treatment of copd and its comorbidities

8/19/2019 Treatment of COPD and Its Comorbidities

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Treatment of Chronic Obstructive Pulmonary Disease

and Its Comorbidities

Fabrizio Luppi 1, Francesca Franco , !ianca !e"he# 1, and Leonardo $% Fabbri 1

1Department of &espiratory Diseases, 'niversity of $odena and &e""io (milia, $odena, Italy) and Department of Internal $edicine, C%$a"ati *ospital, +candiano, &e""io (milia, Italy

hile chronic obstructive pulmonary disease -COPD. is stillcharac/terized and dia"nosed by lun" function measurements,there is increasin" evidence that the chronic diseases thatfre0uently de/velop ith COPD in response to the common ris2factors -smo2in", a"in", obesity. may contribute si"nificantly to itsclinical manifes/tations and severity% Considerin" thatpharmacolo"ic and nonphar/macolo"ic treatments of COPD, suchas pulmonary rehabilitation, are primarily symptomatic, it isreasonable to hope that a more comprehensive mana"ement ofCOPD that ta2es into account its comorbidities may improve theresponse to treatment and reduce mortality in patients ith COPD%Thus, as comorbidities are often underdia"nosed andundertreated, it is important to search for their coe3istence inCOPD and in all chronic diseases, possibly by adoptin"recommendations for dia"nosis of sin"le diseases% This meansthat hile careful cardiovascular, metabolic, and endocrinolo"ice3ami/nations should be increasin"ly used in assessin" patients

ith COPD, lun" function measurements may become useful in

patients ith chronic cardiovalscular, metabolic, andendocrinolo"ic diseases% The increasin" evidence that activetreatment of comorbidities -by, e%"%, statins and b/bloc2ers. mayreduce morbidity and mortality in patients ith COPD su""ests theur"ent need for randomized clinical trials that hopefully ill providethe evidence for more comprehensive clinical "uidelines for thesepatients%

4ey ords5 chronic obstructive pulmonary disease) comorbidities)statins) an"iotensin/convertin" enzyme) steroids

Chronic diseases make up a huge proportion of human illness. Ithas been estimated that in 2005 more than 35 million people diedfrom heart disease, stroke, cancer, and other chronic diseases (1– 3 . Cardio!ascular diseases, chronic respirator" diseases, anddiabetes are the most fre#uent chronic degenerati!e disorders,

particularl" in the elderl"$ more than half of all elderl" peopleha!e at least three chronic medical conditions, and a significant

proportion ha!e fi!e or more (% , that are often unrecogni&ed anduntreated (5 . 'ecause of an e pected sharp increase in chronicdiseases in the ne t 10 "ears, this is an important area of concernfor health authorities (1–3, ) . Chronic diseases share largel"

pre!entable risk factors, in particular poor socioeconomic con*ditions, poor diet, smoking, obesit", and h"pertension (+ .

Chronic diseases such as chronic heart failure (C - and chronicobstructi!e pulmonar" disease (C / often de!elop together

ith one or more co*morbid conditions and ne!er alone (+, . ot onl" ma" a coe isting chronic disease contribute to theclinical manifestations and the se!erit" and life e pectanc" ofthe patients (4 , but it ma" also influence the efficac" and safet"of patient management. hile common clinical practice is totreat chronic disease as a single condition, there is an urgent needto

-&eceived in ori"inal form +eptember 6, 778) accepted in final form +eptember 9,778.

Correspondence and re0uests for reprints should be addressed toLeonardo $% Fabbri, $%D%, Department of &espiratory Diseases, 'niversityof $odena and &e""io (milia, :ia del Pozzo, ;1, m Thorac +oc :ol ?% pp 8


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COPD > D IT+ C*&O IC CO$O&!IDITI(+

C / is still defined as a disease state characteri&ed b" poorl"re!ersible airflo limitation induced b" cigarette smoke and6orother no ious particle and gases, and spirometr" is recommen*ded to establish the diagnosis and assess the se!erit" of airflolimitation (10 . o e!er, spirometric assessment poorl" corre*lates ith the clinical manifestations of C / , and a large

proportion of smokers ith chronic respirator" s"mptoms do notmeet the spirometric criteria (11, 12 .

Cigarette smoking, the most important and best*established riskfactor for C / , is also a ma7or risk factor for all other chronicdiseases and cancer, not onl" because it damages the lungdirectl", but also because it ma" simultaneousl" cause s"stemiceffects affecting all organs (13, 1% .

8he most common comorbidities of C / that are possibl"related to the s"stemic effects of smoking are C -, arrh"th*mias,h"pertension, peripheral and coronar" arter" diseases, diabetesand metabolic s"ndrome, osteoporosis, cancer (partic*ularl" lungcancer , pulmonar" !ascular abnormalities, ps"chi*atricdisorders, cache ia, skeletal muscle abnormalities, and infections(+, 15, 1) .

8hus, the s"stemic effects of smoking ma" significantl"

contribute not onl" to the respirator" abnormalities, s"mptoms,

and functional impairment associated ith C / , but also to theclinical respirator" and nonrespirator" clinical manifesta*tionsrelated to the chronic diseases often associated ith C / (+,1+ . 9o *grade s"stemic inflammation induced b" smoking andother risk factors has also been implicated in the pathogenesis ofcardio!ascular e!ents and chronic m"opath" of the skeletalmuscle$ since patients ith C / suffer from e cess morbidit"and mortalit" related to cardio!ascular e!ents, it has beensuggested that s"stemic inflammation ma" be the common link(1 .

C / is an independent risk factor for cardio!ascular disease(14 . :rterial all stiffness, hich relates to cardio!ascular risk,is increased in patients ith C / compared ith controlsub7ects ho smoke (20, 21 . 8his suggests that C / ma"result in s"stemic endothelial d"sfunction, hich ma" be amechanism for the enhanced cardio!ascular risk in C / (14 .;"stemic arterial all stiffness is also independentl" related toemph"sema as assessed b" C8 scanning (22, 23 and correlates

ith osteoporosis, another s"stemic complication of C / (20 .8hese studies raise the intriguing possibilit" that mechanismsthat result in al!eolar all destruction and emph"sema ma" also

produce increased cardio!ascular risk and osteoporosis in patients ith C / .

Comorbidities are highl" likel" to affect health outcomes inC / , and patients ith C / are more likel" to die ofcardio!ascular complications or cancer than of respirator" failure(2% . /rogressi!e respirator" failure accounts for appro imatel"one third of C / *related deaths$ therefore, factors other than

the progression of lung disease must pla" a substantial role.

Luppi, Franco, !e"he#, et al%5 COPD and Its Comorbidities

8he number of pree isting comorbidities in patients ith C /is associated ith increased in*hospital mortalit" (25 . Co*morbid conditions that ha!e been associated ith an in*creasedmortalit" risk in patients ith C / include chronic renalfailure, cor pulmonale (2) , and pulmonar" !ascular disease.? 1 is an independent predictor of all*cause mortalit" (31 anda strong risk factor for cardio!ascular disease, stroke, and lungcancer (32 . 8hus, considering the fre#uent comorbidities, theconcept of C / as a disease diagnosed and monitored ith

lung function (e.g., ->? 1 is becoming outdated and likel"compromises patient care. It is suggested that patients ould

benefit from an earlier, broad*based, and aggressi!e approach tomanagement (33 .

COPD >+ > CO$O&!IDITE OF OT*(&

C*&O IC DI+(>+(+

;moking and obesit" are the t o ma7or risk factors for chronicdiseases (3%, 35 . bese indi!iduals ho smoke ha!e a markedl"reduced life e pectanc", and smoking and obesit" ma" interacts"nergisticall" in a !icious circle at different le!els and ithdifferent mechanisms, causing endothelial d"sfunction and car*


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dio!ascular disease (35, 3) . 'oth obesit" and smoking areassociated ith insulin resistance, o idati!e stress, and increasedconcentrations of !arious (adipo c"tokines and inflammator"markers, all of hich ultimatel" lead to endothelial d"sfunctionand cardio!ascular diseases (30 . Conse#uentl", eight loss canre!erse man" of these problems.

n the other side ( vide infra , cache ia and e!en lo bod"eight in patients ith C / are associated ith impaired

pulmonar" status, reduced diaphragmatic mass, lo er e ercisecapacit", and higher mortalit" rate hen compared ith ade*#uatel" nourished indi!iduals ith this disease. utritionalsupport ma" therefore be a useful part of their comprehensi!ecare (3+, 3 .

/atients ith peripheral and coronar" arter" diseases (34, %0 ,C - (%1 , increased cardio!ascular risk (20 , diabetes andmetabolic s"ndrome (%2 , cerebro!ascular disorders (%3 , cancer(%% (particularl" lung cancer @%5A , osteoporosis (%)–% ,chronic inflammator" bo el diseases (%4, 50 , chronic renalfailure (51, 52 , rheumatoid arthritis (53 , psoriasis (5% , and

premature aging (55 directl" or indirectl" share the same ma7orrisk factors, particularl" smoking and aging (5)–5 , and6or ha!ean increased risk of de!eloping C / .

CLI IC>L 'ID(LI (+ FO& COPD > D

C*&O IC DI+(>+(+

Clinical practice guidelines ha!e been sho n to significantl"impro!e the #ualit" of clinical care. o e!er, most guidelinesignore the fact that the ma7orit" of indi!iduals ith a chronicdisease ha!e one or more comorbidities. C / , C -, periph*eral arter" disease, diabetes, and non–life*threatening cancer

8


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/harmacologic treatment ma" relie!e s"mptoms, reduce thefre#uenc" and se!erit" of e acerbations, impro!e health status,and impro!e e ercise tolerance. :lthough the mechanisms are

poorl" understood, bronchodilators, particularl" inhaled bron*chodilators, are central to pharmacologic management of C / ,

both on an as*needed basis to relie!e intermittent or orsenings"mptoms, and on a regular basis to suppress persistents"mptoms and pre!ent e acerbations. onpharmacologictreatment in*cludes rehabilitation, o "gen therap", and surgicalinter!entions ()2–)% , all of hich pro!ide relief from s"mptomsand ma" also increase life e pectanc".

In the follo ing sections e discuss the potential effects of amore comprehensi!e approach to the treatment of C / , b"anal"&ing the e!idence suggesting that ( 1 treatments for C /ma" positi!el" affect morbidit" and mortalit" linked to comor*

bidities of C / , and ( treatments for comorbidities ma"

positi!el" affect morbidit" and mortalit" linked to C / . e donot discuss ( 1 mechanisms of s"mptomatic effects (e.g.,

potential effects of different treatments on respirator" s"mptomsor e acerbations , ( ad!erse effects of treatments of C / oncomorbidities (e.g., s"stemic steroids used for C / e acerba*tions in patients ith C / and diabetes , or ( 6 ad!erse effectsof treatment of comorbidities on C / (e.g., b*blockers in

patients ith both asthma and C / .

(FF(CT+ OF T&(>T$( T OF COPD O IT+CO$O&!IDITI(+

8here is e!idence to suggest that some inter!entions in patientsith C / ma" affect mortalit" because of their effects on co*

morbid conditions.


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8?7 P&OC((DI + OF T*( >$(&IC> T*O&>CIC +OCI(TE :OL ? 778

+mo2in" Cessation

:nthonisen and co orkers () sho ed in a 1%.5*"ear follo *up of patients ith C / e amined in the 9ung ealth ;tud", thatsmoking cessation reduces all*cause mortalit", e!en hen successfulin onl" a minorit" of participants.

Interestingl", the main effect of smoking cessation is on mortalit"due to m"ocardial infarction and cancer. Indeed, the leading causesof death in the 9ung ealth ;tud" ere lung cancer and coronar"heart disease, and smoking cessation as of benefit in both (-igure1 . 8his confirms the findings of pre!ious cohort and case*controlstudies that sho ed a decline in death from coronar" heart diseaseand lung cancer after smoking cessa*tion. Importantl", these resultssuggest that mechanisms b" hich smoking induces coronar" e!ents

and lung cancer are apparentl" re!ersible to some e tent, at least inthe short term.

&ehabilitation

/ulmonar" rehabilitation is an essential component of the com* prehensi!e management of patients ith s"mptomatic C / ()4 .Behabilitation includes teaching and super!ising of re*spirator"therap" techni#ues (e.g., o "gen, inhalers and nebu*li&ers, breathing

techni#ues, chest ph"sical therap", postural drainage , e erciseconditioning (upper and lo er e tremities , and acti!ities of dail"li!ing ( ork simplification, energ" conser*!ation ()3 . /ulmonar"rehabilitation can change outcomes that predict sur!i!al (+0 and canimpro!e the s"stemic component of C / and its comorbidities

ith a potential effect on sur!i!al (+1 . 'ecause e ercise training isthe most important component of a pulmonar" rehabilitation

program, and because comorbid*ities are !er" fre#uent in patientsundergoing rehabilitation (+2 , the positi!e effect of e ercise trainingon cardio!ascular (+3 , metabolic (+%, +5 , and endocrine (e.g.,osteoporosis (+) com*ponents is highl" likel".

+upplemental O3y"en Therapy

9ong*term supplemental o "gen therap" reduces mortalit" from allcauses in patients ith h"po emic C / (++, + , but hether itspecificall" reduces cardio!ascular, respirator", metabolic, or cancermortalit" is not kno n. o e!er, in addition to its effect on

mortalit", long*term o "gen therap" reduces d"spnea, pol"*c"themia, pulmonar" arter" pressures, sleep disorders, nocturnalarrh"thmias, and neurops"chiatric abnormalities and impro!ese ercise tolerance, suggesting that its effects go far be"ond the

lungs (+4, 0 . :n interesting model comes from the e!idence thato "gen therap" impro!es renal function in patients ith C / ( 1 .

Pharmacolo"ic Treatment

8he first and onl" C / randomi&ed clinical trial to address theeffect of pharmacologic combination therap" ith salme*terol andfluticasone on o!erall mortalit" in C / as the 8 BC trial(8o ard a Be!olution in C / ealth @ 2A . 8he stud" initiall"in!ol!ed ),112 patients ith moderate*to*se!ere C / , and its

primar" endpoint as to compare the effect of salmeterol6fluticasone!ersus placebo on all*cause mortalit" o!er 3 "ears. 8he effect on all*cause mortalit" almost reached statistical significance. Interestingl",careful anal"sis of the cause of indi!idual deaths b" a panel ofe perts sho ed thatDin this populationDthe cause*specificmortalit" as 2+E cardio!ascular, 35E respirator", 21E cancer,10E other, and E unkno n. -ort" percent of deaths ere definitel"or probabl" related to C / ( 3 . In addition, the effect ofcombination treatment, although statisticall" not significant, asalmost e#uall" distributed bet een respirator" and other causes,suggesting that this treatment also has nonpulmonar" effects.

8he effects of inhaled steroids on mortalit" in patients ith C / iscontro!ersial. : pooled anal"sis, based on intention to treat, ofindi!idual patient data from se!en randomi&ed trials of at least 12monthsF duration in patients ith stable C / suggested thatinhaled corticosteroids ma" markedl" reduce all*cause mortalit"( % . o e!er, the 3*"ear prospecti!e 8 BC stud" not onl" didnot confirm the effect on mortalit", but it sho ed a trend to ardincreased mortalit" in patients treated ith inhaled corticosteroidsalone. 8his striking discrepanc" should further recommend thatretrospecti!e anal"sis be con*sidered purel" h"pothesis generating,rather than solid e!i*dence.

(FF(CT OF T&(>T$( T+ OF CO$O&!IDITI(+ OCOPD


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/harmacologic treatment of chronic disease is comple , espe*ciall"considering that drugs are usuall" de!eloped for single diseases.

o e!er, drugs designed for one specific disease ma" alsofa!orabl" affect other diseases. -or e ample, glucose control

Fi"ure 1% $ortality rates at 1s , and angiotensin receptor

blockers (:B's ma" ha!e dual cardiopulmonar" protecti!e properties, thereb" substantiall" altering the prognosis of pa*tients

ith C / ( .8he combination of statins and :C> inhibitors or

:B's as associated ith a reduction in C / hospitali&ation andtotal mortalit" in all patients ith C / , in

8?1

both the high and the lo cardio!ascular risk cohorts. -urther*more,this drug combination reduced m"ocardial infarction in the C /cohort ith high cardio!ascular risk. 'enefits ere similar hensteroid users ere included (-igure 2 . ;tatins ma" also reduce thedecline in pulmonar" function, independentl" of the underl"ing lungdisease ( 4 . In another case*control stud", statins e!en appeared to

protect against the de!elopment of lung cancer (40 .

;tatins are used primaril" as lipid*lo ering agents in the treatmentof metabolic s"ndrome, but the" also ha!e potent anti*inflammator"

properties that might e plain their positi!e effect on fre#uentcomorbidities of both metabolic s"ndrome, for e ample, C - and!ascular disease, and C / (41–4% . 8he interest in these agents

as further enhanced b" the disco!er" that statins ma" cause

regression of atherosclerosis lesions (45, 4) (-igure 3 , an effectthat has not pre!iousl" been obser!ed in C / ith an"inter!ention, not e!en after successful smoking cessation (4+ .

Considering that statinsF effects on mortalit", e!en in sub7ects at riskof de!eloping cardio!ascular diseases (4 , 44 , significantl" reducescardio!ascular morbidit" and mortalit", the results of these studieson cardio!ascular diseases increase the hopes of reducing mortalit"from other chronic diseases, such as C / .

>C(s and >&!s

:s pre!iousl" mentioned, =ancini and colleagues sho ed that thecombination of statins and :C> inhibitors or :B's is


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Fi"ure % Fully ad usted ris2 ratios are plotted for the end points of hospitalization for COPD, myocardial infarction, death, and myocardialinfarction or death% Treatments analyzed ere an"iotensin/convertin" enzyme ->C(. inhibitors, an"iotensin receptor bloc2ers ->&!., statins, andthe combination of statins ith >C( inhibitors or an"iotensin receptor bloc2ers -combination. in the population of patients ith COPD ith priorrevascularization -hi"h ris2.% -&eproduced by permission from &eference 88%.


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8? P&OC((DI + OF T*( >$(&IC> T*O&>CIC +OCI(TE :OL ? 778

associated ith a reduction in C / hospitali&ation and totalmortalit" in all patients ith C / ( (-igure 2 . 8he renin*angiotensin s"stem pla"s a ke" role in maintaining blood pressurehomeostasis, as ell as fluid and salt balance. :ngiotensin II, a ke"effector peptide of the s"stem, causes !asoconstriction and e ertsmultiple biological functions. :C> pla"s a central role in generatingangiotensin II from angiotensin I, and capillar" blood !essels in thelung are one of the ma7or sites of :C> e pression and angiotensin II

production in the human bod". 8he rennin– angiotensin s"stem has been implicated in the pathogenesis of pulmonar" h"pertension andfibrosis, both of hich potentiall" de!elop in C / (100 :lso, in

C / the s"mpathetic ner!ous s"stem, as ell as the renin– angiotensin s"stem, ma" be acti!ated ith possible negati!es"stemic effects on skeletal muscles (101 . :ngiotensin II t"pe*1receptor blockers inhibit the s"mpathetic and renin–angiotensins"stems and might thus impro!e skeletal and respirator" musclestrength in patients in hom these s"stems are acti!ated.


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Fi"ure 6% (3ample of re"ression of atherosclerosis induced by sta/tintreatment in a patient in the >+T(&OID trial% (($ ? e3ternal elasticmembrane% -&eprinted by permission from &eference 9?%.

a fre#uent comorbidit" of C / . o e!er, there is some concernthat prescribing b*blockers for patients ith C / ma" cause

bronchoconstriction and orsen respirator" s"mp*toms, e!en thoughthere is increasing e!idence that cardioselec*ti!e b blockade is #uitesafe in patients ith C / . In fact, a recent metaanal"sis thate!aluated the relationship bet een cardioselecti!e b*blockers and

C / found no significant differ*ences in ->? 1 or respirator"s"mptoms bet een those treated ithacardio*selecti!e b*blockerandthosetreated ithaplacebo, e!en in patients ith se!ere C /(103–105 . 8he anal"sts concluded that, gi!en their demonstrated

benefit in conditions such as heart failure, coronar" arter" disease,and h"pertension, cardioselecti!e b*blockers should not be routinel"

ithheld from patients ith C / .

8 o recent studies suggested that b*blockers ma", in fact, ha!e positi!e effects in patients ith C / ith cardio!ascular diseases.

ransfield and co orkers e amined a large population of inpatientsadmitted for acute e acerbations of C / , and found that the use of b*blockers as associated ith reduced in*hospital mortalit". 8he

benefit of b*blockers as obser!ed de*spite the fact that those horecei!ed the drugs ere older, had longer hospital sta"s, and had agreater pre!alence of congesti!e heart failure and cerebro!asculardisease, all factors that are independent predictors of in*hospitalmortalit" (10) . !an Gestel and colleagues sho ed that the use ofcardioselecti!e b*blockers is associated ith reduced mortalit" in

patients ith C / undergoing !ascular surger", and suggested thatin selected patients ith C / , the use of cardioselecti!e b* blockers ma" be safe and associated ith reduced mortalit" (10+ .

Luppi, Franco, !e"he#, et al%5 COPD and Its Comorbidities

eurohumoral acti!ation in patients ith C / , similar to that inC - and other diseases, ma" ha!e negati!e effects such as s"stemicinflammation, cache ia, effects on !entilation, and skeletal muscled"sfunction, that might e plain the increased cardio!ascularmorbidit" and mortalit" in patients ith C / . 8hus, b*blockers

and other agents that are no pro!ed to be ell tolerated in C / ,such as :B's or :C>s ( see above , might ha!e une pected

beneficial effects on C / and its comorbidities (101 .

8reatments for other important comorbidities of C / , such ascache ia, anemia, and chronic renal failure, should be e ploredfurther.


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8he causes of cache ia in patients ith C / are multifac*torialand include decreased oral intake, increased ork of breathing dueto abnormal respirator" mechanics, and chronic s"stemicinflammation and comorbidities (3+, 3 . hile acti!e nutritionalsupplementation in undernourished patients ith C / ma" lead to

eight gain and impro!ements in respira*tor" muscle function ande ercise performance, a recent meta*anal"sis pro!ided no e!idencethat nutritional support has a significant effect on anthropometric

measures, lung function, or e ercise capacit" in patients ith stableC / (10 . In contrast, repeated administration of ghrelin, a no!elgro th hormone–releasing peptide that is reduced in C / (104 ,ma" impro!e bod" composition, muscle asting, and functionalcapacit" in cachectic patients ith C / , suggesting the pos*sibilit"of re!ersing some of the s"stemic aspects of C / (110 . Inconclusion, it remains unkno n hether long*term eight gain b"using enhanced caloric intake, ith or ithout anabolic steroids orappetite stimulants, furthers sur!i!al or pro!ides other benefits to

patients ith C / . o e!er, there are indications from single*center trials that this is an a!enue ell orth e ploring (3+ .

:nemia fre#uentl" occurs in patients ith C / , and in*ade#uatehemoglobin le!els could aggra!ate tissue h"po ia and ha!e anegati!e prognostic impact (111, 112 . 'lood cell trans*fusion inanemic patients ith C / reduces minute !entilation and the ork of breathing (113 , suggesting that correcting lo hemoglobin le!elscould alle!iate d"spnea and impro!e e ercise capacit". In a small setof anemic !entilator*dependent patients ith C / , raisinghemoglobin le!els to more than 12 g6dl seemed to impro!e patientsF

breathing enough to make !entilator eaning possible (11% .

Chronic renal failure is a gradual and progressi!e loss of the abilit"of the kidne"s to e crete astes, concentrate urine, and conser!eelectrol"tes. It ma" range from mild d"sfunction to se!ere renalfailure and end*stage renal disease, hich is associ*ated ithsignificant comorbidities (51, 115 . iabetes and h"pertension (high

blood pressure account for the ma7orit" of cases of chronic renalfailure and end*stage renal disease, and both renal failure andischemic heart disease are highl" rele!ant to the prognosis of

patients ith C / discharged from the hospital after an acutee acerbation. 8hese co*morbid diseases probabl" act as markers of

frailt" b" increasing the fatalit" rate of later C / e acerbations(11) .

CO CL'+IO +

:s mentioned, most clinical practice guidelines ignore the fact thatthe ma7orit" of indi!iduals ith a chronic disease ha!e one or morechronic comorbidities (e.g., C -, peripheral arter" disease, diabetes,or non–life*threatening cancer , that ma" ha!e a ma7or impact on

C / and on chronic diseases in general (4 . 8hus, althoughcomorbidities are #uite common in patients ith C / , most recente!idence*based guidelines pro!ide little guidance in caring for

patients ith C / ith multiple chronic


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8?6

diseases ()2–)% . =ost patients ith chronic diseases are gi!enmultidrug regimens, hich clearl" pro!ide added disease*specific

benefits for at least some subpopulations of patients, unlike single*drug therap". 9ess clear, ho e!er, are the long*term net benefits andharm associated ith the combination of medica*tions that are takenin adherence to disease*specific guidelines b" patients ith se!eralcoe isting health conditions (11+, 11 . 8hus, as comorbidities areoften underdiagnosed and under*treated, it is important to search fortheir co*e istence ith C / and ith all chronic diseases, possibl"

b" adopting recommen*dations for the diagnosis of single diseases.8his means that, hile careful cardio!ascular, metabolic, andendocrinologic e amina*tions should be increasingl" used inassessing patients ith C / , lung function measurements ma" beuseful in patients ith chronic cardio!ascular, metabolic, andendocrinologic dis*eases as ell.

Considering that pharmacologic ()2–)% , and e!en nonphar*

macologic treatment of C / such as pulmonar" rehabilitation()4 , are primaril" s"mptomatic, and considering the fre#uentchronic comorbidities of C / (+ , it is reasonable to hope that amore comprehensi!e approach to C / together ith itscomorbidities ma" identif" no!el targets for treatment and modif"the natural course of the disease ()0, )1 . 8his is particularl"rele!ant for those conditions that appear more pre*!entable andtreatable than C / , such as cardio!ascular and metabolicdisorders. 8he increasing e!idence that treatment of comorbiditiesma" reduce morbidit" and mortalit" in patients ith C / suggeststhe urgent need for randomi&ed clinical trials that hopefull" ill

pro!ide the e!idence for more compre*hensi!e clinical guidelines for these patients.

Conflict of Interest +tatement5 F%L% does not have a financial relationship ith acommercial entity that has an interest in the sub ect of this manuscript% F%F% doesnot have a financial relationship ith a commercial entity that has an interest inthe sub ect of this manuscript% !%!% does not have a financial relation/ship ith acommercial entity that has an interest in the sub ect of this manuscript% L%$%F%reports havin" served as a consultant to >ltana Pharma, >straHeneca,!oehrin"er In"elheim, Chiesi Farmaceutici, la3o+mith4line, $erc2 +harp Dohme, ovartis, &oche, and Pfizer% *e has been paid lecture fees by >ltanaPharma, >straHeneca, !oehrin"er In"elheim, Chiesi Farmaceutici,

la3o+mith4line, $erc2 +harp Dohme, ovartis, &oche, and Pfizer% *e hasreceived "rant support from >ltana Pharma, >straHeneca, !oehrin"er In"elheim,$enarini, $iat, +cherin" Plou"h, Chiesi Farmaceutici, la3o+mith4line, $erc2

+harp Dohme, 'C! Pharma, Pfizer, Italian $inistry of *ealth, and Italian$inistry for 'niversity and &esearch%

>c2no led"ments5 The authors are indebted to $% $c4enney for editin" themanuscript and to (% :eratelli for her scientific secretarial assistance%

&eferences

:begunde , =athers C , :dam 8, rtegon =, ;trong H. 8he burden and costsof chronic diseases in lo *income and middle*income countries. Lancet 200+$3+0 1424–143 .

Ga&iano 8:, Galea G, Bedd" H;. ;caling up inter!entions for chronic disease

pre!ention the e!idence. Lancet 200+$3+0 1434– 14%).

orton B. Chronic diseases the case for urgent global action. Lancet 200+$3+0 1 1–1 2.

'o"d C=, arer , 'oult C, -ried 9/, 'oult 9, u : . Clinical practiceguidelines and #ualit" of care for older patients ith multiple comorbid diseasesimplications for pa" for performance. J>$> 2005$ 24% +1)–+2%.

ilper :/, oolhandler ;, 9asser H>, =cCormick , 'or , immelstein


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-abbri 9=, 'oschetto /, =app C>. C / guidelines the important thing is notto stop #uestioning. >m J &espir Crit Care $ed 200+$1+) 52+–52 .

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