COPD is common and is mostly due to smoking. Patients with COPD represent a large proportion of inpatient (~12% of all general medical admissions) and outpatient work for the chest physician.
• Fixed airflow obstruction
• Minimal or no reversibility with bronchodilators
• Minimal variability in day-to-day symptoms
• Slowly progressive and irreversible deterioration in lung function, leading to progressively worsening symptoms.
95% of cases are smoking-related, typically >20 pack years. COPD occurs in 10–20% of smokers, indicating that there is probable genetic susceptibility. COPD is increasing in frequency worldwide, particularly in some developing countries, due to high levels of smoking, but also because of biomass fuel exposure. Smoking tobacco with marijuana increases COPD risk. It can also be caused by environmental and occupational factors such as dusts, chemicals, and air pollution.
• Mucous gland hyperplasia, particularly in the large airways, with mucous hypersecretion and therefore a chronic productive cough. Other mucosal damage from smoke:
• Squamous metaplasia Replacement of the normal ciliated columnar epithelium by a squamous epithelium
• Loss of cilial function This leads to impairment of the normal functioning of the mucociliary escalator, another reason for the chronic productive cough
• Chronic inflammation and fibrosis of small airways, characterized by CD8 lymphocyte, macrophage, and neutrophil infiltration, with release of pro-inflammatory cytokines. Recurrent infections may perpetuate airway inflammation
• Emphysema due to alveolar wall destruction, causing irreversible enlargement of airspaces distal to the terminal bronchiole (the acinus), with subsequent loss of elastic recoil and hyperinflated lungs
• Panacinar emphysema can occur with dilated airspaces evenly distributed across acini
• Centriacinar or proximal emphysema can occur with dilated air spaces found in association with the respiratory bronchioles
• Periacinar or paraseptal emphysema can occur with dilated air spaces at the edge of the acinar unit and abutting a fixed structure such as the pleura or a vessel
• Thickened pulmonary arteriolar wall and remodelling occur with hypoxia. Leads to increased pulmonary vascular resistance, PHT, and impaired gas exchange.
The cause of the increase in airways resistance, and hence expiratory flow limitation, is multifactorial. Small airway inflammation reduces the airway lumen. Emphysema destroys the radial attachments to the small airways, which normally hold them open and resist dynamic compression.
COPD is increasingly being recognized as having features not only of pulmonary, but also systemic, inflammation, and this may be the cause of the comorbidities found in patients with COPD. Daily activities are often modified to avoid dyspnoea, which can lead to deconditioning, muscle weakness, and wasting, meaning standing and walking become even harder. This leads to a vicious cycle of inactivity.
• Chronic cough, may be productive
• Decreased exercise tolerance
Significant airflow obstruction may be present before the patient is aware of it. Symptoms are rare below age 35 and should prompt consideration of alternate diagnoses.
depend on the severity of the underlying disease.
• Raised RR
• Hyperexpanded/barrel chest
• Prolonged expiratory time >5s, with pursed lip breathing
• Use of accessory muscles of respiration
• Quiet breath sounds (especially in the lung apices) ± wheeze
• Quiet heart sounds (due to overlying hyperinflated lung)
• Possible basal crepitations
• Signs of cor pulmonale and CO2 retention (ankle oedema, raised JVP, warm peripheries, plethoric conjunctivae, bounding pulse, polycythaemia. Flapping tremor if CO2 acutely raised).
NICE clinical guideline 101. Management of COPD in adults in primary and secondary care (partial update), June 2010. http://www.nice.org.uk/cg101.
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• Obstructive spirometry and flow–volume loops
• Reduced FEV1 to <80% predicted or FEV1 >80% with other respiratory symptoms such as cough or breathlessness. COPD severity scale is shown in Table 21.1 and MRC dyspnoea scale in Box 21.1). FEV1 is the measurement of choice to assess progression of COPD, but it correlates weakly with the degree of dyspnoea. Changes in FEV1 do not reflect the decline in a patient’s health
• FEV1/FVC <0.7 (post-bronchodilation)
• Minimal bronchodilator reversibility (<15%, usually <10%) and minimal steroid reversibility (how to perform these, see p. [link]). It is not necessary to test these in most patients but is useful if there is diagnostic uncertainty or if the patient is thought to have both COPD and asthma
• Raised total lung volume, FRC, and RV because of emphysema, air trapping, and loss of elastic recoil
• Decreased TLCO and kCO because presence of emphysema decreases surface area available for gas diffusion.
Table 21.1 COPD severity according to NICE guidelines 2004 (which differ slightly from the GOLD guidelines)
FEV1 50–80% predicted. May or may not be symptomatic with cough or sputum
FEV1 30–49% predicted. Increased FRC, reduced TLCO. Likely to be symptomatic (cough, sputum, dyspnoea), often managed by patient’s GP
FEV1 <30% predicted. Marked hyperinflation, TLCO usually low. Usually hypoxic, with signs of cor pulmonale. Symptomatic, often needing hospital admissions
is not required for diagnosis, and repeated CXR is unnecessary, unless other diagnoses are being considered (most importantly, lung cancer or bronchiectasis).
• Hyperinflated lung fields, with attenuation of peripheral vasculature—’black lung sign’; >7 posterior ribs seen
• Flattened diaphragms (best CXR correlate of post-mortem degree of emphysema)
• More horizontal ribs
• May see bullae, especially in lung apices, which, if large, can be mistaken for a pneumothorax due to loss of lung markings (CT can differentiate).
α1-AT levels (see pp. [link]–[link]), FBC to ensure not anaemic or polycythaemic (suggesting persistent hypoxia), TFT if unduly breathless. CRP is slightly increased in COPD but decreases after steroid treatment. It may be related to the presence of comorbidities and may aid the assessment of the systemic effects of COPD, particularly in the research setting. ECG and echo to assess cardiac status if features of cor pulmonale.
is based on the history of smoking and progressive dyspnoea, with evidence of irreversible airflow obstruction on spirometry. Asthma is the most important differential diagnosis. Asthma is steroid- and bronchodilator-responsive. Nearly all patients with COPD will have a smoking history; this is not universal in asthma. Symptoms are common under the age of 35 in asthma; rare in COPD. Chronic productive cough is common is COPD and uncommon in asthma. Breathlessness is progressive and persistent in COPD but variable in asthma. In asthma, there is significant diurnal or day-to-day variability of symptoms, and night-time waking with SOB or wheeze is common; these symptoms are uncommon in COPD. Some patients have both.
BODE index (see Table 21.2) is a simple multidimensional grading system for COPD, using BMI, airflow Obstruction, Dyspnoea, and Exercise capacity as its scoring variables. It has been shown to be better than FEV1 at predicting risk of hospitalization and death in patients with COPD, as it is multidimensional. Patients are scored as having a BODE index of between 0 and 10, with higher scores indicating a higher risk of death. It is being increasingly used, with recommendations to calculate it in the clinical setting to give prognostic information (Celli BR et al. New Engl J Med 2004; 350: 1005–12).
Table 21.2 BODE index
Points on BODE index
FEV1 (% predicted)
Distance walked in 6min (m)
MRC dyspnoea scale
Aims of COPD management should include:
• Ensuring the diagnosis is correct
• Stopping smoking
• Optimizing treatment by minimizing symptoms where possible
• Helping the patient maintain their QoL.
Management should be delivered by a multidisciplinary team (MDT).
No treatment has yet been shown to modify disease progression in the long term, except for stopping smoking.
is the only intervention that is proven to decrease the smoking-related decline in lung function. All patients with COPD who smoke should be encouraged to stop at every opportunity. Fig. 21.1 shows the accelerated decline in FEV1 in susceptible smokers and the delay in this acceleration from stopping smoking; susceptible smokers, however, never regain the original curve. Nicotine replacement therapy (NRT) should be used to aid smoking cessation (see p. [link]).
is a multidisciplinary programme, with RCT evidence that it improves exercise tolerance, QoL, and reduces hospital admissions. Muscle mass, particularly in the lower limbs, is reduced in people with COPD, compared with age-matched healthy controls. This is an independent predictor of mortality and disability, independent of the severity of the underlying lung disease, and may reflect the systemic nature of COPD. The mainstay of rehabilitation is graded exercise to improve muscle function but also includes breathing techniques and education.
Programmes vary but are usually run on an outpatient basis over several weeks, with multidisciplinary involvement (see p. [link]). Should be made available to all appropriate patients with COPD, including after hospitalization for acute exacerbation.
Weight loss is recommended if the patient is obese to minimize respiratory effort. If the patient is very breathless, calorific intake may be low and a catabolic state may exist. A low BMI is associated with impaired pulmonary status, decreased diaphragm mass, lower exercise capacity, and increased mortality rate, compared with people with a normal BMI. Nutritional supplementation may therefore be necessary. Maintaining body weight and muscle mass correlates well with survival.
Pharmacological management aims to relieve symptoms and reduce exacerbations but will not modify disease. Increase treatment in a stepwise fashion. Exacerbations require additional therapeutic support (see p. [link]).
Simple pulmonary function testing may not show significant bronchodilator reversibility of FEV1, but bronchodilators provide therapeutic benefit in the long term by reducing dyspnoea, perhaps by decreasing chest hyperinflation.
• Initially prescribe short-acting β2 agonists, as required, for symptom relief
• If the patient remains symptomatic and FEV1 >50% predicted: prescribe LABA or long-acting anticholinergic
• If symptoms and FEV1 <50% predicted: try LABA with inhaled steroid in combination, or an anticholinergic
• If still breathless or exacerbations despite this regime (regardless of FEV1): add long-acting anticholinergic to the LABA and inhaled steroid combination. Reduces exacerbation frequency
• Oral methylxanthines, such as theophyllines, can be used as maintenance therapy and may improve symptoms. Add after inhaled bronchodilators and trial of inhaled steroids; continue only if symptoms improve. Method of action is unclear, but they may have an anti-inflammatory effect. Care regarding therapeutic/toxic levels, especially in elderly patients
• Inhaler therapy provides adequate bronchodilator doses for most patients, especially when used with a spacer device. Check patient’s inhaler technique
• Nebulizer therapy is indicated if the patient is unable to use inhalers or if they are disabled or distressed with breathlessness despite maximal inhaler therapy. Only those with a clear response, with reduction in symptoms or improvement in activities of daily living, should continue with long-term domiciliary nebulized treatment (usually with salbutamol and ipratropium), as there is a significant placebo effect.
should be prescribed to all patients with FEV1 ≤60% predicted, who have had two or more exacerbations per year requiring treatment with antibiotics or oral steroids. Clinical trials of inhaled steroids have shown a reduction in exacerbation frequency and severity in severe COPD, but no slowing in lung function decline. Warn patients regarding side effects, and document. Use in combination with bronchodilator. Evidence of increased risk of pneumonia (without associated increase in mortality) with some inhaled steroids. Use in combination with bronchodilator.
are not recommended as a maintenance therapy in COPD. It may, however, be difficult to withdraw them in patients with severe COPD following an exacerbation. If so, keep the dose as low as possible, and prescribe osteoporosis prophylaxis if indicated. Warn regarding steroid side effects, and document.
can be administered via a cylinder for short-burst O2 therapy (SBOT), as required, for symptomatic relief, such as after climbing stairs (there is little trial evidence to support this use—only continue if improvement in breathlessness documented), or as long-term O2 therapy (LTOT) via an O2 concentrator. The latter is for patients in respiratory failure, with a PaO2 <7.3kPa or PaO2 of 7.3–8kPa with any of 2° polycythaemia, peripheral oedema, or PHT present, to use for a minimum of 15h/day (including sleep). Additional ambulatory cylinders can be provided. Low-flow O2, such as 2–4L/min via nasal prongs, is usually adequate. Small changes in CO2 retention with O2 administration can be tolerated if asymptomatic and no respiratory acidosis. Associated OSA is a risk factor for CO2 retention (for O2 prescribing, see p. [link]).
Influenza vaccine annually and pneumococcal vaccine. Meta-analysis showed a decrease in exacerbations occurs 3 weeks after receiving influenza vaccine, and there is no evidence of an earlier increase in exacerbations due directly to vaccination.
In general, not recommended prophylactically. Some prescribe low-dose rotating antibiotics, particularly over the winter in those with severe exacerbations. Mixed data. Some newer evidence for low-dose azithromycin 250mg three times per week in those with frequent exacerbations despite optimal therapy. Reduces exacerbation frequency and time to exacerbation, compared to placebo, but possible hearing impairment and nasopharyngeal colonization with more resistant organisms. Moxifloxacin 400mg PO has also been given as prophylaxis for 5 days every 8 weeks for six cycles, with beneficial effect on exacerbation rate, no increased resistance, but some GI side effects. Azithromycin favoured.
(carbocisteine, mecysteine hydrochloride) may benefit some patients with chronic productive cough to facilitate expectoration by reducing sputum viscosity. Prescribe for a 4-week trial period, and only continue if there is evidence of improvement. Meta-analyses show mucolytics cause a significant decrease in the number of COPD exacerbations and decrease the number of days of disability, although the benefit may only apply if the patient is not taking inhaled steroids. Worth trying in those with moderate to severe COPD, with frequent or prolonged exacerbations, or those repeatedly in hospital with COPD exacerbations. Caution if known peptic ulcer disease.
Palliative care/respiratory sedation
Use of low-dose sedatives, such as morphine sulfate solution 10mg prn or diazepam 2mg bd, can be used as a palliative measure (see pp. [link]–[link]), aiming to relieve the sensation of dyspnoea and associated anxiety, in those with severe COPD. Dose may need to be titrated against any rise in CO2 (surprisingly uncommon).
Newer anti-inflammatory drugs
is a thiol compound with effects on bacterial adhesiveness as well as antioxidant and mucoactive properties. RCT in moderate COPD showed decreased exacerbations vs placebo over 8 months, no loss of lung function, and improved health-related QoL.
are PDE-4 inhibitors, which elicit anti-inflammatory effects. RCT of roflumilast in moderate to severe COPD showed a significant improvement in FEV1 over 24h vs placebo and a reduction in the rate of mild exacerbations. Long-term studies are required to evaluate its efficacy and role further. Cilomilast has shown similar results.
An approach to COPD in the outpatient clinic
• Establish diagnosis and severity—PFTs, CXR
• Ensure there are no other causes for symptoms, e.g. anaemia, PE, heart failure, ILD, thyroid dysfunction, pneumothorax, large bulla, arrhythmia, depression
• Consider chest CT only if CXR abnormalities require clarification or symptoms disproportionate to spirometry or if surgery being considered
• Encourage the patient to stop smoking
• Review current treatment—optimize bronchodilatation and inhaled steroids
• Assess whether there is any need for a nebulizer
• Check O2 saturation, and perform blood gas if <92%. Consider LTOT
• Consider pulmonary rehabilitation
• Consider sputum culture if persistent purulent sputum
• Check vaccinations are up to date
• Involve respiratory nurse specialist for input in the community, if appropriate
• Follow-up in clinic if ongoing medical issues, including whether patient may be a lung transplant candidate (see p. [link]). Otherwise, discharge back to GP
• Inform GP of all the above decisions.
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Measure FEV1 and slow VC before and after:
• Either a high-dose inhaled steroid for 6–8 weeks, or
• A 2-week course of oral prednisolone 30mg/day.
Over 15% increase in FEV1 implies steroid reversibility, and patient is likely to have asthma.
Over 15% increase in slow VC suggests significantly reduced air trapping and may indicate significant asthma. May occur with a significantly smaller change in FEV1.
Document results of trial clearly in notes.
Testing for bronchodilator reversibility to help distinguish asthma from COPD
• Check FEV1. Give patient a short-acting β2 agonist, either nebulized or inhaled via spacer; 15–30min after this, recheck the FEV1.
• Subtract the pre-test value from the post-test value; divide the difference by the pre-test value, and express as a % increase from baseline; >15% increase or >200mL indicates bronchodilator reversibility
• Avoid short-acting bronchodilator in the preceding 6h, a long-acting bronchodilator in the preceding 12h, or a long-acting anticholinergic or slow-release theophylline in the preceding 24h.
Exacerbations may cause mild symptoms in those with relatively preserved lung function but can cause considerable morbidity in those with limited respiratory reserve. It has been increasingly recognized that significant numbers of patients do not regain their premorbid lung function or QoL following an exacerbation, and those with frequent exacerbations experience a more rapid FEV1 decline than those with fewer exacerbations. Exacerbation frequency increases with COPD severity. Exacerbations are 50% more likely in winter (possibly viruses survive better in the cold, and people crowd together indoors). An exacerbation is essentially a clinical diagnosis of an acute increase in symptoms beyond normal daily variation.
may be infective organisms, either viral or bacterial, or non-infective causes such as pollution or temperature fall. Common bacterial pathogens are Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, and the commonest viral pathogens are rhinovirus, RSV, influenza, parainfluenza, coronavirus, human metapneumovirus, and adenovirus. Consider the possibility of PE or pneumothorax.
include increased cough, increased sputum volume and/or purulence, increasing dyspnoea or wheeze, chest tightness, fluid retention.
There is increased airway resistance due to bronchospasm, mucosal oedema, and increased sputum. This worsens expiratory flow limitation, and expiration takes longer. Shallow rapid breathing further limits the time for expiration. This promotes dynamic hyperinflation, and this itself causes mechanical compromise within the lung and the airway. Maximal recruitment of the accessory muscles is required, and thoraco-abdominal dysynchrony is often present.
• Assess the severity of the exacerbation by measuring RR, O2 saturations, degree of air entry, tachycardia, BP, peripheral perfusion, conscious level, mental state
• Exclude a pneumothorax clinically
• If hypoxic, give controlled 24–35% O2 via Venturi face mask to aim for SaO2 88–92%, salbutamol nebulizer; establish venous access
• Check blood gas
• Request a CXR
• Perform ECG
• Check bloods for WCC, CRP, potassium, etc.
• Optimize volume status
• Take a brief history, if possible. Important to know what patient’s normal functional status is like such as exercise tolerance and the need for help with activities of daily living. Old hospital notes are helpful regarding severity of disease and whether previous decisions have been made regarding ventilation or resuscitation
• Nebulized bronchodilators—salbutamol 2.5–5mg and ipratropium 500 micrograms on arrival and 4–6-hourly. Run nebulizer with air, not O2
• Continued O2 therapy, aiming to maintain saturations between 80% and 90%. Repeat blood gases after 60min to ensure improvement if hypoxic or acidotic. Repeat if clinical deterioration
• Consider antibiotics
• Oral steroids
• Consider IV aminophylline if not improving with nebulizers
• Consider intensive care—ideally, consultant-led decision with the patient, their family, and ITU regarding invasive mechanical ventilation. Document in the medical notes. Consider resuscitation status
• Consider NIV—pH 7.3 or less, hypoxia, hypercapnia, conscious level. Decide if this is the ceiling of therapy
• Consider doxapram if NIV not available or not tolerated
• DVT prophylaxis
• Early mobilization
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• Assess the severity of the exacerbation: increase in dyspnoea, tachypnoea, use of accessory muscles, new cyanosis, pedal oedema, or confusion
• Exclude alternative diagnoses such as pneumothorax, PE, pulmonary oedema
• Can the patient self-care and self-medicate? In the presence of severe symptoms, with possible comorbid disease and decreased functional activities, the patient is likely to need hospital management
• Investigate with CXR, ABGs, ECG, FBC, and U&Es. Admission arterial pH is the best predictor of survival. A pH <7.25 is associated with a rapidly rising mortality. A raised pH may imply an alternative diagnosis, not associated with worsening airways obstruction. Check theophylline level if patient is taking regularly; consider sending sputum for culture if it is purulent.
• Antibiotics if sputum purulent, pyrexial, high CRP, new changes on CXR. Recently published study found increased risk of cardiovascular events in people with COPD exacerbation treated with clarithromycin (hazard ratio 1.7, BMJ 2013;346:f1235). Effect not seen with β-lactams or doxycycline—further data set studies required
• Systemic steroids for all patients with exacerbations of COPD who are admitted to hospital or are significantly more breathless than usual. Give prednisolone 30mg/day for 1–2 weeks, unless there are specific contraindications. Optimum dose and length of steroids not established. This improves FEV1 and symptoms, and shortens recovery time. Avoid long-term steroid treatment due to side effects. If the patient has a longer course of steroids, or repeated courses due to repeated exacerbations, the dose will need to be tailed off slowly. Frequent short courses of steroids may merit long-term bone protection
• Inhaled or nebulized bronchodilators Breathless unwell patients may benefit from nebulizer therapy in the acute period to reduce symptoms and improve airflow obstruction
• Controlled O2 therapy 24–35% via Venturi face mask, with oximetry, ABGs, or capillary gas monitoring. Guidelines suggest maintaining saturations between 88% and 92%, balancing hypoxia, hypercapnia, and pH (see pp. [link]–[link]). Too little O2 causes anaerobic metabolism and metabolic acidosis (probably SaO2 >80% would prevent this); too much O2 (SaO2 >92%) can cause hypercapnia and a respiratory acidosis. A deteriorating pH to below 7.25 has a much poorer prognosis. Make sure your instructions to the ward staff are clear as to the need to keep the SaO2 within this window by changing the % O2 delivered as necessary. Falling conscious level is the best clinical marker of significant CO2 retention and acidosis
• IV aminophylline Evidence is lacking, but it may be beneficial, particularly if the patient is wheezy and has not improved with nebulizers alone. Give a loading dose, unless the patient is on regular oral aminophylline, followed by a maintenance infusion. Monitor aminophylline levels daily. Main side effects are tachycardia and nausea
• NIV Effective in supporting patients during an exacerbation when maximal medical treatment has not been effective. Appropriate for conscious patients with ongoing respiratory acidosis (pH 7.35 or less), hypoxia, and hypercapnia. May avoid intubation. Ceiling of treatment should be determined before its use (see p. [link])
• Doxapram IV respiratory stimulant. Can be used to drive RR (if <20/min) and depth in COPD exacerbation and hence improve hypoxia, hypercapnia, and respiratory acidosis, particularly when induced by O2 therapy. It can overdrive breathing to the point of respiratory muscle fatigue, collapse, and death and causes metabolic acidosis, agitation, and cardiac arrhythmias. It should only be used at the lowest possible dose (0.5–3mg/min) in the short term (usually 24–36h), aiming to reduce PaCO2 (and raise pH) by only a small amount. Its use has largely been replaced by NIV but may be used if NIV is not available or not tolerated
• Acetazolamide generates a metabolic acidosis by reducing the kidney’s ability to secrete [H+] into urine (blocks carbonic anhydrase that interconverts CO2 and H+/HCO3–). There is only one situation in which provoking a metabolic acidosis might be appropriate: following a transient period of hypoventilation (perhaps due to pump failure/increased airways obstruction) or after permissive hypercapnia on the ICU, the previous appropriate compensatory rise in blood [HCO3–] can now be too high for the improving PaCO2. This generates a blood alkalosis (pH >7.4), which itself depresses ventilation, and delays the return of PaO2 and PaCO2 to normal. The judicious use of a few doses of acetazolamide (250mg od), but only safe when the pH is alkaline, can hasten the recovery
• Intubation/intensive care If the patient is not responding to medical therapy, a decision regarding invasive mechanical ventilation needs to be made. This may be considered to be appropriate if the patient usually has a good functional status, with minimal other comorbidity. These decisions should ideally be discussed with the patient, their family, their consultant, and the ITU consultant and documented in the medical notes. Resuscitation decisions should also be made
• Early rehabilitation to prevent muscle wasting and deconditioning
• Acute respiratory assessment service (ARAS)/’hospital at home’ Respiratory nurse-led service supporting early discharge of COPD patients after hospital assessment and providing ongoing respiratory care at home. CXR, SaO2, and baseline spirometry (if this is first presentation) should be performed prior to discharge. Reduces length of inpatient stay and hence is an economic alternative. Unsuitable patients are those with impaired GCS, acute confusion, pH <7.35, acute changes on CXR, concomitant medical problems requiring inpatient stay, insufficient social support (including living far from the hospital and not having a telephone), new hypoxia with SaO2 <90%, and unable to provide O2 at home.
In young patients (below 60–65) with severe disease, often due to α1-AT deficiency, lung transplant may be an option. Local transplant teams will advise regarding local criteria (see pp. [link]–[link]).
Suitable for selected patients who are breathless, have FEV1 <50% predicted, and isolated large bulla seen on CT. Improves chest hyperinflation.
Lung volume reduction surgery (LVRS)
Resection of areas of bullous emphysema to reduce chest hyperinflation and improve diaphragmatic function, elastic recoil, physiology of the lungs, and hence functional status of the patient. Patients who may be considered are those with FEV1 20–30% predicted, with symptomatic dyspnoea despite maximal medical therapy, and with upper lobe-predominant emphysema on CT, giving target areas to resect. PaCO2 should be <7.3kPa and TLCO >20% predicted. Patients should have completed pulmonary rehabilitation and have stopped smoking. Preoperative assessment: PFTs, 6MWT, QoL and dyspnoea indicators. Surgery is performed in specialist centres via median sternotomy or by thoracoscopy. Usually, the upper lobe is stapled below the level of the emphysema and then removed. Improvements are seen in FEV1 and RV, dyspnoea, and QoL scores. These effects are maximal between 2 and 6 months post-surgery. Symptomatic improvement is sustained for about 2–4y. Post-operative complications: persistent air leak >7 days in 30–40%, pneumonia in up to 22%, respiratory failure in up to 13%. Reported post-operative mortality 2.4–17%.
The National Emphysema Treatment Trial (NETT, Michigan, USA)
randomized 1, 218 patients to receive medical treatment or LVRS. Mean airflow limitation of the subjects was 27% predicted. The most recent analysis, published after 4y of follow-up, has shown LVRS demonstrating an overall survival advantage, compared with medical therapy alone. Improvements in maximal exercise and health-related QoL were also found over 3y and 4y, respectively. The greatest survival benefits, improved exercise and symptoms over 5y, were in those with both low exercise capacity and upper lobe-predominant emphysema. Those with high exercise capacity and upper lobe-predominant emphysema obtained no survival advantage, but exercise and health-related QoL improved. Interim analysis had shown increased mortality from LVRS for patients with FEV1 or TLCO <20% predicted, or with homogeneous emphysema. Surgery is not therefore recommended for these groups.
Bronchoscopic lung volume reduction surgery (bLVR)
refers to techniques to reduce emphysematous hyperinflation via a flexible bronchoscope and thus avoid potential mortality and morbidity associated with surgery. Now this mainly refers to one-way valves, placed within the segmental and subsegmental bronchi that supply the hyperinflated lobes. They allow mucus to leave the bronchus but no air to enter. Two sizes are currently available and are inserted under direct bronchoscopic vision. It is a minimally invasive variation on LVRS, with the aim of improving lung function and QoL. Pilot studies in end-stage emphysema (mean FEV1 30% predicted) have shown the procedure to be safe, although a small subset of patients developed pneumothorax and one death (in 98 patients) has been reported. Significant improvements in RV, FEV1, FVC, and 6MWT were found at 30 and 90 days. Inclusion and exclusion criteria were similar to the NETT protocol, with patients with FEV1 <20% predicted, hypercapnia, PHT, or DLCO <25% predicted excluded. A multicentre RCT (the VENT trial) has been completed of best medical care (including pulmonary rehabilitation) vs best medical care plus unilateral endoscopic bronchial valve, with CT determination of lobe to target. There were 321 patients randomized, FEV1 15–45% predicted. There were small, but significant, improvements in FEV1 and 6MWT in the valve group, with those with intact interlobar fissures on CT having a much greater improvement than those with incomplete fissures (which allow collateral ventilation, and thus occluding the segmental bronchi with valves does not isolate the lobe). Lobar occlusion appears to be essential for clinically significant improved outcomes. Intrabronchial valves, coils, biological sealants, and thermal airway (steam to cause inflammation, and subsequent fibrosis and contraction) have also been used in small studies. Knowledge and skill are improving in this area, and more programmes are developing. Clearly, there are different COPD phenotypes, and those with a greater degree of CT heterogeneity are more likely to have intact fissures with areas of worse emphysema which may be more amenable to these therapies.
aims to improve respiratory mechanics by creating new exit pathways for air trapped in emphysematous lungs. The wall of a segmental bronchus is punctured under bronchoscopic guidance, and a drug-eluting stent is inserted, creating an internal bronchopulmonary communication for expiration. Hence, hyperinflation decreases and lung mechanics are improved. Multicentre Exhale Airway Stents for Emphysema (EASE) trial randomized 208 people to bypass or sham bronchoscopy. There was no difference between groups at 12 months.
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This is an inherited condition that is associated with the early development of emphysema. It is common (estimated 1 in 2, 000–5, 000 individuals) and is probably under-diagnosed, as it is often asymptomatic in non-smokers.
α1-AT is a glycoprotein protease inhibitor produced by the liver. It is secreted via the bloodstream into the lungs and opposes neutrophil elastase, which destroys alveolar wall connective tissue. Elastase is produced in increased levels by pulmonary neutrophils and macrophages in response to smoking and lung infections. If α1-AT is deficient, the elastase cannot be opposed, and subsequently basal emphysema develops. The disease is worse in smokers and can cause COPD at a young age (40s and 50s). There may also be associated liver dysfunction, chronic hepatitis, cirrhosis, and hepatoma, as abnormal protein secretion accumulates in the liver. Predisposition also to skin disease (panniculitis) and vasculitis (especially ANCA +ve).
α1-AT deficiency is inherited as an autosomal co-dominant disorder. So far, >100 different alleles have been identified for this gene (SERPINA 1) on the long arm of chromosome (Chr) 14. The commonest alleles are the allele (normal), the partially defective S allele, and the almost fully defective Z allele (lysine is substituted for glutamic acid at position 342, leading to abnormal folding, preventing post-translational processing with retention within cells), commonest in Scandinavia.
• MM, the normal phenotype. Background population risk of emphysema
• MS, MZ have 50–70% of normal α1-protease inhibitor (Pi) levels. Background risk of emphysema
• SZ, SS have 35–50% of normal levels. 20–50% risk of emphysema
• Homozygous ZZ has only 10–20% of normal levels. 80–100% risk of emphysema.
for the defect should be carried out, especially in patients <40 with COPD or minimal smoking history or family history. Also patients with unexplained liver disease should be screened. Send blood for α1-AT concentrations and genotyping if levels are low. Siblings should be screened and the particular importance of not smoking and avoiding passive smoking emphasized. Non-smokers are usually asymptomatic.
includes usual therapy for COPD. Specialist centre involvement recommended. Specific treatment is known as augmentation therapy, with ideally weekly, but also 2-weekly or monthly infusions, of purified α1-AT from pooled human plasma. This raises concentrations in serum and epithelial lining fluid above the protective threshold. It appears to be safe, with minimal side effects, and is well tolerated. A large cohort study showed reduced mortality amongst infusion recipients, with a slowing of lung function decline (by 27mL/y, p = 0.03) in a subgroup with moderate emphysema. An RCT showed no significant differences between augmentation and control groups, although there was a trend towards slower loss of lung tissue on CT scan in the augmentation group (p = 0.07). It has, however, been recommended as a treatment by groups, including the American Thoracic Society (ATS) and European Respiratory Society (ERS), for those with moderate (FEV1 35–60% predicted) emphysema due to α1-AT deficiency, who are non-/ex-smokers, but not those with mild disease (optimal therapy unclear) or severe disease (less clinical efficacy) or those post-lung transplant for α1-AT deficiency, except during episodes of acute rejection and infection (when inflammation causes free elastase activity). It is expensive, and its cost effectiveness in terms of cost per year of life saved is high. It is, however, the only specific therapy available at present.
Inhaled α1-AT may provide a way of delivering the enzyme to the lower respiratory tract to have its action locally and potentially reduce inflammation. Gene therapy is under development, finding ways of delivering the α1-AT gene into the cell. Other strategies include inhibition of hepatic polymerization of α1-AT, promotion of hepatic secretion, inhibition of neutrophil elastase by synthetic inhibitors to avoid the use of human plasma, and pegylation of α1-AT to prolong its serum half-life.
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Review series: α1-antitrypsin deficiency. Thorax 2004;59:64–9, 259–64, 441–5, 529–35, 708–12, 904–9.Find this resource:
UK α1-antitrypsin deficiency UK support group. http://www.alpha1.org.uk.