167 COPD is increasingly being recognized as having features not only of pulmonary, but also sy stemic in \202 ammation and this may be the cause of the comorbidities found in patients w ith COPD. Daily activities are often modi \201 ed to avoid dyspnoea, which can lead to dec onditioning, muscle weakness, and wasting, meaning standing and walking become even harder. This leads to a vicious cycle of inactivity. Clinical features \200 \200 \200 \200 Dyspnoea Productive cough Decreased exercise tolerance Wheeze. Signi \201 cant air \202 ow obstruction may be present before the patient is aware of it. Signs depend on the severity of the underlying disease. \200 \200 \200 \200 \200 \200 \200 \200 Raised respiratory rate Hyperexpanded/barrel chest Prolonged expiratory time >5 s, with pur sed lip breathing Use of accessory muscles of respiration Quiet breath sounds (especially i n the lung apices) 9 wheeze Quiet heart sounds (due to overlying hyperin \202 ated lung) P ossible basal crepitations Signs of cor pulmonale and CO2 retention (ankle oedema, raised J VP, warm peripheries, plethoric conjunctivae, bounding pulse, polycythaemia. Flapping tremo r if CO2 acutely raised). Further information NICE guidelines for COPD. February 2004. www.nice.org.uk ERS Consensus Statement \200\224optimal assessment and management of COPD. ERJ 1995; 8: 139 8 \200\223420 MacNee W, Calverley PMA. Management of COPD. Thorax 2003; 58: 261 \200\2235 www.copd-international.com, www.lunguk.org/copd. Patient information websites 168 CHAPTER 21 Chronic obstructive pulmonary disease Investigations Pulmonary function tests \200 \200 Obstructive spirometry and \202 ow-volume loops Reduced FEV1 to <80% predicted (FEV1 is t he measurement of choice to assess progression of COPD, but it correlates weakly with the d egree of dyspnoea. Changes in FEV1 do not re \202 ect the decline in a patient \200\231s h ealth) FEV1/FVC <0.7 Minimal bronchodilator reversibility (<15%, usually <10%) and minimal steroid reversibility (how to perform these, see p 175). It is not neces- sary to test thes e in most patients, but is useful if there is diagnostic uncertainty or if the patient is t hought to have both COPD and asthma Raised total lung volume, FRC, and residual volume beca use of emphy- sema, air trapping, and loss of elastic recoil Decreased TLCO and kCO because presence of emphysema decreases surface area available for gas diffusion. \200 CXR is not required for diagnosis and repeated CXR is unnecessary unless other diagnoses ar e being considered (most importantly lung cancer or bronchiectasis). \200 Hyperin \202 ated lung \201 elds with attenuation of peripheral vasculature \200\224 \200\230black lung sign \200\231. More than 7 posterior ribs seen Flattened diaphragms (bes t CXR correlate of post-mortem degree of emphysema) More horizontal ribs May see bullae, es pecially in the lung apices, which if large can be mis- taken for a pneumothorax due to the loss of lung markings (CT can differentiate). \200 Consider checking 1-antitrypsin levels (see p 182), FBC to ensure not anemic, TFT if undu ly 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. Diagnosis is based on the history o f smoking and progressive dyspnoea, with evidence of irreversible air \202 ow obstruction on spirometry. Asthma is the most important differential diagnosis. Asthma is steroid and b ron- chodilator 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 COP D. Chronic productive cough is common is COPD and uncommon in asthma. Breathlessness is pro gressive and persistent in COPD, but variable in asthma. In asthma there is signi \201 can t diurnal or day-to-day variability of symptoms, and night-time waking with SOB or wheeze a re common; these symptoms are uncommon in COPD. Some patients have both. INVESTIGATIONS 169 COPD severity according to NICE guidelines 2004 (which differ slightly from the GOLD guidelines) Mild FEV1 50 \200\22380% predicted. May or may not be symptomatic with cough or sputum Moderate FEV1 30 \200\22349% predicted. Increased FRC, reduced TLCO Likely to be symptomatic (cough, sputum, dyspnoea), often managed by patient \200\231s GP Severe FEV1 <30% predicted. Marked hyperin \202 ation, TLCO usually low. Usually hypoxic, with si gns of cor pulmonale. Symptomatic, often needing hospital admissions MRC dyspnoea scale 1 Not troubled by breathlessness except on strenuous exercise 2 Short of breath when hurryi ng or walking up a slight hill 3 Walks slower than contemporaries on level ground because o f breathlessness or has to stop for breath when walking at own pace 4 Stops for breath afte r walking about 100 m or after a few minutes on level ground 5 Too breathless to leave the house, or breathless when dressing or undressing. BODE Index Variable Points on BODE index 0 1 2 3 FEV1, (% predicted) Distance walked in 6 min (m) \211 65 50 \200\22364 36 \200\22349 \211 35 \211 350 250 \200\223349 150 \200\223249 \211 149 MRC dyspnoea scale 0 \200\2231 2 3 4 Body mass index \211 21 \211 21 This is a simple multidimensional grading system for COPD, using BMI, air \202 ow Obstruct ion, Dyspnoea and Exercise capacity as its scoring variables. It has been shown to be bette r than FEV1 at predicting risk of hospitalization and death in patients with COPD. Patients are scored as having a BODE index of between 0 and 10, with higher scores indicating a hig her risk of death. It is being widely used, particularly in research studies (Celli BR et a l. NEJM 2004; 350: 1005 \200\22312). 170 CHAPTER 21 Chronic obstructive pulmonary disease Non-pharmacological management of stable COPD Aims of COPD management should include: \200 \200 \200 \200 Ensuring the diagnosis is correct Stopping smoking Optimizing treatment by minimizing sympt oms where possible Helping the patient maintain their quality of life. Management should be delivered by a multi-disciplinary team. No treatment has yet been show n to modify disease progression in the long term, except for stopping smoking. Smoking cess ation is the only intervention that is proven to decrease the smoking-related decline in lu ng function. All patients with COPD who smoke should be encouraged to stop at every opportu nity. Figure 21.1 shows the accelerated decline in FEV1 in susceptible smokers and the dela y in this acceleration from stopping smoking; susceptible smokers, however, never regain th e original curve. Nicotine replacement therapy should be used to aid smoking cessation (see p 730). Never smoked or not susceptible to smoke 100 ) 5 2 75 e g a t a Smoked regularly and susceptible to its effects e u l a v Stopped at 45 50 f o % ( Disability 25 1 V E F Stopped at 65 Death 0 25 50 75 Age (years) Fig. 21.1. Modi \201 cation of the Fletcher \200\223Peto diagram of FEV1 decline in suscep tible smokers Education can improve ability to manage illness and stop smoking. Pulmonary rehabilitation is a multidisciplinary program, with RCT evidence that it improves exercise tolerance, qual ity of life, 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 inde pendent predictor of mortality and disability, independent of the severity of the underlyin g lung disease and may re \202 ect the systemic nature of COPD. The mainstay of rehabilita tion is graded exercise to improve muscle function, but also includes breathing techniques and education. NON-PHARMACOLOGICAL MANAGEMENT OF STABLE COPD 171 Programs vary, but are usually run on an out-patient basis over several weeks, with multidi sciplinary involvement (see p 723). Should be made available to all appropriate patients wi th COPD. Diet Weight loss is recommended if the patient is obese, to minimize respiratory e ffort. If the patient is very breathless, calori \201 c intake may be low and a catabolic state may exist. A low BMI is associated with impaired pulmonary status, decreased diaphrag m mass, lower exercise capacity and increased mortality rate compared with people with a no rmal BMI. Nutritional supplementation may therefore be necessary. Maintaining body weight a nd muscle mass correlates well with survival. Psychosocial support Practical support at hom e, day centers; car dis- ability badge; assess for signs of anxiety and depression. 172 CHAPTER 21 Chronic obstructive pulmonary disease Pharmacological management of stable COPD Pharmacological management aims to relieve sympto ms and reduce exac- erbations, but will not modify disease. Increase treatment in a stepwis e fashion. Exacerbations require additional therapeutic support (see p 176). Bronchodilator s Simple pulmonary function testing may not show sig- ni \201 cant bronchodilator reversib ility of FEV1, but bronchodilators provide therapeutic bene \201 t in the long term by red ucing dyspnoea, perhaps by decreasing chest hyperin \202 ation. \200 \200 Initially prescribe short-acting 2-agonists as required for symptom relief If the patient remains symptomatic, prescribe short-acting 2-agonist with short acting anti-cholinergic If symptoms persists, try therapeutic trial of regular long-acting bron- chodilator, with or without an anti-cholinergic. Stop if no bene \201 t (expensive). Continue if the patien t has 2 or more exacerbations per year, as there is evidence for a reduction in exacerbatio n frequency and hence decreased health resource utilization Oral methylxanthines, such as t heophyllines, can be used as a main- tenance therapy and may improve symptoms. Add after in haled bron- chodilators and trial of inhaled steroids; continue only if symptoms improve. T heir method of action is unclear, but they may have an anti-in \202 ammatory effect. Take care regarding therapeutic/toxic levels, especially in elderly patients Inhaler therapy pro vides adequate bronchodilator doses for most patients, especially when used with a spacer d evice. It is important to check the patient \200\231s inhaler technique Nebulizer therapy i s 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, wit h reduction in symptoms or improvement in activities of daily living, should continue with long-term domiciliary nebulized treatment (usually with salb- utamol and ipratropium), as t here is a signi \201 cant placebo effect. Inhaled steroids should be prescribed to all patients with an FEV1 \211 60% predicted, who have had 2 or more exacerbations per year requiring treat- ment with antibiotics or oral s teroids. Clinical trials of inhaled steroids have shown a reduction in exacerbation frequen cy and severity in severe COPD, but no slowing in the decline in lung function. Warn patien ts regarding steroid side-effects and document. Use in combination with bronchodilator. Ora l steroids are not recommended as a maintenance therapy in COPD. It may, however, be dif \201 cult to withdraw them in patients with severe COPD following an exacerbation. If so, k eep the dose as low as possible and prescribe osteoporosis prophylaxis if indicated. Warn r egarding steroid side-effects and document. Oxygen can be administered via a cylinder for s hort burst oxygen therapy as required for symptomatic relief, such as after climbing stairs (there is PHARMACOLOGICAL MANAGEMENT OF STABLE COPD 173 little trial evidence to support this use \200\224only continue if improvement in breathles sness documented), or as long-term oxygen therapy (LTOT) via an oxygen concentrator. The la tter is for patients in respiratory failure, with a PaO2 <7.3 kPa or PaO2 of 7.3 \200\2238 kPa with any of secondary poly- cythaemia, peripheral oedema, or pulmonary hypertension pre sent, to use for a minimum of 15 h per day (including sleep). Additional ambulatory cylinde rs can be provided. Low \202 ow oxygen, such as 2 \200\2234 L/min via nasal prongs, is us ually adequate. Small changes in CO2 retention with oxygen administration can be tolerated if asymptomatic and no respiratory acidosis. Associated OSA is a risk factor for CO2 retent ion. (For further informa- tion on prescribing oxygen, see p 703.) Vaccination In \202 uen za vaccine annually and pneumococcal vaccine. Meta-analysis showed a decrease in exacerbati ons occurs 3 weeks after receiving in \202 uenza vaccine and there is no evidence of an ea rlier increase in exacerbations due directly to vaccination. Antibiotics No trials of antib iotic prophylaxis have been done. Many respiratory physicians prescribe low-dose rotating a ntibiotics, particularly over the winter. Trials are urgently required. It is likely that t his strategy would be more effective than inhaled steroids. Mucolytics (carbocisteine, mecy steine hydrochloride) may bene \201 t some patients with chronic productive cough to facil itate expectoration by reducing sputum viscosity. Prescribe for a 4-week trial period and o nly continue if there is evidence of improvement. Meta-analyzes show muco- lytics cause a s igni \201 cant decrease in the number of COPD exacerbations and decrease the number of day s of disability, although the bene \201 t may only apply if the patient is not taking inha led steroids. Worth trying in those with moderate to severe COPD, with frequent or prolonge d exac- erbations, or those repeatedly in hospital with COPD exacerbations. Caution if know n peptic ulcer disease. Palliative care/respiratory sedation Use of low-dose sedatives, suc h as morphine sulfate solution 10 mg as required or diazepam 2 mg bd, can be used as a pall iative measure (see pp 720 \200\22321), aiming to relieve the sensation of dyspnoea and ass ociated anxiety, in those with severe COPD. Dose may need to be titrated against any rise i n CO2 (surprisingly uncommon). New anti-in \202 ammatory drugs Erdosteine is a thiol compound with effects on bacterial a dhesiveness as well as anti-oxidant and mucoactive properties. RCT in moderate COPD showed decreased exacerbations vs. placebo over 8 months, no loss of lung function, and improved h ealth-related quality of life. Ro \202 umilast and cilomilast are phosphodiesterase 4 inhi bitors, which elicit anti-in \202 ammatory effects. RCT of ro \202 umilast in moderate to severe COPD showed a signi \201 cant improvement in FEV1 over 24 h vs. placebo and a redu ction in the rate of mild exacerbations. Long-term studies are required to evaluate its ef \201 cacy and role further. Cilomilast has shown similar results. 174 CHAPTER 21 Chronic obstructive pulmonary disease An approach to COPD in the out-patient clinic \200 \200 Establish diagnosis and severity \200\224pulmonary function tests, CXR Ensure there are no other causes for symptoms, e.g. anemia, pulmo- nary emboli, heart failure, interstitial lun g disease, thyroid dysfunction, pneumothorax, large bulla, arrhythmia, depression Encourage the patient to stop smoking Review current treatment \200\224optimize bronchodilatation an d inhaled steroids Assess whether there is any need for a nebulizer Check oxygen saturation and perform blood gas if <92%. Consider LTOT Consider pulmonary rehabilitation Check vacci nations are up to date Involve respiratory nurse specialist for input in the community if a ppropriate Follow up in clinic if ongoing medical issues, including whether patient may be a lung transplant candidate (see p 318). Otherwise discharge back to GP Inform GP of all th e above decisions. \200 \200 \200 \200 Further information Poole PJ et al. In \202 uenza vaccination for patients with COPD. Coch rane Database Syst Rev 2006; 1: CD002733 Poole PJ, Black PN. Mucolytic agents for chronic bronchitis or COPD. Cochrane Database Syst Rev 2006; 3: CD001287 Black P et al. Prophylactic antibiotic therapy for chronic bronchitis. Cochrane Database Sy st Rev 2003; 1: CD004105 PHARMACOLOGICAL MANAGEMENT OF STABLE COPD 175 How to perform a steroid trial to help distinguish asthma from COPD (if diagnosis unclear) Measure FEV1 and slow VC before and after: \200 \200 either a high-dose inhaled steroid for 6 \200\2238 weeks or a 2-week course of oral prednis olone, 30 mg/day >15% increase in FEV1 implies steroid reversibility and patient is likely to have asthma. > 15% increase in slow VC suggests signi \201 cantly reduced air trapping and may indicate s igni \201 cant asthma. May occur with a signi \201 cantly smaller change in FEV1. Documen t results of trial clearly in notes. Testing for bronchodilator reversibility to help distinguish asthma from COPD \200 Check FEV1. Give patient a short acting B2 agonist, either nebulized or inhaled via spacer. 15 \200\22330 min after this, recheck the FEV1. Subtract the pre-test value from the post- test value, divide the differ- ence by the pre-test value, and express as a percentage incr ease from baseline. >15% increase or >200 ml indicates bronchodilator reversibility Avoid s hort-acting bronchodilator in the preceding 6 h, a long-acting bronchodilator in the preced ing 12 h, or a long-acting anticholinergic or slow release theophylline in the preceding 24 h. 176 CHAPTER 21 Chronic obstructive pulmonary disease COPD exacerbations Exacerbations may cause mild symptoms in those with relatively preserved lung function, but can cause considerable morbidity in those with limited respiratory rese rve. It has been increasingly recognized that signi \201 cant numbers of patients do not r egain their premorbid lung function or quality of life following an exacerbation, and those with frequent exacerbations experience a more rapid FEV1 decline than those with fewer exa cerbations. Exacerbation frequency increases with COPD severity. Exacerbations are 50% more likely in winter (possibly viruses survive better in the cold and people crowd together in doors). An exacerbation is essentially a clinical diagnosis. Causes may be infective organi sms, either viral or bacterial, or non-infective causes, such as pollution or temperature f all. Common bacterial pathogens are Haemophilus in \202 uenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, and the commonest viral pathogens are rhinovirus, RSV, in \202 u- enza, coronavirus, and adenovirus. Consider the possibility of PE or pneu- mothorax. Sym ptoms include increased sputum volume and/or purulence, increasing dyspnoea or wheeze, ches t tightness, \202 uid retention. Pathophysiology There is increased airway resistance due to bron- chospasm, mucosal oedema, and increased sputum. This worsens expira- tory \202 ow limitation and expiration takes longer. Shallow rapid breathing further limits the time for expiration. This promotes dynamic hyperin \202 a- tion and this itself causes mechanic al compromise within the lung and the airway. Maximal recruitment of the accessory muscles is required and thoraco-abdominal dysynchrony is often present. COPD EXACERBATIONS 177 22 Management summary: acute exacerbation of COPD \200 Assess the severity of the exacerb ation by measuring respiratory rate, oxygen saturations, degree of air entry, tachycardia, BP, peripheral perfusion, conscious level, mental state Exclude a pneumothorax clinically I f hypoxic, give controlled 24 \200\22335% oxygen via Venturi facemask to aim for SaO2 88 \200\22392%, salbutamol nebulizer, establish venous access Check blood gas Request a CXR Pe rform ECG Check bloods for WCC, CRP, potassium, etc. Optimize volume status Take a brief hi story if possible. Important to know what patient \200\231s normal functional status is lik e, such as exercise tolerance and the need for help with activities of daily living. Old ho spital notes are helpful regarding severity of disease, and whether previous decisions have been made regarding ventilation or resuscitation Nebulized bronchodilators \200\224salbuta mol 2.5 \200\2235 mg and ipratropium 500 g on arrival and 4 \200\2236-hourly. Run nebuliz er with air not oxygen Continued oxygen therapy, aiming to maintain saturations between 80% and 90%. Repeat blood gasses after 60 min to ensure improvement if hypoxic or acidotic. Re peat if clinical deterioration Consider antibiotics Oral steroids Consider intravenous amin ophylline if not improving with nebulizers Consider intensive care \200\224ideally consulta nt-led decision with the patient, their family, and ITU regarding invasive mechanical venti lation. Document in the medical notes. Consider resuscitation status Consider non-invasive ventilation \200\224pH 7.3 or less, hypoxia, hypercapnia, conscious. Decide if this is the ceiling of therapy Consider doxapram if NIV not available or not tolerated DVT prophylaxis Early mobilization Nutrition. \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Further information Intermediate care Hospital-at-Home in COPD: BTS guideline. Thorax 2007; 62: 200-210 Ram FSF et al. Hospital at home for patients with acute exacerbations of COPD: systematic r eview of the evidence. BMJ 2004; 329: 315 \200\22318 Review series: COPD exacerbations. Thorax 2006; 61: 164 \200\2238, 250 \200\2238, 440 \200 \2237, 535 \200\22344, 354 \200\22361 178 CHAPTER 21 Chronic obstructive pulmonary disease Management of exacerbations \200 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 p neumothorax, PE, pulmonary oedema) Can the patient self-care and self-medicate? In the pres ence 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, a nd 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 associ ated with worsening airways obstruction. Check theophylline level if patient is taking regu larly; consider sending sputum for culture if it is purulent. Treatment \200 \200 Antibiotics if sputum purulent, pyrexial, high CRP, new changes on CXR Systemic steroids fo r all patients with exacerbations of COPD who are admitted to hospital or are signi \201 c antly more breathless than usual. Give prednisolone 30 mg/day for 1 to 2 weeks, unless ther e are speci \201 c contraindications. Optimum dose and length of steroids not established. This improves FEV1, improves symptoms, and shortens recovery time. Long-term steroid treat ment should be avoided 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 slo wly Inhaled or nebulized bronchodilators Breathless unwell patients may bene \201 t from n ebulizer therapy in the acute period to reduce symptoms and improve air \202 ow obstructio n Controlled oxygen therapy 24 \200\22335% via Venturi facemask, with oximetry, arterial bl ood gasses, or capillary gas monitoring. Guidelines suggest maintaining saturations between 88% and 92%, balancing hypoxia, hypercapnia, and pH. Too little oxygen causes anaerobic me tabolism and metabolic acidosis (probably SaO2 >80% would prevent this); too much oxygen (S aO2 >92%) can cause hypercapnia and a respiratory aci- dosis. 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 necessar y. Falling conscious level is the best clinical marker of signi \201 cant CO2 retention an d acidosis Intravenous aminophylline Evidence is lacking regarding the effective- ness of I V aminophylline, but it may be bene \201 cial, particularly if the patient is wheezy and h as not improved with nebulizers alone. Give a loading dose, unless the patient is on regula r oral aminophylline, followed by a maintenance infusion. Need to monitor aminophylline lev els daily. Main side-effects are tachycardia and nausea. MANAGEMENT OF EXACERBATIONS 179 Non-invasive ventilation (NIV) Effective in supporting patients during an exacerbation, whe n 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 intuba tion. Ceiling of treatment should be determined before its use (See p 693.). Doxapram Intra venous respiratory stimulant. Can be used to drive respiratory rate (if below 20 /min) and depth in COPD exacerbation and hence improve hypoxia, hypercapnia, and respiratory acidosis , par- ticularly when induced by oxygen 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 \200\2233 mg/min) in the short term (usually 24 \200\22336 h), 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 i s not available or not tolerated. Acetazolamide generates a metabolic acidosis by reducing the kidney \200\231s ability to secrete [H+] into urine (blocks carbonic anhydrase that int er- \200\223). There is only one situation in which converts CO2 and H+/HCO3 provoking a m etabolic acidosis might be appropriate: following a tran- sient period of hypoventilation ( perhaps due to pump failure/increased airways obstruction) or after permissive hypercapnia on the ICU, the \200\223] can now previous appropriate compensatory rise in blood [HCO3 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 (250 mg OD), but only safe when the pH is alkaline, can ha sten the recovery. Intubation/intensive care If the patient is not responding to medical th erapy, a decision regarding invasive mechanical ventilation needs to be made. This may be c onsidered to be appropriate if the patient usually has a good functional status, with minim al other comorbidity. These decisions should ideally be discussed with the patient, their f amily, their consultant, and the ITU consultant, and documented in the medical notes. Resus citation decisions should also be made. Early rehabilitation to prevent muscle wasting and deconditioning Nutrition Acute respiratory assessment service (ARAS)/ \200\230Hospital at h ome \200\231 Respiratory nurse-led service supporting early discharge of COPD patients afte r hospital assessment and providing ongoing respiratory care at home. CXR, SaO2, and baseli ne spirometry (if this is \201 rst presentation) should be performed prior to discharge. Reduces length of in-patient stay and hence is an economic alternative. Unsuitable patients are those with impaired GCS, acute confusion, pH<7.35, acute changes on CXR, concomitant m edical problems requiring in-patient stay, insuf \201 cient social support (including livi ng far from the hospital and not having a telephone), new hypoxia with SaO2 <90%, and unabl e to provide oxygen at home. \200 \200 180 CHAPTER 21 Chronic obstructive pulmonary disease Surgical treatment Lung transplant In young patients (below 60 \200\22365) with severe dise ase, often due to 1-antitrypsin de \201 ciency, single lung transplant may be an option. Local transplant teams will advise regarding local criteria. Bullectomy Suitable for selec ted patients who are breathless, have FEV1 <50% predicted, and isolated large bulla seen on CT. Improves chest hyperin \202 ation. Lung volume reduction surgery (LVRS) Resection of areas of bullous emphysema to reduce chest hyperin \202 ation and improve diaphrag- matic function, elastic recoil, physiology of the lungs, and hence functional status of the patie nt. Patients who may be considered are those with FEV1 20 \200\22330% predicted, with sympt omatic dyspnoea despite maximal medical therapy, and with upper lobe predominant emphysema on CT, giving target areas to resect. PaCO2 should be less than 7.3 kPa and TLCO >20% predi cted. Pre-operative assessment: PFTs, 6 min walk test, quality of life, and dyspnoea indica tors. Surgery is performed in specialist centers via median sternotomy or by thoracoscopy. Usually the upper lobe is stapled below the level of the emphysema and then removed. Improv ements are seen in FEV1 and RV, dyspnoea, and quality of life scores. These effects are max imal between 2 and 6 months post-surgery. Symptomatic improve- ment is sustained for about 2 \200\2234 years. Post-operative complications: per- sistent air leak >7 days in 30 \200 \22340%, pneumonia in up to 22%, respiratory failure in up to 13%. Post-operative mortality 2.4 \200\22317% reported. The National Emphysema Treatment Trial (Michigan, USA) randomized 1218 patients to receive medical treatment or LVRS. Mean air \202 ow limita- tion of the subjects was 27% predicted . The most recent analysis, pub- lished after 4 years of follow-up, has shown LVRS demonstr ates an overall survival advantage compared with medical therapy alone. Improvements in max imal exercise and health-related quality of life were also found over 3 and 4 years, respec tively. The greatest survival bene \201 ts, improved exercise and symptoms over 5 years, w ere in those with both low exer- cise capacity and upper-lobe-predominant emphysema. Those with high exercise capacity and upper-lobe-predominant emphysema obtained no survival advan tage, but exercise and health-related quality of life improved. Interim analysis had shown increased mortality from LVRS for patients with FEV1 or TLCO <20% predicted, or with homoge neous emphysema. Surgery is not, therefore, recommended for these groups. Bronchoscopic lun g volume reduction is under evaluation, with one-way valve implants placed within the segme ntal and sub-segmental bronchi that supply the hyperin \202 ated lobes. It is a minimally invasive variation on lung volume reduction surgery, with the aim of improving lung functio n and quality of life. 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. Signi \201 cant improvements in RV, FEV1 , FVC and 6 min walk were found at 30 and 90 days. A multi-center RCT (the VENT trial) has been completed of best medical care (including pulmonary rehabilitation) vs. SURGICAL TREATMENT 181 best medical care plus unilateral endoscopic bronchial valve. Early presented results (ERS 2007) of 321 patients after 6 months of follow up (220 in the valve group) showed a signi \201 cant improvement in FEV1 and 6 min walk test in the valve group. Knowledge and skill i s improving in this area and further studies are planned. Airway bypass aims to improve respiratory mechanics by creating new exit pathways for air t rapped in emphysematous lungs. The wall of a segmental bronchus is punctured under bronchos copic guidance and a stent is inserted, creating an internal bronchopulmonary communication for expi- ration. Hence, hyperin \202 ation decreases and lung mechanics are improved. Th is is at an early stage of research. Further information Naunheim KS et al. Long term follow-up of patients receiving LVRS vs. m edical therapy for severe emphysema by the NETT research group. Ann Thoracic Surg 2006; 82: 431 \200\22343 Fishman A et al. A randomized trial comparing lung-volume-reduction surgery with medical th erapy for severe emphysema. N Engl J Med 2003; 22: 2059 \200\22373. Criner GJ et al. Prospective randomized trial comparing bilateral LVRS to pulmonary rehabil itation in severe COPD. Am Resp Crit Care Med 1999; 160: 2018 \200\22327 Geddes D et al. Effect of LVRS in patients with severe emphysema. NEJM 2000; 343: 239 \200 \22345 Toma TP et al. Bronchoscopic volume reduction with valve implants in patients with severe e mphysema. Lancet 2003; 361: 931 \200\2233 Benditt JO. Surgical therapies for COPD. Respir Care 2004; 49: 53 \200\22363 182 CHAPTER 21 Chronic obstructive pulmonary disease a1-antitrypsin (a1-AT) de \201 ciency This is an inherited condition that is associated wi th the early development of emphysema. It is common (estimated 1 in 2000 \200\2235000 indiv iduals) and is probably under-diagnosed, as it is often asymptomatic in non-smokers. Pathop hysiology A1-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 macro- phages in response to smoking and lung infections. If A1-AT is de \201 cient, t he elastase cannot be opposed, and subsequently basal emphysema develops. The disease is wo rse in smokers and can cause COPD at a young age (40s and 50s). There may also be associate d liver dysfunction, chronic hep- atitis, cirrhosis, and hepatoma, as abnormal protein secr etion accumulates in the liver. Predisposition also to skin disease (panniculitis) and vasc ulitis (especially ANCA +). Genetics A1-AT de \201 ciency is inherited as an autosomal co- dominant dis- order. So far more than 100 different alleles have been identi \201 ed for t his gene (SERPINA 1) on the long arm of chromosome 14. The commonest alleles are the M alle le (normal), the partially defective S allele, and the almost fully defective Z allele (lys ine is substituted for glutamic acid at position 342, leading to abnormal folding, preventi ng post-translational processing with retention within cells), commonest in Scandinavia. \200 \200 MM, the normal phenotype. Background population risk of emphysema MS, MZ have 50 \200\22370 % of normal A1-protease inhibitor (Pi) levels. Back- ground risk of emphysema SZ, SS have 3 5 \200\22350% of normal levels. 20 \200\22350% risk of emphysema Homozygous ZZ has only 10 \200\22320% of normal levels. 80 \200\223100% risk of emphysema \200 Screening for the defect should be carried out especially in patients <40 with COPD. Also p atients with unexplained liver disease should be screened. Send blood for A1-AT concentrati ons and genotyping if levels are low. Siblings should be screened and the particular import ance of not smoking and avoiding passive smoking emphasized. Non-smokers are usually asympt omatic. Treatment includes usual therapy for COPD. Speci \201 c treatment is known as augm entation therapy, with weekly/2-weekly/monthly infusions of puri \201 ed A1-AT from pooled human plasma. This raises concentrations in serum and epithelial-lining \202 uid above t he protective threshold. It appears to be safe, with minimal side-effects. A large cohort s tudy showed reduced mortality amongst infusion recipients, with a slowing of lung function decline (by 27 ml/year, p = 0.03) in a subgroup with moderate emphysema. An RCT showed no s igni \201 cant differences between augmentation and control groups, although there was a t rend 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 ATS and ERS A1-ANTITRYPSIN DEFICIENCY 183 for those with moderate (FEV1 35 \200\22360% predicted) emphysema due to A1-AT de \201 cie ncy, but not those with mild or severe disease or those post lung transplant for A1-AT de \201 ciency, except during episodes of acute rejection and infection (when in \202 ammatio n causes free elastase activity). It is expensive and its cost-effectiveness in terms of co st per year of life saved is high. It is, however, the only speci \201 c therapy available at present. Future developments Inhaled A1-AT may provide a way of delivering the enzyme t o the lower respiratory tract to have its action locally and potentially reduce in \202 am mation. Gene therapy is under development, \201 nding ways of delivering the A1-AT gene i nto the cell. Other strategies include inhi- bition of hepatic polymerization of A1-AT, pro motion of hepatic secretion, inhibition of neutrophil elastase by synthetic inhibitors to a void the use of human plasma, and pegylation of A1-AT to prolong its serum half-life. Further information ADAPT program (Antitrypsin de \201 ciency Assessment and Program for T reatment) www. aatregistry.org/ukusa.html headed by Prof R Stockley, Queen Elizabeth Hospit al Birmingham. Aims to have a comprehensive database of all patients with 1-antitrypsin d e \201 ciency in the UK, as well as offering assessment and treatment in a single UK cente r. Stoller JK, Aboussouan LS. 1-antitrypsin de \201 ciency. Lancet 2005; 365: 2225 \200\223 36 Review series: 1-antitrypsin de \201 ciency. Thorax 2004: 59: 64 \200\2239, 259 \200\223 64, 441 \200\2235,529 \200\22335, 708 \200\22312, 904 \200\2239 UK alpha1 antitrypsin de \201 ciency support group www.alpha1.org.uk/index.html This page intentionally left blank 185 Chapter 22 Connective tissue disease and the lung Differential diagnosis and standard tests 186 Rheumatoid arthritis (RA) 188 Systemic lupus erythematosus (SLE) 190 Polymyositis and dermatomyositis 192 Systemic sclerosis 194 Sj gre n \200\231s syndrome 196 Ankylosing spondylitis 197 Beh et \200\231s syndrome 198 186 CHAPTER 22 Connective tissue disease and the lung Differential diagnosis and standard tests Patients with connective tissue diseases can deve lop pulmonary compli- cations, for which they might be referred to a chest physician. Patie nts typically present with symptoms of dyspnoea, cough, fever, or chest pain. They may ofte n be on immunosuppressive drugs. Differential diagnosis In practice, the main differential diagnosis lies between: Opportunistic pulmonary infection \200 May be in those on immunosuppressive drugs, or functionally immuno- suppressed from underly ing disease Any usual organism, also TB, non-tuberculous mycobacteria, PCP, fungi, cytomega lovirus Often acute onset with non-speci \201 c features of low-grade fever, productive co ugh, raised in \202 ammatory markers Can be very unwell and need full supportive treatment with ITU. Original connective tissue disease now affecting the lung \200 \200 Often in \202 ammation or \201 brosis Usually more indolent presentation, with dry cough and dyspnoea, but can become acutely unwell with background of chronic lung disease Fine i nspiratory crackles on auscultation Consider development of pulmonary hypertension in patie nts with systemic sclerosis. \200 New pulmonary pathology \200 Unrelated to the original condition, including pulmonary thromboembolic disease. Drug side-effects \200 