Asthma Lancet 2013

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1360 www.thelancet.com Vol 382 October 19, 2013

Asthma

Fernando D Martinez, Donata Vercelli

Asthma is a heterogeneous group of conditions that result in recurrent, reversible bronchial obstruction. Although thedisease can start at any age, the first symptoms occur during childhood in most cases. Asthma has a strong geneticcomponent, and genome-wide association studies have identified variations in several genes that slightly increase therisk of disease. Asthma is often associated with increased susceptibility to infection with rhinoviruses and with changesin the composition of microbial communities colonising the airways, but whether these changes are a cause orconsequence of the disease is unknown. There is currently no proven prevention strategy; however, the finding thatexposure to microbial products in early life, particularly in farming environments, seems to be protective againstasthma offers hope that surrogates of such exposure could be used to prevent the disease. Genetic and immunologicalstudies point to defective responses of lung resident cells, especially those associated with the mucosal epithelium, ascrucial elements in the pathogenesis of asthma. Inhaled corticosteroids continue to be the mainstay for the treatmentof mild and moderate asthma, but limited adherence to daily inhaled medication is a major obstacle to the success of

such therapy. Severe asthma that is refractory to usual treatment continues to be a challenge, but new biologicaltherapies, such as humanised antibodies against IgE, interleukin 5, and interleukin 13, offer hope to improve thequality of life and long-term prognosis of severe asthmatics with specific molecular phenotypes.

IntroductionAsthma is characterised by recurrent episodes of airwayobstruction, which reverse either spontaneously or afteruse of medication, and is usually associated withbronchial hyper-responsiveness and evidence of chronicairway inflammation. More elaborate definitions havebeen proposed and there is no clear consensus on how todefine asthma; fortunately, most cases are mild and arenot diffi cult to diagnose and treat by family doctors.

However, at the more severe end of the asthma spectrum,comorbidities overlap with chronic obstructive pul-monary disease (COPD), and refractoriness to availabletherapy make asthma troublesome and costly for health-care systems.

A previous Seminar on asthma was published inThe Lancet more than a decade ago.1 Here, we mainlyreview information emerging thereafter. During thisperiod, there have been substantial advances in ourunderstanding of the genetics, pathogenesis, and naturalcourse of the disease, offering great hope for thedevelopment of new, targeted therapies, particularly forsevere asthma. For now, the main therapeutic methodcontinues to be the so-called adrenal substance

recommended for treatment of asthma by Solis-Cohen2in 1900, when he noted It hasserved to cut short aparoxysm [and] been useful in averting the recurrence

of paroxysms and in finally bringing about a state offreedom from fear of their recurrence. As much can besaid today for the available corticosteroids and beta-adrenergic agonists, which are close relatives of thenatural products contained in the Burroughs &Wellcomes tablets (to be taken as 5 grains once daily,then twice, then three times daily) mentioned bySolis-Cohen.2

EpidemiologySurveys based on questionnaire data, in which thedisease is usually defined as current episodes ofwheezing or a physicians diagnosis, show that asthmaaffects 516% of people worldwide.3Rates vary widelyin different countries,4 reflecting differences inprevalence and in diagnostic standards. Prevalenceincreased markedly worldwide during the second halfof the 20th century,5 but seems to have plateauedthereafter, particularly in countries with the highestasthma rates, such as the UK.6 An exception is theUSA, where asthma prevalence increased from 73% to84% between 2001 and 2010,3and continues to mainlyaffect children, African-Americans, and the poor;

112% of people with incomes lower than the povertylevel had asthma, compared with 87% for those withincomes up to twice the poverty level, and 73% forthose with higher incomes. Asthma-related hosp-italisations and emergency room visits remained stablein the USA from 200110, and mortality decreasedslightly.3 There have been large increases in asthmaexpenditures in the USA, which were calculated atUS$18 billion per year for adults alone in 200305. 7Moreover, the costs of asthma medication as aproportion of total costs have substantially increased;in 1985, 57% of asthma expenditures were foremergency room visits and hospitalisations,8 whereasdrug treatment now accounts for up to 75% ofasthma costs.9

Lancet2013; 382: 136072

Published Online

August 23, 2013

http://dx.doi.org/10.1016/

S0140-6736(13)61536-6

Arizona Respiratory Center and

BIO5 Institute, University of

Arizona, Tucson, AZ, USA

(Prof F D Martinez MD,

Prof D Vercelli MD)

Correspondence to:

Prof Fernando D Martinez,

University of Arizona, Arizona

Respiratory Center,

1501 N Campbell, Tucson,

AZ 85724, USA

[email protected]

Search strategy and selection criteria

Since roughly 51 000 articles have been published on asthma

since 2002, when the last LancetSeminar on the disease was

published, we did a non-systematic review of articles

published in English and collected by the authors. We

searched PubMed, using the term asthma, from January,

2002, to March, 2013. We gave priority to randomised

controlled trials when available, to larger studies, and to

articles published in high-quality journals.
http://crossmark.crossref.org/dialog/?doi=10.1016/S0140-6736(13)61536-6&domain=pdf


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studies assessing factors that increase risk of the disease.The most influential studies were those in which childrenin advanced societies who were raised on farms werecompared with those raised in the same rural com-munities but away from farms, or those raised in cities.43,44

These surveys consistently found that the protectiveeffects of living on a farm are stronger if they occur inutero and during early life, that protection against asthmamight be associated with microbial diversity, a hallmarkof the farm environment, and that protective factors forasthma are different from those for allergic sensitisation.A parallel finding is that exposure to day care in early lifeis associated with decreased risk of asthma duringschool years.45Also, the microbial communities of housedust differ significantly depending on whether thehousehold includes children exposed versus unexposedto day care.46

The specific environmental factors that account forthese effects have not been identified, but the mostaccepted hypothesis is that exposure to a range of mainly

innocuous micro-organisms, largely bacteria, triggersprotective responses in the developing immune system.Strong support for this hypothesis has come from studieswith animals, which have shown that mice raised undergerm-free conditions were more likely to develop

experimental allergic asthma than animals exposed tonormal microbial flora.47After germ-free young mice wereexposed to standard mouse-colony bacteria and intestinalmicrobiota were re-established, predisposition for asthmawas reversed; this effect was not achieved in adult, germ-free mice. Similarly, oral exposure to bacterial extractsprotects animals against the development of experimentalmodels of asthma.48,49These studies suggest that exposureto environmental micro-organisms might affect asthmarisk by modifying the type of bacteria that colonise the gut,and these changes could have profound effect on the riskfor asthma and other diseases.50These effects are probablyactivated through innate immune receptors such asTLR2,51 and might affect the development of responsesmediated by several cell types, including basophils and

Figure : Asthma genes identified through genome-wide association studies (GWAS)

The National Human Genome Research Institute catalogue of published GWAS was searched using asthma as disease, and childhood asthma as trait.37

112

23

22

21

12

11212

13

212

213

22

23

24

243

SLCA

24

23

21

1312

12

13

21

22

313233

34

IL

ACO

TLE-

CHCHD

363362

361353423332

32

41

424344

31

31

22

22232425

21

21

13

12

12

ATPAF

GNAI

PYHIN

CHIL

Corf

ILR

CRCT

DENNDB

CRB

1

2524

23

22

22

23

24

31

321

32333

343536

37

21

21

16

14

141143

13

13

12

12

112

112 ILRL

ILR

2

2526

26272829

22

2324

2625

24

22

13

13

21

21

11

14

13

12

ILRA

3

16

153

151141312

12

13

21

22

24

26

27

28

31

3132

333435

LOC

GAB

4

153

151

14

1312

112

12

13

14

15

21

22

23

31

3233

34

35

PDED

TSLP

SLCARADIL

NDFIP

TNIP

ADRAB

ADAM

5

252423

22

21

21

12

12131415

16

21

22

23

24

252627 GAPDHP-T

NOTCH

PBX

Corf

HLA-DQA

HLA-DQB

HLA-DPB

HLA-DRA

HLA-DOA

BTNL

6 8 9

KIRREL-ETS

CRTAM

151413

12

112

112

21

22

23

24

25

26

LOC 15

14

1312

112

12

13

14

2122

IKZF

CDK

22

23

241242243

21

15

14

13

RORA

SMAD

KIAA

PRNP

1312112

121415

21

222324

25

26

12

112

12

13

23

2425

LRRC

13

14

21

22

31

323334

12

1121213

DCLK

SCG PERLDPCDH

Corf

PRKG

10 11 12

1312112

112

12

13

13

HSSTA-

CDRTP

GSDMAGSDMB

ORMDL

13

12112

11212

21222324

25

12

112

11212131

133

ILRB

13 15 17 20 22


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The epithelium in particular transduces mechanical

stresses, and in both fetal and mature airways, epithelialcells interact with mesenchymal cells to coordinateremodelling of tissue architecture in response to themechanical environment.8688 The ability of mechanicalstress by itself to regulate airway structural changesmight contribute to the dissociation between airwayremodelling and inflammation, and might also explainwhy patterns of fluctuations in airway function seem topredict asthma exacerbations89,90 and loss of asthmacontrol after withdrawal of inhaled corticosteroids.91

Despite the complexity of asthma pathogenesis, confi-dence in the fundamental role of Th2 cells in asthmapathobiology has led pharmaceutical and biotechnologycompanies to develop new asthma treatments that target

Th2 cytokines or their receptors. These therapies haveconsistently blocked Th2 inflammation and associatedstructural changes in the airways of antigen-challengedanimal models; however, few have been successful whenmoved to the clinic.85Recent findings might help explainthese results. Phenotypic heterogeneityprobably a reflec-tion of the diverse genetic and environmental factors thatunderpin asthma pathogenesisis an evolving conceptthat has clinical implications.92 Early clinically-baseddefinitions of asthma focused on two main phenotypes;extrinsic asthma is defined as typically developing inchildhood and accompanied by IgE-mediated allergic

disease, whereas intrinsic asthma typically develops later

in life and is not associated with allergic sensitisation.Concerns over the ability of these biased definitions tocapture the diversity of asthma characteristics, and thecontinued lack of biomarkers for asthma phenotypes,prompted efforts to develop alternative, unbiased strategiesthat sought to define asthma phenotypes based on statis-tical methods, such as cluster analysis93,94and latent classanalysis.95 Figure 3 shows results obtained using clusteranalysis, a method that combines variables so that objectsin the same group, or cluster, are more similar to eachother than to those in other clusters. In a study of clinicalphenotypes of adult asthma,93 clusters of patients weredefined according to their relative expression of symptomsand eosinophilic inflammation. Patients with greater

discordance between symptoms and inflammation weremore diffi cult to treat and required treatment in specialisedasthma centres. Although the reasons for this discordancewere unclear, measures of airway inflammation in thesesubgroups were clinically informative; managementaimed at reducing eosinophilic inflammation was betterthan usual treatment in both discordant groups.

The results of unbiased studies of asthma phenotype aremore similar than they are different, even though thestatistical methods and variables analysed are not thesame. Moreover, results overlap with those obtained usingearlier, biased phenotype approaches. All studies of asthma

Early-ons

etato

picasth

ma

Conc

ordantsym

ptoms

,infla

mmati

on,

anda

irwaydysf

uncti

on

Early-symptom predominantEarly onset, atopic;

normal BMI, high symptom expression

Obese non-eosinophilicLater onset, female preponderance; high

symptom expression

Discordant symptoms

Discordant inflammation

Monitoring inflammationallows downtitration ofcorticosteroids

Symptom-based approachto therapy titration mightbe sufficient

Benign asthmaMixed middle-aged cohort;

well controlled symptoms andinflammation, benign

prognosis

Symptoms

Monitoring inflammation allows

targeted corticosteroids to lowerexacerbation frequency

Inflammation predominantLate onset, greater proportion of males;

few daily symptoms but active

eosinophilic inflammation

Eosinophilic inflammation

Concordant disease

Primary careSecondary care

Figure : Clinical phenotypes of adult asthma, identified by cluster analysis93

Clusters of patients are plotted according to their relative level of symptoms and eosinophilic inflammation. The plot highlights that patients with greaterdiscordance between symptoms and inflammation are more diffi cult to treat and should usually be followed up in specialised asthma centres.


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www.thelancet.com Vol 382 October 19, 2013 1365

phenotype found age at disease onset to be a crucial

differentiating factor. Early-onset disease is consistentlyassociated with a more allergic condition over a range ofseverities, whereas later-onset disease is associated witheosinophilic inflammation and obesity, is more commonin women, and is generally less allergic. Despite theassociation of early-onset disease with atopy and allergy,none of the unbiased approaches found variablesassociated with these conditions (such as atopy and totalIgE) to be key distinguishing features of subgroups.92

An important step towards integrating asthma pheno-types and pathogenesis was made by a 2009 analysis ofmolecular phenotyping in adult patients with mild,corticosteroid-naive asthma.96 Expression profiling ofbronchial biopsies identified a Th2-high asthma pheno-

type that is detectable in around 50% of adults withasthma, and is marked by overexpression of interleukin-13-dependent genes (ie, POSTN, CLCA1, and SERPINB2).Patients classified as Th2-high were subsequently foundto have higher amounts of tissue interleukin 13 andinterleukin-5 mRNA, greater numbers of eosinophils andmast cells, and showed more atopy and thickening of thesubepithelial basement membrane. These patientsresponded to inhaled corticosteroids, whereas the Th2-low group did not.97 Moreover, asthmatics with highserum concentrations of the interleukin-13-induced bio-marker periostin were more likely than those with lowconcentrations of periostin to show improved lungfunction in response to anti-interleukin-13 treatment.98,99Although long-term studies are needed to assess thestability of these phenotypes, understand them in moredetail, and further integrate them with relevant patho-biology and appropriate biomarkers, these results suggestthat combining clinical and molecular approaches mightmove us closer to the identification of true asthmaendotypesie, disease subtypes that are defined bydistinct pathophysiological mechanisms and can betreated accordingly.100 The table presents an integratedview of major clinical and molecular asthma phenotypeswith relevant pathobiology and biomarkers.

A truly modern view of asthma pathogenesis shouldalso incorporate the notion that a Th2 cytokine signature

might not simply reflect an adaptive Th2 cellularresponse; thus, there might be more to asthma than Th2-cell-dependent, IgE-mediated allergic inflammation.Indeed, asthma is increasingly seen as a disease that hasa strong innate immune component and begins at theairway epithelium. Far from being just a structuralbarrier, the airway epithelium responds to environmentalinsults such as protease-containing allergens, pathogens,cigarette smoke, and pollution by secreting inflammatorymediators and antimicrobial peptides.101 Moreover,a damaged epithelium releases interleukin 25, inter-leukin 33, and the cytokine protein TSLP, which acti-vate natural-killer T cells, mast cells, eosinophils, andbasophils, and stimulate newly discovered lineage-nega-tive cells (ILC2, also known as natural type-2 helper cells

or nuocytes).102105 ILC2 cells require the transcription

factor ROR for their development,

106

reside in themucosa, and respond to epithelial distress signals byrapidly releasing large amounts of Th2 cytokines (mainlyinterleukin 13 and interleukin 5).107,108 ILC2 are alsoactivated by interleukin 33 released by alveolar macro-phages during influenza virus infection,109 providing acommon pathway for allergen-induced and virus-inducedTh2-type responses. ILC2 have been shown to benecessary for allergic lung inflammation in mice,110,111although their role in human asthma remains to bedetermined. These cells have been found in human fetaland adult lung tissue, and in human peripheral blood.112

The identification of innate lymphoid cells that secreteTh2 cytokines in response to airway epithelial damage

might fill a crucial gap in our understanding of asthmapathogenesis, by providing a long-sought link betweenTh2 inflammation and lung-based mechanisms of diseaseinitiation. The ability of these cells to produce interleukin13 and interleukin 5 is consistent with the classic cytokinesignature of asthma, but emphasises the role of innatemechanisms in promoting adaptive Th2 responses. Analtered epithelial barrier could allow the entry of otherwiseinnocuous antigens that, in the pro-Th2 milieu created byepithelium-activated innate type-2 cytokines, couldpromote Th2 differentiation eventually leading to IgEproduction. Continued stimulation of epithelial cells,smooth muscle cells, and fibroblasts by Th2-cell-derivedand ILC2-derived interleukin 13 would lead to airwayhyper-responsiveness and remodelling (figure 4). Thisupdated view of asthma pathogenesis still emphasises therole of Th2 cytokines, but focuses on both their innate andadaptive cellular sources. Genetic evidence from GWAShas independently pointed to the importance of the

Natural history Clinical and

physiological features

Pathobiology and

biomarkers

Response to therapy

Th2-high phenotype

Early-onset

allergic

Early onset,

mild to severe

Allergic symptoms and

other diseases

Thick subepithelial

basement

membrane, specific

IgE, Th2 cytokines

Corticosteroid-responsive,

Th2-targeted

Late-onseteosinophilic

Adult onset,often severe

Sinusitis, less allergic Corticosteroid-refractory,

eosinophilia,

interleukin 5

Responsive to antibody tointerleukin 5 and cysteinyl

leukotriene modifiers,

corticosteroid-refractory

Th2-low phenotype

Obesity-

related

Adolescent and

adult onset

Women mainly

affected, very

symptomatic, airway

hyper-responsiveness

less clear

Lack of Th2

biomarkers,

oxidative stress

Responsive to weight loss,

antioxidants, and possibly

to hormonal therapy

Neu trophi lic Adu lt o nset Lo w FEV1, more a ir

trapping

Sputum

neutrophilia, Th17

pathways,

interleukin 8

Possibly responsive to

macrolide antibiotics

Th2=T-helper-type-2 cytokine. FEV1=forced expiratory volume in 1 s.

Table: An integrated view of clinical and molecular asthma phenotypes92


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epitheliumILC2 axis in asthma pathogenesis byidentifying IL33, the IL33 receptor IL1RL1 (ST2), TSLP,RORA, and IL13as major asthma susceptibility genes.33,113

Cytokine profiles resembling a typical T-cell-derived,adaptive response but sustained by innate lymphoid cellsare not limited to the Th2 type. A parallel system of cellslacks antigen receptors yet produces an array of effectorcytokines (interferon , interleukin 17, and interleukin 22)that match the variety of cytokines secreted by subsets ofT-helper cells. These cells function in lymphoid organo-genesis, tissue remodelling, and antimicrobial immunityand inflammation, particularly at barrier surfaces. Theirability to promptly respond to insults inflicted by stress-

causing microbes suggests these cells are crucial forfirst-line immunological defenses.114 Changes in theseinnate mechanisms might also be involved inasthma pathogenesis, by contributing to lower airwayvulnerability to otherwise innocuous respiratory tractviral infections, particularly those caused by rhinoviruses.

PreventionThere is currently no established strategy for primaryprevention of asthma or for preventing the developmentof airflow limitation in patients with asthma. Avoidingexposure to house dust mite during pregnancy and earlyinfancy had no effect on asthma outcomes by age 8 years

RORA

Mast cellBasophil

Fibroblasts

Smooth muscle cells

Epithelial cells

Allergen proteases, viruses

Allergen

Eosinophil

Soluble mediators

Airway hyper-responsiveness,remodelling

Mechanical stress

Interleukin 13

Interleukin 13

Interleukin 13

Interleukin 13

Interleukin 33

Interleukin 13

Interleukin 13

Interleukin 5

IL5R

Interleukin 5

Interleukin 4IL4R

IL4R

Interleukin 4

Interleukin 4

Interleukin33

IL33RIL25R

Interleukin25

Interleukin 10

TSLP

ILC2

IgE

FcRIB

FcRIB

Allergicinflammation

B cellTh2 cellTh cell

CD14

TLR

TSLP

TGF1

Treg cell

TLR

Dendritic cell

MHCclass II

TCR

Antigen

GATA3STAT6

STAT6

Figure : Major immune pathways involved in asthma pathogenesis

Innate and adaptive components of allergic inflammation are shown, including the recently discovered ILC2 cells that release Th2 cytokines in response to epithelial damage. The links between

immune responses and structural changes in the lung are also depicted. TLR=toll-like receptor. TSLP=thymic stromal lymphopoietin. TGF1=transforming growth-factor 1. TCR=T-cell receptor.

Treg=regulatory T cell. Th=T-helper cell. Th2=T-helper-type-2 cell.


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in Australia or the Netherlands.115,116Two trials in which

high-risk infants (defined by parental history of allergicdisease) were randomly assigned to extensive en-vironmental and dietary interventions or to usual careshowed reductions in prevalence of asthma, as assessedby questionnaire, by age 18 years and age 7 years; 117,118however, the generalisability of these results is limited bysmall numbers, highly selected populations, unfeasibilityto mask the interventions, and losses to follow-up.The consistent protection against development of asthmaseen with exposure to high microbial burden in early lifehas suggested the possibility that innocuous surrogatesof such exposure could be used to prevent asthma,119butno data is yet available to support this hypothesis.

Results of several trials have disproved the contention

that chronic use of inhaled corticosteroids could block thenatural course of asthma and the development of airflowlimitation. 4 years of twice daily treatment with inhaledcorticosteroids in school-age children with asthma had noeffect on lung function or clinical outcomes 4 years afterdiscontinuation of therapy.13 In preschool children withwheezing, administration of inhaled corticosteroids forseveral years and with different methods had no effect onlong-term, asthma-related outcomes.120122

TreatmentThe two most important aspects of asthma therapy areenvironmental control and pharmacological therapy. Forsevere asthma, treatment of comorbidities is also crucial.Most asthma trials have been done in developed countries.In less-developed countries, treatment of asthma facesmany challenges, including underdiagnosis, access tocare, ability of health-care workers to manage asthma, andavailability and affordability of inhaled therapy.123 Theseobstacles might substantially increase asthma-associatedmorbidity and mortality in developing countries,124 butstudies specifically addressing this issue are lacking.

Although there is consensus that environmentalexposures are important causative agents in asthma, therole of environmental control and allergen avoidance inthe treatment of asthma remains controversial. Even incases of occupational asthma, where the offending

agent can often be directly identified, only a third ofpatients show symptomatic recovery after cessation ofexposure.25 A comprehensive environmental interven-tion to reduce exposure to indoor allergens amongchildren with asthma who live in inner cities, includingreducing exposure to cockroach and dust mite aller-gens, resulted in reduced asthma-associated morbidity.125Data from adult studies are less convincing, with moststudies showing that use of allergen-avoidancemeasures as a single intervention is clinically ineffectivein asthma management.126

Therapeutic approaches to mild and moderate asthmaInhaled corticosteroids, with or without long-actingbeta agonists (LABA), continue to be the mainstay of

pharmacological treatment for mild to moderate asthma.

When taken regularly, inhaled corticosteroids effectivelycontrol everyday asthma symptoms, improve lungfunction, and decrease the risk for exacerbations.127Controlled trials have consistently shown that inhaledcorticosteroids are better than leukotriene receptorantagonists, such as montelukast, at controllingsymptoms, improving lung function, and reducingexacerbations,128,129 yet results of a pragmatic trial, inwhich the study settings attempted to mirror those ofusual medical practice, suggested that montelukastseems to be as effective as inhaled corticosteroids.130 Inthis real-life setting, adherence to once daily oral therapywas better than adherence to twice daily inhaledtherapy,130 suggesting that adherence to inhaled therapy

is a key obstacle to achieving success with asthmatreatment. In community-based studies, adherence tosuch therapy can be as low as 20%. In well controlledtrials, adherence is very high initially but wanes there-after; several months into trials, participants do not takemore than 50% of their prescribed doses. 131 Evidencesuggests that taking at least 75% of inhaled corticosteroiddoses is necessary to attain the expected decrease inexacerbations.132 Although behavioural and other inter-ventions have been proposed to increase medicationadherence, results are not encouraging.133

Three approaches to improve or circumvent dailyadministration of asthma medicines have been proposed.Supervised therapy for children, in which use of inhaledcorticosteroids was overseen by study staff memberseach school day for 15 months, showed some improve-ment in asthma outcomes,134 but the cost of such anapproach would probably only make it worthwhile forsevere cases. In patients with milder asthma, replacing adaily dose of inhaled corticosteroids with inhaled cortico-steroids taken together with albuterol (salbutamol)whenever the latter is needed showed improved rates ofasthma exacerbations compared with placebo, andsimilar exacerbation rates to those seen with daily inhaledcorticosteroids.127,135 By contrast, a strategy based ondoubling the daily dose of inhaled corticosteroids whenasthma control deteriorates has proven ineffective,136

although quadrupling the dose showed some evidence ofdecreased exacerbation risk.137Although the role of theseas-needed approaches in asthma therapy remainscontroversial,138,139it is well established that patients oftenhave different asthma control goals and different viewsof the importance of medication side-effects than thoseof practitioners and in guidelines.140 Considering thepatients perspective when developing treatment planscould help solve the conundrum of inhaled corticosteroidstherapyie, that high effi cacy in clinical trials is notmatched by a similar improvement in community-basedasthma outcomes.

Several clinical trials have shown that patients who arestill symptomatic after treatment with inhaled cortico-steroids benefit from the addition of a LABA, and a larger


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proportion of such patients respond better to adding

LABAs than to doubling the dose of inhaled cortico-steroids or adding a leukotriene receptor antagonist.129Ina small proportion of patients, reduced responsiveness toinhaled corticosteroids might be explained by cortico-steroid resistance.141For patients in whom exacerbationsare a main source of morbidity, as-needed use of inhaledcorticosteroids plus formoterol, a fast-onset LABA, hasproven effective in preventing exacerbations.142However,daily use of inhaled corticosteroids plus LABA is notbetter that inhaled corticosteroids alone in controllingexacerbations in inhaled-corticosteroid-naive patients.143Nevertheless, in more than 60% of asthma patients in theUSA144and in other countries,145the inhaled corticosteroidformulation most widely used to treat asthma consists of

an inhaled corticosteroid plus LABA, with inhaledcorticosteroids alone being used by a smaller proportionof patients. A possible explanation for the excessive use ofinhaled corticosteroids plus LABA combinations isinsuffi cient asthma control due to lack of adherence toinhaled corticosteroids, which could lead patients andpractitioners to believe that taking inhaled corticosteroidsalone leads to an insuffi cient response, warranting theaddition of another medicine. This use of combinationtreatments over inhaled corticosteroids alone markedlyincreases drug costs,9 and could unnecessarily exposepatients to rare but potentially deleterious side-effects ofLABAs. Increased risk for severe asthma attacks anddeath has been reported in patients taking LABAs alone,and it is uncertain whether inhaled corticosteroids com-pletely prevent such unwanted outcomes.146,147

These safety concerns have prompted the search foralternative add-on therapies in patients whose asthma isnot well controlled with inhaled corticosteroids alone. Ina 14-week crossover study, tiotropium, a long-actinganticholinergic agent approved for use in COPD whenadded to inhaled corticosteroids, showed similar clinicalimprovements to those obtained when salmeterol, aLABA, was added to inhaled corticosteroids, and greaterimprovements than those achieved with higher doses ofinhaled corticosteroids.148 Larger and longer studies areneeded to determine if this drug could be an effective

alternative to LABAs.

Therapeutic approaches to severe asthma: targeteddrugs on the horizonTreatment for patients with severe asthma, who remainuncontrolled and have frequent exacerbations even withhigh-dose inhaled corticosteroids plus LABA or with oralcorticosteroids, remains a significant challenge. Thesepatients account for a high proportion of the directfinancial costs of asthma, and this societal burden, addedto the debilitating morbidity of severe asthma, justifiescontinued efforts to find new treatments. A major shiftin potential treatment approaches to severe asthma hascome from advances in our understanding of diseasepathogenesis. There is now clear evidence that severe

asthma is heterogeneous, and unbiased hierarchical

clustering methods have described several subphenotypesin adults and children.149One hypothesis is that differentasthma subphenotypes have unique pathogenic mechan-isms, and identifying such mechanisms could allow formore targeted and specific therapy.

Many patients with severe asthma, especially children,are highly atopic. Omalizumab, a humanised monoclonalantibody against IgE, decreased asthma exacerbations by30% in a large, inner city study of patients of all severities,150with effects being particularly strong in patients sensitisedand exposed to cockroaches. In adults with severe asthma,omalizumab also decreased exacerbations, but had lessimpressive effects on everyday symptoms.151 High costsand unfeasibly large doses in patients with very high

serum IgE concentrations limit the use of this drug.The finding that several asthma subphenotypes had

evidence of sputum eosinophilia94 and were prone toexacerbations suggested the possibility that humanisedmonoclonal antibodies against interleukin 5, the mostpotent eosinophil stimulant and chemoattractor, couldhave a role in preventing such exacerbations. A recentstudy supported this hypothesis; patients 12 years orolder with severe asthma and direct or indirect evidenceof eosinophilic inflammation showed a substantialdecrease in exacerbation rates with different doses ofmepolizumab, an anti-interleukin 5 antibody, comparedwith placebo.152The effects were specific for exacerbations,the primary outcome, and there was no significantimprovement in measures of global asthma control orlung function.

The central role of interleukin 4 and interleukin 13 inthe pathogenesis of some cases of asthma has alsoprompted studies using humanised monoclonal anti-bodies against these cytokines and against the commoncomponent of their receptors, the interleukin 4R chain.Although these studies have shown less impressive resultsthan those with anti-interleukin 5 antibody, specificsubgroups of patients did show benefits. For example,compared with patients with low concentrations, patientswith high concentrations of serum periostin, a marker ofinterleukin 13 activation,153showed larger improvement in

lung function when treated with lebrikizumab, ahumanised monoclonal antibody to interleukin 13.99Similarly, those with more severe disease showed someclinical improvement after administration of AMG317,a monoclonal antibody against interleukin 4R.154

Therapies targeting other possible inflammatorymediators have been developed, but none have shownclear evidence of clinical benefit. Anti-tumour-necrosis-factor drugs are highly effective in other inflammatoryconditions but showed few clinical benefits andsubstantial unwanted effects in patients with severeasthma.155 Pharmacological advances have occurred inthe development of phosphodiesterase-4 (PDE4) inhib-itors, which are effective against neutrophilic inflam-mation156 and could be effective in treatment of severe


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asthma. Roflumilast is an oral PDE4 inhibitor that has

been shown to decrease allergen-induced inflammation

157

and is currently approved for use in severe COPD.However, PDE4 inhibitors cause frequent nausea, vomit-ing, and diarrhoea, which limit their clinical usefulness.In summary, the development of therapies specificallytargeted to inflammatory pathways and mediators,identified by use of biomarkers, is the most promisingapproach to treatment of severe forms of asthma that arerefractory to available treatment.

Severe asthma: thermoplastyIn patients with severe, refractory asthma, reduction ofhypertrophied bronchial muscle might induce symptomrelief and improvement in lung function. Bronchial

thermoplasty, an outpatient procedure in whichcontrolled thermal energy is applied in consecutivesessions through a bronchoscope, has been used withthis goal in mind. A study that compared thermoplastyversus a control group without sham procedure showedbenefits in exacerbation rates and symptoms; however,hospitalisation for adverse respiratory events was morefrequent shortly after thermoplasty procedures than inthe control group.158 A larger clinical trial, in whichbronchial thermoplasty was compared with a shamprocedure, showed modest improvements in asthmasymptoms and exacerbations after treatment.159Bronchialthermoplasty was approved for use in severe asthma bythe US FDA in 2010, but it remains unclear whether itsbenefits outweigh its potential risks.160

ConclusionsThere have been major advances in the past decade inour understanding of the genetics, natural history, andpathogenesis of the diverse clinical syndromes identifiedas asthma. There is renewed hope that novel preventionstrategies, and therapies targeted specifically against themechanisms responsible for disease processes, willdecrease the worldwide burden in health-care costs andmorbidity caused by this still mysterious disease.

Contributors

The authors contributed equally to the literature search, writing and

editing of the manuscript, and the generation of figures and table.Conflicts of interest

FDM has received honoraria from Abbott Laboratories for invitedlectures. DV has participated in peer discussion groups supportedby Merck.

Acknowledgments

The authors were funded by grants from the US National Heart, Lung,and Blood Institute and the US National Institute of Allergy andInfectious Diseases.

References1 Tattersfield AE, Knox AJ, Britton JR, Hall IP. Asthma. Lancet2002;

360:131322.

2 Solis-Cohen S. The use of adrenal substance in the treatment ofasthma.JAMA1900; 34:116466.

3 Akinbami LJ, Moorman JE, Bailey C, et al. Trends in asthmaprevalence, health care use, and mortality in the United States,

20012010. Hyattsville, MD, USA: National Center for HealthStatistics, 2012.

4 Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends inthe prevalence of symptoms of asthma, allergic rhinoconjunctivitis,

and eczema in childhood: ISAAC Phases One and Three repeatmulticountry cross-sectional surveys. Lancet2006; 368: 73343.

5 Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med2006; 355:222635.

6 Anderson HR, Gupta R, Strachan DP, Limb ES. 50 years of asthma:UK trends from 1955 to 2004. Thorax2007; 62:8590.

7 Sullivan PW, Ghushchyan VH, Slejko JF, Belozeroff V, Globe DR,Lin SL. The burden of adult asthma in the United States: evidencefrom the Medical Expenditure Panel Survey.J Allergy Clin Immunol2011; 127:36369.

8 Weiss KB, Gergen PJ, Hodgson TA. An economic evaluation ofasthma in the United States. N Engl J Med1992; 326:86266.

9 Bedouch P, Marra CA, FitzGerald JM, Lynd LD, Sadatsafavi M.Trends in asthma-related direct medical costs from 2002 to 2007 inBritish Columbia, Canada: a population based-cohort study.PLoS One2012; 7:e50949.

10 Sears MR, Greene JM, Willan AR, et al. A longitudinal,population-based, cohort study of childhood asthma followed toadulthood. N Engl J Med2003; 349:141422.

11 Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD.Wheezing and bronchial hyper-responsiveness in early childhood aspredictors of newly diagnosed asthma in early adulthood:a longitudinal birth-cohort study. Lancet2008; 372:105864.

12 Rasmussen F, Taylor DR, Flannery EM, et al. Risk factors forhospital admission for asthma from childhood to young adulthood:a longitudinal population study.J Allergy Clin Immunol2002;110:22027.

13 Covar RA, Strunk R, Zeiger RS, et al. Predictors of remitting,periodic, and persistent childhood asthma.J Allergy Clin Immunol2010; 125:35966.

14 Vonk JM, Postma DS, Boezen HM, et al. Childhood factorsassociated with asthma remission after 30 year follow up. Thorax2004; 59:92529.

15 Haland G, Carlsen KC, Sandvik L, et al. Reduced lung function atbirth and the risk of asthma at 10 years of age. N Engl J Med2006;

355:168289.16 Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD.

Poor airway function in early infancy and lung function by age22 years: a non-selective longitudinal cohort study. Lancet2007;370:75864.

17 Bisgaard H, Jensen SM, Bonnelykke K. Interaction between asthmaand lung function growth in early life. Am J Respir Crit Care Med2012; 185:118389.

18 Turner SW, Palmer LJ, Rye PJ, et al. The relationship betweeninfant airway function, childhood airway responsiveness, andasthma. Am J Respir Crit Care Med2004; 169:92127.

19 Morgan WJ, Stern DA, Sherrill DL, et al. Outcome of asthma andwheezing in the first 6 years of life: follow-up through adolescence.Am J Respir Crit Care Med2005; 172:125358.

20 Strunk RC, Weiss ST, Yates KP, Tonascia J, Zeiger RS, Szefler SJ.Mild to moderate asthma affects lung growth in children andadolescents.J Allergy Clin Immunol2006; 118:104047.

21 James AL, Palmer LJ, Kicic E, et al. Decline in lung function in theBusselton Health Study: the effects of asthma and cigarettesmoking. Am J Respir Crit Care Med2005; 171:10914.

22 Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacerbationspredict excess lung function decline in asthma. Eur Respir J2007;30:45256.

23 Mortimer K, Neugebauer R, Lurmann F, Alcorn S, Balmes J, Tager I.Air pollution and pulmonary function in asthmatic children: effectsof prenatal and lifetime exposures. Epidemiology2008; 19:55057.

24 Anees W, Moore VC, Burge PS. FEV1 decline in occupationalasthma. Thorax2006; 61:75155.

25 Rachiotis G, Savani R, Brant A, MacNeill SJ, Newman Taylor A,Cullinan P. Outcome of occupational asthma after cessation ofexposure: a systematic review. Thorax2007; 62:14752.

26 Gowers AM, Cullinan P, Ayres JG, et al. Does outdoor air pollutioninduce new cases of asthma? Biological plausibility and evidence;a review. Respirology2012; 17:88798.

27 Savenije OE, Granell R, Caudri D, et al. Comparison of childhood

wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA.J Allergy Clin Immunol2011; 127:150512.


11/13

Seminar


28 Illi S, von Mutius E, Lau S, Niggemann B, Gruber C, Wahn U.Perennial allergen sensitisation early in life and chronic asthma in

children: a birth cohort study. Lancet2006; 368:76370.29 Simpson A, Tan VY, Winn J, et al. Beyond atopy: multiple patterns

of sensitization in relation to asthma in a birth cohort study.Am J Respir Crit Care Med2010; 181:120006.

30 Rodriguez A, Vaca M, Oviedo G, et al. Urbanisation is associatedwith prevalence of childhood asthma in diverse, small ruralcommunities in Ecuador. Thorax2011; 66:104350.

31 Mallol J, Castro-Rodriguez JA, Cortez E, Aguirre V, Aguilar P,Barrueto L. Heightened bronchial hyperresponsiveness in theabsence of heightened atopy in children with current wheezing andlow income status. Thorax2008; 63:16771.

32 Ferreira MA, Matheson MC, Duffy DL, et al. Identification of IL6Rand chromosome 11q13.5 as risk loci for asthma. Lancet2011;378:100614.

33 Torgerson DG, Ampleford EJ, Chiu GY, et al. Meta-analysis ofgenome-wide association studies of asthma in ethnically diverseNorth American populations. Nat Genet2011; 43:88792.

34 Moffatt MF, Gut IG, Demenais F, et al. A large-scale,consortium-based genomewide association study of asthma.N Engl J Med2010; 363: 121121.

35 Ober C, Tan Z, Sun Y, et al. Effect of variation in CHI3L1 on serumYKL-40 level, risk of asthma, and lung function. N Engl J Med2008;358:168291.

36 Sleiman PM, Flory J, Imielinski M, et al. Variants of DENND1Bassociated with asthma in children. N Engl J Med2010; 362:3644.

37 Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etiologicand functional implications of genome-wide association loci forhuman diseases and traits. Proc Natl Acad Sci USA2009;106:936267.

38 Zhang Y, Moffatt MF, Cookson WO. Genetic and genomicapproaches to asthma: new insights for the origins.Curr Opin Pulm Med2012; 18:613.

39 Burrows B, Martinez FD, Cline MG, Lebowitz MD. The relationshipbetween parental and childrens serum IgE and asthma.Am J Respir Crit Care Med1995; 152:1497500.

40 Holberg CJ, Elston RC, Halonen M, et al. Segregation analysis ofphysician-diagnosed asthma in Hispanic and non-Hispanic whitefamilies. A recessive component? Am J Respir Crit Care Med1996;154:14450.

41 Tennessen JA, Bigham AW, OConnor TD, et al. Evolution andfunctional impact of rare coding variation from deep sequencing ofhuman exomes. Science2012; 337:6469.

42 Torgerson DG, Capurso D, Mathias RA, et al. Resequencingcandidate genes implicates rare variants in asthma susceptibility.Am J Hum Genet2012; 90: 27381.

43 Ege MJ, Mayer M, Normand AC, et al. Exposure to environmentalmicroorganisms and childhood asthma. N Engl J Med2011;364:7019.

44 Wlasiuk G, Vercelli D. The farm effect, or: when, what and how afarming environment protects from asthma and allergic disease.Curr Opin Allergy Clin Immunol2012; 12:46166.

45 Custovic A, Rothers J, Stern D, et al. Effect of day care attendanceon sensitization and atopic wheezing differs by Toll-like receptor 2genotype in 2 population-based birth cohort studies.J Allergy Clin Immunol2011; 127:39097.

46 Maier RM, Palmer MW, Andersen GL, et al. Environmentaldeterminants of and impact on childhood asthma by the bacterialcommunity in household dust. Appl Environ Microbiol2010;76:266367.

47 Olszak T, An D, Zeissig S, et al. Microbial exposure during early lifehas persistent effects on natural killer T cell function. Science2012;336:48993.

48 Strickland DH, Judd S, Thomas JA, Larcombe AN, Sly PD, Holt PG.Boosting airway T-regulatory cells by gastrointestinal stimulation asa strategy for asthma control. Mucosal Immunol2011; 4:4352.

49 Navarro S, Cossalter G, Chiavaroli C, et al. The oraladministration of bacterial extracts prevents asthma via therecruitment of regulatory T cells to the airways. Mucosal Immunol2011; 4:5365.

50 Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the

gut microbiota on human health: an integrative view. Cell2012;148:125870.

51 Round JL, Lee SM, Li J, et al. The Toll-like receptor 2 pathwayestablishes colonization by a commensal of the human microbiota.

Science2011; 332:97477.52 Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma

after bacterial colonization of the airway in neonates. N Engl J Med2007; 357:148795.

53 Charlson ES, Bittinger K, Haas AR, et al. Topographical continuityof bacterial populations in the healthy human respiratory tract.Am J Respir Crit Care Med2011; 184:95763.

54 Huang YJ, Nelson CE, Brodie EL, et al. Airway microbiota andbronchial hyperresponsiveness in patients with suboptimallycontrolled asthma.J Allergy Clin Immunol2011; 127:37281.

55 Hilty M, Burke C, Pedro H, et al. Disordered microbialcommunities in asthmatic airways. PLoS One2010; 5:e8578.

56 Marri PR, Stern DA, Wright AL, Billheimer D, Martinez FD.Asthma-associated differences in microbial composition of inducedsputum.J Allergy Clin Immunol2013; 131:34652.

57 Nicholson KG, Kent J, Ireland DC. Respiratory viruses andexacerbations of asthma in adults. BMJ1993; 307:98286.

58 Johnston SL, Pattemore PK, Sanderson G, et al. Community studyof role of viral infections in exacerbations of asthma in 9-11 year oldchildren. BMJ1995; 310:122529.

59 Message SD, Laza-Stanca V, Mallia P, et al. Rhinovirus-inducedlower respiratory illness is increased in asthma and related to virusload and Th1/2 cytokine and IL-10 production.Proc Natl Acad Sci USA2008; 105:1356267.

60 Jackson DJ, Gangnon RE, Evans MD, et al. Wheezing rhinovirusillnesses in early life predict asthma development in high-riskchildren. Am J Respir Crit Care Med2008; 178:66772.

61 Kusel MM, de Klerk NH, Kebadze T, et al. Early-life respiratory viralinfections, atopic sensitization, and risk of subsequent developmentof persistent asthma.J Allergy Clin Immunol2007; 119:110510.

62 Holt PG, Sly PD. Viral infections and atopy in asthma pathogenesis:new rationales for asthma prevention and treatment. Nat Med2012;18:72635.

63 Jackson DJ, Evans MD, Gangnon RE, et al. Evidence for a causalrelationship between allergic sensitization and rhinovirus wheezing

in early life. Am J Respir Crit Care Med2012; 185:28185.64 Stern DA, Guerra S, Halonen M, Wright AL, Martinez FD. Low

IFN-gamma production in the first year of life as a predictor ofwheeze during childhood.J Allergy Clin Immunol2007;120:83541.

65 Macaubas C, de Klerk NH, Holt BJ, et al. Association betweenantenatal cytokine production and the development of atopy andasthma at age 6 years. Lancet2003; 362:119297.

66 Contoli M, Message SD, Laza-Stanca V, et al. Role of deficient typeIII interferon-lambda production in asthma exacerbations. Nat Med2006; 12:102326.

67 Sykes A, Edwards MR, Macintyre J, et al. Rhinovirus 16-inducedIFN-alpha and IFN-beta are deficient in bronchoalveolar lavagecells in asthmatic patients.J Allergy Clin Immunol2012;129:150614.

68 Bosco A, Ehteshami S, Stern DA, Martinez FD. Decreasedactivation of inflammatory networks during acute asthmaexacerbations is associated with chronic airflow obstruction.Mucosal Immunol2010; 3:399409.

69 Reponen T, Vesper S, Levin L, et al. High environmental relativemoldiness index during infancy as a predictor of asthma at 7 yearsof age. Ann Allergy Asthma Immunol2011; 107: 12026.

70 Boitano S, Flynn AN, Sherwood CL, et al. Alternaria alternata serineproteases induce lung inflammation and airway epithelial cellactivation via PAR2. Am J Physiol Lung Cell Mol Physiol2011;300:L60514.

71 Van Dyken SJ, Garcia D, Porter P, et al. Fungal chitin fromasthma-associated home environments induces eosinophilic lunginfiltration.J Immunol2011; 187:226167.

72 Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG.Association of asthma with serum IgE levels and skin test reactivityto allergens. N Engl J Med1989; 320:27177.

73 Hogg JC. Pathology of asthma.J Allergy Clin Immunol1993; 92:15.

74 Bentley AM, Maestrelli P, Saetta M, et al. Activated T-lymphocytesand eosinophils in the bronchial mucosa in isocyanate-induced

asthma.J Allergy Clin Immunol1992; 89:82129.


12/13

Seminar


75 Bentley AM, Meng Q, Robinson DS, Hamid Q, Kay AB,Durham SR. Increases in activated T lymphocytes, eosinophils, and

cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies afterallergen inhalation challenge in atopic asthmatics.Am J Respir Cell Mol Biol1993; 8:3542.

76 Bradley BL, Azzawi M, Jacobson M, et al. Eosinophils,T-lymphocytes, mast cells, neutrophils, and macrophages inbronchial biopsy specimens from atopic subjects with asthma:comparison with biopsy specimens from atopic subjects withoutasthma and normal control subjects and relationship to bronchialhyperresponsiveness.J Allergy Clin Immunol1991; 88:66174.

77 Cohn L, Elias JA, Chupp GL. Asthma: mechanisms of diseasepersistence and progression. Annu Rev Immunol2004; 22:789815.

78 van Oosterhout AJ, Bloksma N. Regulatory T-lymphocytes inasthma. Eur Respir J2005; 26:91832.

79 Umetsu DT, Akbari O, Dekruyff RH. Regulatory T cells control thedevelopment of allergic disease and asthma.J Allergy Clin Immunol2003; 112:48087.

80 Larche M. Regulatory T cells in allergy and asthma. Chest2007;132:100714.

81 Ege MJ, Bieli C, Frei R, et al. Prenatal farm exposure is related tothe expression of receptors of the innate immunity and to atopicsensitization in school-age children.J Allergy Clin Immunol2006;117:81723.

82 Illi S, Depner M, Genuneit J, et al. Protection from childhoodasthma and allergy in Alpine farm environments-the GABRIELAdvanced Studies.J Allergy Clin Immunol2012; 129:147077.

83 Schaub B, Liu J, Hoppler S, et al. Maternal farm exposuremodulates neonatal immune mechanisms through regulatoryT cells.J Allergy Clin Immunol2009; 123:77482.

84 Wadsworth SJ, Sandford AJ. Personalised medicine and asthmadiagnostics/management. Curr Allergy Asthma Rep2013; 13:11829.

85 Holgate ST. Pathophysiology of asthma: what has our currentunderstanding taught us about new therapeutic approaches?J Allergy Clin Immunol2011; 128:495505.

86 Tschumperlin DJ, Dai G, Maly IV, et al. Mechanotransduction

through growth-factor shedding into the extracellular space. Nature2004; 429:8386.

87 Tschumperlin DJ, Drazen JM. Chronic effects of mechanical forceon airways. Annu Rev Physiol2006; 68:56383.

88 Chu EK, Foley JS, Cheng J, Patel AS, Drazen JM, Tschumperlin DJ.Bronchial epithelial compression regulates epidermal growth factorreceptor family ligand expression in an autocrine manner.Am J Respir Cell Mol Biol2005; 32:37380.

89 Frey U, Brodbeck T, Majumdar A, et al. Risk of severe asthmaepisodes predicted from fluctuation analysis of airway function.Nature2005; 438:66770.

90 Thamrin C, Zindel J, Nydegger R, et al. Predicting future risk ofasthma exacerbations using individual conditional probabilities.J Allergy Clin Immunol2011; 127: 1494502.

91 Thamrin C, Taylor DR, Jones SL, Suki B, Frey U. Variability of lungfunction predicts loss of asthma control following withdrawal ofinhaled corticosteroid treatment. Thorax2010; 65: 40308.

92 Wenzel SE. Asthma phenotypes: the evolution from clinical tomolecular approaches. Nat Med2012; 18:71625.

93 Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinicalasthma phenotypes. Am J Respir Crit Care Med2008; 178:21824.

94 Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthmaphenotypes using cluster analysis in the Severe Asthma ResearchProgram. Am J Respir Crit Care Med2010; 181: 31523.

95 Siroux V, Basagana X, Boudier A, et al. Identifying adult asthmaphenotypes using a clustering approach. Eur Respir J2011;38:31017.

96 Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driveninflammation defines major subphenotypes of asthma.Am J Respir Crit Care Med2009; 180:38895.

97 Dougherty RH, Sidhu SS, Raman K, et al. Accumulation ofintraepithelial mast cells with a unique protease phenotype inT(H)2-high asthma.J Allergy Clin Immunol2010; 125: 104653.

98 Takayama G, Arima K, Kanaji T, et al. Periostin: a novel componentof subepithelial fibrosis of bronchial asthma downstream of IL-4

and IL-13 signals.J Allergy Clin Immunol2006; 118:98104.

99 Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumabtreatment in adults with asthma. N Engl J Med2011; 365:108998.

100 Lotvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a newapproach to classification of disease entities within the asthmasyndrome.J Allergy Clin Immunol2011; 127:35560.

101 Fahy JV, Locksley RM. The airway epithelium as a regulator of Th2responses in asthma. Am J Respir Crit Care Med2011; 184:39092.

102 Mjosberg J, Spits H. Type 2 innate lymphoid cells-new members ofthe type 2 franchise that mediate allergic airway inflammation.Eur J Immunol2012; 42:109396.

103 Saenz SA, Siracusa MC, Perrigoue JG, et al. IL25 elicits amultipotent progenitor cell population that promotes T(H)2cytokine responses. Nature2010; 464:136266.

104 Price AE, Liang HE, Sullivan BM, et al. Systemically dispersedinnate IL-13-expressing cells in type 2 immunity.Proc Natl Acad Sci USA2010; 107:1148994.

105 Neill DR, Wong SH, Bellosi A, et al. Nuocytes represent a newinnate effector leukocyte that mediates type-2 immunity. Nature2010; 464:136770.

106 Wong SH, Walker JA, Jolin HE, et al. Transcription factor RORalphais critical for nuocyte development. Nat Immunol2012; 13:22936.

107 Locksley RM. Asthma and allergic inflammation. Cell2010;140:77783.

108 Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma:phenotype shaped by innate and adaptive immunity. Nat Immunol2010; 11:57784.

109 Chang YJ, Kim HY, Albacker LA, et al. Innate lymphoid cellsmediate influenza-induced airway hyper-reactivity independently ofadaptive immunity. Nat Immunol2011; 12:63138.

110 Halim TY, Krauss RH, Sun AC, Takei F. Lung natural helper cellsare a critical source of th2 cell-type cytokines in proteaseallergen-induced airway inflammation. Immunity2012; 36:45163.

111 Wolterink RG, Kleinjan A, van Nimwegen M, et al. Pulmonaryinnate lymphoid cells are major producers of IL-5 and IL-13 inmurine models of allergic asthma. Eur J Immunol2012; 42:110616.

112 Mjosberg JM, Trifari S, Crellin NK, et al. Human IL-25- andIL-33-responsive type 2 innate lymphoid cells are defined by

expression of CRTH2 and CD161. Nat Immunol2011; 12: 105562.113 Moffatt MF, Gut IG, Demenais F, et al. A large-scale,

consortium-based genomewide association study of asthma.N Engl J Med2010; 363:121121.

114 Spits H, Cupedo T. Innate lymphoid cells: emerging insights indevelopment, lineage relationships, and function. Annu Rev Immunol2012; 30:64775.

115 Toelle BG, Ng KK, Crisafulli D, et al. Eight-year outcomes of theChildhood Asthma Prevention Study.J Allergy Clin Immunol2010;126:38889.

116 Gehring U, de Jongste JC, Kerkhof M, et al. The 8-year follow-up ofthe PIAMA intervention study assessing the effect ofmite-impermeable mattress covers. Allergy2012; 67:24856.

117 Scott M, Roberts G, Kurukulaaratchy RJ, Matthews S, Nove A,Arshad SH. Multifaceted allergen avoidance during infancy reducesasthma during childhood with the effect persisting until age18 years. Thorax2012; 67:104651.

118 Chan-Yeung M, Ferguson A, Watson W, et al. The CanadianChildhood Asthma Primary Prevention Study: outcomes at 7 yearsof age.J Allergy Clin Immunol2005; 116:4955.

119 Martinez FD. New insights into the natural history of asthma:primary prevention on the horizon.J Allergy Clin Immunol2011;128:93945.

120 Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaledcorticosteroids in preschool children at high risk for asthma.N Engl J Med2006; 354:198597.

121 Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A.Secondary prevention of asthma by the use of Inhaled Fluticasonepropionate in Wheezy INfants (IFWIN): double-blind, randomised,controlled study. Lancet2006; 368:75462.

122 Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F.Intermittent inhaled corticosteroids in infants with episodicwheezing. N Engl J Med2006; 354:19982005.

123 Zar HJ, Levin ME. Challenges in treating pediatric asthma indeveloping countries. Paediatr Drugs2012; 14:35359.


13/13

Seminar

124 Ostergaard MS, Nantanda R, Tumwine JK, Aabenhus R. Childhoodasthma in low income countries: an invisible killer?

Prim Care Respir J2012; 21:21419.125 Morgan WJ, Crain EF, Gruchalla RS, et al. Results of a home-based

environmental intervention among urban children with asthma.N Engl J Med2004; 351: 106880.

126 Marinho S, Simpson A, Custovic A. Allergen avoidance in thesecondary and tertiary prevention of allergic diseases: does it work?Prim Care Respir J2006; 15:15258.

127 Martinez FD, Chinchilli VM, Morgan WJ, et al. Use ofbeclomethasone dipropionate as rescue treatment for children withmild persistent asthma (TREXA): a randomised, double-blind,placebo-controlled trial. Lancet2011; 377:65057.

128 Szefler SJ, Baker JW, Uryniak T, Goldman M, Silkoff PE.Comparative study of budesonide inhalation suspension andmontelukast in young children with mild persistent asthma.J Allergy Clin Immunol2007; 120: 104350.

129 Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapyfor children with uncontrolled asthma receiving inhaledcorticosteroids. N Engl J Med2010; 362:97585.

130 Price D, Musgrave SD, Shepstone L, et al. Leukotriene antagonistsas first-line or add-on asthma-controller therapy. N Engl J Med2011;364:1695707.

131 Nikander K, Turpeinen M, Pelkonen AS, Bengtsson T, Selroos O,Haahtela T. True adherence with the Turbuhaler in young childrenwith asthma. Arch Dis Child2011; 96:16873.

132 Williams LK, Peterson EL, Wells K, et al. Quantifying the proportionof severe asthma exacerbations attributable to inhaled corticosteroidnonadherence.J Allergy Clin Immunol2011; 128:118591.

133 Apter AJ, Wang X, Bogen DK, et al. Problem solving to improveadherence and asthma outcomes in urban adults with moderate orsevere asthma: a randomized controlled trial.J Allergy Clin Immunol2011; 128:51623.

134 Gerald LB, McClure LA, Mangan JM, et al. Increasing adherence toinhaled steroid therapy among schoolchildren: randomized,controlled trial of school-based supervised asthma therapy.Pediatrics2009; 123:46674.

135 Papi A, Canonica GW, Maestrelli P, et al. Rescue use ofbeclomethasone and albuterol in a single inhaler for mild asthma.N Engl J Med2007; 356:204052.

136 Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling thedose of inhaled corticosteroid to prevent asthma exacerbations:randomised controlled trial. Lancet2004; 363: 27175.

137 Oborne J, Mortimer K, Hubbard RB, Tattersfield AE, Harrison TW.Quadrupling the dose of inhaled corticosteroid to prevent asthmaexacerbations: a randomized, double-blind, placebo-controlled,parallel-group clinical trial. Am J Respir Crit Care Med2009;180:598602.

138 Turpeinen M, Pelkonen AS, Selroos O, Nikander K, Haahtela T.Continuous versus intermittent inhaled corticosteroid (budesonide)for mild persistent asthma in childrennot too much, not too little.Thorax2012; 67: 10002.

139 Ducharme FM. Continuous versus intermittent inhaledcorticosteroids for mild persistent asthma in children: not toomuch, not too little. Thorax2012; 67:10205.

140 Horne R, Price D, Cleland J, et al. Can asthma control be improved byunderstanding the patients perspective? BMC Pulm Med2007; 7:8.

141 Barnes PJ. Corticosteroid resistance in patients with asthma andchronic obstructive pulmonary disease.J Allergy Clin Immunol2013;131:63645.

142 Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effectof budesonide in combination with formoterol for reliever therapyin asthma exacerbations: a randomised controlled, double-blindstudy. Lancet2006; 368:74453.

143 Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM.Addition of inhaled long-acting beta2-agonists to inhaled steroids as

first line therapy for persistent asthma in steroid-naive adults andchildren. Cochrane Database Syst Rev2009; 2009:CD005307.

144 Chowdhury B. Long acting beta-agonist safety trials, 2010. http://www.fda.gov/downloads/advisorycommittees/committees-meetingmaterials/drugs/pulmonary-allergydrugsadvisory-committee/ucm206722.pdf (accessed Sept 5, 2012).

145 Bisgaard H, Szefler S. Long-acting beta2 agonists and paediatricasthma. Lancet2006; 367:28688.

146 Beasley R, Martinez FD, Hackshaw A, Rabe KF, Sterk PJ,Djukanovic R. Safety of long-acting beta-agonists: urgent need toclear the air remains. Eur Respir J2009; 33:35.

147 Drazen JM, OByrne PM. Risks of long-acting beta-agonists inachieving asthma control. N Engl J Med2009; 360:167172.

148 Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromidestep-up therapy for adults with uncontrolled asthma. N Engl J Med2010; 363:171526.

149 Jarjour NN, Erzurum SC, Bleecker ER, et al. Severe asthma: lessons

learned from the National Heart, Lung, and Blood Institute SevereAsthma Research Program. Am J Respir Crit Care Med2012;185:35662.

150 Busse WW, Morgan WJ, Gergen PJ, et al. Randomized trial ofomalizumab (anti-IgE) for asthma in inner-city children.N Engl J Med2011; 364: 100515.

151 Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severeallergic asthma inadequately controlled with standard therapy:a randomized trial. Ann Intern Med2011; 154:57382.

152 Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severeeosinophilic asthma (DREAM): a multicentre, double-blind,placebo-controlled trial. Lancet2012; 380:65159.

153 Masuoka M, Shiraishi H, Ohta S, et al. Periostin promotes chronicallergic inflammation in response to Th2 cytokines.J Clin Invest2012; 122:2590600.

154 Corren J, Busse W, Meltzer EO, et al. A randomized, controlled,phase 2 study of AMG 317, an IL-4Ralpha antagonist, in patientswith asthma. Am J Respir Crit Care Med2010; 181:78896.

155 Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized,double-blind, placebo-controlled study of tumor necrosis factor-alphablockade in severe persistent asthma. Am J Respir Crit Care Med2009; 179:54958.

156 Kubo S, Kobayashi M, Iwata M, Miyata K, Takahashi K, Shimizu Y.Anti-neutrophilic inflammatory activity of ASP3258, a novelphosphodiesterase type 4 inhibitor. Int Immunopharmacol2012;12:5963.

157 Gauvreau GM, Boulet LP, Schmid-Wirlitsch C, et al. Roflumilastattenuates allergen-induced inflammation in mild asthmaticsubjects. Respir Res2011; 12:140.

158 Cox G, Thomson NC, Rubin AS, et al. Asthma control during theyear after bronchial thermoplasty. N Engl J Med2007; 356:132737.

159 Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety ofbronchial thermoplasty in the treatment of severe asthma:a multicenter, randomized, double-blind, sham-controlled clinicaltrial. Am J Respir Crit Care Med2010; 181:11624.

160 Wahidi MM, Kraft M. Bronchial thermoplasty for severe asthma.Am J Respir Crit Care Med2012; 185:70914.

Asthma Lancet 2013

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