may help in monitoring the response to therapy. 12-lead ECG. \200 CXR. This should be no different from a radiograph when the patient is stable, but may show features of underlying COPD such as hyper-expansion and pulmo- nary ar tery enlargement. The major reason to perform the radiograph is to exclude alternative caus es of dysp- noea in a patient with underlying COPD. General management principles 1. Make the diagnosis. Exacerbation of COPD is a clinical dia gnosis of exclusion \200\223 there is no diagnostic test. It is important to consider, and where appropriate exclude other possible causes of breathlessness in a patient with underl ying COPD, for example pneumonia, pulmonary embolus, pneumothorax and cardiac failure. ABG. The following tests are generally unhelpful: \200 Sputum culture, as the presence of bacteria in sputum does not imply causation. Many patients have the same species of bacter ia in sputum even when clinically stable, a phenomenon called \200\230bacterial coloni- sa tion \200\231. The most common isolates are Haemophilus influenzae, treptococcus pneumoniae and Moraxella catarrhalis 2. Assess severity. Whilst there is no uniformly accepted method of assessing exacerbation severity, clinical assess- ment is important to judge the intensity of the treatment requir ed, and the need for hospital care. In general, the presence of new onset respiratory failu re, the need for treatment unavailable in the community, multiple co-morbidities or the abs ence of adequate social sup- port all indicate the need for specialist assessment and possi ble hospital admission. LFTs including serial peak-expiratory \202 ow measure- ments, as the changes in individua l patients are small, and the tests are dif \201 cult to perform in patients who are acute ly dyspnoeic. Therapy Fig. 5.6.2 summarizes the disease-modifying, and supportive aspects of therapy at e xacerbation of COPD, described in further detail in later sections. It is important to emph asize the need for prompt therapy: this reduces exacerbation length which is one measure of exacerbation severity. 3. Institute treatment. Therapy is administered step-wise, described further below, and fol lowing the basic principles illustrated in Fig. 5.6.1 that includes disease-modifying treat ments, interventions designed to support respiratory function until such disease-modifying treatments have had time to act, assessment and treatment of co-morbidities, and the instit ution of appropriate preventative strategies to reduce the risk of further exacerbation. Supportive therapy Increasing severity Increase dose/frequency of bronchodilators Controlled oxygen Disease- modifying therapies Attention to co-morbidities Supportive therapies Add systematic corticosteroids Prophylactic anticoagulation Fluid balance Management principles at an exacerbation of COPD Add antibiotics (if a change in the character of sputum) Non-invasive ventilation Invasive ventilation Consider adding additional therapies, e.g. theophyllines Palliative interventions Assess need for preventative therapies Disease-modifying therapy Management co-morbidities Fig. 5.6.2 Disease-modifying and supportive aspects of therapy Fig. 5.6.1 Basic principles of therapy Disease-modifying therapy Bronchodilators \200 Some exacerbations will respond to an incr eased use of bronchodilators alone, including B2-agonists and anti-cholinergic drugs, and t his forms the basis of therapy in all exacerbations. These drugs target the additional Investigations The purpose of investigations at exacerbation of COPD is to provide addition al information in excluding other diagnoses, identifying co-morbidities and assessing exace rbation severity. CHAPTER 5.6 Management of an exacerbation of COPD 113 An aminopenicillin, tetracycline or quinolone would be a reasonable empiric choice, though local resistance pat- terns should be considered. bronchoconstriction and hyperin \202 ation present at exac- erbation, which is presumed to result from increased airway in \202 ammation. Intravenous therapy is rarely required. \200 7 \200\22310 days of therapy is generally ad equate. Additional therapies \200 Methyxanthines, usually IV aminophylline, may be used i n patients not responding to the described measures, although evidence of bene \201 t from these drugs is generally absent. Theophyllines are said to have a variety of effects on th e respiratory, cardiovascular and immune systems which are of potential benefit during exac erbations. Against this, the narrow therapeutic index, side effects and drug interactions m ake administration dif \201 cult. Short-acting B2-agonists are preferred as they have a more rapid rate of action than short- acting anti-cholinergics. \200 Although most guidelines suggest the use of both classes o f drug together when the response to one or other is inadequate, there is in fact no eviden ce that this is supe- rior to B2-agonists alone. There is also no evidence that nebulisers are superior to administration via an inhaler and spacer. Nebulisation may be preferred in patients who are acutely dyspnoeic. The nebuliser driving gas should be prescribed, and is usually air with any additional oxygen administer ed separately. \200 Long-acting bronchodilator drugs have no role acutely, but patients p rescribed long-acting B2-agonists when stable would normally continue on such therapy. It i s not recommended that patients receive both long- and short- acting anti-cholinergics simu ltaneously but the bene \201 ts of one therapy over the other have not been reported. \200 There is no evidence supporting the use of intravenous The use of central respiratory stimulants has declined with the availability of non-invasiv e ventilation (NIV). Doxapram is still occasionally used as a holding measure prior to NIV, when NIV is inappropriate or unavailable, or (with specialist advice) in conjunction with NIV. There is currently no de \201 ned role for mucolytics at exacerbation of COPD. salbutamol at exacerbation of COPD. Sputum clearance techniques and nebulised saline are also not supported by available eviden ce and therefore not recommended routinely. Systemic corticosteroids \200 These drugs should be added in all exacerbations not respon ding to an increase in bronchodilators alone. The rationale is to attenuate the additional airway in \202 amma- tion that occurs during exacerbations, and which results in the sympt omatic and physiological deterioration. \200 The most robust evidence suggests that these drugs improve the rate of recovery of lung function, but effects on other outcome measures are more variable, and there is no evidence of a mortality bene \201 t. There is no strong data to support the use of leukot- riene receptor antagonists, intraveno us magnesium or Heliox (helium and oxygen) at exacerbation of COPD. Controlled oxygen Oxygen therapy is indicated in all exacerbations associated with respirat ory failure. This may be the result of a severe exacerbation in a patient with milder under lying disease, or be pre-existing in those with more advanced COPD. As a proportion of pati ents with COPD are at risk of developing hypercapnia with high- \202 ow oxygen, oxygen sho uld be administered at the minimum concentration able to maintain saturations at 90 \200 \22392%. Failure to achieve this without a rise in PaCO2 or fall in pH suggests the need fo r ventilatory support. Most guidelines recommend 30 \200\22340mg of prednisone for between 10 \200\22314 days, lon ger courses (and tapering the dose) are not of additional bene \201 t and are associ- ated with a greater chance of side-effects, especially hyperglycaemia. Nebulised budesonide appears equally effective to oral dosing but is more expensive. Inhaled corticosteroids have an important role in pre- venting exacerbations discussed belo w, and patients already prescribed these drugs would normally continue on this therapy duri ng an exacerbation, but there is no role for initiating inhaled corticosteroids in the acut e setting. AUTHOR \200\231S TIP Attention to co-morbidities: Co-morbidities are com- mon in COPD, and it is appropriate to consider and optimize co-existent medical conditions. Antibiotics \200 Pathogenic bacteria may be isolated in sputum from approximately 50% of patients with moderately-severe COPD at the time of exacerbation. Despite this, antibi- oti cs are of limited ef \201 cacy. This, in part, re \202 ects the presence of bacterial col onization as already described. More recently it has been suggested that exacerbations resu lt from change in the colonizing strain, though the situation is complex as not all strain changes are associ- ated with exacerbation, and not all exacerbations are associated with s train change. Prophylactic anticoagulation In the absence of contra-indications it is our practice to adm inister prophylaxis against venous thromboembolism in patients at exacerbation of COPD. Thi s in part re \202 ects the risk of such complications developing, but also the potentially serious consequences of pulmonary embolus in a patient with already impaired gas exchange. NIV \200 NIV refers to the provision of ventilatory support via a nasal or full-face mask and the patients own upper air- way, rather than an endotracheal tube. Respiratory viruses, particularly rhinoviruses, are also commonly isolated at the time of e xacerbation and this is a further reason why antibiotics are of limited bene \201 t. \200 Sputum purulence is a reliable indicator of the presence of bacteria, and in general anti biotics are only indicated if there has been a change in the sputum volume or purulence. Primarily by reducing the complications associated with invasive ventilation, NIV is associ ated with reduced mortality, hospital stay and health-care costs. It may also be used earli er, intermittently, outside an intensive-care J HURST & J WEDZICHA 114 Summary \200 Exacerbations are important events in COPD. \200 Exacerbation of COPD is a clinical diagnosis of exclusion. \200 The principles of exacerbation therapy consist of sup- porting gas exchange while disease-modifying therapies have time to act, addressing co -morbidities, and consid- ering appropriate interventions to reduce the likelihood of subse quent exacerbation. environment (with trained staff) and facilitates patient communication, nutrition and physi otherapy. NIV is usually administered as pressure-cycled bi-level positive airway pressure. Instigation of NIV should be made with a clear plan of progression to invasive ventilation or palliation in the event of treatment failure. Invasive ventilation Patients with exacerbations of COPD do not have worse outcomes followi ng invasive ventilation than those with respiratory failure from other causes. However, the deci- sion to institute invasive ventilation can de difficult and should consider the prio r functional status of the patient, the reversibility of the insult, the presence of co-mor bidities and the wishes of the patient and their family. An increase in the dose of short-acting bronchodilators with oral corticosteroids form the basis of therapy for most exacerbations, with antibiotics added when there is a change in t he character of the sputum. Oxygen is necessary for all patients in respiratory failure. \200 NIV has revolutionized the management of hypercapnic respiratory failure. There are a number of evidence-based strategies able to reduce the risk of further exacerba tion and hospitalisa- tion in COPD including drugs, vaccines and pulmonary rehabilitation. Palliative interventions For patients failing to improve on maximal therapy, or in whom esc alation of therapy is inappropriate, a range of palliative measures may be instituted inclu ding benzodiaz- epine and opiate drugs for relief of terminal dyspnoea. Further reading Wedzicha JA, Martinez F (eds). Chronic Obstructive Pulmonary Disease Exacer bations. Lung Biology in Health and Disease, 2008. London: Informa Healthcare. Preventative therapy Following an exacerbation it is important to consider the introduction of interventions that may reduce the likeli- hood of a subsequent exacerbation. Such appro aches to reduce the impact of exacerbations and hospitalisations in COPD are illustrated in Fig. 5.6.3. Not every treatment is appropriate for every patient. Pharmaco-prevention: inhaled corticosteroids, long acting 2- agonists, long acting anti-cholinergics, mucolyt ics, macrolide antibiotics Strategies to prevent or reduce the impact of COPD excerbations and hospitalisations Vaccination: Influenza, Pneumococcus Other interventions: pulmonary rehabilitation, long term oxygen therapy, domiciliary NIV Access to EARLY exacerbation therapy Fig. 5.6.3 Approaches to reduce the impact of exacerbations and hospitalizations. This page intentionally left blank P FROESCHLE 116 5.7 Surgery for COPD History Surgical treatment of emphysema was \201 rst contemplated in the early 20th centu ry. Costochondrectomies of the upper ribs in conjunction with transverse sternotomy as well as paravertebral thoracoplasty were performed until it was commonly accepted that the hype rin \202 ated chest was the result of emphysema rather than its cause. Abdom- inal belts, phrenic nerve paralysis and pneumoperitoneum were aimed at restoring the curvature of the \202 attened diapahragm. In 1954 in an attempt to treat the airway component of COPD, Niss en proposed tracheoplasty using prosthetic devices to support the membranous trachea. Each of these procedures was ultimately found to be ill-advised, and surgical morbidity outweigh ed by far their clinical bene \201 ts. Brantigan and colleagues at the University of Maryl and/Vir- ginia have to be credited with the introduction of basic principles of lung volume reduction surgery (LVRS) in 1957. They postulated that surgically reducing hyperin \202 a - tion of the emphysematous lung would restore radial traction on terminal bronchioles, imp rove respiratory air \202 ow obstruction and diaphragmatic movement. The modern concept of LVRS was introduced by J. Cooper in 1993, performing bilateral stapled wedge resections on patients with heterogeneous emphysema and evidence of hyperin \202 ation. In his early se ries of 20 patients the objec- tive improvement in FEV1 6 months after surgery was reported to be 82%. Between 1997 and 2002 the National Emphysema Treat- ment Trial (NETT) randomize d 1218 patients to undergo LVRS or continued medical care. The outcomes published in 2003 t ogether with the results of a number of case con- trolled series and smaller randomized tri als are best avail- able evidence for the choice of emphysema patients to be considered for surgery. Surgical management Treatment of bullous emphysema (giant bullous lung disease) Bullae are de \201 ned as air- \202 illed spaces within the lung parenchyma, lined by a \201 brous wall and trabeculated by remnants of alveolar septae. These air- \201 lled spaces can dev elop as a result of generalized emphysema or in the setting of a normal underlying parenchy ma. In 1989 Morgan introduced the concept of bullae representing areas of parenchymal weakn ess being ventilated preferentially, in disagreement with the check valve concept of bullae for- mation which had been adopted until then. Patient selection DeVries and Wolfe subdivided patients with bullous emphy- sema in four gr oups based on the anatomy of the bulla and the quality of the underlying parenchyma taking into account their surgical prognosis: \200 Group I: large single bulla/normal underlying lung. \200 Group II: multiple bullae/normal underlying lung. \200 Group III: multiple bullae/diffusely emphysematous underlying lung. Group IV: multiple bullae/underlying lung with other diseases. The principles of surgery in the context of bullous disease are based on the concept of re- expanding compressed normal lung parenchyma and restoring physiological chest wall excursio ns rather than focusing on the resection of areas of dead space ventilation. Good functiona l results are therefore more likely to be achieved in deVries Groups I and II, whereas the role of surgery in Groups III and IV remains controversial. Surgical indications Inclusion criteria (modi \201 ed Greenberg et al. criteria): \200 I ncapacitating dyspnoea related to single/multiple bulla/ ae (included in NICE guidelines for COPD). Bulla/ae occupying at least one-third of hemithorax. \200 Complications related to bulla/ ae (pneumothorax, infec- Pathophysiology The typical physiologic change of COPD is progressive expiratory air \202 ow limitation caused by chronic in \202 amma- tion. Following remodeling and obstruction o f the small airways a loss of alveolar attachment and decreased elastic recoil of the lung parenchyma sets in. A decrease in the FEV1 ratio to FVC is a \201 rst indicator of develo ping air \202 ow limitation. Small air \202 ow obstruction is revealed by severe reductio n in the forced expiratory \202 ow in the 25 \200\22375% range. The reduction in diffusio n capacity for carbon monoxide (DLCO) re \202 ects the degree of paren- chymal destruction . In advanced disease, hypoxemia is mainly caused by a com- bination of airway obstruction, parenchymal involvement and changes in the ventilation/perfusion (V/Q) ratio as a conseque nce of pulmonary vascular abnormalities. Severe V/Q mismatch, increased dead space ratio, a lveolar hypov- entilation and inspiratory muscle dysfunction potentially lead to exertional and/or resting hypercapnia. Radiographic signs of diaphragmatic \202 attening, increased retrosternal air space, and increased lucency of the lung \201 elds, go along with the p hysiologic changes mainly consist- ing of hyperin \202 ation. tion, haemoptysis, cancer). CT chest/V/Q scan con \201 rming deVries Groups I or II. \200 6MWT of >600 feet. Preoper ative preparation To include: \200 Pulmonary function testing (PFT), with gas transfer an d ABG analysis. CT chest. \200 V/Q scan. \200 Pulmonary rehabilitation (not mandatory). \200 Smoking cessation >6 months. \200 Maximal medical treatment of associated airway disease and nutritional de \201 cits. Surgical technique Three surgical techniques have emerged: \200 Video assisted thoracosco py (VATS) with stapled excision of bullous parenchyma. Advantages: minimal invasive access, rapid postoperative convalescence, good cosmetic result. Open bullectomy with excision of bullous parenchyma through (anterior) thoracotomy. Advanta ges: suitable for CHAPTER 5.7 Surgery for COPD 117 Preoperative preparation See Treatment of bullous emphysema, p. 116. In addition: \200 6M WT. \200 Completion of questionnaires assessing dyspnoea and patients not tolerating one-lung ventilation, technically less challenging procedure compar ed to VATS. Intracavitary drainage (modi \201 ed Monaldi procedure) adopting rib resection and direct drainage of bulla with Foley catheter. Advantages: suitable for high-risk patients not tole rating one-lung ventilation and/or excisional procedures, and for selected patients in deVr ies Groups III and IV. quality of life. Surgical technique The most common LVRS procedure is a bilateral stapled resection of emphy sematous lung parenchyma, perfor- med by \200 median sternotomy; \200 bilateral VATS or ; \200 unilateral staged VATS. The NETT trial has con \201 rmed that there is no signi \201 cant difference in the incidence of complications as well as outcome after LVRS by VAT S or median sternotomy. Unilateral staged VATS requires two anesthetics and creates an \200\230unbalanced mediastinum \200\231 during the interval between procedures, explaining why it is currently the least preferred of these three surgical approaches. Factors predicting outcome Better results are anticipated for: \200 Bulla/ae occupying >5 0% hemithorax with normal underlying lung. Younger patients with no comorbidity, no weight loss and rapidly progressing dyspnoea. \200 Normal and slightly decreased FVC. \200 FEV1 >40 % predicted. \200 Normal DLCO and ABG analysis. Results \200 Perioperative mortality ra nging from 0% to 8%. \200 Morbidity primarily related to prolonged air leaks. \200 Post operative clinical and symptomatic improvements Factors predicting outcome NETT (RCT) \201 ndings: \200 Upper lobe disease/low exercise capacity l improve- ment in survival, exercise tolerance, quality of life (com- pared to m edical group). may be better than re \202 ected by PFT results. LVRS LVRS provides an opportunity for palliation of symptoms and improvement of quality of life for patients with severe end-stage emphysema, and since 2005 its use is supported by N ICE. LVRS implies resection of target areas of emphysematous lung and aims at: \200 Impro ving V/Q matching by allowing compressed lung to Upper lobe disease/high exercise capacity l improve- ment in exercise tolerance and quality of life; no differ- ence in survival. Non-upper lobe disease/low exercise capacity l improvement in quality of life; no differenc e in survival and exercise tolerance re-expand. Non-upper lobe disease/high exercise capacity l higher Restoring outward traction on small airways. \200 Restoring physiological chest wall and inspiratory mus- risk of death. Overall exercise tolerance in 2 years after LVRS nearly back to base-line level, whilst pro gressive decline in medical group. cle excursions by reducing hyperin \202 ation. Natural history studies of emphysema have shown that 50% of patients with a FEV1 of <30% pr edicted will die within 3 \200\2234 years. The Kaplan \200\223Meier estimate of survival af ter LVRS at 5 years published by Cooper et al. in 2003 was 68%, with an in-hospital mortali ty of 4.8%. Negative prognostic factors: low FEV1 (<20%) in combi- nation with either DLCO <20% or homo geneous pattern of emphysema. Findings of Cooper et al. (prospective controlled consecu- tive case series): \200 Improv ement in FEV1, residual volume (RV), DLCO and quality of life sustained for 5 years in majo rity of patients when compared to preoperative values. Patient selection As in NICE guidelines for COPD: \200 Incapacitating dyspnoea due to sev ere COPD despite maximal medical therapy (incl. rehabilitation). Upper lobe predominant emphysema. \200 FEV1 >20% predicted. \200 DLCO >20% predicted. \200 PaCO2 <55 mm Hg The inclusion criteria published by Cooper et al. emphasize the impor tance of radiographic patient evaluation and in summary turn out to be less restrictive tha n the NICE guidelines: \200 Incapacitating dyspnoea despite rehabilitation. \200 Marked emphysema, airflow obstruction and hyper- Improvement in 6MWT and dyspnoea score maintained for 3 years. Negative prognostic factors: advanced age, male gender, low FEV1, reduced 6MWT, PaCO2 >50 m mHg, lower lobe disease. Results \200 Perioperative mortality ranging from 4 \200\2236%. \200 Prolonged air leak s most common complication (45%), with overall re-exploration rate of 4.5%. Cost-effectiveness (NETT): incremental cost per quality- adjusted life-years (QALY) gained with LVRS relative to medical therapy after 3 years of treatment 190,000 USD. \200 To tie this in with potential costs borne by the society: about 1% of estimated two million patie nts with emphy- sema in the US were potentially considered eligible for LVRS by Ramsey in 2 003, this being called a conservative estimate. in \202 ation. Heterogeneous distribution of emphysema with target zones of poorly perfused lung. DLCO <50% predicted and >10% predicted. \200 PaCO2 <60 mm Hg. \200 Essentially normal c ardiac ejection fraction with mean pulmonary artery (PA) pressure of <35 mmHg. P FROESCHLE 118 The other techniques mentioned are currently either trialed at animal level or as Phase I s tudies. Endoscopic lung volume reduction The concept of removing hypoventilated and non-fun ctional areas of lung and the favorable results of the NETT have led to the development of various bronchoscopic tech- niques to provide alternative means of achieving the results of LVRS. Concepts: \200 To promote atelectasis in emphysematous lung (using endobronchial valves, \201 brin-based glue or \201 brin-hydrogel and thrombin). Lung transplantation More than 8000 lung transplantations were performed worldwide between 1995 and 2001, and emphysema was the main indication for these procedures. Patient selection As in NICE guidelines for COPD: \200 Incapacitating dyspnoea due to sev ere COPD despite maximal medical therapy. Radiofrequency-induced fenestrations in segmental Considerations to include age, FEV1, PaCO2, homogene- ous distribution of emphysema, elevat ed PA pressure with progressive deterioration. bronchi to enhance expiratory air \202 ow. Wan et al. have recently published the results of a multicen- tre trial including 98 patien ts after insertion of a silicone- based one-way endobronchial valve (Fig. 5.7.1). They repo rt improvements in FEV1, FVC, RV and exercise tolerance at follow-ups 90 days after the pro cedure. 8% of their patients had serious perioperative complications. The Endobronchial Val ve for Emphysema Palliation Trial (VENT) is ongoing in the US. Further reading Brantigan O, Mueller E, Kress M. A surgical approach to pulmonary emphysema. Am Rev Respir Dis 1959; 80: 194 \200\223202. Ciccone AM, Myers BF, Guthrie TJ, et al. Long-term outcome of bilateral lung volume reducti on in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg 2003; 125: 513 \200 \223125. Cooper JD, Trulock EP, Trianta \201 llou AN, et al. Bilateral pneumonec- tomy (volume redu ction) for chronic obstructive pulmonary dis- ease. J Thorac Cardiovasc Surg 1995; 109: 106 \200\223119. Greenberg JA, Singhal S, Kaiser L. Giant bullous lung disease: evalu- ation, selection, tec hniqes and outcomes. Chest Surg Clin N Am 2003; 13: 631 \200\223649. Max \201 eld RA. New and emerging minimally invasive techniques for lung volume reduction. Chest 2004; 125: 777 \200\223783. National Emphysema Treatment Trial Research Group. A rand- omized trial comparing lung-volu me-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348: 205 9 \200\2232073. National Institute for Clinical Excellence. Chronic Obstructive Pulmonary Disease; NICE Clinical Guideline 2004; 12. Ramsey SD. Cost effectiveness of lung volume reduction surgery. Chest Surg Clin N Am 2003; 13: 727 \200\223738. Wan IY, Torna TP, Geddes DM, et al. Bronchoscopic lung-volume- reduction for end-stage emph ysema. Chest 2006; 129: 518 \200\223526. Fig. 5.7.1 The Emphasys Medical endobronchial valve. This page intentionally left blank U EKEOWA & D LOMAS 120 5.8 Alpha-1-antitrypsin de \201 ciency Oxidants in cigarette smoke can inactivate AAT as an The most important genetic factor in the development of COPD is A1-antitrypsin (AAT) de \201 ciency. It is found in 1 \200\2232% of affected individuals. AAT is an acute phase gly coprotein that is synthesized in the liver and secreted into the plasma where it is the mos t abundant circulating protease inhibitor. Its primary role is to inhibit neutrophil elasta se. Severe AAT de \201 ciency (de \201 ned as a plasma level <0.5g/l) is an autosomal co- dominant condition that results from point mutations in the AAT gene. inhibitor of neutrophil elastase. PI*Z individuals have marked variability in the severity of COPD suggesting that factors ot her than smoking are important in the development and progression of air \202 ow obstructi on. The PI*MZ phenotype is associated with vari- ably increased risk of lung disease in smo kers. Clinical features Symptomatic COPD usually presents between 30 \200\22340 years of age in s mokers and is rare before the third decade. The symptoms are similar to those of non-AAT de ficient COPD and may include: \200 Episodic wheeze and dyspnoea suggestive of asthma. The prevalence of asthmatic features is higher in severe AAT de \201 ciency and symptoms occu r early in the devel- opment of airway disease. Molecular epidemiology The Z variant (Glu342Lys) accounts for 95% of cases of severe AAT de \201 ciency. Homozygotes (PI*Z) have plasma AAT levels that are 10 \200\22315% of those s een in individuals with normal M alleles (PI*M). Approximately 4% of North- ern Europeans a re heterozygous for the Z allele (PI*MZ) with 1 in 1600 \200\2232000 being homozygotes. Oth er rare vari- ants of AAT that are associated with severe plasma de \201 - ciency are AAT Siiyama (Ser53Phe) in Japan, AAT Mmalton (del 52Phe) in Sardinia and the rare Null variants that have no detectable AAT in the plasma. The S allele (Glu264Val; PI*MS) is found in 28% of southern Europeans but is infre- quently associated with clinical disease as plasma lev els in homozygotes are 60% of normal. Allergic rhinitis which may precede airway obstruction. \200 Fatigue. No one physical sig n is speci \201 c for detecting the AAT- de \201 cient individual. Exacerbations occur mo re frequently in individuals with chronic bronchitis and more severe dis- ease and are asso ciated with a greater degree of in \202 amma- tion than in those with COPD without AAT-de \201 ciency. There is little evidence that airway hyper-responsiveness is more prevalent i n this group Pathophysiology of COPD Cigarette smoking is the most important environmental factor for ac celerated decline in lung function in individuals with AAT de \201 ciency. Several pathway s are recognized to predispose to early onset panlobular emphysema in the Z AAT homozygote (Fig. 5.8.1). \200 The retention of AAT within hepatocytes reduces the AAT that is availa ble to protect the lungs from uncon- trolled proteolytic digestion by neutrophil elastase. AUTHOR \200\231S TIP The presence of bronchiectasis in AAT-de \201 cient individ- uals is well recognized but remains controversial. It may be a consequence of emphysema in PI*Z pat ients rather than a primary effect. The AAT phenotype distribution and gene frequencies are not different between patients with bronchiectasis and control subjects. The Z AAT that enters the lung is 5-fold less effective at inhibiting neutrophil elastase t han is normal M AAT. \200 Monomeric Z AAT spontaneously forms polymers within the alveoli thereby inactivating AAT as a protein- ase inhibitor. Extra pulmonary manifestations \200 Liver disease \200\223 the Z mutation allows one AAT molecule to lock into a second which then extends to form chains of pathogenic loop-sheet polymers (Fig. 5.8.2a and 5.8.2b). These accumulate within the endoplasmic reticu- lum of h epatocytes as PAS positive inclusions (Fig. 5.8.2c) that are associated with neonatal hepat itis, cirrhosis and hepatocellular carcinoma. Z AAT de \201 ciency is the most common gene tic indication for liver transplantation in childhood. Only a subpopulation of AAT-de \201 cient indi- viduals develop signi \201 cant liver injury and these appear to have inef \201 cient intracellular degradation mechanisms for the removal of retained Z AAT protein. Polymeric Z AAT is chemotactic for human neutrophils. This proin \202 ammatory effect of p olymers may explain the progression of lung disease and airway obstruction after smoking ce ssation in PI*Z individuals. Zantitrypsin Panniculitis that is characterized by painful red nodules on the thighs or buttocks. It res ults from uncontrolled proteolysis within the skin. Oxidation Polymerisation Plasma deficiency Reduced inhibitory activity ANCA positive systemic vasculitis and Wegener \200\231s granu- lomatosis are rare complications. Nephropathy with membranoproliferative glomerulone- phritis especially in children and youn g adults. This may be a consequence of the associated liver disease. Inactivation Pro-inflammatory Investigations PI*Z AAT de \201 ciency is suspected where plasma AAT levels are abnormally low (< 0.5g/l) in individuals with associated diseases. The diagnosis is con \201 rmed by identifying abnor- mal AAT phenotypes by isoelectric focusing. Genotyping offers diagnosis at the molecular level. EMPHYSEMA Fig. 5.8.1 Mechanisms for the pathogenesis of emphysema. CHAPTER 5.8 Alpha-1-antitrypsin de \201 ciency 121 (a) Fig. 5.8.2a Mutants of AAT (left) cause the protein to link together as dimers (middle) tha t extend to form chains of polymers that are retained within hepatocytes. Fig. 5.8.3 Emphysema with basal radiolucency. Lung function tests \200 Spirometry, static lung volumes, ABG analysis and gas transfer s hould be measured at baseline and generally mirror abnormalities seen in \200\230usual \200\231 COPD except in being out of proportion to the smoking history. \200 FEV1 is the most important predictor of survival. \200 There is a wide variation in bronchodilator re sponse which may explain why some cases of AAT-de \201 cient COPD are diagnosed as asthma. (b) Fig. 5.8.2b Polymers of Z AAT that are retained within hepatocytes. Some individuals have discordant physiology with marked emphysema and little airway disease or vise versa for reasons that remain unclear. Natural history Liver dysfunction represents the major clinical problem before the third de cade while lung function is preserved. Lung dysfunction begins thereafter. A more rapid rat e of FEV1 decline is associated with: \200 male sex; \200 age between 30 to 44 years; \200 current smoking; \200 FEV1 between 35 \200\22360% predicted; \200 bronchodilator response (asthmatic features); \200 chronic bronchitis; \200 previous episodes of pneum onia. Severe AAT de \201 ciency is associated with shortened life expectancy and survival falls exponentially as FEV1 declines to <35% predicted. Median life expectancy for smokers is between 40 \200\22349 years and 65 \200\22369 years for never smokers. Emphysema and cir rhosis are the most common causes of death (72% and 10% respectively) and account for the e xcess mortality. (c) Fig. 5.8.2c The accumalation of Z AAT causes cirhosis (left) and cherry red PAS positive in clusions (right). Radiology \200 The CXR is normal in early disease. Hyperin \202 ation, dia- phragmatic \202 attening and increased lower lung radiolu- cency may be evident in advanced disease ( Fig. 5.8.3). \200 HRCT is more sensitive for detecting emphysema in AAT de \201 ciency. It allows assessment of the severity of associated bullous disease and bronchiectasis. AUTHOR \200\231S TIP Cirrhosis in adults is more commonly the underlying cause of death in non smokers which is consistent with cirrhosis affecting survivors over the age of 50 years . U EKEOWA & D LOMAS 122 Management and treatment Preventing the development of COPD is solely depend- ent on early smoking cessation and limiting exposure to environmental pollutants. The prevalence of smok ing in PI*Z adolescents who are aware of their diagnosis is half that of age-matched peers. Guidelines for treatment of \200\230usual \200\231 COPD are applicable to individuals wit h AAT-de \201 cient lung disease including bron- chodilators, oxygen, pulmonary rehabilita tion, nutritional advice, in \202 uenza vaccinations and surgery (bullectomy and transplan tation). Lung volume reduction surgery offers only short-term bene \201 ts in AAT de \201 ciency emphysema and is generally not recommended. Liver transplantation remains the only treatment for liver cirrhosis. treatment until FEV1<35% when the costs of other general COPD treatments are included. Aero solised delivery of recombinant AAT has been devel- oped for daily administration but is of unproven ef \201 cacy. Novel strategies Novel therapeutic approaches include strategies using: \200 All-trans re tinoic acid to initiate the growth of new alveoli in emphysematous lungs. Rat studies have demonstrated encouraging results and human trials are ongoing. Identifying small molecules capable of preventing the polymerisation of AAT within hepatocy tes or rescuing misfolded AAT protein (chaperone therapy). Adeno-associated viral vectors to deliver and express Augmentation therapy The IV administration of pooled plasma puri \201 ed AAT has been the mainstay of treatment for severe AAT de \201 ciency in a limited number of countries since 1987. A protective threshold above 0.5g/l of AAT is thought to limit proteo- lytic lung in jury and so guard against the development of emphysema. Exogenous doses are administered on ce a week to achieve a trough level above this threshold but the interval can be extended t o 14 or 21 days to achieve ade- quate concentrations. There is good evidence that IV augmen tation therapy raises serum levels above the pro- tective threshold and AAT is detectable i n bronchoalveolar lavage \202 uid. The largest studies looking for evidence of clinical e f \201 cacy have been obser vational cohort studies which indicate a lower overall mortali ty and a slower rate of annual decline in FEV1 in recipients with moderate COPD (FEV1 of 35 \200\22365% predicted). In addition IV AAT use has been associated with a reduction in the frequency of respiratory tract infections, a signi \201 cant decline in sputum markers of in \202 ammation and relatively few serious side effects. The only randomized control tri al of IV augmenta- tion therapy showed no signi \201 cant difference in the rate of FEV1 d ecline or the rate of loss of lung density as de \201 ned by CT densitometry although ther e was a trend in favor of the active treatment group. Analyzes of IV AAT therapy suggests a n incremental cost effectiveness ratio of 103,400 per quality of life-years for AAT in the liver and other tissues. Transplantation of hepatocytes as an alternative to whole liver transplantation. Support groups and useful websites: \200 Alpha-1 UK (www.alpha1.org.uk). \200 Alpha-1 F oundation (www.alphaone.org). \200 Alpha-1 National Association (www.alpha1.org). \200 British Liver Trust (www.britishlivertrust.org.uk). Further reading ATS/ERS statement: Standards for the diagnosis and management of individual s with AAT de \201 ciency. Am J Respir Crit Care Med 2003; 168: 818 \200\223900. DeMeo DL, Sandhans RA, Barker AF, et al. Determinants of air \202 ow obstruction in severe alpha-1-antitrypsin de \201 ciency. Thorax 2007; 62: 806 \200\223813. Lomas DA, Mahadeva R. A1-Antitrypsin polymerization and the ser- pinopathies: pathobiology and prospects for therapy. J Clin Invest 2002; 110: 1585 \200\2231590. Needham M, Stockley RA. A1-Antitrypsin de \201 ciency. 3: Clinical manifestations and natu ral history. Thorax 2004; 59: 441 \200\223445. Perlmutter DH, Brodsky JL, Balisteri WF, et al. Molecular pathogen- esis of Alpha -1- Antitrypsin de \201 ciency- associated liver dis ease: A meeting review. Hepatology 2007; 45: 1313 \200\2231323. Stoller JK, Aboussouan LS. A1-antitrypsin de \201 ciency. Lancet 2005; 365: 2225 \200\2232236. 123 Chapter 6 Oxygen Chapter contents 6.1 Home oxygen therapy 124 J WEDZICHA 124 6.1 Home oxygen therapy