CURRENTOPINION Comorbidities of asthma: current knowledge and

tia, Luigino Calzettab, and Paola Rogliania

s, mmo

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nflaprogression of several comorbidities. However, the roleUnderstanding mechanism(s) that link(s) asthma and its c

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Keywords

INTRODUCTION

Asthma is often associities, which may affeseverity, and with whpathophysiological mcomorbidities interact

EPIDEMIOLOGICAL

Several population-bwhich used health admthat asthmatic patienrates of many diffe[3,4

&

,5,6&

].The analysis of th

tive data for British Columbia showed that asth-matic adults were significantly moa variety of comorbidities, includinfectiowith asasthmapulmoadult

aDepartment of System Medicine, University of Rome Tor Vergata and

620900633; e-mail: mario.cazzola@uniroma2.it

www.c

REVIEWnary disease, compared with 1.6% in theservice user population. Among asthma

Curr Opin Pulm Med 2013, 19:3641

DOI:10.1097/MCP.0b013e32835b113a

o-pulmonarymedicine.com Volume 19 Number 1 January 2013thma had depression [3]. One in five adultpatients also had chronic obstructive

Univer+39 0e in four adults Correspondence to Mario Cazzola, Dipartimento di Medicina dei Sistemi,sita` di Roma Tor Vergata,Via Montpellier 1, Rome 00133, Italy. Tel:ns and allergic rhinitis. OnIRCCS, Rome, Italyre likely to haveing respiratory

bDepartment of Pulmonary Rehabilitation, San Raffaele Pisana Hospital,ated with different comorbid-ct its clinical intensity andich it may share a commonechanism [1]. However, howwith asthma is still unclear [2].

STUDIES

ased retrospective studies,inistrative data, have shownts have significantly higherrent types of comorbidity

e health services administra-

patients at least 56 years old, the proportionincreased to 38% for men and 28% for women.Asthmatic children had a lower comorbidity burdenthan adults, but 12.6% had a chronic medical con-dition, with depression as the most prevalentcomorbidity. Adults with asthma had a strong andcomplex comorbidity burden, particularly in termsof multiple chronic conditions.

A study that used information obtained from theHealth SearchDatabase owned by the Italian Collegeof General Practitioners suggested that asthma isweakly associated with cardiovascular disease,depression, diabetes mellitus, dyslipidaemia, osteo-porosis and rhinosinusitis [4

&

]. In contrast, it isasthma, comorbidities, obesity, systemic inflammationtherapeutic approach.

SummaryIn the future, researchers must identify the weight of amechanism(s) that link(s) it to asthma and act on theseConversely, we do not think it reasonable that the gemight affect the link(s) between asthma and its comorfuture research needs

Mario Cazzolaa,b, Andrea Segre

Purpose of reviewAsthma is often associated with different comorbiditieallergic rhinitis, but also obesity, depression, diabetesaffect its clinical intensity and severity. The prevalencestudies. Nevertheless, it imposes a significant reflectio

Recent findingsBoth clinical and basic studies have established that iainly gastro-oesophageal reflux disease andellitus and cardiovascular disease, which mayf these comorbidities varies tremendously betweenn the need to explore the phenomenon in depth.

mmation plays a vital role in the initiation andof systemic inflammation in asthma is still unclear.omorbid diseases is essential to design an effective

comorbidity in patients with asthma, find the trueechanisms that probably create a vicious circle.alization of treatment with a holistic approachities.

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KEY POINTS

The prevalence of comorbidities in asthma is extremelyhigh

It is ethe nimplimech

Wemechand,genemighits co

Comorbidities of asthma Cazzola et al.

1070-528y associated with gastro-oesophageal reflux(GORD) and, particularly, allergic rhinitis.ntly, age does not affect the association ofwith comorbidities, whereas sex has a differ-act according to the comorbidity.evaluation of the Norwegian Prescription

se documented that 59% of the asthmatiction 829 years old had at least one of ninediseases examined, compared with 18% ineral population [5]. Few individuals withhad more than one additional chronic dis-% of male individuals and 8% of femaleuals). Standardized morbidity ratios wereed for all diseases except diabetes. This pat-as observed in both age groups (819 andyears) and sexes. Allergy and GORD hadstandardized morbidity ratios (range 3.2

hereas the other diseases were in the range.study of the health administrative data onviduals living in Ontario, Canada, revealedmpared with people without asthma, asth-ndividuals had at least 50% or more comor-as indicated by health services utilization,iratory disease (other than asthma) in all

POSCOM

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.

ssential to understand their origin, real impact onatural history and severity of asthma andcations for asthma therapy, and also theanisms by which they could affect asthma.

do not think that it will be possible to oversimplifyanism(s) that link(s) asthma and each comorbidityconsequently, we do not believe that theralization of treatment with a holistic approacht actually affect the link between asthma andmorbidities.oups, psychiatric disorders in individualsars and under and age 1844 years, perinatalrs in individuals 17 years and under andlic and immunity and hematologic disordersren 4 years and under [6

&

].prevalence of comorbidities in asthmatic

s varies between studies, probably becausel do not know whether the comorbiditiesctly or indirectly related to asthma, but it isely high in severe asthma [2]. These datathe need to investigate the problem

arefully in order to understand its origin,l impact on the natural history and severityma, the mechanisms by which it could

Moreovthe chways. Ianismemanatriggerslation,sites watory trisms ofimbalatissues,cellulaexposu

7 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-pulmonarymedicine.com 37te immune responses involving IL-8-inducedphilic airway inflammation [12]. Apparently,ic inflammation is increased in asthmatics with neutrophilic airway inflammation

c rhinitis

atients with asthma suffer from symptomsgic rhinitis [4

&

]. A systemic pathway linkinger and lower airways, involving both blood-and bone marrow has been suggested [14].IL-5, blood eosinophils, and adhesion mol-xpression are increased after local allergenge in individuals with allergic rhinitis.er, mucosal inflammation extends fromallenged organ throughout the whole air-t has been suggested there is a central mech-behind the link, with eosinophil precursorsting from the bone marrow in response tomigrating not only to the site of stimu-such as the nasal mucosa, but also to otherithin the airway, including the lower respir-act [15]. There are other suggested mechan-noselung interaction such as autonomic

nce via changes in neural tone to effectorrelease of neuropeptides and interplay withr recruitment [16], increased lower airwayre to airborne contaminants from mouthIBLE MECHANISMS OF ASTHMARBIDITIES ASSOCIATION

mation plays a vital role in the initiation andsion of several comorbidities [7]. Togias [8]ed that although the initialmanifestations ofsal allergic reaction are localized, a systemicnent develops. This systemic componenteed back into and perpetuate the originalaction and lead to the development of dis-cal reactions [8]. In asthmatic patients,ic dissemination of local lung inflammationccur, leading to an overspill effect [9].y, systemic inflammation occurs in asthma,n increase in circulating proinflammatoryes, such as interleukin (IL)-6 and tumors factor-a [10] and also in high-sensibilityive protein [11].wever, the role of systemic inflammation intic patients is still unclear and, consequently,. Airway inflammation in asthma is hetero-s in nature and may involve an allergen-acquired immune response with IL-5-medi-

breathing and increased demand for conditioningthe inspired air [17].

ObesitNumeration bof causponent of the metabolic syndrome, which is also aform othat thdromeinflammadipoksymptocirculatincreashyperremodulaother tated alpressurand abon theness orassociacould bassociaassocia

Diabetes mellitus

Severalbetweein womdoubleChroniinvolve[25,26]the effemay bewhich,diabeteglucoseness ofcellularmuscle(ROCK1 (pMYthese cmationtion th

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altered respiratory physiology in asthma patientsmay predispose them towards GORD [30]. Respirat-ory obstruction can result in negative pleural press-

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reporteeaadtidbdenecardiovascular disease in women are strongerthrosonialastayoryonestma. Hntas

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38studies have found significant correlationsn asthma and type 2 diabetes, [23,24], at leasten [4

&

], with a risk of asthma that is almostd in individuals with type 2 diabetes [23].c airway inflammation in asthma may bed in the pathogenesis of both type 2and type 1 diabetes [27]. However, part ofct of the presence of asthma as comorbidityassociated with the use of corticosteroids,in turn, may result in the unmasking ofs [24]. Recently, we documented that highconcentrations leads to hyperresponsive-

human isolated bronchi and enhanced intra-calcium release in cultured airway smoothcells via a Rho/Rho-associated kinase

) and myosin phosphatase targeting subunitPT1)-dependent pathway, suggesting thatrucial pathways, but not systemic inflam-, may contribute to the reduced lung func-at is observed in diabetic patients [28

&

].

-oesophageal reflux

s with asthma are also at a significantlyed risk of developing GORD [4

&

,29]. The

ary hcase,carowithlinethickandthanathematicardandairwdilatpulmsuggasthtionvariawithmor

Nasthasth[44]

www.co-pulmonarymedicine.comf systemic inflammation, it is to be expectedere is a relationship between metabolic syn-and asthma [19]. In fact, systemic markers ofation are elevated in obesity [20], and

ines, correlate, albeit weakly, with asthmams [21]. Proinflammatory adipokines in theion could induce airway inflammation ore its severity, and thus contribute to airwaysponsiveness or asthma [22]. Obesity mayte airway inflammation through pathwayshan traditional immunoglobulin (Ig)E-medi-lergic mechanisms [22]. However, also thee of the increased tissuemass in the chest walldomen, which has direct mechanical effectslungs, could modify airway hyperresponsive-increase symptoms directly [22]. Besides, thetion between obesity and asthma symptomse merely an epiphenomenon, and the truetion is due to comorbidities or lifestyle factorsted with obesity [22].

matican da vagindirtoryairwtionincrerelea

Ibronsphiacid

Card

Somassoc[33,3roundisealogicyous studieshavedemonstrateda strongassoci-etween obesity and asthma, but the directionality is unclear [18]. Because obesity is a com-

ures,thorreflusympose observed inmen [34,36,38&

]. Asthma andclerosis occur on a background of inflam-. Animal studies have shown increased myo-vulnerability in rabbits with systemic allergyhma [39]. A fascinating report revealed thatallergen exposure results in impaired vaso-response of the aorta in a murine model ofary allergic response [40]. This findings that systemic inflammation associatedwithmay adversely affect cardiovascular func-owever, the documentation of sequences affecting eosinophil numbers associatedthma and myocardial infarction is an eventriguing discovery [41].ertheless, cardiovascular complications intic patients have largely been attributed totreatment [42,43]. Interestingly, Zhang et al.cumented that patterns of risks ofmyocardial

Volume 19 Number 1 January 2013creasing the pressure gradient between theand abdominal cavity, thus, promoting

[30]. However, GORD may induce asthmams either by direct effects on airway hyper-siveness or via aspiration-induced inflam-. In fact, microaspiration of gastric acidectly result in airway constriction stimulatingresponse promoting bronchoconstriction ortly through induction of chronic inflamma-anges, which eventually can lead to increasedreactivity [31]. Interestingly, acid provoca-s been shown to lead to a dose-dependente in lung resistance that is mediated byof tachykinins from peripheral nerves [31].any case, b-agonist and methylxanthineodilators may decrease lower oesophagealer tone, which potentially could promoteflux [32].

vascular disease

pidemiological studies reported a significanttion of asthma with cardiovascular disease, but there is a conflict in the literature sur-ng the asthma-related risk of cardiovascularidentified in large, longitudinal epidemio-tudies. For example, Schanen et al. [35]d an increased risk of stroke, but not coron-rt disease, associated with asthma. In anyult-onset asthma is associatedwith increasedatherosclerosis in women [36], and patientsronchial hyperresponsiveness to methacho-monstrated increased carotid intimamediass [37]. Apparently, relationships of asthma

infarction were similar between inhaled short-act-ing b2-agonists, long-acting b2-agonists and inhaledcorticosteroids. For each of these therapies, hazardrates foafter thafter. Hlong-teasthmascribedinfarctiminghafindingsymptois, in aischaemworthyassociacardial infarction [4

&

].

Anxiet

Theredepressof psymortaldepressbecauseence woutcomexplaindepresspossibieither eof bothinflammand hiused fotoxicityit has bis unlikdepression in patients with asthma [46

&

].

FUTUR

The ideintegrasystempresencthey arimpact

Unwhethebiditiesimprovis altersuggest

b2-adrenoceptor inverse agonists, such as nadolol,lower airway responsiveness in patients with asthma[51], and the simultaneous administration of nado-

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asthmaabntt aptitymueeotfics,mungraech

Comorbidities of asthma Cazzola et al.

1070-528E RESEARCH NEEDS

ntification of comorbidities must become anl part of the core management of asthma. Aatic evaluation is necessary, not only of theire, is necessary, and we must also ensure thate adequately treated/controlled so that theiron asthma is minimized [1].fortunately, it has not been established yetr controlling asthma would reduce comor-occurrence, or whether their treatment

es asthma control, or treatment of asthmaed by the presence of comorbidity. There isive documentation that escalating doses of

probpatieis noacceobesaccubetwphenbenetypeaccu

Ilow-on thbron

7 2012 Wolters Kluwer Health | Lippincott Williams & Wilkinsy and depression

is a significant overlap between anxiety,ion and asthma, with a higher prevalencechological problems [3,4

&

] and a higherity rate [46

&

] in patients with asthma andion. This latter finding can be explainedconcurrent depression leads to poor adher-ith asthma treatments and, thus, to pooreres [47]. IgE-mediated mechanisms do notthe relationship between asthma and

ion. Increasingly, evidence supports thelity that one or more independent factors,nvironmental or genetic, may affect the riskasthma and anxiety disorders [48]. Systemication may also play a role [49]. Frequent

gh doses of systemic corticosteroid therapyr severe asthmatic patients may cause neuro-and lead to cognitive impairments [50], buteen documented that oral corticosteroid useely to be the cause of the increased rate of

ent psiderwhicphenthe eus dasthbiditand

Iextreencephenundetigatspecintrifact,obesnotstresexter myocardial infarction were increased soone initiation of treatment and reduced there-azard rates were also increased in heavy,rm users (13 prescriptions of the sametherapy in the year prior). In patients pre-asthma medication, the risk of myocardialon was powerfully associated with the Fra-m myocardial infarction risk score. Theses suggest that the initial presentation withms evoking asthma (dyspnoea presumably)large proportion of cases, the appearance ofic heart disease [45]. However, it is note-that we were unable to register concrete

tion of asthma with acute or previous myo-

lol aindegivenMoreffecthergatinapprlink(

Ilink(thesmenan ea corticosteroid is more effective at reducings of airway inflammation than either drugalone, at least in an asthma model [52

&

].er, emerging evidence suggests beneficialof statins in asthma management [53

&

]. Fur-ospective studies should consider investi-these issues, although this is an empiricalch failing reliable information about thebetween asthma and its comorbidities.fact, it is still unclear what mechanism(s)asthma and its comorbidities. Understandinginks is essential to design an effective treat-o overcome them. However, this will not bey task, mainly because asthma is highlyeneous. At present, we identify many differ-enotypes of asthma. Moreover, there is con-le overlap between the various phenotypes,often makes it difficult to accept a specificype [54]. The available data, mainly due toreme heterogeneity of asthma, do not yet letermine whether a specific phenotype ofmay be related to a specific type of comor-and then the possible link(s) between asthmais comorbidity.any case, the available information is stillely limited to accept the idea that the pres-a specific comorbidity per semay represent aype of asthma. Although the mechanismsing obesity in asthma require further inves-, it has been suggested that obesity is aphenotype of the disease [55]. This is an

ing idea, but it does not tell us anything. Inthis was true, we should speculate that allatients could suffer from asthma, and this ise case. Systemic inflammation, oxidativend mechanical events may be more or lessvely involved in the link between obesity and, but it is likely that there is a driver, which isly genetic in its nature, that allows the obeseto become asthmatic. Obviously, this drivervailable in all obese patients. Currently, wethe existence of distinct phenotypes ofdepending on compartments for body fatlation, with a significant associationn some candidate gene polymorphisms andypes [56]. It should be possible to predictial and detrimental effects of these pheno-depending on compartments for body fatlation [56].addition, we still do not know whether thede systemic inflammation has local effectslung parenchyma and causes or enhances theial inflammation. If inflammation affects the

www.co-pulmonarymedicine.com 39

systemic circulation, anti-inflammatory treatmentmight have the potential to reduce the risk ofcomorbidities. However, always remaining in theparadigtype ofdifficulinflamm[57]. Onatory vWe totmay rebecomeimpactof aggravating comorbid factors including GORDand obapproaasthmaon intratherof com

CONC

The preTherefoorigin,severitytherapythey cgeneraleach coestablispatientism(s)mechanConvergeneralmight abidities.

Ackno

None.

Confli

There a

REFERREADPapers ofbeen highl& of spe&& of outsAdditionalWorld Lite

1. Boule33:89

2. Boule2011;

3. Prosser R, Carleton B, Smith A. The comorbidity burden of the treated asthmapatient population in British Columbia. Chronic Dis Can 2010; 30:4655.

4.&

Cazzola M, Calzetta L, Bettoncelli G, et al. Asthma and comorbid medicalillness. Eur Respir J 2011; 38:4249.

This article reports the prevalence of comorbidities in a large Italian population,da

rlsta29 yepidershmorspethat

higher rateouteamnnegias04;

9. Magnumonar

09;gasstruspirlvanway12;

urdo0:2oodass9

restthmoutaunam

iceoracwe-thmusqthmgogidat26.n Hulatioustaromttanipok5:5rahknooms

type 2568.

dbavelo

e SHng

seasactulcatienchm

abetdiat

azzoss o

ell My dovenee in1.vemstro07;rdind asccialler

Asthma

40wledgements

cts of interest

re no conflicts of interest.

ENCES AND RECOMMENDEDINGparticular interest, published within the annual period of review, haveighted as:cial interesttanding interest

references related to this topic can also be found in the Currentrature section in this issue (pp. 8687).

t LP. Influence of comorbid conditions on asthma. Eur Respir J 2009;7906.t LP, Boulay ME`. Asthma-related comorbidities. Expert Rev Respir Med5:377393.

24. Rodeth

25. SodiPr

26. Gpa

27. RadiPe

28.&

CneC

A studsponsienhancpMYPT29. Ha

ga20

30. Haan

31. RiJ A

www.co-pulmonarymedicine.comstructive sleep apnoea [58]. The therapeuticch of obese patients with difficult-to-treatshould, therefore, not be primarily focused

ensifying anti-inflammatory treatment buton weight reduction and adequate controlorbid factors.

LUSION

valence of comorbidities is extremely high.re, it is now essential to understand theirreal impact on the natural history andof asthma and implications for asthma

, and also identify themechanisms by whichould affect asthma. However, we cannotize mechanism(s) that link(s) asthma andmorbidity. In the future, researchers musth the specific weight of any comorbidity ins with asthma, understand the real mechan-that link(s) it to asthma, and act on theseisms that probably create a vicious circle.sely, we do not think it reasonable that theization of treatment with a holistic approachffect the link between asthma and its comor-

2010. Hi

obRe

11. Haair20

12. M69

13.&

Wis86

An intewith asclinical14. Br

infl15. Pr

Th16. Ro

as17. Bo

As18. Lu

ox11

19. vare

20. GTh

21. Kaad12

22. Faun

23. Thally agree that obese patients with asthmaveal more severe asthma symptoms or evendifficult to treat because of an unfavourableof overweight on lung function, or because

7. Winflco

8. To20olume in 1 sec and less airwm of obesity that we are using as the proto-comorbidities in asthma, obese patients witht-to-treat asthma do not have more airwayation as compared with nonobese patientsthe contrary, they have higher forced expir-

ay inflammation.

using a5. Ka

8-co

6.&

Gco

A retrofoundtabase of general practitioners.d O, Nafstad P, Tverdal A, et al. Comorbidities in an asthma populationears old: a study from the Norwegian Prescription Database. Pharma-emiol Drug Saf 2012; 21:10451052.on AS, Guan J, Wang C, et al. Describing and quantifying asthmabidity: a population study. PLoS One 2012; 7:e34967.ctive cohort study of a large, complete, real-world population, whichcompared to people without asthma, those with asthma had notablys of many different types of comorbidity that varied according to age.rs EF, Reynaert NL, Dentener MA, Vernooy JH. Systemic and local

mation in asthma and chronic obstructive pulmonary disease: is there action? Proc Am Thorac Soc 2009; 6:638647.

A. Systemic effects of local allergic disease. J Allergy Clin Immunol113:S8S14.ssen H, Watz H. Systemic inflammation in chronic obstructive pul-

y disease and asthma: relation with comorbidities. Proc Am Thorac Soc6:648651.

himoto Y, Yamagata Y, Taya S, et al. Systemic inflammation in chronicctive pulmonary disease and asthma: similarities and differences.ology 2008; 13:128133.i A, Tahghighi F, Nadooshan HH. Evaluation of correlation betweenand serum inflammatory markers in asthmatic patients. Lung India29:143146.ch JR, Lloyd CM. Chronic inflammation and asthma. Mutat Res 2010;439.LG, Baines KJ, Fu J, et al. The neutrophilic inflammatory phenotype

ociated with systemic inflammation in asthma. Chest 2012; 142:3.ing study suggesting that systemic inflammation is increased in patientsa with neutrophilic airway inflammation and associated with worsecomes.stahl GJ. United airways concept: what does it teach us about systemicmation in airways disease? Proc Am Thorac Soc 2009; 6:652654.D. Asthma and allergic rhinitis: linked in treatment and outcomes. Ann

Med 2010; 5:6364.Jones JM. The link between the nose and lung, perennial rhinitis anda: is it the same disease? Allergy 1997; 52 (Suppl. 36):2028.uet J, Khaltaev N, Cruz AA, et al. Allergic Rhinitis and its Impact ona (ARIA) 2008 update. Allergy 2008; 63 (Suppl. 86):8160.o NL, Bappanad D, Kraft M. Obesity, metabolic dysregulation andive stress in asthma. Biochim Biophys Acta 2011; 1810:1120

isstede A, Braunstahl GJ. Obesity and asthma: co-morbidity or causalnship? Monaldi Arch Chest Dis 2010; 73:116123.fson B. Adipose tissue, inflammation and atherosclerosis. J Atherosclerb 2010; 174:332341.M, Kumar R, Bloomberg GR, et al. Asthma control, adiposity, and

ines among inner-city adolescents. J Allergy Clin Immunol 2010;84592.CS, Salome CM. Asthma and obesity: a known association but

wn mechanism. Respirology 2012; 17:412421.en SF, Duffy DL, Kyvik KO, et al. Risk of asthma in adult twins withdiabetes and increased body mass index. Allergy 2011; 66:562

rd HW, Bays HE, Gavin JR 3rd, et al. Rate and risk predictors forpment of self-reported type-2 diabetes mellitus over a 5-year period:IELD study. Int J Clin Pract 2012; 66:684691.

Y, Klevak A, Manson JE, et al. Asthma, chronic obstructive pulmonarye, and type 2 diabetes in the Womens Health Study. Diabetes Res Clin2010; 90:365371.n E, Bulut I, Toker A, Gulcan A. Evaluation of glucose tolerance status ints with asthma bronchiale. J Asthma 2009; 46:207209.iel M, Bloch O, Shaul AA, et al. Young patients with both type 1

es mellitus and asthma have a unique IL-12 and IL-18 secretory pattern.r Diabetes 2011; 12:596603.la M, Calzetta L, Rogliani P, et al. High glucose enhances responsive-f human airways smooth muscle via Rho/ROCK pathway. Am J Respirol Biol 2012; 47:509516.cumenting that the link between diabetes mellitus and airway hyperre-ss is not systemic inflammation, but high glucose concentrations thattracellular calcium release in smooth muscle cells via a Rho/ROCK and

ann BD, Henderson CA, El-Serag HB. The association between-oesophageal reflux disease and asthma: a systematic review. Gut56:16541664.g SM, Richter JE. The role of gastroesophageal reflux in chronic coughthma. Chest 1997; 111:13891402.

rdolo FL, Gaston B, Hunt J. Acid stress in the pathology of asthma.gy Clin Immunol 2004; 113:610619.

Volume 19 Number 1 January 2013

32. Parsons JP, Mastronarde JG. Gastroesophageal reflux disease and asthma.Curr Opin Pulm Med 2010; 16:6063.

33. Appleton S, Ruffin R, Wilson D, et al. Asthma is associated with cardiovas-cular disease in a representative population sample. Obes Res Clin Pract2008; 2:9199.

34. Cazzola M, Calzetta L, Bettoncelli G, et al. Cardiovascular disease in asthmaand COPD: a population-based retrospective cross-sectional study. RespirMed 2012; 106:249256.

35. Schanen JG, Iribarren C, Shahar E, et al. Asthma and incident cardiovasculardisease: the Atherosclerosis Risk in Communities Study. Thorax 2005;60:633638.

36. Onufrak S, Abramson J, Vaccarino V. Adult-onset asthma is associatedwith increased carotid atherosclerosis among women in the AtherosclerosisRisk in Communities (ARIC) study. Atherosclerosis 2007; 195:129137.

37. Talukder MA, Morrison RR, Jacobson MA, et al. Targeted deletion ofadenosine A3 receptors augments adenosine-induced coronary flow inisolated mouse heart. Am J Physiol Heart Circ Physiol 2002; 282:H2183H2189.

38.&

Lee HM, Truong ST, Wong ND. Association of adult-onset asthmawith specific cardiovascular conditions. Respir Med 2012; 106:948953.

A study suggesting that coronary heart disease is the major cardiovascularcondition associated with asthma.39. Hazarika S, Van Scott MR, Lust RM. Myocardial ischemia-reperfusion injury is

enhanced in a model of systemic allergy and asthma. Am J Physiol Heart CircPhysiol 2004; 286:H1720H1725.

40. Hazarika S, Van Scott MR, Lust RM, Wingard CJ. Pulmonary allergic reactionsimpair systemic vascular relaxation in ragweed sensitive mice. Vascul Phar-macol 2010; 53:258263.

41. Gudbjartsson DF, Bjornsdottir US, Halapi E, et al. Sequence variants affectingeosinophil numbers associate with asthma and myocardial infarction. NatGenet 2009; 41:342347.

42. Varas-Lorenzo C, Rodriguez LAG, Maguire A, et al. Use of oral corticosteroidsand the risk of acute myocardial infarction. Atherosclerosis 2007; 192:376383.

43. Appleton SL, Ruffin RE, Wilson DH, et al. Cardiovascular diseaserisk associated with asthma and respiratory morbidity might be mediatedby short-acting b2-agonists. J Allergy Clin Immunol 2009; 123:124130.

44. Zhang B, de Vries F, Setakis E, van Staa T-J. The pattern of risk of myo-cardiaGener1492.

45. Squiremyoca

46.&

Walters P, Schofield P, Howard L, et al. The relationship between asthma anddepression in primary care patients: a historical cohort and nested casecontrol study. PLoS One 2011; 6:e20750.

A historical cohort and nested casecontrol study using data derived from theUnited Kingdom General Practice Research Database documenting that asthma isassociated with depression and there is an increased mortality rate in depressedpatients with asthma. This association is not related to asthma severity or oralcorticosteroid use, but to service use.47. Cluley S, Cochrane GM. Psychological disorder in asthma is associated with

poor control and poor adherence to inhaled steroids. Respir Med 2001;95:3739.

48. Roy-Byrne PP, Davidson KW, Kessler RC, et al. Anxiety disorders andcomorbid medical illness. Gen Hosp Psychiatry 2008; 30:208225.

49. Pace TW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatoryresponses in male patients with major depression and increased early lifestress. Am J Psychiatry 2006; 163:16301633.

50. Wolkowitz OM, Lupien SJ, Bigler ED. The steroid dementia syndrome: apossible model of human glucocorticoid neurotoxicity. Neurocase 2007;13:189200.

51. Hanania NA, Singh S, El-Wali R, et al. The safety and effects of the b-blocker,nadolol, in mild asthma: an open-label pilot study. Pulm Pharmacol Ther 2008;21:134141.

52.&

Nguyen LP, Singh B, Okulate AA, et al. Complementary anti-inflammatoryeffects of a b-blocker and a corticosteroid in an asthma model. NaunynSchmiedebergs Arch Pharmacol 2012; 385:203210.

In a murine asthma model, the simultaneous administration of a corticosteroid anda b2-adrenoceptor inverse agonist was more effective at reducing indexes ofairway inflammation than either drug given alone, suggesting that nadolol maypossess corticoid-sparing properties.53.&

Lokhandwala T, West-Strum D, Banahan BF, et al. Do statins improve out-comes in patients with asthma on inhaled corticosteroid therapy? A retro-spective cohort analysis. BMJ Open 2012; 2:e001279.

This is a retrospective cohort study using Mississippi Medicaid data for 20022004 that suggests beneficial effects of statins in asthma management.54. Nair P, Dasgupta A, Brightling CE, Chung KF. How to diagnose and

phenotype asthma. Clin Chest Med 2012; 33:445457.55. Lugogo NL, Kraft M, Dixon AE. Does obesity produce a distinct asthma

phenotype? J Appl Physiol 2010; 108:729734.56. Kring SII, Larsen LH, Holst C, et al. Genotype-phenotype associations in

obesity dependent on definition of the obesity phenotype. Obesity Facts2008; 1:138145.

n Veen IH, TenBrinke A, Sterk PJ, et al. Airway inflammation in obese andnobese patients with difficult-to-treat asthma. Allergy 2008; 63:570574.ahaditatupt.

Comorbidities of asthma Cazzola et al.

1070-528I. Shortness of breath, prescription of bronchodilators and the risk ofrdial infarction. J Hypertens 2009; 27:13581359.

58. Mlimj.p

7 2012 Wolters Kluwer Health | Lippincott Williams & Wilkinsev S, Farah CS, King GG, Salome CM. Obesity, expiratory flowion and asthma symptoms. Pulm Pharmacol Ther 2012;doi:10.1016/2012.0F5.004. [Epub ahead of print]

www.co-pulmonarymedicine.com 41l infarction in patients taking asthma medication: a study with theal Practice Research Database. J Hypertens 2009; 27:1485

57. vano