Intravenous aminophylline or magnesium \200 Aminophylline offers acute bronchodilatation via a dif- ferent mechanism than either B-agon ist or ipratropium, and anecdotally, individual patients get clinically useful bene \201 t from aminophylline despite having responded poorly to inhaled agents. However, it is dif \201 cult to dem- onstrate bene \201 t from the addition of aminophylline in controlled st udies, so such patients appear to be rare. Side effects are not uncommon, and use of aminop hyl- line is therefore con \201 ned to those patients with life- threatening asthma who ha ve not responded to initial treatment. The potential indications for IV magnesium are simil ar to those of aminophylline. Unlike aminophylline, intrave- nous magnesium given as a sing le bolus dose has been shown to be of bene \201 t in acute severe asthma, and side effects appear less common. Bene \201 t from magnesium is less obvious in adults than in children . Moreover, some of the studies showing bene \201 t from magnesium are not of high standar d, and bene \201 t is not observed in all studies. Magnesium and aminophylline have not be en compared directly against one another. Critical care unit Any feature of life-threatening asthma should prompt immediate discussion with the critical care team, whether present on admission and failing to improve quickly, or if developing d espite treatment. Such features are: \200 \200 \200 \200 \200 \200 deteriorating PEF; hypoxia which fails to improve; elevated CO2; acidosis on blood gas anal ysis; exhaustion, drowsiness or confusion; respiratory arrest. Other agents \200 Antibiotics are often given to patients with an exacerba- tion of asthma who feel that the attack has been caused by an infection \200\230going to my chest \200\231. Whilst infectio ns are certainly implicated in acute asthma, these are almost always viral rather than bact erial. Routine prescription of antibiotics is therefore not indicated, and their use should be the exception rather than the rule. Heliox (helium/oxygen mixture containing 70 \200 \22380% helium) improves the \202 ow of an inspired breath because It is dif \201 cult to be dictatorial about the need for intubation since this depends to some degree on the time which ther- apy has had to work, and the rate of change of vital si gns. The decision should be made by the most experienced available medical staff. However, the clear indications for intubation are development of type-2 respiratory failure and decr eased consciousness. CHAPTER 4.5 Acute asthma 81 PEF 33 \200\22375% and no life- threatening features PEF <33% or any life- threatening features PEF >75% Take usual bronchodilator. Monitor symptoms and PEF High-dose bronchodilator \200 Prednisolone High flow O2 \200 Nebulised bronchodilator \200 Prednisolone If improved, continue treatment PEF 50 \200\22375% If symptoms fail to settle, consider need for short prednisolone course. If PEF falls to \211 75%, give short course of prednisolone If no improvement consider : \200 IV magnesium \200 continuous nebulisation PEF >75% PEF <50% Repeat high-dose bronchodilator Observe. Once PEF > 75% consider completing prednisolone course at home Fig. 4.5.1 Overview of the management of acute asthma attacks. Management is guided by symp toms and an objective measure of severity, usually PEF \200\223 decision to admit to hospi tal is in \202 uenced by a number of factors including symptom severity, PEF level, histor y of previous life-threatening attacks, and social ciircumstances. Further reading Anderson HR, Gupta R, Strachan DP, et al. Time trends in allergic Parameswaran K, Belda J, Rowe BH. Additions of intravenous aminophylline to beta2-agonists in adults with acute asthma. Cochrane Database Syst Rev 2000; 4: CD002742. disorders in the UK. Thorax 2007; 62:85 \200\22390. Pauwels RA, Lofdahl C-G, Postma DS, et al. Effect of inhaled for- moterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337:140501411. British Guideline on the Management of Asthma. Thorax 2003; 58 (Suppl 1): i1 \200\223i84. Camargo CA, Spooner CH, Rowe BH. Continous versus intermit- tent beta-agonists in the treat ment of acute asthma. Cochrane Database Syst Rev 2003; 4:CD001115. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergies in the treatment of children and adults w ith acute asthma: a systematic review with meta-analysis. Thorax 2005; 60:640-646. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006; 2:CD000052. Rowe BH, Bretzlaff JA, Bourdon C, et al. Magnesium sulfate for treating exacerbations of ac ute asthma in the emergency department. Cochrane Database of Syst Rev 2000; 1: CD001490. Tr avers A, Jones AP, Kelly K, et al. Intravenous beta2-agonists for acute asthma in the emerg ency department. Cochrane Database of Syst Rev 2001; 1: CD002988. Global strategy for asthma management and prevention, Global Initiative for Asthma (GINA) 2006. http://www.ginasthma.org Harrison TW, Oborne J, Newton S, et al. Doubling the dose of inhaled corticosteroid to prev ent asthma exacerbations: ran- domised controlled trial. Lancet 2004; 363: 271 \200\223275. Walsh LJ, Wong CA, Cooper S, et al. Morbidity from asthama in relation to regular treatment : a community based study. Thorax 1999; 54:296 \200\223300. Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacer- bations of asthma in adults. Br Med J 1993; 307:982 \200\223986. P HALDER & I PAVORD 82 4.6 Chronic asthma management Overview Between 10 \200\22315% of adults in Western societies have a diagnosis of asthma, and for the majority the disorder is chronic. This represents a signi \201 cant burden on economic and healthcare resources. In the UK, it is estimated that asthma-management costs exceed 850 million per year to the health service and result in the loss of 12.5 million working days. Despite therapeutic advances, asthma-related mortality has failed to decline signi \201 cantly and remains at approximately 1400 deaths per year. Con \201 dential enq uiries of asthma mortality suggest over 80% are preventable. Together, these statistics hig hlight both the impact of asthma as a chronic disease to society and the de \201 ciencies that remain in its management. to anxiety and depression that can lead to a vicious cycle of deteriorating control. Exacerbations Exacerbations are defined as periods of poor asthma control manifest by an in crease in symptoms and deterio- ration in lung function that are not adequately managed by the individual \200\231s usual therapeutic regimen. They are fre- quently precipitated by a llergen exposure or viral infec- tions. Severe exacerbations may lead to hospitalization an d are the major cause of asthma mortality. Although exacerbations may be precipitated by a number of different aetiologies, recent evidence suggests a close rela- tionship between th e future risk of a severe asthma exac- erbation and present levels of eosinophilic airway i n \202 ammation. Moreover, controlling this in \202 ammation with corticosteroids leads t o a reduction in the exacerbation risk. GP consultations, 63 million Lung function decline Chronic asthma is associated with accelerated decline in lung functio n that is considered a function of persistent airway in \202 ammation. Clinically importan t decrease in lung function is seen most commonly in those with severe childhood asthma tha t impacts upon lung development and manifests as \201 xed air \202 ow obstruction in adu lthood. An accelerated rate of decline in adults is seen with: \200 \200 \200 Hospital admissions, 49 million Dispensing, 117 million severe, non-atopic disease; frequent exacerbations; smokers. Although interventions preventing decline are poorly understood, it is likely that smoking cessation, early removal from occupational sensitisers and (possibly) optimization of corti costeroid therapy are effective. Prescriptions, 659 million AUTHOR \200\231S TIP As with other chronic diseases, management options for asthma should b e viewed in terms of whether they palli- ate symptoms only or whether they impact upon medi um- and long-term goals and are therefore disease modifying. Fig. 4.6.1 Diagram of asthma economic costs. Aims The aims of management in chronic asthma are focused on both short- and long-term goals. Th ese are: \200 \200 Principles of asthma management In common with other chronic diseases, the management of as thma requires a multidisciplinary approach that is patient-centered. An algorithm highlight ing the general principles of asthma management is shown (Fig. 4.6.2). Management intervent ions incorporate both pharmaco- logical and non-pharmacological measures. Although pharmaco therapy forms the basis of care, non-pharmaco- logical strategies can effectively complemen t this and in many cases, help avoid over-treatment. Management strategies should therefore be tailored to the individual and will depend primarily upon careful clinical assessment. Controlling asthma symptoms (short term) Reducing the risk of future asthma exacerbations ( medium to long term) Preventing accelerated lung function decline (long term) The relations hip between short- and longer-term goals is complex. There is a growing body of evidence th at sup- ports the importance of considering these goals independ- ently, both in clinical p ractice and in the assessment of outcome measures in clinical trials. Asthma symptoms The clinical expression of asthma symptoms is frequently multifactorial and depends predominantly on the degree of physiological air \202 ow obstruction and percepti on of this limitation, which has an important psychological element. Air \202 ow obstructi on is due to airway smooth muscle con- tractility and airway in \202 ammation causing muco sal oedema. Chronic in \202 ammation can lead to structural changes in the airway wall (re modeling) that may contribute to persistent air \202 ow limitation. Symptoms lead to both physical and psychological morbidity if poorly controlled, predisposing Patient assessment This should address the following important areas: \200 \200 Assessing control of symptoms and asthma severity. Identifying aetiological factors that ma y confound or exacerbate asthma symptoms. Assessing future severe asthma exacerbation risk. A careful history provides the most valuable information and will determine the plan of inv estigation and management to follow. CHAPTER 4.6 Chronic asthma management 83 Patient factors \200 Establish asthma diagnosis Exposure to triggers that precipitate and exacerbate airway in \202 ammatory and bronchoco nstrictor responses (Table 4.6.1). Poor adherence with recommended care. Identify aggravating and precipitating factors Patient assessment Table 4.6.1 Common triggers aggravating asthma symptoms Trigger Comments Cold air exercise Altered osmolarity of the bronchial mucosa activates mast cell release of pro-in \202 amma tory and bronchoconstrictor molecules Assess disease severity Aeroallergens E.g. pollen, pet allergens HDM, fungal spores Referral to other healthcare disci- plines, as indicated Non-speci \201 c irritants E.g. perfumes, cigarette smoke E.g. B-blockers, aspirin and NSAIDs, ACE inhibitors Drugs Patient education Occupational agents E.g. isocyanates (spray painting), \202 our, wood dust, gluteraldehyde/latex (healthcare) , solder/colophony (welding and soldering) Management Prescribe treatment appropriate to severity Poor adherence Occupational asthma It is estimated 10 \200\22315% of adult-onset asthma may be attrib- uta ble in part to occupation. Mechanistically, occupational agents may be broadly subdivided i nto those causing hypersensitivity (90%) and those that are direct irritants (10%). The lat ter cause sudden symptoms at \201 rst exposure whereas hypersensitivity is predominantly IgE mediated and leads to symptoms that develop after a variable latent period of exposure. Early avoidance may prevent persist- ent disease and accelerated lung function decline. Th e diag- nosis is suspected when there is a clear improvement in symptoms and peak \202 ow measurements during a period away from work. Referral to a specialist is recommended in al l cases. Alternative or additional Diagnosis (Table 4.6.2) Review and further assessment Consider reasons for poor control Unidentified aggravating factors (Table 4.6.1) Control achieved Control not achieved Inadequate therapy Consider step down of treatment Escalate treatment AUTHOR \200\231S TIP Consider occupational asthma in all patients presenting. Fig. 4.6.2 Overview of the principles of asthma management. Assessing adherence Adherence problems with therapy are a generic problem in the management of chronic diseases. In asthma, adherence rates are estimated to range between 30 \200\223 70%. Poor adher- ence is more frequently seen in: \200 \200 \200 Assessing control of symptoms There are several well-validated questionnaire tools for meas uring symptom control in asthma. The favored clini- cal tool in the UK is the RCP 3 questio ns as it is concise and ideal for use in busy clinical practice. RCP 3 QUESTIONS 1. Have yo u had dif \201 culty sleeping because of asthma Younger and elderly patient groups. Frequent attenders at emergency departments. Patients w ith coexistent psychosocial morbidity. Studies show a positive correlation between self-reported non-adherence and formal measurem ent of prescription collections. Patients should therefore be questioned about their adhere nce patterns. Further strategies for investigat- ing adherence include: \200 \200 symptoms? 2. Have you had your usual asthma symptoms during the day? 3. Has your asthma interfered with your usual daily activities? Monitoring frequency of prescription collections. Measuring plasma levels of medication (e. g. theophylline levels or prednisolone levels in conjunction with cortisol). Measuring leve ls of exhaled NO (see Exhaled NO, p. 84). A positive response to any question indicates persistent symptoms and should prompt a manag ement review. Factors associated with poor control of symptoms The consideration and identi \201 cation of factors that can mimic or aggravate asthma symptoms is clearly important. These may be c ategorized as patient factors and disease factors, although considerable overlap exists. Disease factors \200 Disorders that coexist with asthma and contribute to the clinical expression of asthma-like symptoms (Table 4.6.2) P HALDER & I PAVORD 84 Disorders that may mimic asthma in their clinical expression (Table 4.6.2) MINI NIOX (Aerocrine) A handheld device for measuring exhaled NO Table 4.6.2 Differential diagnosis of disease factors associated with poor control of clini cal symptoms Without air \202 ow obstruction With air \202 ow obstruction Normal spirometry Restrictive spirometry Dysfunctional breathing* Cardiac failure \200 COPD* Vocal cord dysfunction* Pulmonary \201 brosis Bronchiectasis* \200 (including allergic bronchpulmonary aspergillosis) Gastroesophageal re \202 ux disease* Churg \200\223Strauss syndrome* Pulmonary vascular disease Inhaled foreign body \200 Chronic cough syndromes Obliterative bronchiolitis Fig. 4.6.3 Measuring eosinophilic airway in \202 ammation. Large airway stenosis Sarcoidosis \200 AUTHOR \200\231S TIP Patients with recurrent exacerbations requiring frequent oral corticos teroids may have uncontrolled eosinophilic airway in \202 ammation. Optimizing therapy in these patients may be facilitated by monitoring eosinophilic airway in \202 ammation. These conditions may coexist with asthma \200 These conditions may be associated with nor mal spirometry AUTHOR S TIP As Table 4.6.2 highlights, the likely differential diagnosis of disease factor s for patients with asthma and poorly con- trolled symptoms will depend upon whether there is evidence of air \202 ow obstruction. Identifying high-risk patients Patients at high risk of severe exacerbations should be iden ti \201 ed early in Primary Care as they contribute dispro- portionately to asthma mortali ty (Table 4.6.3). Prompt referral to a specialist respiratory physician for further assessm ent is recommended. Evaluating future exacerbation risk \200\223 measuring eosinophilic airway in \202 ammati on It has been traditionally presumed that exacerbation risk is closely related to symptom control. Although controlling symptoms effectively reduces the risk of exacerbations, sever al studies identify the level of underlying eosinophilic airway in \202 ammation to be a p owerful objective predictor of future exacerbation risk. In most instances, titrating thera py to control symptoms will control underlying eosi- nophilic in \202 ammation. However, a disparity between symp- toms and in \202 ammation should be suspected in patients that ha ve recurrent exacerbations on a background of good symptom control between episodes. These patients may have poor perception or under-report symptoms. The former will contribute to p oorer therapy adherence and the latter to inadequate dosing. Objective, non-invasive measur ement of eosinophilic airway in \202 ammation is now possible: Table 4.6.3 Risk factors for asthma mortality Previous mechanical ventilation for asthma Major risk factors Previous admission to intensive care Recent exacerbation (<12 months) requiring hospital admission Asthma requiring oral steroid or theophylline for control Minor risk factors High short acting beta agonist consumtion Factors associated with poor compliance Pharmacological management of asthma Pharmacotherapy forms the mainstay of asthma manage- m ent. Details of drug pharmacology are discussed else- where. Here we discuss the principles of their use in clinical practice. The ef \201 cacy of different asthma medications for a chieving the major goals of asthma care is summarized in Table 4.6.4. 1. Sputum induction This involves administering nebulised hypertonic saline to promote expe ctoration of bronchial sputum. The cellularity of obtained samples is studied microscopical ly (Fig. 4.6.3) and is representative of the inflammatory pro \201 le within the proximal lower airways. Stepwise algorithm for asthma pharmacotherapy Present BTS guidelines recommend a stepwise a pproach to the titration of asthma therapy that is based upon achieving control of asthma s ymptoms (Fig. 4.6.4) at the lowest dose of therapy. Changes in therapy should be reviewed e very 3 months until stability is achieved. This algorithm assumes a close correlation betwe en clini- cal symptoms and underlying disease activity. However, 2. Exhaled NO A more recent technique is the measurement of NO in exhaled air. NO is a prod uct of the in \202 ammatory process and levels are closely related to the extent of eosino philic airway in \202 ammation. It is easily measured in clinical prac- tice (Fig 4.6.3), though its place in asthma management is yet to be determined. CHAPTER 4.6 Chronic asthma management 85 symptoms are often multifactorial and several studies have indicated dissociation between a irway in \202 ammation and clinical symptoms. Nevertheless, more than 80% of patients achi eve satisfactory control in Primary Care. maintenance therapy that contributes to poor therapy adherence. Single inhaler therapy More recently, studies have shown the use of formoterol and budesoni de in a single combination inhaler (Symbicort ) for both symptoms relief and maintenance of asthma control is associated with signi \201 cant improvements in lung function, reduc tion in exacerbation frequency and better control of symptoms, when compared with standard therapy. This approach exploits the association between symptoms and airway in \202 ammati on such that patients receive more fre- quent dosing with inhaled corticosteroids when symp toms are poorly controlled that may be suf \201 cient to suppress worsening underlying eos inophilic airway in \202 ammation and avert the onset of an exacerbation. Although a long- acting beta agonist, formoterol has a rapid onset of action comparable to salbutamol that permits its use as a reliever. Single inhaler therapy is theoretically attractive for its p otential impact on improving therapeutic adherence. The combination inhaler of budesonide w ith formoterol has recently been granted a license for use in this way. Table 4.6.4 Effectiveness of different pharmacological treatments for achieving goals of as thma therapy Controlling symptoms Preventing exacerbations Preserving lung function Corticosteroids +++ +++ ? Long acting beta agonists ++ +(*) \200\223 Anti-leukotrienes + + \200\223 All bronchodilators ++ \200\223 Long-acting beta agonists are only ef \201 cacious at preventing exacerbations when used in conjunction with a corticosteroid Combination therapy of inhaled LABA and corticosteroid It is notable that step 3 of the tre atment ladder advocates the addition of a LABA to low-dose inhaled corticosteroid. This str ategy is preferred to the escalation of corticoster- oid dose as studies have shown a compa rable improve- ment in lung function and fall in exacerbation rate with this strategy at a lower dose of corticosteroid. There is also molecular evidence of synergy between the two d rug classes. In clinical practice, this means that patients are likely to be co-prescribed both drugs at an early stage. Several combination inhalers have been developed to overcome the problem of multiple inhaler use for AUTHOR \200\231S TIP Single inhaler therapy with a combination inhaler of budesonide and fo rmoterol may be tried in place of steps 3 and 4 of the BTS algorithm. It may be a particula rly useful strategy in cases of suspected poor therapeutic adherence. Leukotriene inhibitors This class of drugs incorporates different mechanistic subgroups tha t inhibit the formation or function of Oral prednisolone * (lowest dose to maintain adequate control) Consider other treatments to minimize use of steroid tablets Step up therapy if symptoms poorly controlled STEP 5 REFER FOR SPECIALIST CARE Increase inhaled steroid (in increments to a maximum of 2000mcg/day) Addition of a fourth d rug e.g. LTRA, theophylline, agonist tablet STEP 4 Add inhaled LABA (6 week trial) If no response to LABA, stop and increase inhaled steroid dose to 800 mcg/day If partial re sponse, continue LABA and increase inhaled steroid dose to 800 mcg/day STEP 3 Add inhaled steroid 200 \200\223800 mcg/day. (Usual starting dose 400 mcg/day) STEP 2 Consider step down therapy if symptoms well controlled for at least 3 months Inhaled short acting -agonist, as required STEP 1 LABA: long acting -agonist LTRA: leukotriene receptor antagonist Patients requiring maintenance or frequent courses of oral prednisolone should be referred for a bone mineral density scan and consideration given to bone protection therapy Fig. 4.6.4 Stepwise algorithm for chronic asthma therapy in adults. P HALDER & I PAVORD 86 leukotriene mediators. These mediators are signi \201 cantly elevated in the subgroup of a sthma with aspirin intoler- ance and/or nasal polyps due to a constitutive de \201 ciency in prostaglandin E2 that is an important regulator of leukot- riene production. The use of leukotriene inhibitors as add on therapy are therefore theoretically favorable in this clin ical setting and have also been advocated for the man- agement of exercise induced asthma. In practice however, clinical outcomes with the use of these agents have been disappointing . Table 4.6.5 Effectiveness of different non-pharmacological tools for achieving goals of ast hma therapy \200 Prevention of exacerbations Preservation of lung function Control of asthma symptoms Patient education ++ + Trigger avoidance ++ + Smoking cessation Steroid-sparing therapies Between 5 \200\22310% of patients have asthma that requires ther- apy at step 4 or above. Regular maintenance oral corticos- teroid therapy or frequent shor t courses for exacerbations contribute to the iatrogenic burden of disease in these patient s. Targeting corticosteroid therapy according to lev- els of underlying eosinophilic airway in \202 ammation may help optimize corticosteroid dosing. However, the devel- opment of e f \201 cacious steroid-sparing agents is a major focus of pharmacological research in asth ma. +++ ? ++ Breathing retraining techniques \200 It is notable that non-pharmacological measures are g enerally effective for improving asthma symptoms. Only smoking cessation has a signi \201 cant disease modifying effect. * Early identi \201 cation and avoidance of occupational tr iggers can prevent the onset of chronic asthma and arrest decline in lung function. ++ ? Monoclonal antibody therapy and omalizumab A number of monoclonal antibodies are being deve loped to target key pro-in \202 ammatory mediators that are believed to be signi \201 can t for perpetuating chronic airway in \202 ammation in asthma. Of these, omalizumab (IgE re ceptor antagonist) is the \201 rst to receive a license for use in patients with uncon- t rolled allergic asthma. Monoclonal therapies may have lim- ited side effects in view of the ir speci \201 city. However, this limits their ef \201 cacy as heterogeneity in the clini cal and pathophysiological expression of disease is increasingly rec- ognised within the as thma population. It is likely that such therapies will only be effective in well de \201 n ed subgroups. Personalized asthma action plans Previously known as self management plans, these pro- gram mes incorporate personalized information for patients, facilitating a successful patient-ce ntered approach (Table 4.6.7) that includes: \200 \200 Structured education, reinforced with written plans. Speci \201 c advice about recognizing loss of asthma control, assessed by symptoms, peak \202 ow or both. Action to take if as thma deteriorates that is appropriate to clinical severity. This includes temporarily incre asing inhaled steroids, commencing a rescue course of oral steroids or seeking emergency he lp. Immunosuppressants and methotrexate A number of different non-steroidal immunosuppressants have been trialed for their steroid-sparing properties in refractory asthma. Of these, meth otrexate has the most convincing evidence of bene \201 cial effect; a recent meta- analysi s concludes methotrexate may have a modest ster- oid-sparing effect. The response in indivi dual cases is however unpredictable and should be weighed up against potential treatment to xicity. Although asthma action plans vary in their detail, they are effective at improving asthma m orbidity and reducing the frequency of hospitalisations and unscheduled doctor visits. Stud ies have shown symptoms and peak \202 ow meas- urements to be similar in their ef \201 c acy for monitoring asthma control. However, peak \202 ow monitoring may be more helpful i n cases where patients exhibit poor percep- tion of worsening of lung function. Non-pharmacological aspects of asthma management Non-pharmacological measures play an impor tant role in the management of asthma. The different commonly employed strategies and the r ole of allied healthcare pro- fessionals in the various aspects of care is summarized in Ta bles 4.6.5 and 4.6.6. AUTHOR S TIP All patients that are hospitalized for an asthma exacerba- tion should receive a personalized asthma action plan from an asthma healthcare specialist prior to discharge. Table 4.6.6 Multidisciplinary approach to asthma care Patient education A central principle in the long-term care of all patients with chronic di sease is a patient-centered approach that gives patients a degree of control over their dis ease. The success of this approach relies on effective patient education, to which there ar e several components in asthma: \200 Specialist asthma nurses Review of potential asthma triggers Relevant advice about disease and treatment, including providing self- management plans Review of inhaler technique Physiotherapy Physical training and breathing retraining techniques Identifying and avoiding asthma triggers, most impor- tantly smoking cessation. Understandi ng the role of prescribed therapies. This can improve adherence and forms a necessary pre-r equisite for implementing an asthma action plan Ensuring correct inhaler technique Recordin g and monitoring peak \202 ow measurements Following a personalized asthma action plan Education and advice about therapies Adherence assessments Pharmacist Dieticians Avoidance strategies for identi \201 ed food allergens, including salicylate-free diets fo r aspirin sensitive asthma \200 \200 Smoking cessation service CHAPTER 4.6 Chronic asthma management 87 Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2000; 2: CD000391. Table 4.6.7 Generic asthma action plan Peak \202 ow Monitoring (% best or symptoms predic ted) Risk strati \201 - cation Recommended action General Register Of \201 ce collated in Of \201 ce for National Statistics mortality statistics for England and Wales. Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil count s: a randomized controlled trial. Lancet 2002; 360(9347): 1715 \200\2231721. Increased dose of inhaled steroids and continue higher dose until symptoms have settled for >1 week. Use reliever as needed. Effects of reliever should last >3 hours 60 \200\22375% Mild to moderate exacerbation More frequent symptoms or new nocturnal symptoms requiring reliever use Juniper EF, O \200\231Byrne PM, Guyatt GH, et al. Development and valida- tion of a questio nnaire to measure asthma control. Eur Respir J 1999: 14(4): 902 \200\223907. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004; 113(1): 59 \200\22365. Newman Taylor AJ, Cullinan P, Burge PS, et al. BOHRF guidelines for occupational asthma. Thorax 2005; 60(5): 364 \200\223366. Powell H, Gibson PG. Options for self-management education for adults with asthma. Cochrane Database Syst Rev 2003; 1: CD004107. Contact GP Commence oral steroids 50 \200\22360% Moderate to severe exacerbation Effects of reliever lasting <2 hours Rabe KF, Atienza T, Magyar P, et al. Effect of budesonide in combina- tion with formoterol for reliever therapy in asthma exacerba- tions: a randomized controlled, double-blind study . Lancet 2006; 368(9537):744 \200\223753. <50% Acute severe exacerbation Call emergency services immediately No improvement with reliever or failing to improve with oral steroids after 2 days Robinson DS, Campbell D, Barnes PJ. Addition of leukotriene antag- onists to therapy in chr onic persistent asthma: a randomized double-blind placebo-controlled trial. Lancet 2001; 35 7(9273): 2007 \200\2232011. Walker S, Monteil M, Phelan K, et al. Anti-IgE for chronic asthma in adults and children. C ochrane Database Syst Rev 2006; 2: CD003559. Further reading British Guideline on the Management of Asthma: A national clinical guideline. British Thora cic Society and Scottish Intercollegiate Guidelines Network. Revised edition July 2007 http ://www. brit-thoracic.org.uk/c2/uploads/asthma_full- guideline2007.pdf This page intentionally left blank 89 Chapter 5 Chronic obstructive pulmonary disease Chapter contents 5.1 COPD genetics and epidemiology 90 5.2 COPD pathophysiology 92 5.3 Investigations in COP D 98 5.4 Pharmacological therapy (including cor pulmonale) 100 5.5 Non-pharmacological mana gement for COPD 106 5.6 Management of an exacerbation of COPD 112 5.7 Surgery for COPD 116 5.8 Alpha-1-antitrypsin de \201 ciency 120 J DODD & B PATEL 90 5.1 COPD genetics and epidemiology Background The air \202 ow obstruction in smoking-related COPD is the result of small airw ays disease (obstructive bronchiolitis) and alveolar destruction (emphysema). These are dis crete pathological processes, each of which may make an inde- pendent contribution to the o verall burden of air \202 ow obstruction in an affected individual. Irreversible air \202 ow obstruction may develop in a number of other respiratory disease including chronic asth ma, bronchiectasis (and cystic \201 brosis), obliterative bronchiolitis and sarcoidosis. These diseases have a different etiology, pathology and natural history and therefore it is essential that they are consid- ered as separate conditions to COPD. in later life amongst childhood smokers is mainly the result of extra pack years smoked. Th e recognition that not all smokers are equally suscepti- ble to the development of COPD and the identi \201 cation of a subgroup of susceptible smokers means that other fac- tors, e nvironmental or genetic, must interact with cigarette smoke to predispose some individuals to developing COPD. AUTHOR \200\231S TIP Smoking is the major risk factor for COPD but variation in susceptibil ity between smokers means other factors are important. Epidemiology Cigarette smoking is the major environmental risk factor for the development o f COPD. The exact prevalence of COPD is unknown as the disease may be asymptomatic in its e arly stages, however: \200 In 1996 COPD accounted for more than 2 million deaths Environmental exposures A number of environmental exposures other than smoking have been as sociated with a reduced FEV1 or air \202 ow obstruction. These include: \200 occupationa l exposures (e.g. underground tunnel worldwide workers); \200 domestic fuels; \200 low birth weight; \200 childhood exposure to pass ive smoking; \200 viral respiratory tract infections; \200 social economic class. Sever al population-based studies have shown an inverse association between dietary antioxidants (found in fruit and vegetables), lung function and/or symptoms. It is pos- tulated that the se antioxidants may provide protection against harmful free radicals in cigarette smoke. Ho wever, there is no evidence to suggest that increasing intake of dietary antioxidants prote cts against smoking-related COPD. Compared to the effect of cigarette smoking, the effect o f other identi \201 ed environmental exposures is rela- tively weak and none of the curren tly identi \201 ed environ- mental exposures adequately explains the variation in suscepti bility to COPD seen amongst smokers. In 2004 more than 26,000 deaths in the UK were attrib- uted to COPD The prevalence of COPD in the UK may be as high as 1 million. In the USA it is estimated that 6.6% of the adult popula- tion have spirometrically de \201 ned COPD. The prevalence of COPD amongst women has risen because of the increased number of women who smoke. With the increased prevalence of cigarette smoking in China and developing countrie s it has been predicted that the global prevalence of COPD will increase so that by 2020 it will account for more than 4.5 million deaths, mak- ing it the third most common cause of death worldwide. COPD and smoking \200 Cigarette smoking is the single greatest risk factor for COPD. The relationship between cumulative smoking and forced expiratory volume in 1 second (FEV1) is relatively weak within a population, with less than 10% of variation in FEV1 explained by differences in pack years smoked (one pack year is equivalent to 20 cigarettes a day for a year). Genetic factors To date the only identi \201 ed genetic risk factor for the devel- opment of COPD is de \201 ciency of 1-antitrypsin ( 1-AT). This is an important inhibitor of t he enzyme neutrophil elastase, and homozygotes for 1-AT de \201 ciency are at an increas ed risk of developing emphysema if they smoke. However, 1-AT de \201 ciency accounts for only 1 \200\2232% of all cases of COPD seen in clinical practice. Studies which have recru ited families through the identi \201 cation of an individual with early onset COPD in the absence of 1-AT de \201 ciency (referred to as a proband), have shown that smoking sib- lings of the proband have a 3 \200\2234-fold greater risk of COPD than unrelated smokers. The non-smoking siblings of these probands have relatively normal lung function, which sug- gest that it is not shared environment that is the cause of this familial clustering. The increased prevalence of COPD among smoking siblings of probands is independent of pack year s smoked and supports the hypothesis that there are other, as yet unidenti \201 ed, genes that predispose to the development of COPD. A large number of studies have aimed to identif y genes that predispose to the develop- ment of COPD: the most common types of studies are candidate gene studies and linkage analysis. In their longitudinal study of middle age smokers, Fletcher and Peto identi \201 ed a sub- group of smokers who showed an accelerated decline in FEV1. These \200\230susceptible smokers \200\231 represented about 15% of the smoking population. This data is often misinterpreted as suggesting that the prevalence of COPD among smokers i s 15%. This is not the case. The prevalence of spirometrically-de \201 ned COPD in older populations of smokers is sign i \201 cantly greater than 15%. The most susceptible individuals may have more advanced disease at an earlier age. People who start to smoke in childhood may not achieve their maximum FEV1 in adulthood and therefore may be sus- ceptible to even a modest increase in rate of decline in FEV1. Curren t evidence suggests that the increased risk of COPD CHAPTER 5.1 COPD genetics and epidemiology 91 and genes, increasing the risk of a type I statistical error if a p value of 0.05 is used. AUTHOR \200\231S TIP 1-AT de \201 ciency is currently the only proven genetic risk facto r for COPD and can be screened for by blood levels. Linkage analysis Linkage analysis is a more complex method of identify- ing areas of the ge nome that segregate with the disease phenotype within a population. This has been made poss i- ble through the identi \201 cation of a large number of single nucleotide polymorphisms (SNPs) throughout the human genome. Linkage analysis studies have the advantage that they may allow the identi \201 cation of previously unidenti \201 ed genes that may be associa ted with COPD. For example, Silverman and colleagues identi \201 ed linkage of FEV1/FVC to a region on chromosome 2q. These studies may provide important future insights into the ge netic basis of COPD. Candidate gene studies Candidate gene studies are popular because they are rela- tively sim ple to undertake. In brief, investigators identify a gene that they hypothesize may be impo rtant in the devel- opment of COPD and compare the prevalence of a muta- tion in this candi date gene in individuals with COPD with the prevalence in individuals without COPD. If a mu tation or polymorphism is more prevalent in the COPD popula- tion, it supports the hypothes is that the gene may predis- pose to COPD. These studies rely on the identi \201 cation of possible candidate genes. Most genes that have been studied have coded for proteins that a re antioxidants, antiproteinases or mediators of in \202 ammation, in keeping with current hypotheses on the mechanism of COPD pathogenesis.