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Respiratory Medicine (2007) 101, 1049–1065

0954-6111/$ - see frodoi:10.1016/j.rmed.

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HISTORICAL REVIEW

One hundred years of chronic obstructivepulmonary disease (COPD)

Mario Cazzolaa,�, Claudio F. Donnerb, Nicola A. Hananiac

aDepartment of Internal Medicine, Unit of Respiratory Diseases, University of Rome ‘Tor Vergata’, Rome, ItalybMondo Medico, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), ItalycPulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USAAvailable online 23 March 2007

KEYWORDSCOPD;Chronic bronchitis;Emphysema;Epidemiology and riskfactors of COPD

nt matter & 20072007.01.015

thor.

ario.cazzola@uni

SummaryChronic obstructive pulmonary disease (COPD) is an increasing health problem and one ofthe leading causes of morbidity and mortality worldwide, but knowledge about itspathogenesis has increased substantially in recent years. The disease results frominteraction between individual risk factors (like enzymatic deficiencies) and environmentalexposures to noxious agents, like cigarette smoking, occupational dusts, air pollution andinfections in childhood. The main mechanisms that may contribute to airflow limitation inCOPD are fixed narrowing of small airways, emphysema and luminal obstruction withmucus secretions. COPD is characterised by a chronic inflammatory process in thepulmonary tissue, with a pattern different from bronchial asthma, associated withextrapulmonary effects and is considered now a complex, systemic disease. Optimaltherapeutic targeting of COPD depends on a clear understanding of the precisemechanisms of these complex processes and on early and correct evaluation of diseaseseverity. A combination of pharmacological and non-pharmacological approaches is used totreat COPD. Bronchodilators are the mainstay of COPD treatment and can be combinedwith inhaled corticosteroids for greater efficacy and fewer side effects. The use of LTOT forhypoxemic patients has resulted in increased survival, and expanded drug therapy optionshave effectively improved dyspnoea and quality of life. Recent studies have documentedthe benefits of pulmonary rehabilitation. In addition, non-invasive mechanical ventilationoffers new alternatives for patients with acute or chronic failure.& 2007 Elsevier Ltd. All rights reserved.

Elsevier Ltd. All rights reserved.

roma2.it (M. Cazzola).

Epidemiology and risk factors of chronicobstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a relativelynew term for an old disease. Terms such as ‘‘bronchitis’’,‘‘emphysema’’, ‘‘asthmatic bronchitis’’ and ‘‘chronic bron-chitis’’ were more commonly used in the past to describe

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what we currently define as COPD. This review will highlightimportant papers published on the topic over the last 100years in Respiratory Medicine and its previous versionsBritish Journal of Tuberculosis, British Journal of Tubercu-losis and Diseases of Chest and British Journal of Diseases ofChest.

Several publications have addressed the risk factors ofCOPD in the general population although early ones includedonly cohorts of working men with limited income.1,2

Rimington1 analysed data from mass radiography units andconcluded that patients with chronic bronchitis were morelikely to be old, heavy smokers and belong to a low socialclass. The mean age-adjusted prevalence rate for chronicbronchitis in that cohort was 12.3% in all men and 5.6% in allwomen. However, this was highest in patients who smoked20 or more cigarettes per day (20% and 18.5% in men andwomen, respectively). In a subsequent publication, thesame author demonstrated that the prevalence of chronicbronchitis in individuals who inhaled while smoking was 50%higher than in those who did not.2 It is unclear why only aminority of smokers develop a clinically significant disease.In addition to smoking, genetic risk factors such as alpha1-antitrypsin deficiency play an important role in somepatients.3–5

The impact of COPD

COPD is associated with significant morbidity and mortalityworldwide and is currently a global health priority. In 1954,a study by Stuart-Harris6 evaluated the epidemiology andevolution of chronic bronchitis and described morbidity datacollected from practitioners’ visits, industrial records andNational Insurance data. These data revealed that in 1950,‘‘bronchitis’’ was the second leading cause of incapacityfrom sickness and the sixth most common cause of claims ofsickness in both men and women in Great Britain. Bronchitis,as a cause of sickness, was scattered over the whole ages inwomen but was more common in old men than young men.However, the author admits that there was no way todifferentiate acute bronchitis from chronic bronchitis fromthat database. The same paper evaluated another fieldsurvey of patients with bronchitis and described a group ofsymptomatic patients with a ‘‘triple complex’’ syndrome ofcough, sputum and disability (dyspnea or history of exacer-bation). Patients with this ‘‘triple complex’’ were morelikely to be old and had a high incidence of hospitalization.This was one of the few papers published at that time whichattempted to classify the severity of COPD. In a subsequentpaper published in 1964, the formation of a bronchitisregistry in East London was described and patients weredivided into three groups (Group 0, 1 and 2) according toseverity of symptoms and lung function abnormality.7 Theauthors further analysed the characteristics and the impactof the disease in these groups demonstrating that patientsbelonging to Group 2 had the highest morbidity and hadmore time lost from work than patients in the other twogroups.7 The burden of COPD in different countries was afocus of several publications over the last 100 years.8–13 In areport published in 1960 from the East London cohort,Caplin and Silver8 reported that unemployment and timelost from work were significant in patients with chronic

bronchitis. The authors concluded that ‘‘the chronicbronchitic suffers from two disabilities which may make itdifficult for him to retain his usual employment or find a newemployment. These are increasing shortness of breath onexertion and lung infections which force him to be awayfrom worky’’. It is of great interest that almost 50 yearslater, the same problems are major causes of disability inpatients with COPD. Utilization of healthcare services andhospitalizations driven by disease severity account for amajor component of the total cost of COPD worldwide.13–20

The confronting COPD in North America and Europe surveywhich was the first large-scale international survey of theburden of COPD estimated the annual cost of healthcareutilization in the US at $4119 per patient with COPD, withindirect cost of $1527 per patient. The annual estimatedsocietal cost was $5646 per patient. Inpatient hospitaliza-tion accounted for the majority of this cost ($2891).9 Thesame survey revealed that patients with COPD oftenunderestimate the severity of their illness. Exacerbationsof COPD account for 35–45% of the total per capita health-care costs for COPD; however, these costs vary considerablywith the severity of the exacerbation as well as the severityof COPD.20

COPD in special populations

Although COPD has for a long time been considered a diseaseof old Caucasian men, recent data from the US show thatmortality is rising faster among women and African-Amer-icans.21 In a recently published study describing thecharacteristics of patients with COPD from a researchdatabase, Caucasians had less loss of lung function perpack-year smoked than African–Americans which was alsoless in men than women suggesting that indeed African–A-merican women are most susceptible to the ill effects ofsmoke compared to other groups of men and women.22

Findings from the Confronting COPD International Survey,also indicate that gender differences in COPD care andoutcomes do exist and need to be further explored.23

Women with COPD were less likely to have had spirometrytesting, but more likely to have received smoking cessationadvice. Furthermore, women were more likely to reportsevere dyspnoea, had similar cough but less sputumproduction than men.

While any patient above the age of 40 is at risk ofthis disease, patients with advanced age are at higher riskof complications and increased morbidity from this dis-ease.24 A report from the obstructive lung disease innorthern Sweden studies demonstrated that almost 50% ofelderly smokers fulfilled the criteria for COPD according toboth the BTS and GOLD guidelines.25 However, whileguidelines recommend the use of a post-bronchodilatorratio of forced expiratory volume in 1 s (FEV1)/FVC o70% todefine COPD, the physiologic cutoffs for the defining COPD inelderly patients is still unknown. Furthermore, COPD inthe elderly is associated with impaired health statuswhich may not necessary be predicted by lung functiontests.26,27 Important determinants of health status in thispopulation include activity of daily living (ADL) andemotional status.27

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Clinical manifestations and diagnosis of COPD

The clinical presentation of patients with COPD is far fromuniform. This fact has been very well described in severalclassic publications in the British Journal of Diseases of theChest.28–30 Most patients with COPD present in the fifth orsixth decade of life although patients with alpha1-anti-trypsin deficiency may present at a younger age.4,5

Furthermore, symptoms of COPD vary among patients.While most patients with COPD present with symptoms ofcough and shortness of breath on exertion, many othershave minimal symptoms early in their disease process.Several screening questionnaires have been developed foruse in everyday clinical practice to facilitate the diagnosis ofCOPD in a primary care setting.31–33

A complete assessment of a COPD patient should includephysiologic measures of lung function. Spirometry is themost widely used and feasible test which can be performedin the primary care setting.34 The diagnosis of COPD is madeif the post-bronchodilator FEV1/FVC ratio is o70% althoughthe FEV1/FEV6 ratio may be used as an alternative as it hasbeen shown to correlate with FEV1/FVC.

35 Evaluation ofacute bronchodilator response should not be used alone asan index to differentiate asthma from COPD as manypatients with COPD demonstrate significant reversibility toacute bronchodilator administration.36 Other tests of lungfunction such as measurement of lung volumes (e.g.;inspiratory capacity at rest and during exercise) can shedmore details on the physiologic abnormalities present inCOPD although such tests are rarely needed on routineassessment.37,38 Exercise intolerance in patients with COPDcan be assessed either by measuring the walking distance(e.g., six minute walk test) or by performing formal exercisetesting using treadmill or cycle ergometry.39–41

Diagnosis of COPD in the community is more likely inpatients with worse lung function and health status and inpatients who are symptomatic.42 However, attaining acorrect and early diagnosis in the primary care settingremains challenged by the delay and infrequent use ofspirometry in that setting due to lack of adequate training inits use and interpretation.43 This is compounded by the lackof knowledge about COPD by patients at risk such as heavysmokers.44 Furthermore there is no clear correlationbetween symptoms, effort intolerance, and objectivemeasures of lung function.45,46 This has been clearlydescribed in a classic article published in the British Journalof Diseases of the Chest in 1961 which studied a group of in-patients with chronic obstructive airway disease attendingthe London Chest Hospital.45 Despite being a pilot study, thismanuscript sets out to grade the severity of disease andassess the clinical value of using various tests in patientswith ‘‘chronic obstructive airway diseases’’. The authorsstudied effort intolerance, lung function, arterial blood gasanalysis and exercise desaturation and suggest that asses-sing severity of the disease should include more than onemeasure. It is of interest that 60 years later, grading theseverity of COPD continues to be an important clinicaldilemma. While current guidelines suggest using the percentpredicted FEV1 to assess severity of the disease, recentstudies suggest that the use of multidimensional gradingsystems may be more useful in assessing the severity andimpact of COPD.47 Furthermore, the use of radiological

studies to evaluate the lung parenchyma and airway wallthickness may aid in differentiating between the differentCOPD severity phenotypes.48,49

Management guidelines for COPD

Several guidelines for the management of COPD have beenpublished.50–56 While the main goals for these guidelines areto achieve better standards for the diagnosis, treatment andprevention of COPD, unfortunately these guidelines have notbeen widely implemented.55–57 Furthermore, primary carephysicians who treat the majority of patients with COPDoften find the guidelines complicated and thus show a majorgap in the knowledge of all core elements of theseguidelines.57 A major problem with existing guidelines isthat they are usually based on efficacy and not oneffectiveness studies, and do not properly focus the processof behavioural changes of health professionals and pa-tients.56 Furthermore, as rapid changes may occur in thetreatment of COPD, future guidelines should be able toadapt to these rapid adjustments.

Prognostic factors and health outcomes inCOPD

COPD has a progressive course especially in patients whocontinue to smoke. Several studies have addressed riskfactors associated with progression of COPD.58–60 Earlystudies performed on case series of patients with COPD,demonstrate that the severity of airflow obstruction,hypoxaemia, hypercapnia and dyspnoea, and the presenceof co-morbidities such as congestive heart failure areimportant indicators of poor prognosis in COPD.59,60 A morerecent paper described important gender differences in thepredictors of decline of lung function in mild to moderateCOPD.58

Although lung function remains the most importantobjective outcome in assessing the severity and prognosisof patients with COPD, success of treatments for this diseaseis usually evaluated by measuring the impact of suchtreatments on a range of patients health outcomes.61,62

The course of patient reported outcomes such as healthstatus, dyspnoea and psychological status often deterioratesignificantly over time and may not strongly correlate withchanges in lung function parameters such as FEV1.

63

Change in symptoms of COPD is an important healthoutcome although cannot be accurately measured. TheBreathlessness, Cough and Sputum Scale was shown to be areliable, valid and responsive patient-reported outcomemeasure of symptom severity in patients with COPD and canbe used in clinical trials.64,65 Several instruments to measurehealth status were developed, tested and validated inpatients with COPD.66–72 Heath status in COPD correlateswith severity of the disease and hypoxaemia, and thepresence of co-morbidities.73 One study which compared theresponsiveness of six instruments used to measure healthstatus, confirmed that the Chronic Respiratory Question-naire (CRQ) and the Saint Georges Respiratory Questionnaire(SGRQ) were substantially more responsive than genericmeasures, and suggested particularly strong responsivenessfor the self-administered CRQ.67 ADL may be severely

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restricted in patients with COPD and their assessmentrequires evaluation of the impact of disability and handicapon daily life. The London Chest Activity of Daily Living Scale(LCADL) was shown to be a valid tool for assessment ofpatients with severe COPD.74 In a subsequent study, thisscale was also shown to be a valid outcome measure which isreliable and responsive to change.75

Co-morbidities of COPD

COPD is a multicomponent disease. These componentsaffect the lungs and organs outside the lungs.76,77 Theimpact of the systemic co-morbidities of COPD is substan-tial,72,78 and although some studies have addressed thepotential mechanisms underlying these co-morbidities,many important questions remain to be answered. Systemicmanifestations of COPD include musculoskeletal,79–81 psy-chological,82–84 nutritional depletion,85,86 anaemia andsexual dysfunction.87 Other pulmonary co-morbidities ofCOPD include cardiovascular complications and pulmonaryhypertension,88–91 obstructive sleep apnoea92 and lungcancer.93 Thus a comprehensive assessment of a patientwith COPD should also include assessing the systemic co-morbidities of this disease.

Acute exacerbation of COPD

Acute exacerbation of COPD is associated with increasedmorbidity and mortality.94 A variety of definitions for acuteexacerbation of COPD have been used in clinical studies.These have been traditionally based on change in patients’symptoms or their requirement for antibiotic therapy, oralsteroids or hospitalization.95 The importance for a standarddefinition has been recently emphasized.95 From a recentsurvey from 1100 subjects with symptoms compatible withCOPD,96 exacerbations generated a mean of 5.1 medicalvisits/year (SD ¼ 4.6) with the mean duration of exacerba-tion symptoms being 10.5 days. Increased coughing was theexacerbation symptom having the strongest impact on well-being (42%). Fifty-five percent of patients declared thatquicker symptom relief was the most desired requirementfor treatment.

The role of bacterial and viral infections as causativefactors of acute exacerbation of COPD was extensivelydescribed in several publications over the last 50 years.97–99

In one of these classic publications, Calder et al.98 describedtheir experience from a 5-year study of prophylacticantibiotic therapy in patients with chronic bronchitis. Inthat study, the use of prophylactic antibiotics reduced thenumber of exacerbations and the isolation of sputumpathogens; however, it did not influence the rate of declinein ventilatory function. This was one of the very firstlongitudinal studies that utilized what later became the goldstandard outcome in assessing the natural history of thedisease; the decline in lung function.

Many patients with acute exacerbation of COPD may needhospitalization. The presence of concurrent diseases such asheart disease and pneumonia prolong the hospital episodesof COPD patients78 and the use of long-term oxygen therapy(LTOT) and of short-acting b-agonists were associated with alate recovery from acute exacerbation of COPD.100 Factors

that have been associated with re-admission for acuteexacerbation of COPD include: hospital admission within 1year prior to the current exacerbation, nursing homeresidency, dependency in self-care activities, right heartstrain pattern on electrocardiogram, the use of high doses ofinhaled corticosteroids (ICSs) and a serum bicarbonate level425mmol/l.101

Management of COPD

Recent research has focussed on examining the multi-component nature of COPD (including impairments ofmetabolism and inflammation) more carefully, and deter-mining the effects of treatment on both the systemic andphysiological aspects of COPD. In effect, the multicompo-nent nature of COPD has provided a challenging environmentin which to develop successful treatments.

Obviously, many questions remain to be answered, but acomprehensive approach is now considered essential to thelife-long management of COPD, and will undoubtedly reducethe considerable socio-economic burden of COPD.102 Atpresent time, a combination of pharmacological and non-pharmacological approaches seems to be effective in theattempt to face with these problems.

Pharmacologic management

Pharmacologic management for COPD includes antibiotics,bronchodilators, corticosteroids, and mucolytics. There arealso some other classes of drugs that are still considered ofminor importance, but worthy of clinical investigation.

AntibioticsIn 1943, May103 published an article in which he documentedthat the concentrations of penicillin attainable in thesputum of patients with chronic bronchitis or bronchiectasiswere correlated with the in vitro sensitivity to penicillin ofthe infecting organisms and the clinical and bacteriologicalresponse of the patients to treatment. This observation wasreally interesting and nowadays it is still relevant. In fact,today we consider the interrelationship between pharma-cokinetics and pharmacodynamics extremely important inchoosing the appropriate antibiotic and the dosage regimenfor treating acute exacerbations of chronic bronchitis.104 Itmust be highlighted that in May’s paper each penicillinregime investigated gave sputum levels higher than thesensitivity level of pneumococci, which responded satisfac-torily to all penicillin preparations. Unfortunately, duringthe ensuing decades, penicillin-resistant pneumococci hasbecome an area for great clinical concern worldwidebecause it has been associated with treatment failure.

Up to 1980, the journal published a large amount ofpapers105–128 on the use of antibiotics in the treatment orprophylaxis of acute exacerbation of chronic bronchitis. Ineffects, at that time there was a lot of interest for theantibiotic therapy. This likely happened because the ‘‘Britishhypothesis’’, which raised the concept that chronic bron-chitis could predispose to infection, which in turn damagedthe airways and/or the alveoli, leading to progressiveairflow limitation. The continuous introduction into themarket of new anti-infective agents certainly facilitated the

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production of data relating to the use of such agents.Unfortunately, most of these clinical trials of antibioticshave compared new drugs with standard therapy in patientswith exacerbations who, in most cases, would have neverrequired an antibiotic if treated in real-life conditions. Ingeneral, these studies might have been required for thepharmaceutical companies to launch their new antibiotics,but offered limited, if any, useful information to theclinician. In any case, May105 wrote a review that was reallyimportant for those times. He described in extremelycritical manner the problems related to the bacteriologyand chemotherapy of chronic bronchitis. In his conclusions,May expressed an anticipatory view. It was his opinion that itwas possible that failure of penetration of antibiotic intomucoid bronchial secretions in patients whose infection wascontrolled by bacteriostatic therapy might explain thefailure of such therapy to give more lasting benefit. If theorganisms in the secretions were inaccessible to theantibiotic, and there were no phagocytes present, therewas no reason why they should not remain viable indefinitelyand able to cause a fresh infection as soon as the bronchialtissue was freed from protective antibiotic. For this reason,he suggested that the approach to chemotherapy of chronicbronchitis had to change from bacteriostatic, which wascommon at that time, to bactericidal and, consequently,treatment courses had to become intensive but for shortperiod. Interestingly, several articles108,111,117,122 havereported that chemoprophylaxis was of no help in prevent-ing acute exacerbations of pulmonary infection although theattacks were milder in nature and the total number ofmonthly purulent sputum specimens was less in the groupgiven a prophylactic antibiotic, it had no effect on time offwork in individual spells of illness and, moreover, it did notinfluence the rate of deterioration in ventilatory function. Itwould be interesting to know why in the following yearsmany researchers have spent time and money for getting thesame conclusions!

Even in the last few years, Respiratory Medicine haspublished some papers devoted to the use of antibiotics inthe treatment of acute exacerbation of chronic bronchi-tis.128–139 Also these studies, however, might have beenrequired for the pharmaceutical companies to launch orsupport their new antibiotics (gemifloxacin, moxifloxacin,telithromycin), but offered limited, if any, useful informa-tion to the clinician. Nonetheless, it must be highlightedthat Banerjee et al.136 reported that treatment of COPDwith clarithromycin during the clinical stable state yields noclinical advantages and therefore cannot be recommendedas means of eliminating sputum bacteria or preventinginfective exacerbations. This does not seem an unexpectedresult that fits well with the prescriptive behaviour ofgeneral practitioners. Miravitlles et al.137 published inter-esting data coming from a Spanish cross-sectional observa-tional study of ambulatory COPD patients. Treatment forexacerbations included inhaled bronchodilators (90%), anti-biotics (89%), ICSs (71%) and oral corticosteroids (43%); thenumber of previous acute exacerbations was the main factorassociated with exacerbation treatment except for oralcorticosteroids, the use of which was associated with moreimpaired pulmonary function. More intriguing is the Hasa-ni’s138 paper, which showed that even only 7 days antibiotictreatment slightly improved tracheobronchial clearance

and significantly decreased cough suggested a significantrole of the antibiotic treatment at least in decreasing therisks of further and greater damage to the airwayepithelium. In any case, pneumococcal vaccination reducesthe risk of Streptococcus pneumoniae-induced COPD ex-acerbations.139

BronchodilatorsThe article by Feinman and Newell140 published in 1963, wasthe first paper in the journal to focus on the use ofbronchodilators for treating an obstructive airway disease. Ithad the great merit of documenting that isoprenaline in adose of 0.4mg delivered by a self-propelled aerosol device,gave an improvement in FEV1 on average 0.10 L better andan improvement in VC 0.16 L better than 3min continuousinhalation of 1% isoprenaline solution using a standardhospital nebulizer driven by an oxygen cylinder. The authorsrecognized that eventhough these differences were notlarge or important clinically, the much smaller dose given bythe self-propelled aerosol device reduced the chance of sideeffects and justified rejection of the more standard methodsof administration that were popular at that time.

The development of newer bronchodilators at the end of1970s slowly moved the interest of the journal towards thisnew therapeutic option.141–148 Berend et al.141 documentedthat the bronchodilator response to salbutamol by inter-mittent positive pressure ventilation (IPPV), was greaterthan by metered dose inhaler (MDI) only in patients sufferingfrom chronic obstructive bronchitis with severe airwaysobstruction and little additional benefit was gained with the10mg dose. Jenkins and Moxham147 suggested that there isminimal if any benefit in terms of functional statusadministering regular doses above the equivalent of 200 mgof salbutamol four times daily in COPD, although pulmonaryfunction (FEV1 and PEFR, but not FVC) results showed atrend towards higher doses producing improved responseand a longer duration of action, with bronchodilationfollowing 2mg significantly greater than 400 mg salbutamol.This study was broadly a forerunner of the actual tendencyto use greater than traditional dosage of long-acting b2-agonists (LABAs), mainly formoterol, to prolong theirduration of action.149

After 1989, the number of articles that have explored theuse of bronchodilators in COPD increased in a dramaticmanner. It is almost impossible to quote all these articles,and, consequently, only those papers that in our opinionhave been innovative, will be discussed. Hansen et al.150 andHansen and Andersen151 in 1994 and 1995 published twointeresting papers that documented that the replacement ofnebulizers with multidose dry powder inhalers was advanta-geous both for the COPD patient, in terms of ease of use andportability, and for the Local Health Service, in terms ofreducing resources spent on inhalation treatment. Cazzolaet al.152 in 1995 published one of the first articles on the useof LABAs in the treatment of COPD. Up to 2000, the majorityof these articles have been focused on the activity ofLABAs153–157 and the possibility of combining these agentswith bronchodilators of other classes.158,159 Importantly, aneditorial published in 1999160 raised for the first time thequestion of considering LABAs an alternative first choiceoption for the treatment of stable COPD.

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More recently, the interest of researches has beenfocused on inhaled long-acting bronchodilators161–176,although some interesting new observations on short-actingbronchodilators have also been published,177–182 particularlythe documentation that prescription of ipratropium wasassociated with increased mortality in both COPD andasthmatic patients.180 Moreover, there have been twointeresting papers on the use of theophylline, now con-sidered a third line agent in the therapy of COPD.183,184 Inparticular, Ram et al.184 have published an evidence-basedreview that has shown that theophylline continues to have arole in the management of stable COPD, and is preferred bypatients over placebo. However, the benefits of theophyllinein stable COPD have to be weighed against the risk ofadverse effects. The documentation that tolerance topharmacologic bronchodilation occurs with LABAs such assalmeterol and not with long-acting inhaled anticholinergicssuch as tiotropium169 is a really intriguing finding. It must behighlighted that the reported diminishment of bronchodi-lator responses was relatively small, and a prospective trialdesigned specifically to examine for tolerance should bedesigned. Nevertheless, the concept of tolerance may needto be considered when re-evaluating COPD patients duringchronic treatment with LABAs, considering the possibility ofusing bronchodilators of different classes. Adams et al.175

have documented that once-daily tiotropium providessignificant improvement in lung function, health status,and dyspnoea when used as maintenance therapy inundertreated COPD patients who were not previouslyreceiving maintenance bronchodilator therapy. In any case,although this potentially important problem, Jones et al.165

have observed that addition of salmeterol to COPD patients’current therapy improved lung function, health status at theexpense of a modest increase in costs compared with usualtherapy. Considering the fact that both LABAs and tiotro-pium are effective agents in the treatment of stable COPD,the present trend is to combine a LABA and tiotro-pium.170,172

The fast onset of action of formoterol161,173 has suggestedtesting this bronchodilator in the treatment of acuteexacerbation of COPD. Preliminary data with LABAs162,164,167

seem to indicate that repeated doses of both formoterol andsalmeterol induce an effective dose-dependent increase inlung function in patients suffering from COPD exacerbations,but only formoterol induces a fast onset of action. Asuggested possible alternative to the use of higher thanrecommended dose of formoterol is the combination offormoterol and tiotropium, although the time course of theeffects of these drugs differs significantly from that in stableCOPD, with a shorter bronchodilation both for tiotropiumand formoterol.185 In any case, because of its pharmacody-namic profile with both a rapid onset of effect, similar tosalbutamol, and a long duration of action, similar tosalmeterol, formoterol is suitable for both maintenanceand as-needed treatment in COPD.174

CorticosteroidsIn 1958, Ogilvie186 published an article on the treatment ofpatients with severe asthma and chronic bronchitis. Thisarticle was surely significant at that time because it had themerit of stressing the fact that the treatment of patients

with severe asthma and chronic bronchitis was perfectlyfeasible, and success might be expected in two-thirds ormore of cases. Moreover, it highlighted the importance ofcalculating the cost because it was becoming increasinglyclear that there was an imperative need to reduce the costof certain remedies of proved and vital importance, whetherby a vast increase in the scale of production, or by othermeans. Unfortunately, Ogilvie considered the treatment ofsevere asthma and chronic bronchitis in the same mannerand suggested that it had to consist of the suppression, firstof all, of infective activity by antibiotic therapy, followed bythe exhibition of a suitable adrenal hormone in adequatedosage. This initial treatment had to be followed bymaintenance therapy, but it was Olgivie’s opinion that itcould fail within 6 months if it consisted of hormone alone(mainly, ACTH or prednisone). Consequently, successfulmaintenance treatment of persistent asthma with chronicbronchitis depended on the use both of antibiotics andhormones on a permanent or semi-permanent basis. In anycase, this paper could be considered important still todaybecause it stressed that the use of ‘‘antispasmodics’’(adrenaline hydrochloride 1 in 1000 by injection, aminophyl-line by mouth, and what he just defined a new aerosolsolution which he was testing prior to introduction forgeneral use) was ineffective in a number of patients that, onthe contrary, responded very well to hormone treatment.This is one of the first reports that patients suffering fromchronic bronchitis may present an irreversible airwayobstruction, although today this information is consideredmisleading. On the contrary, the documentation that the useof bronchodilators as a screening device for the selection ofpatients for hormone treatment is valueless is still relevant.In 1960, Ogilvie and Newell187 tested a maintenancecombined treatment with an oral corticosteroid (methylprednisolone) and an antibiotic (terramycin+novobiovin) in aseries of asthmatics with chronic bronchitis. They concludedthat maintenance treatment by corticosteroid had someclinical effect on certain of these patients, which wasannulled by discontinuing it, a view supported by thefrequent clinical observation that deterioration in thechronic asthmatic with chronic bronchitis occurs much morereadily than the reverse change. This was an intriguingconclusion that is still relevant considering the existingdebate on the use of corticosteroids in stable COPD.188

In 1963, Hurford et al.189 explored the use of prednisolonein chronic bronchitis. They observed that only a smallproportion (20%) of patients with chronic bronchitis andemphysema who did not react to more conservativetreatment showed a response to a week on prednisoloneat a dose of 30mg a day and raised the suspicion that theseresponders were characterized by something differentwhich would explain their heterogeneity. The authors alsoobserved that some patients, who did not respond in theshorter period, responded to corticosteroids after longerperiods than one week. Discussing these results, theyhighlighted a concept that is still a controversial issue,although it is supported by many researchers in the field. Itwas their opinion that if there are occasional cases ofchronic bronchitis in which endobronchial changes andbronchospasm will be relieved by prednisolone, they areprobably much fewer than would appear if this drug is usedwithout close control with ventilatory tests. There is no

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doubt that it can temporarily bring a general feeling of well-being which will lead some patients with chronic bronchitisto feel better able to carry on despite virtually unchangedexercise tolerance. But this is certainly not sufficient excusefor continuing the use of corticosteroids.

In the 1990s, some articles that related the use ofcorticosteroids were published.190–194 Senderovitz et al.194

documented that in outpatients with stable COPD and nosigns of asthma or atopy, 2 weeks treatment with pre-dnisolone seems to be of no value in choosing subsequentlong-term therapy. Strom191 reported an increased mortalityin women receiving oral corticosteroid medication that wasfound to be associated with an increased need of hospitalcare due to longer hospital stays during the terminal stage ofthe disease. This finding has an important clinical impact. Infact, since prescriptions of the same dose of oral corticos-teroid medication to male and female patients in COPDcould result in a greater incidence and severity of side-effects in female patients, this practice should be debated.Jarad et al.193 were able to document that abrupt with-drawal of ICSs may lead to early exacerbation in stableCOPD. This is an important finding because it indicates thatclinicians should be aware of the risk of an exacerbationdeveloping within a few weeks of stopping this treatmentand, consequently they should never suggest to patients todiscontinue treatment with ICSs if this is not giving themimmediate benefit.

Some interesting papers194–203 have focused on theadministration of ICSs to COPD patients. They reachcontrasting results and, consequently, they confirm thedebate existing on this topic.188 Thus, it has been documen-ted198 that early initiation of ICS treatment does not seem toaffect the progressive deterioration of lung function or otherrespiratory health outcomes in subjects with early signs andsymptoms of COPD. Therefore, primary care physiciansshould be careful to base maintenance treatment with ICSsin subjects at risk for, or in an early stage of COPD on a singlespirometric evaluation performed in the first months oftreatment. However, Ayres et al.197 reported that treatmentwith an ICS was associated with statistically significantclinical benefits in patients with moderate-to-severe COPDcurrently symptomatic on regular bronchodilator therapy. Asthe differences in direct and total costs compared withplacebo were small and non-significant, they considered sucha type of treatment cost effective in this patient population.Moreover, Tkacova et al.203 documented that ICS may reduceall-cause mortality in patients with severe COPD and chronichypoxaemia, who require long-term domiciliary oxygentherapy. These data suggest that ICS may indeed play animportant role in improving clinical outcomes in patients withadvanced COPD.

Combination therapyThe benefit that exists when an ICS is combined with a LABAhas been discussed in several articles.204–209 Analysingresults of the TRISTAN study, Vestbo et al.205 did not finddifferences between women and men with COPD in theefficacy and safety outcomes in comparing the salmeterol/fluticasone propionate combination versus placebo. Cazzolaet al.204 suggested that when treating patients withformoterol, it is prudent to check their arterial blood gases

because this bronchodilator can worsen pretreatmenthypoxaemia. However, combined administration of formo-terol and budesonide reduces the potential for acute effectsof formoterol on blood-gas tensions. Mapel et al.209 analysedCOPD patients from two different managed care organiza-tions from different parts of the United States and foundthat patients who used an ICS, a LABA, or an ICS plus a LABAhad better survival than patients who were only using short-acting bronchodilators, and that this survival benefit waspreserved even after adjustment for the other clinicalfactors likely to affect survival, including age, diseaseseverity, comorbid diseases, and smoking history. Theyfound that COPD patients who had a concurrent diagnosisof asthma had better survival than those who did not, butthe benefits of ICS therapy with or without a LABA werepreserved after adjusting for asthma in the models.Interestingly, LABA and the combination treatments arelikely to be cost-effective, at least in the United States.207

Mucolytics agentsSeveral papers on the use of mucolytics agents in COPD werepublished.210–217 In particular, Millar et al.213 were unable tofind significant differences in lung function, mucociliaryclearance curves or sputum viscosity following treatmentwith N-acetylcysteine (NAC) compared to control or placebomeasurements. Even more important, Parr and Huitson214

failed to find any statistically significant difference in thenumber of exacerbations between NAC or placebo groupsafter a 6-month treatment, although there was a slighttrend towards improvement in the NAC group during the first3 months of the trial. It must be highlighted that the dosageof NAC used in these studies was really low (200 mg thricedaily). The possibility of influencing tracheobronchialclearance and in this way, eliciting a beneficial action inchronic bronchitis was tested again administering NAC.However, NAC administered by MDI did not have anysignificant effect on patients’ feeling of well-being, sensa-tion of dyspnoea, intensity of coughing, mucus production,or expectoration or lung function,215 although anotherstudy216 documented that orally administered NAC mayimprove general well-being in patients with mild chronicbronchitis. Considering these findings, it is not surprisingthat a large randomised placebo-controlled long term (3years) trial of the effects of NAC 600mg on a once daily basison the progression of disease and exacerbation rate inpatients with COPD who had frequent exacerbations (i.e., atleast two per year for 2 years) confirmed that NAC at thedosage of 600mg daily is ineffective at prevention ofdeterioration in lung function and prevention of exacerba-tions in patients with COPD.217

These results do not support the use of this drug in COPD,but there has been recent evidence that NAC may beconsidered an antioxidant rather than a mucolyticagent.218–222 Interestingly, van Schayck et al.223 hypothe-sized that that anti-oxidant treatment might be relativelymore effective among those COPD patients who respond lesswell to ICSs (low reversibility and heavy smoking).

Alternative drugsConsidering the need for alternative drugs in the treatmentof COPD, in the last few years the journal published some

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small, but intriguing articles, which described the efficacyof several different new therapeutic possibilities. Theserange from the potential of prescribing montelukast inelderly patients with moderate to severe COPD,224 to theuse of selective phosphodiesterase (PDE)4 inhibitors (cilo-milast and roflumilast) due to their novel mechanism ofaction and potent anti-inflammatory effects, coupled with agood safety and tolerability profile,225 or to the use of a low-dose testosterone to men with COPD in order to counteractprogressive weight loss, and loss of lean body mass that hasspecifically been associated with skeletal muscle dysfunc-tion and is frequent in COPD patients.226 Recently, Gronke etal.227 have shown that H1 receptor antagonist cetirizine wasable to influence hypertonic saline-induced airflow obstruc-tion in moderate-to-severe COPD. In view of the mechanismsinvolved in hypertonic saline responses, it is an openquestion whether stronger effects can be elicited withhigher doses and whether such effects would translate intoclinical benefits, e.g. during exacerbations. The documen-tation that rebamipide, a gastro-protective agent used inthe treatment of gastritis and ulcerative colitis, is able toprevent TNF-a release, neutrophil recruitment into theairways, and MUC5AC mucin synthesis in cigarette smoke-stimulated airway epithelium228 is another intriguing findingbecause it suggests that rebamipide may be used to treatmucus hypersecretion in cigarette smokers.

Chronic respiratory failure is the end stage of COPD.Home oxygen therapy is the only treatment which has beendemonstrated to improve survival of COPD patients withchronic respiratory failure, but the mortality of patientsreceiving LTOT is around 50%. These poor results havespurred the search for coadjuvant or alternative pharmaco-logical treatments. Almitrine bismesylate is a peripheralchemoreceptor agonist which is believed to improveoxygenation, probably by improving the ventilation perfu-sion mismatch. Although when used at doses of 100–200mg/day it shows an improvement in PaO2 greater than 5mmHg,its tolerance is poor, and the number of side-effects such asdyspnoea and peripheral neuropathy was unacceptable. Forthis reason, it has been tested at doses of 1mg/kg/day usingan intermittent schedule in a randomized double-blindplacebo-controlled study,229 but while well tolerated, atthese doses, use of almitrine is not effective in long-termtreatment of chronic hypoxaemia in COPD patients. None-theless, in short-term treatment, the association of almi-trine and medroxyprogesterone acetate seems to be moreefficient than either drug alone at improving arterial bloodgases in these patients.230 Moreover, it has also beendocumented that four days of treatment with almitrineimproved gas exchange in a group of subjects with hepaticcirrhosis.231

Non-pharmacologic management

Non-pharmacologic management for COPD include LTOT,nasal positive pressure ventilation (nPPV), pulmonaryrehabilitation and lung volume reduction surgery (LVRS). Inthe future, it will be important to establish the precise valueof the different management strategies available forCOPD–evaluating both clinical and physiological endpointsand using the data to more accurately define candidate

patients accordingly. The challenge will be to develop thisbase of knowledge in order to shape future research andallow clinicians to deliver tailored COPD managementprograms for the growing number of patients afflicted withthis disease.232

Developing the means to measure the effects of COPD isimportant, both in terms of understanding disease patho-physiology for research purposes, and accurately assessingthe effects of treatment on the patient. Future develop-ments will include computerizing these methodologies topermit faster and more individual patient-centred measure-ments.233

Long-term oxygen therapy (LTOT)Apart from smoking cessation, LTOT is the only treatment todate which has been shown to modify the long-term declinein lung function that is associated with COPD and, therefore,improve survival rates in severe cases; thus its role in COPDis well defined.232

LTOT has also been associated with a variety of benefits inpatients with severe COPD, including increased survival,reduced secondary polycythemia, improved cardiac functionduring rest and exercise, reduction in the oxygen cost ofventilation and improved exercise tolerance. Of particularnote are the results of a longitudinal study showing thatLTOT significantly improved heath-related quality of life(HRQoL) at 2 and 6 months, compared with a progressivedecline in HRQoL in the non-LTOT group. In the LTOT group,67% and 68% of patients (at 2 and 6 months, respectively)showed a clinically significant improvement in their CRQscores.234 Hence, there is a convincing rationale forincluding LTOT in the treatment paradigm for patients withsevere COPD. Patients with PaO2o7.3 kPa (55mmHg; corre-sponding to SaO2o88%) whose disease is stable despitereceiving otherwise comprehensive medical treatmentshould receive LTOT. A patient whose PaO2 is 7.3–7.8 kPa(55–59mmHg; SaO2 89%) should receive LTOT if they showsigns of pulmonary hypertension, cor pulmonale, erythrocy-tosis, oedema from right heart failure or impaired mentalstate. If oxygen desaturation only occurs during exercise orsleep, then oxygen therapy should be considered specificallyunder those conditions. An optimal medical regimen can beestablished incorporating these guidelines, with the chiefaim of achieving an optimized ventilation:perfusion ratiomatching (V0/Q) as a means of correcting hypoxaemia.

COPD patients undergo episodes of O2 desaturation ofarterial blood during rapid eye movement sleep. Fletcher etal.235 revealed that these desaturations occur both in non-hypoxemic patients and in patients who are hypoxemicduring the day. Further research by Plywaczewski et al.236

showed that 47.6% of COPD patients treated with LTOTspent430% of the night with a SaO2 of o90%, and thus requiredincreased oxygen flow during sleep. The administration ofoxygen at a flow-rate higher than the daytime settingusually corrects nocturnal hypoxaemia. Conflicting evidencesurrounds the contention that patients who only desaturateduring sleep will benefit from nocturnal oxygen treatment.But while Fletcher et al.235 found a beneficial effect ofsupplemental oxygen treatment in this patient group, otherwell-controlled studies have not shown that the use ofnocturnal supplemental oxygen alters mortality or clinical

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course, other than slightly lowering pulmonary arterypressure.

Oxygen therapy during exercise decreases dyspnoea andimproves exercise tolerance at submaximal exertion. Themechanical rationale underlying this observation is adecrease in dynamic hyperinflation, and reduced ventilatorydrive. LTOT is prescribed for patients who become morehypoxemic during exercise, or who only become hypoxemicduring exercise, with oxygen settings determined while thepatient is undergoing a typical level of exertion. Studiesevaluating the long-term benefit of oxygen treatment solelyfor exercise have yet to be conducted.

In an interesting paper published in 1989,237 a total of 43severely ill COPD patients already on 24 h, or near 24 h, perday supplemental O2 were randomly assigned to transtra-cheal oxygen delivery (n ¼ 22) or usual delivery of O2 bynasal cannula or face mask (n ¼ 21). A few importantchanges were found in pulmonary function over time such asdecreases of PEFR, FEF and MVV for both experimental andcontrol groups, and FEV1% and FEV3% in experimentalpatients. At the same time, there was a significant decreasein both haematocrit and haemoglobin, and per cent shuntingfor the experimental group and a significant increase in percent shunting in the control group. Physical, social andpsychological assessments showed significant improvementover time for experimental patients and declines for thecontrol group. Lastly, medical costs were positively af-fected, as fewer days were spent in hospital post-studyenrolment by experimental than control groups, and post-enrolment relative to pre-enrolment by experimentalpatients.

Non-invasive ventilationMechanical ventilation increases or substitutes for anindividual’s spontaneous respiration, as in the case of acuterespiratory or ventilatory pump failure.232 Non-invasiveventilation, e.g. intermittent negative pressure ventilation(INPV) or nPPV, have recently re-emerged as popular optionsthat avoid the risks associated with invasive ventilation.232

nPPV is thought to assist ventilation, by improving inspira-tory flow rate and correcting hypoventilation. Other possiblemechanisms of action include resting respiratory musclesand resetting the central respiratory drive.232

In contrast to the evidence supporting the use of nPPV totackle other causes of chronic respiratory failure, there isconflicting evidence regarding the benefits of nPPV inCOPD.232 In a 12-week double-blind study of 184 patientswith severe COPD, no significant difference was observed in6-min walk test results, cycle endurance time, severity ofdyspnoea, HRQoL, respiratory muscle strength or arterialblood gas compared with sham treatment.238 This suggeststhat inspiratory muscle rest has no benefits for patients withsevere stable COPD, although poor patient compliance mayhave contributed to the results.

Regarding the administration of nPPV in patients withsevere COPD, two 3-month crossover trials of similar designcame to different conclusions.239,240 The discrepancybetween these results may be explained by the differencebetween patient sets at baseline: patients with greater CO2

retention and more frequent nocturnal oxygen desaturationsmay benefit more from nPPV administration.

In addition to this conflicting data on physiologicalendpoints there is a lack of data showing whether nPPVtreatment actually improves survival rates. Two largemulticentre trials have focused on nPPV in patients withsevere hypercapnic COPD. One trial published as an abstractby Muir et al.241 which compared home nPPV plus LTOTwithLTOT alone, indicated that there is no overall survivalbenefit in patients receiving nPPV plus LTOT, although theremay be a slight improvement in survival for patients over 65years of age. A 2-year Italian multicentre study alsoexamined the effects of nPPV plus LTOT compared withLTOT alone (N ¼ 122).242 In this trial, nPPV plus LTOTimproved PaCO2 during breathing of the usual oxygeninspiratory fraction. Long-term improvements were alsonoted in dyspnoea and HRQoL in the nPPV plus LTOT group,but survival was similar between treatment groups.

Currently, there is little evidence supporting the use ofmechanical ventilatory support in the routine managementof COPD.233 However, further large studies may be able toidentify subsets of patients for whom nPPV would bebeneficial.

An historical and pioneering paper published in 1958243

showed that inspiratory positive pressure breathing (IPPB)by itself and independently has therapeutic value, particu-larly in asthma, bronchitis and emphysema, concluding thatit probably accomplishes this result by helping to clear thebronchial airways of obstructing secretions and exudations,although other effects as yet unknown may be important.The therapeutic results are erratic and the use of IPPB isjustified only by the otherwise inexorable progress to anasphyxial death of crippling COPD. The authors suggest thatthis technique may also be used as a means of temporarilydiminishing venous return in acute pulmonary oedema, andof expanding collapsed segments of lung in respiratoryparalysis and post-operative immobilization of the lung andthey retain that the hazards of this form of treatmentare slight.

LVRS for emphysemaLVRS was originally proposed as a palliative treatment forpatients with severe emphysema. The rationale for LVRS isbased on the premise that these patients have severehyperinflation and the goal of surgery is to removefunctionally useless emphysematous lung. Generally, thisinvolves the removal of 25–30% of lung tissue from both theleft and the right sides. Benefits associated with LVRS areimproved lung function (reduced lung volume and increasedFEV1) and exercise (including the distance walked in6min).243 Although carefully selected patients benefit fromLVRS, questions remain concerning the magnitude andduration of positive outcome.232

The National Emphysema Treatment Trial (NETT) was setup as a multicentre, randomized, large-scale clinical trial(N ¼ 1218) to evaluate the effects of LVRS.244 Overall resultsfrom the NETT at 2-years post-randomization indicate thatLVRS improves exercise capacity, but does not improvesurvival compared with medical therapy. Patients in theLVRS group also reported improved health status and lessdyspnoea compared with the medical group. Subgroupanalyses showed that patients with upper-lobe predominantemphysema and low exercise capacity had improved survival

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with LVRS, compared with medical therapy; those patientswith245 mainly non-upper-lobe emphysema and high ex-ercise capacity showed reduced survival. From these results,two key outcome predictors can be identified: distributionof emphysema and exercise capacity following pulmonaryrehabilitation. Combined with the factors placing patientsat high risk for LVRS, these predictors allow more targetedpatient selection than was previously possible.

Key questions remaining concern the role of pre-operativepulmonary rehabilitation, the mechanisms by which LVRSimproves lung function and survival, and the impact ofdifferent surgical techniques on LVRS outcomes.232 Theidentification of long-term predictors of LVRS outcomeswould be a welcome development, while investigatingunilateral or repeated LVRS, as well as non-invasivetechniques to reduce lung volume, may prove successful inthe future.

Pulmonary rehabilitationPulmonary rehabilitation complements pharmacotherapyand is now considered central to the management ofsymptomatic COPD.246 This form of management hasnegligible effects on pulmonary function, yet commonlyprovides substantial relief from dyspnoea, increased ex-ercise tolerance and improved HRQoL.246 Pulmonary reha-bilitation appears to work via several mechanisms, includingreducing some of the comorbidity associated with chronicrespiratory disease (such as the physical deconditioningassociated with sedentarism) and providing patients withself-management strategies (through disease-related edu-cation).246 Rehabilitation would also seem to reducesubsequent health care utilization, with the valuable costreductions that this would imply.246

The logical concept of optimizing the pharmacologicmanagement of COPD patients prior to, and during,pulmonary rehabilitation to achieve greater benefit isbecoming more widely recognized. Despite a growing bodyof research evidence, further work is needed to determinewhich patients will benefit most from pulmonary rehabilita-tion, how this form of management is best prescribed, andhow to identify the most suitable practice setting, which isdependent on the stage/phase of the disease.

Pulmonary rehabilitation is defined as an art of medicalpractice in which an individually tailored, multidisciplinaryprogramme is formulated. It is indicated for patientssuffering from complex problems in relation to theirpulmonary disease. The goals of pulmonary rehabilitationare: (1) to decrease the physical and psychologicalmanifestations of the underlying disease, i.e. reduce theimpairment due to the disease; (2) to increase physical andmental fitness and performance, and reduce the disability;(3) to achieve maximal social reintegration of the patient,thus lowering the handicap.247 The ultimate goal is amaximal functional capacity, as allowed by the pulmonarydisturbance and overall situation. The methods by whichthese goals may be achieved are combined in a programmetailored to each individual patient. It consists of: (a) anaccurate diagnosis of the disease and of the functionallimitations of the patient, (b) education about the disease,its pathophysiology, use of medications, use of a peak flowmetre, and the avoidance of harmful or aggravating stimuli,

e.g. smoking, (c) physical training to improve the physicalfitness and performance, and (d) psychosocial support. Theprogramme should be based on an adequate diagnosis of theextent and character of the limitations of the individualpatient.247

Pulmonary rehabilitation is a therapeutic process, whichentails taking a holistic approach to the welfare of thepatient with chronic respiratory illness—most commonlyCOPD—and is considered essential throughout the lifetimemanagement of patients with symptomatic chronic respira-tory disease. It requires the coordinated action of amultidisciplinary healthcare team in order to deliver anindividualized rehabilitation programme to best effect—in-corporating multiple modalities such as advice on smokingcessation, exercise training and patient self-managementeducation, among others. As core components of pulmonaryrehabilitation, exercise training and self-management edu-cation have been shown to be beneficial in improving HRQoLin patients with chronic respiratory disease. Physicaltraining can help to reduce the muscle de-conditioning thatoccurs when the activity of patients is restricted by theirbreathlessness and fatigue, and it is often associated with anincrease in patients’ HRQoL. HRQoL can also be improved bythe use of self-management education, which is designed toprovide the patient with the skills to manage the healthconsequences of their disease. In doing so, patients arebetter able to cope with disease symptoms, potentiallyleading to reduced health care costs.247

In the last decades there was a large debate on theeffectiveness of pulmonary rehabilitation and of its differ-ent components. For example, in a 1982 negative papereight patients with chronic obstructive bronchitis andmoderate disability entered a pilot study on the effects ofcontrolled diaphragmatic breathing. They received 3 weeksof placebo physiotherapy (shoulder exercises) followed bythree weeks of instruction on controlled diaphragmaticbreathing. No beneficial effects were observed on exerciseperformance or the perceived strain of exercise.248

Nevertheless, pulmonary rehabilitation is now supportedby a solid body of scientific evidence and is widely availablein North America and in Europe for patients with COPD. As aparadigmatic example, the feasibility and benefits ofproviding a comprehensive but cost effective pulmonaryrehabilitation programme in a UK district general hospitalhas been reported.249 Two hundred and sixty-seven patientswith respiratory disability were referred for pulmonaryrehabilitation. Patients were assessed and recruited into a7-week outpatient-based pulmonary rehabilitation pro-gramme including elements of exercise and educationwithout longer-term maintenance. For all graduates, shuttledistance increased by 58m (27%) and treadmill endurancetime increased by 15.9min (294%). The Breathing ProblemsQuestionnaire proved sensitive to changes in quality of lifein some domains. The Chronic Respiratory Disease Ques-tionnaire showed significant improvements in all domains ina sub-set of 57 patients who completed it. Longer-termfollow-up of 49 patients at a mean of 10.3 months followingpulmonary rehabilitation revealed that previous gains inexercise performance and quality of life were maintainedwith improvements in shuttle walking distance of 33m (14%over baseline) and endurance time of 16min (280% overbaseline). The Breathing Problems Questionnaire showed no

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overall change but the Chronic Respiratory Disease Ques-tionnaire showed continued improvement in a small numberof patients.

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