes present within the lumen of the bronchial tree. Also, their small airways are also infiltrated by granulocytes. Granulocytes are capable of releasing elastases & proteases, which possibly help to produce emphysema. It's suggested that an imbalance between protease & antiprotease activity may produce the damage. a1-antitrypsin is a major serum antiprotease, which can be inactivated by cigarette smoke. Persistent irritation from inhalation of cigarette smoke causes hypertrophy of mucus glands in larger airways. Smoke has an adverse effect on surfactant, favouring overdistention of the lungs.
* Infections - Patients with COPD cope badly with respiratory infections, which are often the precipitating cause of acute exacerbations of the disease. However, the role of infection in the development of COPD is far less clear.
* a1-antitrypsin deficiency - a1-antitrypsin is an antiproteinase inhibitor produced in the liver, secreted into the blood, & which diffuses into the lung. It then functions as an antiproteinase that inhibits neutrophil elastase. The 3 main phenotypes of this gene are MM (normal), MZ (heterozygous deficiency), & ZZ (homozygous deficiency). About 1:5000 children in the UK are born with ZZ, but not all develop chest disease. About 2% of emphysema is hereditary. Clinical Features Characteristic symptoms of COPD are:
- Cough with production of sputum
- Wheeze & breathlessness following many years of a smokers' cough
- Colds go 'down to the chest'
- Frequent infective exacerbations occur, giving purulent sputum Symptoms can be worsened by factors such as cold, foggy weather, & atmospheric pollution. In mild disease, there are no signs other than 'wheeze' throughout the chest. In advanced disease, breathlessness becomes severe even after mild exercise such as dressing. In severe disease, the patient is tachypnoeic, with prolonged expiration. Accessory muscles of respiration are used & there may be intercostal in-drawing on inspiration & pursing of the lips on expiration. Chest expansion is poor, lungs are hyperinflated, & there is a loss of the normal cardiac and liver dullness. Patients who remain responsive to CO2 are usually breathless & rarely cyanosed. Heart failure & oedema are rare, except as terminal events. Patients who become insensitive to CO2 are often oedematous & cyanosed, but not particularly breathless. Those with hypercapnia may have peripheral vasodilation, a bounding pulse, & when PaCO2 is >10kPa, a coarse flapping tremor of the out-stretched hands. Severe hypercapnia will lead to confusion & progressive drowsiness. Complications
* Respiratory Failure: Later stages of COPD are characterised by development of respiratory failure. PaO2 <8kPa or PaCO2 >7kPa. The persistence of chronic alveolar hypoxia & hypercapnia leads to constriction of the pulmonary arterioles & subsequent pulmonary arterial hypertension. Cardiac output is normal or increased, but salt &
fluid retention occurs as a result of renal hypoxia.
* Cor Pulmonale: Patients with advanced COPD may develop cor pulmonale, which is defined as heart disease secondary to disease of the lung. It is characterised by pulmonary hypertension, right ventricular hypertrophy, & eventually right heart failure. In very severe pulmonary hypertension, there is incompetence of the pulmonary valve. With right heart failure, tricuspid incompetence may develop with a greatly elevated jugular venous pressure, ascites (abnormal accumulation of fluid in the abdomen) & upper abdominal discomfort owing to swelling of the liver.
Secondary Infections: [5, 6] Bacterial infection is one of several important causes of exacerbations of COPD that may coexist. Mucus hypersecretion may be an important risk factor. Patients with chronic bronchitis are more susceptible to bacterial bronchial infections than those at the emphysema or asthma end of the spectrum. Bacteria that are inhaled into bronchial tree may adhere to stationary mucus as mucocilliary clearance is delayed. E.g. pneumonia caused by Streptococcus pneumoniae, influenza caused by Haemophillus influenza, Moraxella catarrhalis, and Pseudomonas aeruginosa. The purulent sputum in the case is indicative of acute bronchitis, a bacterial infection. The green colour is caused by polymorphs and the myeloperoxidase they contain. Pathophysiology of Pneumonia
 Pneumonia is an inflammation of the lung parenchyma & alveoli that is usually caused by bacteria. It usually presents as an acute illness with cough, purulent sputum and fever together with physical signs or radiological changes compatible with consolidation of the lung. Antibiotics have decreased its mortality in young people, but it is still dangerous and is a major cause of death in people over the age of 70. Bacterial pneumonia is more common in alcoholics & HIV-infected people compared to the general population. Typically, the patient presents with high temperature, pleuritic pain, and a dry cough. Rusty-coloured sputum is then present (blood coming from the alveoli), and the patient breathes rapidly and shallowly. The affected side of the chest moves less, and pleural rub may be present. Diagnosis Diagnosis is usually clinical using GOLD (Global Initiative in Obstructive Lung Diseases) criteria. Stage of COPD FEV1 (%) Symptoms 0
[?]80 None I
+/- Variable II 50-79
+ Mild-moderate III 30-49
++ Limit exertion IV
+++ Limit daily activities Identify a history of breathlessness & sputum production in a lifetime smoker. In absence of a cigarette-smoking history, a working diagnosis of asthma is usual unless there's a family history of lung disease suggestive of an a1-antitrypsin deficiency. Patient may have signs of hyperinflation & typical pursed lip respiration. Emphysema is often incorrectly diagnosed on signs of over-inflation of the lungs (e.g. loss of liver dullness on percussion), but this may be asthma. Furthermore, centri-acinar emphysema may be present without signs of over-inflation. Note: Some elderly men without emphysema develop a barrel-shaped chest due to osteoporosis of the spine. Investigations Lung Function Tests Test Use Advantages Disadvantages PEFR (=Low in Monitors changes in Portable - Can be Effort-dependent. COPD) airflow limitation in used at the Poor measure of asthma. bedside. chronic airflow limitation. FEV, FVC, FEV/FVC Assessment of airflow Reproducible. Bulky equipment, but (FEV1/FVC =
limitation. Best single Relatively effortsmaller portable reduced in COPD) test. independent. machines available. Flow-volume curves Assessment of flow at Recognition of Sophisticated lower lung volumes. patterns of flowequipment needed Detection of large volume curves for for full test but airway obstruction, both different diseases. expiratory loop now intra- and extra- thoracic possible with
Airways resistance Lung volumes (Normal or increased in COPD)
(e.g. tracheal stenosis, tumour). Assessment of airflow limitation. Differentiation between restrictive & obstructive lung disease.
Gas transfer (Gas Transfer Coefficient of CO [KCO] = low with significant emphysema) Blood gases
monitoring of extent of interstitial lung disease
Post-operative, sleep studies, & respiratory failure.
Assessment of respiratory failure.
compact Spirometry. Sensitive. Effortindependent. Complements FEV1. Non-invasive (compared with lung biopsy or repeated chest xray &CT). Can detect early lung disease when measured during exercise. Continuous monitoring, noninvasive.
Technique difficult to perform. Sophisticated equipment needed. Sophisticated equipment needed.
Measures saturation only.
In many patients, airflow limitation is reversible to some extent (usually a change in FEV1 of
<15%), and distinction between asthma & COPD can be difficult. How These Tests Are Carried Out PEFR: Extremely simple & cheap. Patients are asked to take a full inspiration & then blow out forcefully into the peak flow meter, which is held horizontally. Lips must be placed tightly around mouthpiece. Best of 3 tests is recorded. It over-estimates lung function in patients with moderate airflow limitation. PEFR is best used to monitor progression of disease & its treatment. Spirometry: Spirometer measures FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity). Both are related to height, age, & sex. Technique involves maximum inspiration followed by a forced expiration (for as long as possible) into the spirometer. The act of expiration triggers the moving record chart, which measures volume against time. Record chart moves for 5 seconds, but expiration should continue until all the air has been expelled from the lungs. FEV1 (as a % of the FVC) is an excellent measure of airflow limitation. In normal people, it's about 75%. With increasing airflow limitation, the FEV1 falls proportionally more than the FVC, so that the FEV1/FVC ratio is reduced. With restricted lung disease, FEV1 and FVC are reduced in some proportion, so ratio remains normal or may even increase due to enhanced elastic recoil. In chronic airflow limitation (e.g. emphysema & asthma), the total lung capacity is usually increased, yet there is nearly always some reduction in the FVC. This is the result of disease in the small airways causing obstruction to airflow before the normal residual volume is reached. This trapping of air causes an increased residual volume. (TLC & RV cannot be measured with a spirometer). Chest x-ray Often normal, even in advanced disease. The classic features are the presence of bullae ("very black" areas), severe over-inflation of the lungs with low, flattened diaphragms, & a large retrosternal airspace on the lateral film. There may also be a deficiency of blood vessels in the periphery of the lung fields compared with relatively easily-visible proximal vessels.
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