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HABILITATION THESIS

Adult and pediatric asthma and related co-morbidities – from research to clinical practice and purposeful education

Domain: Medicine

Author: Ioana Agache

University: Transilvania University of Brasov

Braşov, 2017

Universitatea Transilvania din Braşov

CONTENT

5 Listofabbreviations

7 (A) REZUMAT

15 (B) SCIENTIFIC AND PROFESSIONAL ACHIEVEMENTS AND THE EVOLUTION AND DEVELOPMENT PLANS FOR CAREER DEVELOPMENT

17 (B-i) Scientific and professional achievements

19 Chapter 1. Main research area - development and results: Scientific achievements in adult and pediatric asthma and related co-morbidities

91 Chapter 2. Professional developments

109 Chapter 3. Academic developments

113 (B-ii) The evolution and development plans for career development

115 Chapter 1. Scientific development future plans

119 Chapter 2. Professional development future plans

123 Chapter 3. Academic activity future plans

127 (B-iii) Bibliography

5

Ioana Octavia AgacheHabilitation thesis

List of Abbreviations

List of abbreviations

AAAAI American Academy of Allergy,AsthmaandClinicalImmunology

ACAAI AmericanCollegeofAllergy,Asth-maandClinicalImmunology

ACC allergenchallengechamberACS acutecoronarysyndromesACT asthmacontroltestAD atopicdermatitisAHA ActiveandHealthyAgeingAHR airwayhyperreactivityAIT allergenspecificimmunotherapyANA antinuclearantibodiesAR allergicrhinitisARIA AllergicRhinitisanditsImpacton

AsthmaBMI bodymassindexCARAT Control of Allergic Rhinitis and

Asthma TestCART capnometry-assisted respiratory

training(CART)CDSS clinicaldecisionsupportsystemCOPD chronicobstructivelungdiseaseCS corticosteroidsCLD chroniclungdiseaseCRD componentresolveddiagnosisCRDs chronicrespiratorydiseasesCRS chronicrhinosinusitisDB dysfunctionalbreathingDFS70/LEDGFp75=densefinespeckledau-

toantigenof70kD/lensepitheli-um-derivedgrowthfactorp75

EAACI EuropeanAcademyofAllergyandClinicalImmunology

ED emergencydepartmentEDN eosinophil-derivedneurotoxinEFA European Federations of Allergy

andAirwaysDiseasesPatientsAs-sociations

EMA EuropeanMedicalAgencyEMTU epithelial-mesenchimal trophic

unitENDANA Endotypes of Non-Eosinophilic

AsthmaERS EuropeanRespiratorySocietyEU EuropeanUnionFACS Fluorescence-activated cell sort-

ingFDA FoodandDrugAdministrationFEF25-75 forcedexpiratoryflowat25–75%

offorcedvitalcapacityFeNO Fractional concentration of ex-

halednitricoxideFEV1 volume exhaled during the first

second of a forced expiratorymaneuver started from the leveloftotallungcapacity

GA2LEN GlobalAllergy andAsthma Euro-peanNetwork

GARD GlobalAllianceAgainstRespirato-ryDiseases

GINA GlobalInitiativeforAsthmaGRADE GradingofRecommendations,As-

sessment,DevelopmentandEval-uation.

HCPs healthcareprofessionalsiCAALL International Collaboration in

Asthma,AllergyandImmunologyICON International consensus docu-

mentelaboratedbyiCAALLICPs integratedcarepathwaysICS inhaledcorticosteroidsICT information and communications

technologyIFN interferonIL interleukinILC innatelymphoidcellsINS intranasalcorticosteroidsIP-10 IFN-gammainducibleprotein

6

Ioana Octavia Agache Habilitation thesis

List of Abbreviations

IPCRG International Primary Care Res-piratoryGroup

ITT intentiontotreatJACI JournalofAllergyandClinicalIm-

munologyLABA longactingbeta2agonistsLF lungfunctionLTRA leukotrienereceptorantagonistsMACE majorcardiovasculareventsMASK MACVIA-ARIASentinelNetworK

forallergicrhinitisMAUG Molecular Allergology User’s

GuideMCP-1 monocyte chemoattractant pro-

teinMeDALL Mechanismsof theDevelopment

ofALLergyMEF50 maximalexpiratoryflowat50%of

vitalflowcapacityMEP member of the European Parlia-

mentMIP-1α macrophageinflammatoryproteinMP-AzeFluazelastine+fluticasonepropionate

inasingledeviceNCDs non-communicablediseasesNEA non-eosinophilicasthmaNICE National Institute forHealth and

CareExcellenceNK neurokininNSAID non-steroidal anti-inflammatory

drugsPRACTALLPracticalAspectsofAllergyR&D ResearchandDevelopment

RCT randomisedcontroltrialREG RespiratoryEffectivenessGroupROC receiveroperatingcharacteristicRV rhinovirusSAR seasonalallergicrhinitisSCIT subcutaneous allergen immuno-

therapySCUAD severechronicallergicdiseasesSIAF Swiss Institute for Allergy and

Asthma ResearchSLIT sublingualallergen immunothera-

pySLOW slow breathing and awareness

trainingSNPs singlenucleotidepolymorphismSP substancePSR systematicreviewTARC thymus- and activation-regulated

chemokineTGF transforminggrowthfactorTh ThelpercellTNF-α tumornecrosisfactoralphaTNSS totalnasalsymptomscoreTRPV vanilloid receptor–related tran-

sientreceptorpotentialTSLP ThymicstromallymphopoietinUK UnitedKingdomVAS visualanaloguescaleVEGF vascular-endothelial growth fac-

torWAO WorldAllergyOrganisationWHO WorldHealthOrganisation

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Section A

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Teza de abilitare “Astmul la adult și la copil și co-morbidități – de la cercetare la practica clini-că și la educația ce își atinge obiectivele” este chintesența activității științifice și academice în ultimii 12 ani și include realizările majore științifice, profesionale și academice, cu obiectiv al activității de cercetare astmul la adult și la copil și co-morbidități.

Provocările în managementul astmului de la cercetarea fundamentală și clinică la activități-le educationale și de asigurare a sprijinului și angajamentului social și politic sunt deopotriva dificile și provocatoare. Le-am abordat cu entuziasm, tenacitate și dedicație, cu dorința de a dezvolta și implementa noi metode de analiză și a oferi soluții novatoare care să țină pasul cu mediul științific, academic și medical în continua schimbare. Dezvoltarea mea științifică, profe-sională și academică în ultimii 12 ani reflectă implicarea profundă în direcțiile de management ale astmului detaliate mai jos, cu realizări remarcabile:

a. Programe de cercetare și dezvoltare bazate pe prevenție, mecanismele bolii și biomarkeri, abordare personalizată și descoperirea de noi tratamente curative pentru astm

b. Managementul integrativ al pacientului astmatic la nivel global incluzând ghiduri de noua generație aplicabile la toate nivelele și în toate țările, registre pentru astm, facilitarea acce-sului la diagnostic precoce și îngrijire de calitate, controlul mediului și al co-morbidităților, educația pacientului și a societății, utilizarea cost-eficientă a resurselor și modele de îngrijire centrate pe pacient

c. Recunoașterea astmului ca problemă majoră de sănătate de către societate și factori de decizie politică, cu focus pe povara economica uriașă, afectarea calității vieții și impactul pe dezvoltarea copilului într-un adult sănătos valoros pentru societate

d. Parteneriat strategic între toate părțile implicate (pacienți și familiile acestora, profesio-niști în domeniul sanitar, profesori, factori de decizie politică, industria farmaceutică și de dispozitive medicale) rezultând într-o abordare comunitară pentru a rezolva o problemă comunitară așa cum este astmul

Partea I prezintă realizările științifice, profesionale și academice

Activitatea de cercetare, descrisă în Capitolul 1, s-a concentrat în principal pe:

1. descrierea și validarea fenotipurilor, endotipurilor si biomarkerilor; 2. tratamentul astmului ghidat de endotip și noi metode de abordare terapeutica cu potențial

curativ; 3. controlul mediului (infecții, poluare), a stilului de viață (dieta, efort fizic regulat) și a co-mor-

bidităților astmului (rinita alergică, obezitate, alergia alimentară); 4. prevenția și controlul astmului; 5. dezvoltarea și implementarea de noi modele de management cost-eficient al astmului.

Am publicat 58 articole, cu 2567 citări în ISI Web of Science și 8590 citări in Google Scholar. Am un h-index de 18 în ISI Web of Science și 20 în Google Scholar și i10-index de 32.

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Capitolul 1.1 detaliază contribuția personală în domeniul fenotipurilor și endotipurilor astmu-lui. Definirea relației fenotip-endotip-biomarkeri a constituit o temă fundamentală de cercetare din 2009 reflectată prin publicarea a 12 articole cu 268 citări în reviste cu factor de impact semnificativ, conferințe, comunicări orale și postere susținute la manifestări internațional pre-stigioase și de proiectul PN II pe care îl conduc ce va endotipa pacienții cu astm non-eozinofilic.

Prin cercetarea în acest domeniu am dezvoltat următoarele concepte-cheie:

1. Necesitatea de a lega mecanismele patogenetice fundamentale (endotip) cu fenotipul clinic al astmului (proprietățile vizibile)

2. Validitatea unui endotip trebuie demonstrată prin replicare longitudinală în populații dife-rite și prin evidențierea diferențelor revelatorii între indivizi; endotipul trebuie să reflecte biologia și evoluția naturală a bolii și să prevadă răspunsul la tratament; endotipul trebuie să fie ușor de aplicat în practica clinică curentă și să fie cost-eficient

3. Conceptul de endotip simplu versus complex, utilizând ca prototip pentru endotip complex astmul de tip 2. Pe baza intervențiilor țintite în astm sunt descrise 3 căi majore în astmul de tip 2 mediate de IL-5, de IL-4/IL-13 și de IgE

4. Conceptul de endotip variabil ca răspuns la factorii modulatori externi și interni

5. Efectul disociat al terapiei țintite în astm reprezentând variabilitatea de răspuns la același individ și între indivizi în funcție de parametrii măsurați

6. Abordarea în trepte pentru clasificarea astmului ce încorporează fenotiparea de precizie, încorporarea datelor longitudinale cum ar fi rata exacerbărilor și analiza fluctuației funcției pulmonare sau a NO în aerul expirat, bazat pe cercetarea originală a autoarei, împreună cu identificarea de noi mecanisme și biomarkeri corespondenți (clasificarea astmului bazata pe endotip) și translatarea biomarkerilor în teste de diagnostic specific pentru fiecare meca-nism patogenetic

7. Au fost descrise ariile insuficient acoperite de cercetarea fundamentală și clinică cum ar fi astmul non tip 2 și compartimentul celulelor rezidente (unitatea trofică epitelio-mezenchi-mală – EMTU)

8. Tratamentul astmului ghidat de endotip a fost descris pentru astmul de tip 2, non-tip 2 (ne-utrofilic, influențat de microbiom și de EMTU) și pentru astmul asociat cu obezitatea

9. Legătura dintre clasificarea și managementul astmului ghidat de endotip și conceptul de medicină de precizie în astm

10. Importanța descrierii și validării de noi fenotipuri: epigenetice, neurofenotipuri, etc și de endotipuri evolutive ce se adresează inițierii și progresiei bolii, necesitate majoră pentru a aplica măsuri de prevenție și strategii ce modifică evoluția bolii ca parte a principiului celor 4P din medicina de precizie

Capitolul 1.2 se concentrează pe cercetarea asupra biomarkerilor astmului. Fiind în strânsa le-gătura cu fenotipurile și endotipurile aceasta linie de cercetare a autoarei a completat realizările în descrierea fenotipurilor și endotipurilor bolii și a fost apreciată de către comunitatea știin-țifică internațională prin articole înalt citate, invitații pentru lucrări de sinteză și conferințe și comunicări orale. În 2010 autoarea publică cercetarea de pionierat asupra valorii IL-17 seric ca biomarker pentru astmul sever, urmată de demonstrația recentă a valorii IL-5 și IL-13 serice ca cei mai buni marker predictivi ai eozinofiliei sanguine. În paralel sunt dezvoltate concepte-cheie cum ar fi legătura dintre biomarker și endotip (biomarkerul poate fi marker pentru endotip sau mecanism patogenetic fundamental al acestuia), validitatea (reproductibilitate, ușurința de mă-

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surare și accesibilitatea) și relevanța (specificitatea pentru endotip și relația cu end-point-urile clinic relevante).

Capitolul 1.3 trasează contribuția autoarei la dezvoltarea de noi terapii țintite în astm, cum ar fi quilizumab și imunoterapia specifică cu alergen (AIT). AIT are potențialul de a modifica mecanismele fundamentale ale bolii și are un efect clinic susținut. Autoarea a evaluat recent beneficiile AIT în câteva lucrări de sinteză și consensuri internaționale și este lidera grupului de lucru asupra imunoterapiei specifice cu alergen în astm ca parte a ghidurilor internaționale dezvoltate de Academia Europeana de Alergologie și Imunologie Clinică (EAACI).

Capitolul 1.4 descrie contribuția la implementarea principiilor medicinei de precizie în astm ca o continuare convingătoare a cercetării de pionierat în domeniul fenotipurilor, endotipurilor și biomarkerilor începută în 2009. Ca o recunoaștere a realizărilor în acest domeniu autoarea a fost invitată în 2 Paneluri de Experți prestigioase ce au reunit academiile științifice din domeniul astmului și bolilor alergice – EAACI, Societatea Europeană de Boli Respiratorii (ERS), Societa-tea Europeană de Rinologie și Academia Americană de Alergologie, Astm și Imunologie Clinică (AAAAI).

Capitolul 1.5 cuprinde contribuțiile în domeniul co-morbidităților astmului. Fiind o co-morbi-ditate majoră a astmului rinita alergică a constituit un focus special de cercetare, de la autor al ghidului internațional ARIA, la cercetarea în domeniul epidemiologiei, factorilor de risc și noi tratamente pentru rinita alergică evaluate în studii internaționale multicelulare, la implemen-tarea în viața reală și la dezvoltarea de noi modele de îngrijire. Ca secretar al Secțiunii de Astm a EAACI am inițiat și condus grupul de lucru ce a evaluat impactul stilului de viață asupra ast-mului, evaluare consolidată în documente de consens și luări de poziție bazate pe revizuirea sis-tematică a dovezilor publicate. Ca membră a Panelului de Experți ce a elaborat ghidul interna-țional EAACI de Alergie Alimentară și Anafilaxie am adus expertiza asupra astmului în legătura bi-direcțională cu alergia alimentară. Am condus grupul de lucru ce a elaborat recomandările pentru managementul anafilaxiei în comunitate și am fost membră în grupurile de lucru asu-pra epidemiologiei și prevenției alergiei alimentare. Ca membră a proiectului GA²LEN-DARE finanțat de Comunitatea Europeană am evaluat dovezile pentru rolul virusurilor și bacteriilor în exacerbarea astmatică.

Capitolul 1.6 furnizează informații asupra contribuțiilor autoarei la dezvoltarea de noi planuri de management ale astmului și noi modele de îngrijire. Aceasta direcție de cercetare a fost abordată în capitolul “Cele mai bune intervenții pentru prevenția și controlul astmului” inclus în Global Atlas of Asthma, pentru care am fost editor șef și co-autor. Sunt detaliate cele 10 puncte cheie ce trebuie incluse într-un plan de management eficient al astmului.

Un diagnostic mai performant al astmului este o cerință esențială al unui plan de management eficient. Cercetarea pe care am condus-o asupra diagnosticului in vivo si in vitro al bolilor alergi-ce și al astmului a condus la crearea și conducerea unui grup de lucru în cadrul EAACI ce e eva-luat rolul și standardizarea testelor de provocare în astm și boli alergice și includerea ca autor în ghidurile EAACI de diagnostic molecular.

Un standard înalt calitativ de îngrijire al astmului și bolilor alergice în rețeaua de asistență pri-mară are o influență majoră asupra prevenției și controlului bolii, calității vieții și satisfacției pacientului. Nivelul de cunoaștere asupra astmului și bolilor alergice și accesibilitatea la control regulat sunt esențiale. Am condus grupul de lucru EAACI asupra managementului astmului și bolilor alergice în rețeaua de asistență primară ce a avut ca scop dezvoltarea și implementarea de protocoale de îngrijire înalt calitative pentru medicii de medicina de familie și generaliști ca parte integrate a planului de management al astmului și al bolilor alergice.

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Prioritatea anodină acordată astmului de către programele de sănătate publică datorită întâ-ietății acordate altor boli și lipsei de cunoaștere a bolii de către societate și de către factorii de decizie politică este o barieră apreciabilă în implementarea eficientă a planurilor de manage-ment ale astmului. Două articole recent publicate reflectă activitatea autoarei în augmentarea percepției publice asupra importanței astmului și bolilor alergice ca procedură care facilitează acordarea de resurse pentru cercetarea și pentru managementul eficient al acestor boli.

Capitolul 2 redă dezvoltarea profesională a autoarei. O scurtă prezentare a carierei profesionale este înfățișată în capitolul 2.1 de la absolvirea facultății și teza de doctorat Magna cum laudae la o carieră de cercetare de succes (58 articole cu 2567 citari în ISI Web of Science și 8590 citări în Google Scholar, h-index 18 în ISI Web of Science, respectiv 20 în Google Scholar și i10-index 32), membră în Paneluri de Experți pentru ghiduri și documente de consens internațional, redactor și co-autor de cărți și atlase, referent înalt apreciat și editor asociat pentru reviste cu factor de impact semnificativ, Vice-Președinte și Președinte-Ales al Academiei Europene de Alergologie și Imunologie Clinică (EAACI). Țelul principal al carierei mele a fost dezvoltarea unei combinații unice de calități, de la un medic caritabil și bun dascăl la un cercetător științific de top. Contribuția știin-țifică a tezei de doctorat este trasată în capitolul 2.2 împreună cu aportul în programe de cerceta-re naționale și internaționale ca suport și apoi continuare a cercetării doctorale. Sunt prezentate în detaliu cu obiective și rezultate programul național PN-II-RU-TE-2014-4-2303 – Endotipurile astmului non-eozinofilic al cărui conducător sunt și participarea în proiectele finanțate de Uniu-nea Europeana, COST (COST BM 1201: Early Origins of Chronic Lung Disease) și programul GA-2LEN - DARE (Diary Card Piloting and Validation). Autoarea a fost invitată ca expert în proiectul EARIP (European Asthma Research and Innovation Partnership) și este membră a consorțiului AIRWAYS ICPs. Capitolul 2.3 detaliază dezvoltarea profesională și aprecierea la nivel național și internațional cu descrierea realizărilor ca membră în comitetele directoare și editoriale ce au dez-voltat ghiduri și declarații de consens internațional, activitatea editorială și de referent, calitatea de autor de cărți și monografii și de lector la manifestări internaționale prestigioase. Calitățile de conducere și manageriale sunt discutate în capitolul 2.4.

Capitolul 3 prezintă dezvoltarea academică din 1996 până în prezent, de la Preparator Univer-sitar la Universitatea Transilvania din Brașov la Conferențiar Universitar. În timpul carierei aca-demice ținta a fost implicarea activă a studenților în procesul de învățare și motivarea pentru deprinderea de calități de raționament decizional, în paralel cu promovarea experienței de în-vățare cu însușirea temeinică a noțiunilor predate. Am implementat o nouă metodă de predare bazată pe învățământ interactiv ce încorporează mai multe obiective simultan. O altă abordare inovativă a fost conceptul de cercetare științifică creativă cu scopul de a stimula percepția stu-denților asupra succesului academic. Studenții au fost încurajați să abordeze un comportament pliat pe obiectiv, cu respectarea rigurozității și consistenței în demersul științific, cu aderență la principiile de etică în cercetare. Caracterul proactiv, simțul responsabilității, perspicacitatea și disciplina au fost reiterate ca principii fundamentale ale cercetării științifice creative. Am asigu-rat un mediu propice activității de cercetare de înalta calitate pentru a dezvolta punctele forte în cercetare ale studentului odată cu pregătirea lucrării de diplomă ca deschizător de oportuni-tăți pentru carieră.

Partea a II-a elaborează asupra evoluției viitoare și a planurilor de dezvoltare ulterioare a cari-erei științifice, profesionale și academice.

Realizările în carieră în ultima decadă mă poziționează favorabil în translatarea inovațiilor știin-țifice de la cercetarea fundamentală la practica clinică oferind în paralel un program de instruc-ție și educație în cercetarea medicală de înalt nivel.

Pornind de la rezultatele proiectului PN-II-RU-TE-2014-4-2303 Endotipurile Astmului Non-eo-zinofilic (ENDANA) planurile viitoare de endotipare ale astmului non-eozinofilic vizează valida-

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rea subendotipurilor prin intervenție terapeutică țintită și evaluare longitudinală a entităților descrise. Aceeași abordare este plănuită și pentru subendotipurile astmului de tip 2 folosind abordarea imparțială oferită de analiza topologică a datelor, analiza Bayeziană a rețelei genera-te și evaluarea longitudinală. Extinderea ariei de cercetare către endotipurile astmului pediatric este de asemenea anticipată. Beneficiul așteptat este translatarea cercetării fundamentale a endotipurilor în practica clinică curentă cu protocoale de decizie clinică ce permit selectarea pacientului ce răspunde cel mai bine la o intervenție țintită și cu predicția exactă a evoluției bolii pentru fiecare individ.

În paralel activitatea de cercetare va include biomarkeri și endotipuri pentru imunoterapia spe-cifică cu alergen, elaborarea și implementarea de ghiduri și documente de consens internați-onal, programul Mobile Health/Allergy 2.0 și 3.0 și dezvoltarea de protocoale de intervenție educațională a comunității pentru managementul astmului.

Avem o datorie morală de a promova standarde înalte pentru educația medicală în facultate și ulterior. Voi continua să ofer studenților și profesioniștilor din domeniul sanitar instruire bazată pe obiective care să reflecte dinamica modificărilor în practica medicală, în nevoile pacienților și în sistemul de sănătate precum și modificările în perspectivele generale ale societății asupra modului în care profesioniștii în domeniul sanitar își exercită meseria.

În calitatea de clinician, cercetător și profesor voi continua să dezvolt un portofoliu variat de competențe care să cuprindă informații clinice de ultimă ora, comunicarea eficientă a rezulta-telor cercetării, contextul multidisciplinar al îngrijirii pacientului, principiile de etică, calitățile de comunicare, management și comportamentale, lucrul în echipa, tehnologia informației, criterii-le de audit, etc, cu scopul de a asigura rezultate mai bune și creșterea nivelului de satisfacție al pacienților, studenților și colegilor.

În Iunie 2017 voi deveni Președinte al Academiei Europene de Alergologie și Imunologie Clinică cu un mandat de 2 ani. În paralel cu recunoașterea internațională intenționez să promovez cooperarea dintre societățile internaționale și naționale ca eșafod pentru adaptarea locală și implementarea ghidurilor și a rezultatelor cercetării de top, a practicilor cele mai competitive de îngrijire a pacienților, a politicilor de sănătate eficiente și a acțiunilor de conștientizare a astmu-lui ca problemă majoră de sănătate.

În următorii 4 ani este planificată dezvoltarea unui nou portofoliu educațional pentru student și tinerii profesioniști în domeniul sanitar ce facilitează deopotriva dezvoltarea profesională și a carierei ce îmbină practica clinică cu cercetarea. Voi introduce în practica academică conceptul de educație ce își atinge obiectivele bazat pe experiența directă din practică și beneficiul social. Vor fi dezvoltate noi metode de predare ce facilitează învățământul interactiv cum ar fi tuto-riale pentru studenții la master și la scoală doctorală, programe de învățare multidisciplinară, brainstorming interactiv, buzz-sessions, Think-Pair share, incident process etc. Fiind certificată pentru instruirea didactică în limba engleză voi susține crearea de programe de studii în limba engleză pentru studenții străini în cadrul Facultății de Medicină Brașov.

Întemeierea sentimentului de apartenență la comunitate a studenților și profesorilor cu aug-mentarea participării în procesul de modelare al mediului academic și al promovării culturii organizaționale constituie de asemenea o prioritate.

Atât coordonarea de lucrări de doctorat cât și obținerea titlului de profesor universitar sunt luate în considerare pentru a progresa în activitatea academică în următorii 2 ani. Prin coor-donarea de teze de doctorat voi sprijini activitatea de cercetare a tinerilor doctori și mediati-zarea rezultatelor cercetării doctorale în mediul științific național și internațional. Cercetătorii debutanți vor fi sprijiniți în activitatea de pregătire a tezei doctorale prin proiecte de cooperare dezvoltate împreună cu colegii de la discipline înrudite.

Scientific and professional achievements and the evolution

and development plans for career development

Section B

SCIENTIFIC AND PROFESSIONAL ACHIEVEMENTS

B-i

The habilitation thesis “Adult and pediatric asthma and related co-morbidities – from research to clinical practice and purposeful education” is the epitome of the academic activity in the last 12 years and encompasses the major scientific, professional and academic achievements, with the main research focus on adult and pediatric asthma and its co-morbidities.

This thesis aims to provide a valuable window of information on adult and pediatric asthma and co-morbidities highlighting the innovative and valuable contribution of the author in the field.

The challenges in asthma research, mana-gement and education are both difficult and interesting. I tackled them with enthusiasm, tenacity, and dedication to develop new methods of analysis and provide new solutions to keep up with the ever-changing threats. In this new age of global interconnectivity and interdependence, it is necessary to provide professionals, students, patients, policy makers and healthcare systems with state-of-the art knowledge on the frontiers in adult and pediatric asthma research while encouraging efficient management programmes and high level education. We must ensure that right people can access the right information at the right time.

Research is academia’s favourite source of intelligence on funding opportunities and research policy. My research activity for my PhD Thesis in Internal Medicine “3 Years Evolution in Patients with Acute Coronary Syndromes and Chlamydia Pneumoniae Infection”, appreciated “Magna cum laude”, where I conveyed innovative aspects regarding the immune-inflammatory mechanisns in atherosclerosis, combined with the research and continuos education opportunities

offered by the European Academy of Allergy and Clinical Immunology (EAACI) propelled my research and academic development in the field of immunology of allergic diseases. As any good research starts with the right question my observations were that there are several unmet needs regarding adult and pediatric asthma from bench (endotypes, biomarkers), to translational (precision medicine) and bedside management (lifestyle, healthcare system transformation, resource utilisation).

As a member of the medical profession, a senior specialist in Allergy and Clinical Immunology and a member of the Academia I have proved to posses special knowledge and skills in a widely recognised body of learning derived from research, education and training at a high level, and I was recognised by the my colleagues and reference bodies as such. As a professional I commited to competence, integrity and morality, altruism, and the promotion of the public good within my expert domain and I applied my knowledge and skills in the interest of my patients and my students.

Alongside cutting-edge scientific advance-ments I have also promoted educational programmes ensuring translation of knowledge to new generations of medical students and researchers. Driving standards in asthma and allergy education and raising awareness of these disease amongst all stakeholders is key to reach a better health status for asthma patients.

My entire career is dedicated to creation of new knowledge and/or the use of existing knowledge in a new and creative way so as to generate new concepts, methodologies and understandings to serve the wider purpose of translating asthma research into better clinical management and purposeful education.

Main research area - development and results: Scientific achievements in adult

and pediatric asthma and related co-morbidities

Chapter 1

B-iScientific and

professional achievements

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Main research area - development and resultsScientific and professional achievements

Asthmarepresentsamajorhealthproblem,af-fectingthelivesof300millionpeoplearoundthe globe andwith increasing prevalence indevelopingcountries,withanoverallproject-ed increase inprevalence to400millions intheupcomingthreedecades(1,2,3,4,5,6,7).InEuropeanUnion(EU)30millionscitizensare diagnosedwith asthma (10% of the EUpopulation),themajoritychildrenandadultsbeyond45yearsold (8).Asthmaprevalenceisincreasingespeciallyforpatientsunder15yearsoldaffectingupto25%ofthepedia-tricpopulationinsomeEuropeancountries(1infourchildrenisasthmatic).Asthmaisthemostfrequent chronic disease of childhood andis the leading cause for hospitalization andemergencydepartment(ED)consultationsforthe pediatric populationworldwide.Asthmaimposesasignificantburdentogovernmentsand to society in general due to significantdirect and indirect costs (72.2 billion Euroannual), with major impact on the nationalmacro-economy. Uncontrolled asthma withfrequent exacerbations, hospitalisations to-getherwithmedicationscostsaretheleadingdeterminantsofasthmadirectcosts.75%oftheasthmaeconomicburdenishoweverdueto indirectcosts resulting fromabsenteeismanddecreasedproductivityattheworkplace(9,10,11,12,13).

Therearesignificantunmetneedsintheman-agementofasthmapatientsasaconsequenceofinsufficientsupportforbasic,translationaland clinical research in asthma and for theimplementation of cost-efficient models forasthmamanagement.

An efficient approach to tackle the “asthmaepidemics”needsconcertedeffortsinthefol-lowingdirections:

1. Research and development programmes focusing on prevention, disease mecha-nisms and biomarkers, personalised ap-proaches and development of new treat-ments curing the disease. The synergy

between research centers and national/regional and international research anddevelopment (R&D) programmes is ofparamount importance (14, 15) togetherwith prioritisation of R&D programmestargetingasthmapreventionandcureandcost-effective management. Allergy andasthmaarecloselylinked,withupto90%cases of asthmatic children and 50% ofasthmaticadultshavingtheallergicasth-ma phenotype, thus a rational approachshould include R&D programmes target-ingbothallergyandasthma.

2. Integrative management of asthma pa-tientsatagloballevelincludingnextgen-eration guidelines largely applicable atall levels(primary,secondaryandtertiarycareandself-managementofthedisease)and in any country, registries for asth-ma, improved access to early diagnosisand quality treatment, environment andco-morbidities control, patient and gen-eralpubliceducation,cost-efficientuseofresourcesandpatient-centeredcaremod-els

3. Recognition of asthma as a major health problembythesociety,governments,andpolicymakers (16)withemphasison thehuge economic burden, decreased quali-tyoflifeandimpactofthechilddevelop-mentintoahealthyadultvaluableforthesociety(17)

4. Strategic partnership between all stake-holders (patients and caregivers, doctorsand allied health, pharmacists, teachers,governmentsandpolicymakers,academ-ia and pharmaceutical/devices industry)resulting in a community approach to a community problem targeting asthma.Such a model implemented in Finland(“Zero Tolerance for asthma”) lead to adecreasewith86%ofhospitalisationsforasthma, no asthma deaths and decreasewith50%ofthetotalasthmacosts(18).

FOREWORD

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Scientific and professional achievementsMain research area - development and results

Research activityfocusedmainlyon:1. descriptionandvalidationofpediatricandadultsasthmaphenotypes,endotypesandbiomarkers;

2. endotype driven asthma treatment andnewpotentialcurativeapproaches;

3. tackling environment (infections, pollu-tion), lifestyle (diet, exercise) andasthmaco-morbidities (allergic rhinitis, obesity,foodallergy);

4. asthmapreventionandcontrol;

5. developmentandimplementationofnewmodelsforcost-efficientdiseasemanage-ment.

Professional and academic development with international recognition in pediatricandadultasthmaresearchandmanagementleadto:

A. Leadership of national research pro-grammes (PN-II-RU-TE-2014-4-2303 –Endotypes of Non-Eosinophilic Asthma- ENDANA) and partnerships in COSTactions(COSTBM1201:EarlyOriginsofChronicLungDisease)

B. Membership in steering committees andeditorial boards for the development ofinternational guidelines, internationalconsensuses,booksandmonographs

• ARIA (Allergic Rhinitis and its ImpactonAsthma)(19,20),

• MASK (MACVIA-ARIA Sentinel Net-worKforallergicrhinitis)(21),

• Integrated care pathways for airwaydiseases (AIRWAYS-ICPs) (22),Work-ing Package 10 of the European In-novation Partnership on Active andHealthyAgeing,ActionPlanB3;Mech-anismsoftheDevelopmentofAllergy

• EuropeanAsthmaResearchandInno-vation Partnership (EARIP), WorkingPackage4

• EAACI International Guidelines forClinical Practice for Allergen Specif-ic Immunotherapy (AIT) – Task ForceChairforAITinasthma

• CoordinatingEditor forEAACIGlobalAtlasofAsthma(2013)(23),GlobalAt-lasofAllergy(2014)(24),GlobalAtlasof Allergic Rhinitis and Chronic Rhi-nosinusitis(2015)(25)

• CoordinatingEditor for ImplementingPrecision Medicine In Best PracticesOfChronicAirwayDiseasepublishedbyElsevierinNovember2017

• Member of the expert panel of theiCAALLcollaboration.Fourofthemostinfluentialallergy/immunologyprofes-sionalorganizationshavejoinedforcestolaunchtheInternationalCollabora-tion inAsthma,Allergyand Immunol-ogy (iCAALL). Participating in iCAALLaretheAmericanAcademyofAllergy,Asthma & Immunology (AAAAI), theAmerican College of Allergy, Asthma& Immunology (ACAAI), the Europe-an Academy of Allergy and ClinicalImmunology (EAACI) and the WorldAllergy Organization (WAO). iCAALLisdesignedtocollectanddisseminateconsensus-driven information aboutallergies, asthma and immunologicaldiseases. Communicating this knowl-edge can positively impact diagnosisandtreatment,aswellascostcontain-mentandpolicydecisions.Amajorfo-cusofthis initiativeistheproductionofaseriesofInternationalConsensus(ICON) reports.These documents of-fer general recommendations basedonglobal challenges in caring forpa-tients with allergic and immunologicdiseases.

• Member of the expert panel of thePRACTALL collaboration. The PRAC-TALL program is a common initiativeofEAACIandtheAAAAI.Itfocusesonpractical aspects of allergy to deliverupdated and evidence based recom-mendationsforclinicians

My research, professional and academic de-velopment in the last 12 years reflects the profound implication in the four pediatric and adult asthma management directions outlined above, with notable achievements

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Aclassificationofasthmacontrolandsever-itybasedonsymptoms, lungfunction,exac-erbations, limitation of physical activity andneed for rescuemedications guides asthmatreatment today. This approach has signifi-cantlyreducedasthmamortalityandmorbid-ity,however, all over theworld; thediseasecontinuestoincreasebothinprevalenceandseverity. Current treatment has little or noeffecton thenaturalhistoryofasthma, andcertainlydoesnotcurethedisease.The“onesizefitsall”approachtotherapyanddrugde-velopment has dominated the asthma field.With thismodel, epidemiologic and geneticresearch and development of effective tar-getedtreatmentshasmetlimitedsuccess.

Discoveriesfrombasicscienceresearchinthelastdecadehavebroughtsignificantprogressin knowledgeofpathophysiologicprocessesofallergicdiseases,withacompellingimpactonunderstandingofthenaturalhistory, riskprediction, treatment selection or mecha-nism-specificpreventionstrategies.Theviewof thepathophysiologyof asthmaandaller-gic diseases developed from a mechanisticapproach,withafocusonsymptomsandor-ganfunction,totherecognitionofacomplexnetworkofimmunologicalpathways.Severalsubtypes of inflammation and complex im-mune regulatory networks and the reasonsfortheirfailurearenowdescribed,thatopenthewayforthedevelopmentofnewdiagnos-tictoolsandinnovativetargeted-treatments.

The disease phenotype (26), describes ob-servableand/ormeasurablevisiblepropertiesof the diseasewithout any implication of amechanism(27),whichisdefinedbythedis-ease endotype (28, 29). The understandingof disease endotypes based on pathophysi-ologicalprinciplesandtheirvalidationacrossclinicallymeaningfuloutcomesinasthma(ex-acerbations, lung function) is crucial for thesuccess of precisionmedicine as a new ap-proachtopatientmanagement,withthefinalaimtoimproveefficacyandsafetyforthepa-tients.

A relevant endotype should reflect the cor-respondingphenotypeviabiomarkers. A bi-omarkermeasuredandevaluatedtoexamineany biological or pathogenic processes, in-cluding response to a therapeutic interven-tion (30, 31).The relation phenotype – en-dotype-biomarkeriscrucialfordefiningandvalidatingtheprecision medicineandpreci-sion healthapproachforallergyandasthma(33,34,35).

In2009Ipublishedasfirstauthorthepaper“Antinuclear antibodies in asthma patients - a special asthma phenotype?”where the valueasindependentriskfactorofantinuclearan-tibodies(ANA)forsevereexacerbations,lungfunctiondeclineandhighinhaledcorticoster-oid(ICS)dosestocontrolasthmaisprovedinacohortof100adultswithasthmafollowedfor1year(36).Thepaperisthecontinuationofacross-sectionaltrialfrom2007commu-nicated at the American Academy of Aller-gy,AsthmaandImmunology(AAAAI)annualmeeting evaluating adultswith severe asth-maidentifyingANAasriskfactorsforasthmaseveritywiththesameimpactas“traditional”riskfactorsforasthmaseveritysuchasbloodand sputum eosinophils or associationwithobesityandchronicrhinosinusitis(CRS)(37).The 2009 prospective study identifiedANAin22%asthmapatientswithnosignsofclin-ical or biological activity biologica – “silent”ANA.Thisstudy isoneafewevaluatingtherelation between autoimmunity and asth-maandisvaluablebyhighlightinganunique

1.1. ASTHMA PHENOTYPES AND ENDOTYPES

Defining the relation phenotype – endo-type - biomarkers has a been a constant research theme since 2009 and is reflect-ed by original research and invited review papers in journals with high impact factor, by lectures, oral communications and ab-stracts presented at top level international meetings and by the ongoing PN II research project aiming to endotype patients with non-eosinophilic asthma.

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risk factor for severe asthma (silent ANA),less cited in the literature, and validated inaprospectiveobservation.Theconfirmationof these published data came in the recentyearswhen studies confirm the associationbetween asthma and dense fine speckledANAwithspecificityfortheDFS70/LEDGFp75autoantigen.TheemergingroleofDFS70/LEDGFp75asastressproteinrelevanttohu-man acquired immunodeficiency syndrome,cancer, and inflammationpoints to thepos-sibility that these autoantibodies could besensors of cellular stress and inflammationassociated with environmental factors inasthma(38).Auniquenewphenotypeisthusdescribedforsevereasthmathatmightprovemore responsive to immunemodulation in-steadofclassicanti-inflammatory treatmentwithICS.ThesilentcharacterofANApointsouttotheneedofscreeningforANAinadultswith severe asthma in order to identify thisparticularphenotype.

Theresearchonasthmaphenotypescontin-ueswiththeevaluationoftheimpactofasth-ma co-morbidities, seasonal allergic rhinitisanddysfunctionalbreathing.

Thepaper“Risk factors and asthma phenotypes in children and adults with seasonal allergic rhi-nitis”publishedin2010evaluatestherelationbetweenasthmariskfactorsandphenotypesin adults and childrenwith seasonal allergicrhinitis (SAR) (39).Asthmawasdiagnosed in66.7childrenandin69.5%adultswithSAR.LackofAITprecedingasthmadiagnosiswasan independent risk factorboth forchildrenandadults,observationconfirmedbyseveralotherprospectiveandretrospectivetrials(40,41).ThisisthefirststudydescribingasthmaphenotypesinadultsandinchildrenwithSARaccording to the associated risk factors forasthma:inchildrenbreastfeeding<2monthsand severe rhinitis andmale, polysensitizedandsevererhinitis;inadultspolysensitizationandsevererhinitisormale,exposuretopetsand severe rhinitis or high total serum IgEand polysensitization. The study confirmedwellknownriskfactorsandphenotypictraitssuchlackofAIT,mixedsensitization(season-alandperennialallergens),breastfeeding<2months, male sex in children, polysenzitiza-tion,andsevererhinitisandhighlightednewriskfactorsandphenotypictraitsforasthma

inadultswithSAR,suchmalesexandexpo-suretopets.

Abnormal breathing patterns such as dys-functionalbreathing(DB)maybeassociatedwith asthma and impair asthma control andqualityoflife.Correctandpromptidentifica-tionofabnormalbreathingpatternsinasthmaofferstheopportunityfortreatmentbeyondpharmacologyand for reducingunnecessarymedication to control asthma symptoms. Inthepaper“Dysfunctional breathing phenotype in adults with asthma - incidence and risk fac-tors”publishedin2012(42)weshowedthatthe incidenceofDBvaries according to thetest used (Nijmegen questionnaire versusprogressiveexercisetestingdiagnosinginap-propriateventilation incomparisonwith thebaselinebreathingpatternand inrelationtoobjectiveparameterssuchaswork loadandlung function) highlighting the importanceof use of objectivemethods to properly di-agnoseDBsincesomeoftheasthmasymp-toms such as breathlessness, chest pain,chestconstrictionandacceleratedbreathingoverlap with DB symptoms as depicted byNijmegenquestionnaire.This studywas thefirsttoevaluatetherelationbetweenDBandother asthma co-morbidities. Except psy-chopathology, other asthma co-morbiditiesevaluated (obesity,moderate/severe rhinitis,gastro-esophageal reflux, atopy, high bloodpressure)didnot increasetheriskforDB inthe multiple regression analysis. However,therewas increased incidenceofmoderate/severe rhinitis and gastro-esophageal refluxintheDBgroup,suggestingacarefulexam-ination for DB in patients with asthma as-sociatedwith thesetwoco-morbidities.Theincreased incidenceofmoderate/severe rhi-nitisinasthmaticDBpatientsisnotsurprisingconsideringtheconsequencesoforalbreath-ingandthelinkbetweenrhinitisandasthma,whichmightinvolvecommonabnormalneu-ralpathways.Themajorasthmaco-morbidityincreasingtheriskforDBinasthmapatientsare the anxiety disorders, especially panicdisordersandspecificphobiaofblood,injec-tions,and injuries.Bothpanicdisordersandspecificphobiaswererelatedtoasthma(43),and hyperventilation may provide an inter-esting linkwith asthma, basedon sustainedlevelsofhypocapnia(44,45).Inpatientswith

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panicdisorders raisingCO2 levelsby thera-peuticcapnometryprovedsuperiortocogni-tive-behaviortherapy(44).Themethodisnotyetvalidatedforasthma,since itwastestedonlyinasmalltrial(46).Recentlyalargerclin-icaltrialevaluatedthebenefitsoftherapeuticcapnometryin120asthmapatientsrandom-ly assigned to capnometry-assisted respira-torytraining(CART)forraisingPco2orslowbreathingandawarenesstraining(SLOW)forslowing respiratory rate. Both interventionsprovidedsignificant, sustained,andclinicallymeaningful improvements in asthmacontrolhowever CART was associated with great-er benefits on lung function and long-termsymptomcontrol(47).Wealsoexaminedtherelationbetweenphenotypictraitsofasthmaand DB. In the multiple regression analysislackofasthmacontrolandthefrequentexac-erbatorphenotypewereindependentpredic-torsforDB.TheassociationofthefrequentexacerbatorphenotypewithDBinasthmaisaninterestingobservationofthisstudy,sincewedescribedthisphenotypeasanasthmaticwith at least 3 severe exacerbations requir-ing systemic steroids and/orERvisit and/orhospitalizationforasthmaintheprevious12months.ThepresenceofDBshouldbecare-fullydiagnosed in thesepatients inorder toavoidover-treatmentandtoallowpatienttobenefit from non-pharmacological interven-tions. In theDBgroup therewassignificantincreasedincidenceofsevereasthmaandofbrittleasthma.Thesetwoasthmaphenotypescouldalsobenefitfromnon-pharmacologicaltreatment and possible prevention of asth-ma attacks if DB is correctly and promptlyidentified. Since fast lung function declinewasencounteredmorefrequentlyintheDBgroup, the conditionmight prove importantfor evaluating asthma future risk. Anotheroriginalaspectofthisstudywastheevalua-tionofthelinkbetweenDBandasthmamed-ication.Asthmamedication(longactingbeta2 agonists – LABA or leucotriene receptorantagonists-LTRA)orlackofICSinthepastsixmonths,asameasureofundertreatmentof steroid-responsive asthmatic inflamma-tion associated no increased risk for DB inthemultipleregressionanalysis.Sinceinthenon-DBgrouptherewasanincreasedusageofLTRAasafirstlinecontrollerexploringtheleukotriene pathway in the pathogenesis of

hyperventilationsyndromemightproveofin-terest.

The quest to describe severe or difficultasthma phenotypes continued with anoth-erpaperpublishedin2012,“Predictive value of lung function trend and FeNO for difficult asthma in children”(48).Unlikeinadults,littleis knownabout risk factorsor predictorsofdifficult asthma in children (49, 50).Myhy-pothesiswasthatthecombineduseofclinicalfeatureswithmeasurementsoflungfunctionand airway inflammationwould provide thebestcharacterizationofthedifficultpediatricasthmaphenotype.Howeverasthmaisady-namic disease, hence the fluctuating natureof the parameters used to describe asthmaphenotypes.Fluctuationanalysisisaresearchtoolvalidatedforuseinotherpathologiesorbiologicalprocesseswithafluctuatingcharac-ter(51,52).Recentreportshavehighlightedthevalueofpeakexpiratoryflowfluctuationanalysisincharacterizingasthmacontroldur-ing treatmentwithbronchodilators (53) andin predicting response to asthma treatment(54).Atthatmomentnodatawereavailableon the relationship between lung functionfluctuationandasthmaseverity,andfurther-more,lungfunctionfluctuationhasnotbeenevaluatedyet in thepediatricpopulation. Inadditionpersistentairflowlimitationispreva-lentinadultswithsevereordifficult-to-treatasthma, with rates of 60% reported in theTENOR study (55) andof 49% in theEuro-peancohort (56).Thus,weconsideredacu-mulative end-point merging lung functionfluctuation and persistent airflow limitation.Exhaled NO, measured as fractional con-centrationof exhalednitricoxide (FeNO), isa good surrogate for bronchial eosinophilicinflammation andhasbeenused to identifysteroid-responsive patients, adjust ICS dos-es, and predict relapse during medicationtapering (57). ExhaledNO levelsmight pre-dictchangesinlungfunctionandtheriskoffutureasthmainwheezyinfantsandtoddlers(58).WeconsideredpersistenthighFeNOasameasureofasthmaseverityconsistentwiththeobservationthatincreasedFeNOpredictsaccelerated lung function decline in adultswithsevereasthma(59)andsetthecut-offat45ppbinlinewithapreviousstudyshowingthatacutoffof46ppbhasthebestpositive

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predictive value for asthma diagnosis (60).Childrenwithdifficult had a significantly in-creasedfrequencyofsevererhinitis,psycho-pathology, unfavorable lung function trend,and persistent high FeNO, however in thelogistic regressionanalysis, onlyobesity, se-vererhinitis,andpersistentlyhighFeNOwereindependentriskfactorsfordifficultasthma.Unfavorablelungfunctiontrend(highfluctu-ationand/orpersistentairflowlimitation)didnotreachstatisticalsignificance,notsurpris-ingas,unlike in adults, spirometry is apoorpredictorofseverityinchildren.However,theprevalenceof patientswith highfluctuationwassignificantlyhigherinchildrenwithdiffi-culttotreatasthma.Thereareseveral inno-vativeaspectsof this studysuchas theuseof the multidimensional approach to char-acterise the phenotype, evaluation of lungfunctionand inflammationasdynamic traitsusingtimetrendsandthusrespondingtothefluctuatingnature of asthma and evaluatingseveraldomainsof asthma severity: levelofcurrentprescribedtreatment,asthmacontroloverthepreceding3to4months,andburdenofasthmaexacerbations.Phenotypesidenti-fiedbyamultidimensionalapproachcombin-ing clinical features with pathophysiologicfeatures(lungfunctionandinflammation)aremorecomplex,butarguablymoreobjective.Inadditionthemultidimensionalapproachal-lowsvalidationbyreplicationacrossdifferentpopulationsandmaycontributetoamorere-liabledefinitionofasthmaphenotypes.

By 2012 the experience accumulated fromtheoriginal researchonasthmaphenotypeswas summarized in the review paper “Un-tangling asthma phenotypes and endotypes”publishedasfirstauthorin2012(61),whichreached 176 citations until today by otherpaperspublished inhigh rank journals.Cur-rentconceptsinasthmaphenotypingareex-tensively explained,with a special focus oninflammometry, especially with the use ofsputumcytologyandonnovelstatisticalandmathematicalmethodssuchasclusterorfac-toranalysis,principal-componenttechniquesand machine-learning used to phenotypeasthma. The transition from phenotype toendotype isthenexplained, introducingtwoinnovativeconcepts:

1. Thenecessity to link thekeypathogenicmechanism with a clinical phenotype ofasthma. An acceptable starting point todefineendotypeswouldbetheidentifica-tionofcorrespondingmolecularbiomark-ers for such a pathogenetic mechanism.Severalasthmaendotypesmightbeiden-tifiedfollowingthisapproach(Table1)

2. Thevalidityoftheendotypedemonstrat-edby:

a) longitudinal replication across differ-entpopulationsshouldpredictmean-ingfuldifferencesamongindividuals;

b) observations implicated in such en-dotypes should reflect the diseases’biology,naturalhistoryandpredictre-sponsetotreatment;

c) endotypesshouldbeeasilyapplicableandusefulindailyclinicalpracticeandcost-efficient.

Endotypes are detailed for major asthmaphenotypessuchasallergicasthma,intrinsicasthma, non-eosinophilic asthma, aspirin-in-tolerant asthma and extensive remodelingasthma.Aspecialsubchapterisdedicatedtoasthma endotypes and response to beta-2agonists,inhaledsteroids,antibiotics/antioxi-dantsandtargetedtreatment.Advantagesofendotypingasthmaarealsonicelyexplained(Figure1).

Part of the research on asthma phenotypesand endotypes I focused on the use of in-flammometryevaluatedvia inducedsputum.Startingwith2010IstartedthecollaborationforinducedsputumimmunologicexaminationwiththeSwissInstituteofAllergyandAsthmaResearch(SIAF)inDavos,whereIwasinvitedseveraltimesasvisitingprofessor.Measure-mentofcytokinesininducedsputumprovedvery difficult due to the combined effect ofsputum composition (mucus, proteases) andsputum processing (DTT addition, filtration,and dilution). Thus, together with the SIAFteam,we perfected amethod using dialysisplusultrafiltration(Figure2),whichimprovessignificantlytherateofcytokinedetectionininducedsputum.ThepilotsmallgroupresultswerecommunicatedattheEuropeanRespira-torySocietyInternationalCongressinBarce-lona 2013, both the methodology (62) and

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Phenotype Endotype

Allergic asthma EosinophilicTh2driveninflammationSteroid-responsiveAntiIgEresponsiveAntiIL-5responsiveAntiIL-4/IL-13responsive

Intrinsic asthma EosinophilicNeutrophilicAssociatedwithautoantibodies/superantigensSteroid-responsiveSteroid-resistant

Neutrophilic asthma ActivationofinnateimmuneresponseHDAC2abnormalrecruitmentIncreasedneutrophilsurvivalSteroid-resistantResponsivetoantioxidants/antibioticsAntiTNF-aresponsiveResponsivetoHDACregulators(theophylline)

Aspirin intolerant asthma

EosinophilicAlterationintheeicosanoidmetabolism/sensitivitytoleukotrienesC4,D4,andE4Steroid-responsiveLTRA-responsive

Extensive remodeling asthma

Lackofinflammation/extensiveremodelingAbnormalEMTUactivationAbnormalitiesofASMDefectiverepairmechanismsSteroid-resistantASM-targetedtreatmentresponsiveMMP-targetedtreatmentresponsiveAntiangiogenicresponsive

Table 1Linking essential pathogenic mechanisms with phenotypes of asthma. (Adapted from Agache I, et al. Untangling asthma phenotypes and endotypes. Allergy. 2012;67(7):835-46)

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theendotypingdata(63).In24adultasthmapatientswe demonstrated that sputum andserum cytokine levels correlated, except forIL-9,IL-10andIL-12.Wealsoreportedinter-estingcorrelationsforsputumcytokineswithasthmavisibleproperties: IL-17,eotaxinandRANTESwithsmokerstatus;IL-13andMCP-1 with atopic asthma; IL-5 and IL-10 withasthma associated with CRS; IL-6 with fastlungfunctiondecline;IL-10withcorticoster-oid (CS) responsiveasthma; IL-2withbrittleasthma, VEGF with near-fatal asthma; andIP-10with the frequentexacerbatorpheno-type(63).Theendotypingdatawerepresent-edas anoral communicationand thepaperwashighlyappreciatedandraisedalotofdis-cussion and positive comments.The resultswerevalidated ina largerstudygroupof64patientsandthepaperisinpreparation.

In2013anewinvitedreview(64)publishedininCurrentOpiniononAllergyandClinicalImmunology “From phenotypes to endotypes to asthma treatment” an innovative conceptis introduced regarding the response to atargeted intervention in asthma which mayvarybetweenindividualsorforthesamein-dividualinrelationtotheoutcomemeasures- the so called dissociated effect (Figure 3).Thisarticleisacriticalreviewofthenewap-proachestoclassifyasthmatogetherwiththe

Figure 1Potential advantage of asthma endo-typing. (reproduced from Agache I, et al. Untangling asth-ma phenotypes and endotypes. Allergy. 2012;67(7):835-46)

Figure 2The dialysis-ultrafiltration method patented together with the SIAF asthma research team for measurement of sputum cytokines. (repro-duced from Agache C et al. European Respiratory International Congress, Barcelona, 2013)

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emergingendotype-driventherapeuticstrat-egies.Severalmajorunmetneeds inasthmaendotypingsuchasprofilingtheTh2lowandtheresidentcellcompartmentofasthma(theepithelial-mesenchimaltrophicunit-EMTU)arehighlightedandwillbe tackled in futurepapersoftheauthor.Newphenotypes,suchas epigenetic phenotypes, asthmatic granu-lomatosis,orneurophenotypesaredescribed.This review was cited 30 timessinceitspub-lication including citations in articles fromNature Reviews Immunology, The LancetRespiratoryMedicine,JournalofAllergyandClinical Immunology (JACI), Clinical and Ex-perimentalAllergyandJournalofExperimen-talImmunology.

Astepwiseapproachtoclassifyasthmaispro-posed (Figure 4) incorporating precision (ordeep)phenotyping,longitudinaldatasuchasexacerbationrate,fluctuationanalysisoflungfunctionorexhaledNO,basedontheauthor’spreviousoriginalresearch(48)togetherwithidentificationofnovel causalpathwayswithcorresponding biomarkers (endotype-driv-en asthma classification) and translation ofbiomarkers into pathways-specific diagnos-tic tests, which will represent the area ofresearch of the author from2013 onwards.

Deep phenotyping can be defined as theprecise and comprehensive analysis of phe-notypicabnormalitiesbasedonstratificationintodiseasesubclasseswithacommonbio-logicalbasis.Useofcomputationalresourcesto capture, store, and exchange phenotypicdata followed by sophisticated algorithmstointegrateitwithgenomicvariation,omicsprofiles,andotherclinical information ises-sential(65)andwillopenthegateforpreci-sionmedicineinasthma.Inadditionrapidad-vancesinhealthinformationtechnology(HIT)havecreatedunprecedentedopportunitiestocollect,analyzeandlearnfromvastamountsof“real-world”datathatcurrentlyarelockedaway in unconnected servers and file cab-inets. While clinical trials will likely remainthe gold standard of evidence, crowdsourc-ingbackedupbyHITadvancespromises toovercomethecurrentlimitationsofobserva-tionaldata.Byanalyzinganimmensebodyofobservationaldatainrealtimephysiciansandresearchers can identify trendsandassocia-tionsbetweenmyriadvariablesandgeneratenew hypotheses and draw immediate prac-tice-changingconclusions(66,67).AdvancedHITtools,suchasrapidlearningsystems,willstructurethehugebodyofunbiaseddataby

Figure 3Main determinants influencing the response to a targeted intervention in asthma.Endotype-driv-entreatmentofasthmahasimprovedtheresponseratetotargetedtreatmentbutdidnotsolvecompletelythedissociatedeffectoftheinterventionnorthevariabilityinresponseduetodrugef-ficacyattargetsite(reproduced from Agache IO. From phenotypes to endotypes to asthma treatment. Curr Opin Allergy Clin Immunol. 2013;13(3):249-56)

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normalising similar information even if pro-videdindifferentformats,correctingforthewide variation in data standards.Then datawill be run through correlation and trendanalysistools,revealingconnectionsthatcanbeusedtodrawstatisticallyvalidconclusionsanddeveloprobusthypotheses(67,68).

Thestep-wiseapproachisfurtherdevelopedintotheconceptofendotype driven treatment of asthma in the next review published in2014 (69).ThePRACTALLconsensusreport

proposedseveralparametersfordefininganasthmaendotype:consistentclinicalcharac-teristics,biomarkers,lungphysiology,geneticbackground, histopathology, epidemiology,and treatment response (29). Several endo-typesareproposedforasthma,howevernoneisvalidatedacrossalltheabove-enumeratedcriteria.Translationofbiomarkers intopath-way-specificdiagnostictestsisessentialandshouldguidethedesignoffuturelargeclini-caltrials,incorporatingbothlongitudinaland

Figure 4Step-wise approach to classify asthma.Severalnewapproachesforclassifyingasthmaareavaila-ble,fromprecisionanddeepphenotypingtoidentificationofnovelcausalpathwaysandtransla-tionofbiomarkersintopathway-specificdiagnostictests.(reproduced from Agache IO. From pheno-types to endotypes to asthma treatment. Curr Opin Allergy Clin Immunol. 2013;13(3):249-56)

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mechanism-tailoredendpoints(Figure5).Theselectionofoutcomemeasure isdifficult,asit must reflect themechanistic interventionandshouldberelevantforboththeasthmat-ic population in general and the particularindividualwithasthma.The reviewprovidesdetaileddescriptionoftheevidenceforendo-typedrivenasthmatreatmentasderivedfromclinical trials. Endotype-driven treatment ofasthmaisdescribedforTh2highasthmaandTh2 low asthma (neutrophilic, microbiomeandEMTUdriven)andfortheobeseasthmaphenotype.

Thenextinvitedreviewpublishedin2015(70)focusesonnon-eosinophilic asthma (NEA) en-dotypesandpreparedtheapplicationforfund-ingbynationalresearchprogrammesfinalizedwithwinningthePN-II-RU-TE-2014-4-2303project – Endotypes of Non-EosinophilicAsthma–ENDANA.Inthisreviewpertinentarguments spanning from induced sputumtogenesignaturearedescribedtoargueforNEA as a distinct asthma phenotype with

several relevant clinical features such as in-creased asthma severity, increased remod-elling and lower response to bronchodilatorandanti-inflammatorytreatment.Twomajormechanisms leading to neutrophilic inflam-mationwerepostulatedandwillbetestedbythe ENDANA project: the dysregulated in-nate immune response, including neutrophilintrinsicabnormalities,andtheactivationofthe IL-17-dependent pathway. Several fac-torssuchasage,metabolicorepigeneticfac-torsortheactivationoftheEMTUhavebeenidentified asmodulators.The endotypingofNEA is far behind the eosinophilic asthma,anduntilnow,noendotypedriveninterven-tionshavebeenprovedtobeeffective.

Another invited review (71) “The Complex Type 2 Endotype in Allergy and Asthma: From Laboratory to Bedside” published in 2015 inCurrent Allergy and Asthma Reports intro-ducestheconceptofsimpleversuscomplexendotype,usingthetype2asthmaendotypeas the prototype for a complex endotype.

Figure 5Essential steps to improve response to asthma treatment.Theidentificationofcorrespondingmo-lecularbiomarkersfortheindividualpathogenicmechanismsunderlyingphenotypesorsubgroupswithinaphenotypeandincorporationofmechanism-tailoredend-pointsintoclinicaltrialsarees-sentialtoimprovetheresponseratetotargetedtreatmentinasthma.(Reproduced from Agache et al. presentation at the World Allergy Congress in 2011)

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Threemainpathways(IL-5,IL-4/IL-13andIgEdriven endotypes) are described, supportedbytargetedinterventionsinasthma,togetherwitha thoroughdescriptionofexternal fac-torsmodulating theexpressionofendotype(Figure6).Thetype2endotypewasdescribedforallmajorallergicdiseases:asthma,rhinitis,chronic rhinosinusitis, andatopicdermatitis.Thiscomplexendotypeismainlymediatedbytype2innatelymphoidcells(ILC2)andbyTh2cells,aswellasTh2cytokine-producingNKTcells,whereastheirindividualcontributionisnotknown.Thereviewwasalreadycited 20 times in one year bypaperspublishedinhighrankedjournals.

In2016wepublishedanotherinvitedreview,“Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine”, linking the endotypedrivendiseaseclassificationandmanagementwiththeconceptofprecisionmedicineinal-lergy and asthma (72). The article introduc-es the innovativeconceptofdevelopmentalendotypesaddressingdisease inceptionandprogression highly needed for the outset ofearlypreventionanddiseasemodifyingstrat-egiesaspartofthe4Psofprecisionmedicine.Epigeneticmechanisms link gene regulationtoenvironmentalinfluencesanddevelopmen-taltrajectories(73).Developmentalprogram-

Figure 6The complex network of Th2 endotype in allergic diseases involves the interaction between innate immune response and Th2 cells.Threemajordownstreameffectorpathwayscanbede-scribed:theIgEpathway,theIL-5/eotaxinpathway,andtheIL-4/IL-13pathway.Additionalmod-ulatorsoftheTh2endotypecanbedescribedsuchasTh17orTh1cells,theIL-9/mastcellaxis,activationofthemetabolicpathways,orthedegreeofairwayremodeling.(Reproduced from Agache I, et al. The Complex Type 2 Endotype in Allergy and Asthma: From Laboratory to Bedside. Curr Allergy Asthma Rep. 2015;15(6):29)

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minginducedbytheintrauterineenvironment(cigarettesmoke,nutrition,andstress)affectsthe fetusand itsgerm line,with intergener-ational epigenetic effects. Developmentalprogrammingcanbetransmittedacrossgen-erations(trans-generationaleffects)andcan-notbeanymoreattributedtodirectenviron-mental exposure. New bioinformatics toolsto define multidimensional endotypes aredetailed,togetherwithdata-drivenunbiasedapproach as opposed to investigator-drivendisease clustering. The mixed mixed Th17/Th2endotypeinasthma,CRSoratopicder-matitis (AD) is further described. Th2 cellscandifferentiateintodual-positiveTh2/Th17cells(74)andthesecellswereidentifiedintheBALfluidofasthmaticpatientsandrelatedtoglucocorticoid resistance invitroandairwayobstructionandhyperreactivity (75). InCRSIL-25 receptor (IL-17RB)-expressing Th2 ef-fector cellswere identified inNPtissuebutnot the healthy nasal mucosa or periphery,whileabundantIL-17-producingTcellswere

observed inbothhealthynasalmucosalandpolyp populations, thus suggesting that theTh17responsemightbeimportantinhealthynasalmucosal immunehomeostasis and theNP inflammation and remodeling occurswithinthemixedendotype(76).Anon-type2immuneresponsemixingTh1,Th17andTh22driven inflammation and epithelial dysfunc-tion isalsodescribedforAD innon-lesionalskin and in the chronic remitting-relapsingform of the disease (77, 78, 79).The paperalso highlights the importance of externalmodulatorsofanendotype(Figure7).Crucialdeterminingfactorsforcompleximmunereg-ulation and barrier function include respira-tory infections, microbiome, and nutrition.To further elaborate on the definitionof anendotypeonemustrecognizethatonemajorpathogenicpathwaysuchastype2 immuneresponseishighlycomplex,includingseveraldeterminantswithnonlineardynamicinterac-tions(Figure7)andheterogeneous,sincenotall determinants are present in all patients

Figure 7Factors that affect a disease endotype in allergic diseases.Forprecisionmedicineinallergicdis-ease,moremechanisticapproachesareneeded,basedonanintegratedunderstandingoftheindi-vidualpatient’sbiologicalmechanisms,includingtheinterplaybetweentheimmuneresponseandtheexposome, infectionsandmicrobiome,genetics,epigenetics,psychosocialfactors,nutrition,anatomicalfactorsandmetabolicpathways.(Reproduced from Agache I, Akdis CA. Endotypes of al-lergic diseases and asthma: An important step in building blocks for the future of precision medicine. Allergol Int. 2016;65(3):243-52)

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Figure 8The complex type 2 immune response driven endotype consists of several individual pathways with different preponderance in major allergic diseases.TheIL-5pathwayisatherapeutictargetinasthmavalidatedinmajorphaseIIIclinicaltrialsleadingtoregulatoryapprovalofmepolizumabforsevereasthmaandwastargetedinaproofofconceptstudyinCRSwithNP.TheIL-4/IL-13pathwayseemssimilarlyimportantforasthma,CRSwithNPandAD:targetedinterventionwithdupilumabsignificantlyreducedsymptomburden.TargetingsystemicIgEisawell-validatedinter-ventioninallergicasthmaandnewanti-IgEmonoclonalantibodiesareunderclinicaldevelopment.Anti-IgEtreatmentseemedlessrewardinginAD.LocalIgEproductionisakeypathogeniceventdrivingtheinflammationprocessbothinARandCRS.UptonownotargetedinterventionsweretestedforARasaprimarydiseasephenotype.Continuousline:type2immuneresponseendo-typeswithabeneficial responsetotargetedtreatmentand/orstrongevidencefor involvementindiseasepathogenesis.Dashed line:evidencerelatingtodiseasepathogenesis.CRS=chronicrhinosinusitis;AD=atopicdermatitis(Reproduced from Agache I, Akdis CA. Endotypes of allergic dis-eases and asthma: An important step in building blocks for the future of precision medicine. Allergol Int. 2016;65(3):243-52)

or,inagivenpatient,atalltimepoints(6,7).Wethereforemustembracetheconceptofa“complexendotype”consistingofseveralsub-endotypes as opposed to an endotype thatencompasses a singlemolecularmechanism(67,71).Basedonthebeneficialresponsetotargeted treatment and/or strong evidencefor involvement indiseasepathogenesis thepaper proposes twomodels of complex en-

dotypes for type 2 (Figure 8) and non-type2allergicdiseases(Figure9).Theconceptofcomplex endotypes is supported further bystudiesshowingdifferencesincorticosteroidor anti IL-5 targeted treatment responsive-ness intype2asthmapendingonthe local-izedorsystemicinflammationortheinnateoradaptiveimmuneresponsearmpredominantaspathogeneticmechanism(Table2).

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Figure 9Multiple non-type 2-driven molecular sub-endotypes in major allergic diseases.Growingevidencesupportsaroleforadysregulatedinnateimmuneresponsepromotingneutrophilicinflammationinasthma,rhinitisandCRS.TheIL-17pathwayhasbeenrelatedtodiseaseseverityinasthma,CRSandAD.Tissueremodelingandbarrierdefectsaremajorplayersmodulatingthenontype-2im-muneresponseinasthmaandCRS,whilebarrierdefectiscentralforalldiseasephenotypes.TheneurogenicinflammationpathwayappearsofparticularimportanceinrhinitisandAD.(Reproduced from Agache I, Akdis CA. Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine. Allergol Int. 2016;65(3):243-52)

Type2inflammationlocation

LocalisedPredominanceoftheIL-4/IL-13-mediatedpathwaywitheosinophilcinflammationlocalizedinthebronchialmucosa

Systemic

Drivenbyastrongchemokinesignal(suchasIL-5)

Moreextensiveeosinophilicairwayinflammationinvolvingthesmallairwaysandwithfixedairwayobstruction

Increasedriskofexacerbations

LessresponsivetoICS,requiringOCSand/orantiIL-5

Type2inflammation type

DrivenbyThelper2lymphocytes Corticosteroidresponsive

Drivenbyinnatetype2lymphoidcells

Lessresponsivetocorticosteroids;alternativessuchasantiIL-5orantiIL-4/IL-13areneeded

Table 2

The type and location of the immune-inflammatory responses influences the expression of a complex endotype. (Reproduced from Agache et al presentation at the Hong Kong Allergy Convention 2016)

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Biomarkers, or biological markers, aremeasurableindicatorsusedtoexamineanyas-pectsofhealthordisease.Anytypeofanalysescanbeabiomarkerandmayprovideinforma-tionabout thepathophysiologyof anunder-lyingdisease,thecourseofan illness,and/ortheresponsetotreatment.Theyareexpectedtoinformusifadiseaseispresentorabsent,defineitsseverity,provideinformationaboutitsprogression,servetoselectmosteffectivetreatment,and/orserveasguidanceabouttheaffectedindividual’ssurvival.

A successful endotype should link the keypathogenicmechanismwithaclinicalpheno-typeofasthmaviabiomarkers(64).Inrelationtoanendotypethebiomarkercanbeamarkerorthekeymechanismitself(Figure10).Bothvalidityandrelevanceareimportantforabi-omarker.Validity means that the biomarkershouldbebothreproducible(pendingontheinter-andintra-coefficientofvariability)andusable asdiagnostic test (easilymeasurable,affordable).Relevancereferstothequalityofthebiomarkertobepathwayspecificandtobe related to the relevant clinical end point(pendingon surrogateendpoints). It shouldbenoted thatmost biomarkers are current-ly suited only for research settings and still

need to be validated and qualified (80, 81,82). Steps towards biomarker qualificationare clearly delineated by regulators lead bytheFDA(83).

Biomarkersinasthmaareusedatpresenttopredict treatment response andvery few toforecast disease risk and progression.How-ever, theyarenotsufficientlyspecific tose-lect the endotype specifically responding toa targeted treatment. For example, bloodeosinophils predict response to anti-IL-4/IL-13,anti-IL-5,andanti-IgEantibodies,aswellas CRTH2 antagonists and the clinicianwillfaceachallengeofhowbesttotreatsevereasthmapatientswithhighbloodeosinophils(83,84)(Table3).

1.2. ASTHMA BIOMARKERS

Figure 10A successful endotype should link the key pathogenic mech-anism with a clinical pheno-type of asthma via biomarkers. Understanding the complexrelation between biomarkersand endotypes is even moreproblematicgiventhefactthatthesamebiomarkerisvariableacross age, asthma severityandtime.Longitudinalevalua-tionofthestabilityofanendo-type is therefore essential foritsrelevance.(Reproduced from Agache et al presentation at the EAACI annual meeting 2016)

Being closely linked to asthma phenotypes and endotypes the biomarkers research line of the author complemented the achieve-ments in describing disease phenotypes and endotypes acknowledged by the worldwide scientific community through highly cited research papers, invited review, lectures and oral communications.

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In 2010 the author publishes a pioneeringresearch on serum IL-17 as a biomarker ofsevere asthma: “Increased serum IL-17 is an independent risk factor for severe asthma”(85).Itwasthefirstdetailedstudyoftheval-ue of serum IL-17 in asthma and as such itwas cited 132 timessince itspublication. In2010 IL-17A was a newly described proin-flammatory cytokine secreted by a subtypeof T helper lymphocytes, Th17.1 IncreasedIL-17Aexpressionwasfoundtobeassociat-ed with many chronic inflammatory diseas-es in humans, such as rheumatoid arthritis,asthma, systemic lupus erythematosus andallograft rejection (86). The role of IL-17/

Th17cells in asthmawasunclear,withonlymurinemodelsofasthmashowingthatIL-23andTh17cellsnotonlyinduceTh17-cell-me-diatedneutrophilicairway inflammation,butalso up-regulate Th2-cell-mediated eosino-philic airway inflammation (87). Evaluating87 adult patients with mild, moderate andsevere asthma the study demonstrates thatitcanbeanon-invasivebiomarkerasserumIL-17canbeused topredict asthmaseveri-tysinceitisbothincreasedinsevereasthmacomparedtomild/moderateformsofthedis-ease(Figure11)andvalues>20pg/mlarein-dependentpredictorofsevereasthma(Table4).Theresultsareinconcordancewithother

Biomarker Treatment expected to produce a response

Surrogate end-point value

Comments

BLOOD

Eosinophils Anti-IL5AntiIgEAntiIL-4/IL-13Corticosteroids(CS)

ExacerbationsLFdeclineFixedairwayobstruction

EasilyavailableSignificantfluctuation

SpecificIgE Anti-IgEAIT

Exacerbations -

Periostin Anti-IL13 LFdecline ResearchtypeAssaydependent

INDUCED SPUTUM

Eosinophils AntiIL-5ICS

Exacerbations ResearchtypeSignificantfluctuation

IL-13 AntiIL-13 ? Researchtype

EXHALED BREATH

FeNO AntiIL-5AntiIgEAntiIL-13ICS

Exacerbations,LFdecline EasilyavailablePointofcareSignificantfluctuation

Metabolomics(VOC)

ICS Exacerbationsinchildren Researchtype

Table 3Non-invasive biomarkers in asthma.Noneofthebiomarkersaresufficientlyspecifictoselecttheendotypespecificallyrespondingtoatargetedtreatment,theyaresubjecttosignificantvariabil-ityandnoneofthemisvalidatedandqualified. (Adapted from Muraro A, et al. Precision medicine in patients with allergic diseases: airway diseases and atopic dermatitis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347-58)

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studiesunderlyingthelinkbetweensystem-icinflammationandasthmaseverity(88,89).Thestudyevaluatedinparalleltumornecro-sis factor (TNF)-αas abiomarker for severeasthma.IncreasedserumIL-17wasmoredis-criminative for severe asthma compared toserumTNF-a.Also,therewasnocorrelationbetween increased serum IL-17 and serumTNF-a, thusbothdepictingseparatepheno-typesofasthma,withincreasedserumIL-17morerelevant forasubphenotypeofsevereasthma, non-smokers, without non-steroi-dalanti-inflammatorydrugs (NSAID) intoler-ance,with preserved lung function (LF) andwithnormalserumTNF-α(Table5).Thestudyalsoshowedaninterestingrelationbetweenincreased serum IL-17 and lung function is.Therewas an inverse correlationwith smallairwaysobstruction(asevaluatedbyFEF25-

75andMEF50)andthereisalsoatendencytowardsinverserelation,althoughnotstatis-tically significant,with low lung function asdepictedbyanFEV1valuebelow50%pre-dicted. In the analysis of severe asthmapa-tients subgroup FEV1% predictedwas sig-nificantlyhigherandthenumberofsubjectswithFEV1<50%significantlylowerinassoci-ationwithincreasedserumlevelsofIL-17A.ItseemsthatIL-17isincreasedinsubgroupofsevereasthmapatientswithmorepreservedLF.InanotherstudysputumIL-17wasasso-ciatedwithincreasedbronchialhyperreactiv-itytomethacholine(90).IncreasedIL-17maythuscharacterizeapeculiar lungremodelingwithincreasedbronchialsmoothmuscleandless fibrosis. Unfortunately targeted anti IL-17 treatment with brodalumab in asthmadid not preselect patients based phenotyp-

Figure 11Serum IL-17 is increased in severe asthma compared to mild/moderate forms of the disease.Al-thoughmedianvaluesofserumIL-17werenotdiscriminativeforsevereasthmacomparedtomild/moderateformsofthedisease,thereweresignificantlymoreasthmapatientswithvaluesabove20pg/mlinthesevereasthmagroupcomparedtomildormoderateasthmapatients.VeryhighvaluesforserumIL-17(>100 pg/ml) were encountered only in the severe asthma patient’s subgroup. (Reproduced from Agache I, et al. Increased serum IL-17 is an independent risk factor for severe asthma. Respir Med. 2010;104(8):1131-7)

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Table 4Risk factor for severe asthma.Multipleregressionanalysisrevealedas independentriskfactorsserumIL-17>20pg/ml,non-steroidalanti-inflammatorydrugsintoleranceandlowFEV1.(Adapted from Agache I, et al. Increased serum IL-17 is an independent risk factor for severe asthma. Respir Med. 2010;104(8):1131-7)

BetaStandardError of

BetaB Standard

Error of B t(73) p-level

Smoke 0.010273 0.092371 0.010370 0.093245 0.11121 0.911746

NSAIDintolerance 0.346923 0.097467 0.345615 0.097099 3.55940 0.000649

Atopy -0.076304 0.098527 -0.075581 0.097593 -0.77445 0.441099

Obesity -0.002673 0.104863 -0.002714 0.106457 -0.02549 0.979728

Moderate/severepersistentrhinitis/chronicrhinosinusitis

-0.028323 0.097938 -0.041392 0.143129 -0.28919 0.773233

Bloodeosinophilia -0.094935 0.093798 -0.093847 0.092722 -1.01213 0.314731

FEV1<50%predicted 0.400498 0.092198 0.609701 0.140359 4.34388 0.000043

IL-17>20pg/ml 0.352762 0.091920 0.442894 0.115406 3.83770 0.000257

NSAID=non-steroidalanti-inflammatorydrugs

Table 5Correlations between increased serum IL-17 and other phenotypic features of asthma.SerumIL-17>20pg/mlwasnegativelycorrelatedwithincreasedbloodneutrophilsandwithsmallairwaysandwasnotcorrelatedwiththepresenceofatopy,bloodeosinophilia,smoker,obesity,moderate/severepersistentrhinitisorchronicrhinosinusitis,non-steroidalanti-inflammatorydrugsintoler-ance, FEV1<50%predictedor increased serumTNF-α. (Adapted from Agache I, et al. Increased serum IL-17 is an independent risk factor for severe asthma. Respir Med. 2010;104(8):1131-7)

Parameter Coefficient p value

Atopicstatus 0.1290 0.453

Moderate/severepersistentrhinitisorchronicrhinosinusitis 0.2345 0.169

Smoke -0.1221 0.478

Obesity 0.0075 0.965

NSAIDintolerance -0.1706 0.320

FEV1<50%predicted -0.3091 0.067

Smallairwaysobstruction -0.4526 0.006

Bloodeosinophilia 0.0210 0.247

Bloodneutrophilia -0.3376 0.047

TNF-α>8.2pg/ml 0.0606 0.729

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ic traits and itwas not successful, but, as aconfirmationofourstudyobservations,inthehigh-reversibility subgroup (post-bronchodi-latorFEV1improvement≥20%)theAsthmaControl Questionnaire (ACQ) change withnominalsignificancewasnoted(91).

Thequestformolecularbiomarkersforasth-macontinuedandin2016thepaper“Serum IL-5 and IL-13 consistently serve as the best predictors for the blood eosinophilia pheno-type in adult asthmatics“publishedinAllergyasfirstauthorassessedthebiomarker(s)thatpredictbestthephenotypeofbloodeosino-philiainadultasthmaticpatients.TheresultsofthisstudywerealsopresentedinSeptem-ber2016asanoralpresentationattheERSannualcongressinLondon.Severalpotentialcandidateswereevaluatedsuchasserumlev-elsofperiostin,eosinophil-derivedneurotox-in (EDN),eotaxin,eNO, sputumeosinophils,totalserumIgEaswellastheTh2cytokinesIL-5 and IL-13. To better stratify the type2-high complex endotype, additional serumcytokinesweremeasured:interferon(IFN)-γ,IL-17A, IL-6, IL-7, IL-8, IL-10, IL-12, IL-15,IL-16, IFN-gamma inducible protein (IP)-10,macrophage inflammatory protein (MIP)-1α,monocytechemoattractantprotein (MCP-1),tumournecrosisfactor(TNF)-α,thymus-andactivation-regulatedchemokine (TARC),vas-cular endothelial growth factor (VEGF). Assecondary end-points, the study evaluatedthe relation between biomarkers and clini-cal significant asthma outcomes: night-timeawakenings, exacerbation rate, LF decline,steroidresistance,brittleasthma(type1and2), near-fatal asthma, AHR, asthma controlandseverityasdefinedby theGlobal Initia-tiveforAsthma(GINA).Inaddition,thegainedknowledgewasusedtofurthersubgrouptheasthmapatientsbasedonthemolecularfin-gerprint. According to the receiver operat-ingcharacteristic(ROC)curvesIL-13(AUC=0.922)andIL-5(AUC=0.905)predictedbestabsolutebloodeosinophilnumbersatacut-offvalueof>350eos/µl, followedbyEDNandeNO(Table6).Intheregressiontreemod-el (Figure 12), blood eosinophilia was bestpredictedbyIL-5withacut-offvalueof341eos/µl anda separation levelof0.57pg/mlIL-5.ThenextimportantvariableswereEDNandeNO.Ofnote, the IL-5and IL-13 levels

Table 6Biomarkers predicting blood eosinophilia at a cut-off value for absolute blood eosinophil numbers > 350 eos/µl.Area under the curve(AUC) values for biomarkers are stated. Ac-cording to theReceiveroperatingcharacteris-tic(ROC)curvesIL-13(AUC=0.922)andIL-5(AUC = 0.905) predicted best absolute bloodeosinophilnumbersfollowedbyEDNandeNO. (Adapted from Agache I, et al. Serum IL-5 and IL-13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics. Allergy. 2016;71(8):1192-202)

Biomarker Visit 1 Visit 2

IL-13 0.922 0.743

IL-5 0.905 0.730

EDN 0.826 0.720

eNO 0.713 0.643

VEGF 0.648 0.512

MIP-1b 0.647 0.524

IL-12 0.636 0.548

IL-16 0.615 0.590

Eotaxin-3 0.615 0.567

SputumEos 0.606 -

remainedstableoveraperiodof6weekswithdifferences ≤3%,whereas blood eosinophilsvariedwith-15.455%forabsolutenumbers.Thesubgroupanalysisfocusedontheclinicalrelevant end-points in relation to the inves-tigatedbiomarkers.Aftermultiplicitycorrec-tion, we observed a significant correlationbetweenincreasedlevelsofMCP-1andasth-maseverity(GINA)andfastLFdecline.SerumIL-5 and IL-13 showed a strong correlationwithairwayhyperreactivity(AHR)(Figure13).ThecorrelationbetweenIL-5/IL-13andAHRseemsinterestingandsupportsourprevioushypothesis that IL-13 reflects an inflamma-tiontypethatismorelocalisedintothelungandrelatedtoairwayremodeling (71). IL-13didnotcorrelatedwithsteroidresistanceandtherefore this subendotype might reflect asubgroup of blood eosinophilia asthmaticsrespondingtotopicalICStreatment.Asthmapatients were clustered according to their

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Figure 12Regression tree model.AbsolutebloodeosinophilswerebestpredictedbyIL-5withacut-offof341 eos/µl and a separation level of 0.57 pg/ml IL-5 (figure 4a).The next importantvariableswereIL-13,EDNandeNO(figure4b). (Reproduced from Agache I, et al. Serum IL-5 and IL-13 con-sistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics. Allergy. 2016;71(8):1192-202)

Figure 13Correlation analysis between discrete clinical characteristics with continuous variables.Strengthofthecorrelationisdisplayedonascalefrom0(darkblue)to7(yellow).MCP-1correlatedwithasthmaseverity(GINA)andfastLFdecline.AHRcorrelatedwithserumIL-5andIL-13. (Reproduced from Agache I, et al. Serum IL-5 and IL-13 consistently serve as the best predictors for the blood eosino-philia phenotype in adult asthmatics. (Allergy. 2016;71(8):1192-202)

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lungfunction(FVC,FEV1,PEF),asthmacon-trol test (ACT)score,bloodeosinophiliaandcorrelatedmolecularbiomarkers (IL-5, IL-13,EDN)andlevelsofMCP-1,IL-8,eotaxin.Fivemain clusters can be identified (Figure 14).Therearetwoclustersofpatientswithbloodeosinophilia(BandE)thatdifferbytheiras-sociatedbiomarkers.ClusterB includes fourasthmaticswith a severemixed-typehavingboth blood eosinophilia and increased lev-els of MCP-1 and IL-8. Cluster E includes20 moderate-severe asthma patients withblood eosinophilia. ClusterA includes 5 se-

verepatientswithoutbloodeosinophiliabuthighlevelsofMCP-1,eotaxin,IL-8.ClusterCcontains7mild-moderatepatientsthatshowincreased levelsof IL-8,eotaxinandMCP-1.ClusterDincludes28mild-moderatepatientsthat shownoparticular endotype and goodcontrol of asthma. These results show thatthesubphenotypeofeosinophilicasthmase-lectedbyserumIL-5andIL-13isdividedintomoderate-severeandveryseverepatientsofmixed-type. The value of added biomarkers(MCP-1, IL-8) to stratify for asthma severitywasalsodemonstrated.

Figure 14Hierarchical clustering including serum biomarkers identified by principal component analysis. Asthmapatientswere clustered according to their lung function (FVC,FEV1,PEF),ACT score,bloodeosinophiliaandcorrelatedmolecularbiomarkers (IL-5, IL-13,EDN)and levelsofMCP-1,IL-8,eotaxin.Asthmaseverity(GINA)isdepictedontheverticalaxisusingacolourcode:redformildasthma,greenformoderateasthmaandblueforsevereasthma. (Reproduced from Agache I, et al. Serum IL-5 and IL-13 consistently serve as the best predictors for the blood eosinophilia phenotype in adult asthmatics. Allergy. 2016;71(8):1192-202)

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A. BIOLOGICALSNew and expensive biological therapies forasthma are emerging that are highly effica-cious only for a selected group of patients.Selectionofthetargetgroupofpatientsus-inganendotypedrivendecisionguidedbyabiomarkerdirectlyinvolvedinasthmapatho-genesis together with a clever selection ofoutcomemeasuresshouldbeacknowledgedasanessentialscaffoldforthedesignofsuc-cessfulclinicaltrials(69).

The knowledge accumulated on asthmaphenotypes and endotypes was pursued inamultinational clinical trialwith the resultspublishedin2016inthepaper“A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma” (93).The trial evaluated the roleofIgEinallergicasthmaadultpatientsandtest-edthenewhumanizedIgG1monoclonalanti-body,quilizumab,whotargetstheM1-primesegmentofmembrane-expressedIgE,leadingtodepletionof IgE-switchedandmemoryBcells.QuilizumabmayresettheIgErepertoireby targeting IgE production and provide amoresustainedeffectwithalowerdosefre-

quencycomparedtotheotherantiIgEmon-oclonal antibody that is in use for asthma,omalizumab. InapreviousstudyQuilizumababrogated the increase in challenge-specificIgE inpatientswithmildasthmafollowingawhole-lung allergen challenge, and reducedtheearlyand lateasthmatic reactions, relia-blesurrogateend-pointsforIgEdrivenaller-gicasthma (94).Theprimarypurposeofthestudy was to evaluate the efficacy (severeexacerbations,LF,asthmacontrol,qualityoflife), safety, and pharmacokinetics of quili-zumabafter36weeksoftreatmentinadultswith allergic asthma (at least one positiveaeroallergen-specificIgEoratotalserumIgE≥75 IU/mL) inadequately controlled despitehigh-dose ICS and a second controller. Thestudyalsoevaluatedtheabilityofbiomarkers(serum periostin, blood eosinophils, exhaledNO, and serum IgE) to predict benefit fromquilizumab, using the previousmodels test-edforomalizumabandlebrikizumab(95,96).The studywas terminated early because ofthelackofefficacyfortheprimaryend-point(asthmaexacerbations)atWeek36,withthemediantime in the study at 72weeks (Fig-ure 15), although quilizumab demonstrated

1.3. NOVEL TARGETED TREATMENTS FOR ASTHMA

Figure 15Rate of protocol-defined asthma exacerbations through Week 36 for all patients.M=monthly;Q=quarterly.Quilizumabtreatmentdidnotproduceaclinicallymeaningfulreductionoftherateofasthmaexacerbationsoverthe36-weektreatmentperiod.IntheITTpopulation,thereductionintheasthmaexacerbationraterelativetoplacebowas19.6%.IntheEXTRAstudy(95)thatexam-inedasimilarpatientpopulation,omalizumab,theantiIgEantibodycurrentlyinuse,significantlyreducedasthmaexacerbationsby25%inallpatientsgroup. (Reproduced from Harris JM, et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately con-trolled allergic asthma. Respir Res. 2016;17:29)

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clear pharmacological activity by reducingbothserumtotalandallergen-specificIgEanaverageof30–40%frombaselineinallthreetreatment arms (Figure 16). Subgroup anal-ysisbybaselineserumperiostin(≥50ng/ml,<50 ng/ml), blood eosinophils (≥300 cells/μl, <300cells/μl), FeNO (≥20 ppb, <20 ppb)and serum total IgE (≥200 IU/mL,<200 IU/mL) demonstrated no consistent effect ofquilizumab on the exacerbation rate acrossalldoseswhencomparedtotheintentiontotreat(ITT)population(Figure17).Nosignifi-cantevidenceofimprovedFEV1atWeeks12and 36was observed in quilizumab-treatedpatientscomparedtoplaceboandnomean-ingfuldifferenceswereobservedbetweenthequilizumab dose groups comparedwith theplacebogroupforsymptomscoresandquali-tyoflifescores.Quilizumabpreventsthefor-mationofshort-lived IgEplasmacells intheairway,while long-livedIgEplasmacellsandthe subpopulation of IgG1 memory B cellsthatundergoasecondaryswitchtoIgEwhenreactivated,whichlackIgEonthesurface,arenot targeted thismonoclonal antibody.Thismechanisticstudychallengesthustheroleoflocal IgEproductionby short-lived IgEplas-macells forexacerbationsandotherclinicalendpointsandshowedthatalternatesourcesof IgE play amore dominant role in allergicasthma.Asforthesurrogatemarkeritself(theallergenchallengemodel)usedintheexplor-atorystudywithquilizumabitwasshowntobelessrelevantformoderate/severeasthmacomparedtomildasthma.

B. ALLERGEN IMMUNOTHERAPYAlthoughcurrentasthmapharmacotherapyiseffectiveinmitigatingthefrequencyofasth-maexacerbationsandthelossofdiseasecon-trolitdoesnotofferanylastingbenefitoncetreatmentisstoppedandshowsquitelimitedintrinsicdisease-modifyingeffects.

Allergenimmunotherapy(AIT)hasthepoten-tialofmodifyingthefundamental,underlyingdisease mechanisms and shows sustainedclinicaleffect.EffectiveAITtriggersmultipleimmune-mediated mechanisms, which aresequentially activated, which lead to aller-

gen-specific immune tolerance, suppressionof allergic inflammation and multifacetedclinical improvement (97,98). Ioana Agache recently evaluated the benefits of AIT in areviewpaper “Mechanisms of allergen-specif-ic immunotherapy and novel ways for vaccine development” (99)andtwoconsensusdocu-ments “International consensus on allergy im-munotherapy”,developedbyexpertsfromtheiCAALinitiativeandpublishedinJACI(97,98)

The review paper discusses the recent evi-dence providing a plausible explanation toAITmultiplemechanismsinducingbothrapiddesensitization and long-term allergen-spe-cific immune tolerance, and suppression ofallergic inflammation intheaffectedtissues.During AIT, peripheral tolerance is inducedbythegenerationofallergen-specificregula-toryTcells,whichsuppressproliferativeandcytokineresponsesagainsttheallergenofin-terest.RegulatoryTcellsarecharacterizedbyIL-10andTGF-betasecretionandexpressionof important cell surface suppressive mol-ecules suchas cytotoxicT lymphocyteanti-gen-4andprogrammeddeath-1thatdirectlyorindirectlyinfluenceeffectorcellsofallergicinflammation, such as mast cells, basophilsand eosinophils. RegulatoryT cells and par-ticularly IL-10 also have an influence on Bcells, suppressing IgEproductionand induc-ingtheproductionofblockingtypeIgG4anti-bodies.Inaddition,thedevelopmentofaller-gen-specific B regulatory cells that produceIL-10anddevelop intoIgG4producingplas-macellsrepresentessentialplayersinperiph-eral tolerance.These findings togetherwiththenewbiotechnological approachescreateaplatformfordevelopmentoftheadvancedvaccines.Moreover,reliablebiomarkerscouldbeselectedandvalidatedwiththe intentiontoselect thepatientswhowillbenefitmostfromthisimmune-modifyingtreatment.Thus,AITcouldprovideacompletecureforalarg-ernumberofallergicpatientsandnovelpre-ventive approaches need to be elaborated.Thepaperhighlightswhatisunknowninthemechanisms of AIT (Table 7), describes thecharacteristicsofagoodvaccine(Table8)andofferspossiblesolutionsfornewvaccinesde-velopment(Table9).

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Figure 16Effect of quilizumab on serum total (a-c) and allergen-specific IgE (d-f) from baseline to Week 84. IgElevelsarerepresentedasthemean±standarderror(SE)ofthenaturallogarithm(a,d),themean±SEpercentchangefrombaseline(b,e),andmedianpercentchangefrombaseline(c,f).AllIgEdataanalysisarebasedonobservedvalues.M,monthly;Q,quarterly.Quilizumabdemonstratedclearpharmacologicalactivitybyreducingbothserumtotalandallergen-specificIgEanaverageof30–40%frombaselineinallthreetreatmentarms. (Reproduced from Harris JM, et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. Respir Res. 2016;17:29)

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Figure 17Rate of protocol-defined asthma exacerbations through Week 36 for patients stratified by bio-markers (a: periostin; b: blood eosinophils; c: FeNO; d: serum IgE). Exac = exacerbation; M = month-ly; Q = quarterly. The type 2 biomarkers, serum periostin, blood eosinophils, and FeNO, which identified patients with increased clinical benefit from anti IL-13 (lebrikizumab) (96) and anti IgE (omalizumab) (95), did not consistently enrich for increased benefit from quilizumab in this study. Similarly, patients with elevated serum IgE levels at baseline did not respond better to quilizumab nor was there a correla-tion between serum IgE reduction and exacerbation reduction or FEV1 improvement. (Reproduced from Harris JM, et al. A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma. A randomized trial of the efficacy and safety of quilizumab in adults with in-adequately controlled allergic asthma. Respir Res. 2016;17:29)

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Table 7What is unknown in the mechanisms of allergen immunotherapy.BothTreggenerationandmain-tenanceandtheirroleinotherbiologicalprocessesisyettobediscovered.Ofequalimportancetheroleofthetissue,includingthebarrierfunctionisnotexploredenough.Asforothertargetedinterventionstheroleofbiomarkers,endotypesanddrugefficacypendingonitspharmacologicalprofilearekeypointsforadvancingthefieldforward.(Adapted from Jutel M, et al. Mechanisms of allergen-specific immunotherapy and novel ways for vaccine development. Allergol Int. 2013;62(4):425-33)

MolecularmechanismsofhowTregcellsaregeneratedin vivo

BetteradjuvantsthatspecificallyinduceTregcells

In vivolifespanofTregcellsinducedbyallergen-SIT

IftherearedeleteriousrolesofTregcells,suchasimmunetolerancetotumorantigensandchronicinfectiousagents?

Roleofresidenttissuecellsinimmunetolerance

Molecularmechanismsofspontaneoushealing,remissionsandexacerbationsofallergicdisease

LocaltissueeventsduringSLITandepicutaneousSIT

Earlymolecularmarkersandpredictorstodecidetostart,stopandsuccess

Istheredifferencesinthemechanismsofhighdoseandlowdoseallergen-SIT?

Mechanismsoflongtermmaintenanceofallergentolerance

Isthereanyroleindefectivebarrierfunctioninthesuccessfulresponsetoallergen-SIT?

Table 8Characteristics of a good AIT vaccine.ThefutureneedsofAITincludeincreasedefficacyandpa-tient’sadherence,reducedsideeffectsandcostsandtreatmentduration.Toachievethisaimbettervaccinesneedtobedeveloped.(Adapted from Jutel M, et al. Mechanisms of allergen-specific immuno-therapy and novel ways for vaccine development. Allergol Int. 2013;62(4):425-33)

Shouldinducelongtermallergentolerance(curative)

Shouldachieveclinicalsuccessinshorttimewithfewdoses

Shouldtargetindividualswithallergytoidentifiedallergens

Biomarkersshouldbeidentifiedforpatientselectionandas-sessmentonwhichpopulationshouldbetargeted,whentostartandstop,andhowtofollowthepatients

Tousemultipleallergensatthesametimeshouldbepossi-ble

Sameapproachcouldbeusefulforthepreventivevaccines

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Table 9New AIT vaccines development.SeveralapproachesarecurrentlyunderinvestigationtoachievebetterefficacyandsafetyofAIT:targetingTcells,recombinantallergens,theuseofadjuvantsandimmuneresponsemodifiersandnewroutesofadministration.(Adapted from Jutel M, et al. Mechanisms of aller-gen-specific immunotherapy and novel ways for vaccine development. Allergol Int. 2013;62(4):425-33)

Type of the vaccine/approach Description and mechanism

Bypassing IgE binding and targeting T cells

Fusionofmajorallergensandchimericallergens

Majorallergensortheirfragmentsarefusedandexpressedasasinglerecombi-nantprotein.Tcellreactivityispreserved,IgEbindingisattenuated.PreventiveeffectondevelopmentofIgEisdemonstratedinmice.

Hypoallergenichybridmolecules

DerivedfromDerp1andDerp2,reducedIgEreactivityofhybridproteins,inducehigherTcellproliferationresponses.

Fragmentsofmajorallergens NonIgEbindingfragmentsofmajorallergen(Betv1).IgEbindingisattenuatedandTcellreactivityispreserved.

Peptideimmunotherapy Tcellepitopepeptides(Feld1,Apim1)thatdonotbindIgEandinduceTcelltolerancehavebeenusedincatandbeevenomallergy.

Unrefoldednativeorrecombinantallergens

Majorrecombinantallergens(Apim1,Betv1)arenotrefoldedandlackthenativeconformation.IgEbindingisabolished,Tcellreactivityisprotected.

Polymersofmajorallergens Majorallergen(Betv1)istrimerized.Mastcell,basophildegranulationisattenuated,Tcellreactivityispreservedinvitro.

Reconstitution of the natural extract with mixture of multiple recombinant allergens

Mixtureofseveralmajorrecombinantallergens

Phlp1,Phlp2,Phlp5a,Phlp5b,Phlp6wereusedasamixtureoffiverecombinantgrasspollenallergens.

AllergenscoupledtoadjuvantsthatstimulatevariousaspectsofinnateimmunityGpGoligonucleotide-conjugatedallergens

Toll-likereceptor9-triggeringCpGoligonucleotideisfusedtomajorragweedallergenAmba1.

Allergenscoupledtovirus-likeparticles

Highlyrepetitiveviruscapside-likerecombinantparticlescoupledtohousedustmitemajorallergenDerp1.

Carbohydrate-basedparticles Carbohydrate-basedparticles-boundrPhlp5binducedastrongerantibodyandcytokineresponses.

Hypoallergenicvaccinebasedonallergen-derivedpeptidesfusedtohepatitisBPreS

RecombinantfusionproteinsshowreducedallergenicactivityinbasophilactivationandnoIgEreactivity.

MonophosphoryllipidA(MPL)formulatedwithallergoid

Th1-inducingadjuvantmonophosphoryllipidA(MPL)facilitatesshort-termSITtogetherwithagrasspollenallergoid.

Novel routes of administration

Intralymphaticvaccination Allergen-SITvaccinesadministereddirectlyintoinguinallymphnodeswiththeaimtodeliverhighamountsofallergensintosecondarylymphaticorgans.

Epicutaneousvaccination Highnumbersofantigenpresentingcells(LCs),non-vascularizedarea,safe,needle-free,andpotentiallyself-administrable.

Fusion of allergens with immune response modifiers

TargetingFcγRII FusionofallergenswithhumanFcγhasbeenreportedtoinhibitallergen-inducedbasophilandmastcelldegranulationbycrosslinkingFcγandFcεRIreceptors.

Modularantigentrans-location(MAT)vaccines

Theco-expressionofmajorrecombinantallergenstogetherwithtransactivatoroftranscription(Tat)peptideandtruncatedinvariantchainisabletotargetantigenstotheMHCIImoleculesinthetrans-golgicompartment.

Combination possibility with immune response modifiers

Pre-treatmentwithanti-IgEmAb before SIT

ToreduceSITinducedsideeffects.Toenablerelativelyrapiddoseincrease.Touserelativelyhighdoses.

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The International Consensus on Allergen Immunotherapypapersdescribethecurrentstatus of the AIT, mechanisms explainingthecurativerole(Figures18and19),routes,schedulesanddurationoftreatmentanddis-cussesindetailtheroleandchallengesofAITin themajor allergic diseases: asthma, aller-gicrhinitis,foodallergyandatopicdermatitis.Cost-effectiveness, safety of the interven-tionand regulatoryguidanceare thoroughlyconsidered in balancewith the efficacy andimpactonpatient’squalityoflife.Thepaperconcludes that AIT is effective in reducingsymptomsof allergic asthma and rhinitis. Inaddition,AITmodifiestheunderlyingcourseof disease. However, AIT remains a nichetreatment secondary to symptomatic drugsbecause of its cost, long duration of treat-

ment,andconcernsregardingsafetyandef-fectiveness.WorldwidetheAIT“intentiontotreat”populationisunderserved.Furtherre-search isneededtodevelopnoveltherapiesand optimize current ones and to accuratemeasurecost-efficacy.Totheseends,havingharmonizedefficacycriteria,regulatoryguid-ance, and reagent standardizationwould beof benefit.Also of benefitwould be havingbiomarkers and phenotypes to predict thelikelihood of response. As the mechanismsunderlyingdiseasecontinuetobeelucidated,itisexpectedthatnovelstrategiesforAITwillcontinuetoemerge.InspiteoftheprogressinimprovingtheefficacyandsafetyofAITthereisstill thegreatpotential forfurthermodifi-cations,whicharehopedtobroadenthepoolofcandidatesforAIT,aimingatmuchbetter

Figure 18AIT targets both the innate and the adaptive immune response and the resident cells compart-ment.TandBregulatorycellsareup-regulated,aswellasTh1,whileILC2,basophils,mastcells,eosinophils,Th2,Th17aredownregulated.OnBcellsAITshiftsfromIgEtoIgG4production.Ar-rowsup:cellsareupregulatedbyAIT.Arrowsdown:cellsaredownregulatedbyAIT.?:possibleeffect(Reproduced from Jutel M, Agache I et al. International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics. J Allergy Clin Immunol. 2016;137(2):358-68)

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treatmentandpreventionofallergicdiseasesaswellasotherdiseases related to immunedysregulation.However,themajorbarrierforthe clinical application of these new tech-nologies is the capacity to perform a largenumberofphase3confirmatoryDBPCtrials.ImprovementsofAITvaccinesarekeyfortheprogress intheallergypreventionandtreat-ment.Researchhasfocusedonnewvaccineformulations, which provide better efficacy

andsafetymainlybybypassingIgEresponsesandtargetingTcells.Noveladjuvants,carrierproteinsandnewroutesalsoshowpromisinginsights.Theapplicationoftheadvancedvac-cinesislimitedbythehighcostsofclinicalde-velopment.Thepaperalsooffersabalanceddescriptionofbarriersandfacilitatorsforef-fectiveimplementationofAITatalargerscale(Table10).

Figure 19Effective AIT triggers multiple mechanisms, which are sequentially activated.AIT induced im-munetolerancecontrolsboththeacutephaseoftheallergicreactionandthechronicinflammationleadingtoremodeling.Rapiddesensitisation:Averyearlydecrease inthesusceptibilityofmastcellsandbasophilstodegranulationisobserved.Mediatorsofanaphylaxis(histamineandleukot-rienes)arereleasedduringAITwithoutinducingasystemicanaphylacticresponse.Severalmech-anismshavebeenproposedsuchasup-regulationofhistaminetype2receptorsanddecreasedeffectorcellfunctionasreflectedbyadecreaseinallergen-stimulatedsurfaceexpressionofCD63.EarlychangesinbasophilsensitivitypredictssymptomreliefwithAIT.ImmunetoleranceinvolvesthegradualincreaseinTandBregulatorycellsandtolerogenicantibodies.LongtermtoleranceinducedbyAITinvolveschangesinmemoryTandBcellcompartment,theTh1/Th2shift,functionoftheeffectorandstructuralcells. (Reproduced from Jutel M, Agache I et al. International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics. J Allergy Clin Immunol. 2016;137(2):358-68)

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Table 10Barriers and facilitators in the application of AIT.AIThasbeenusedtotreatallergicdiseasesincetheearly1900s.Despitenumerousclinicaltrialsandmeta-analysesprovingAITefficacious,itre-mainsunderusedandisestimatedtobeusedinlessthan10%ofpatientswithallergicrhinitisorasthmaworldwide. Inaddition, thereare largedifferencesbetweenregions,whicharenotonlydue to socioeconomic status.The international communityof allergy specialists recognizes theneedtoharmonize,disseminate,andimplementthebestAITpractice.TheelaborationofawiderconsensusisofutmostimportancebecauseAITistheonlytreatmentthatcanchangethecourseofallergicdiseasebypreventingthedevelopmentofasthmaandnewallergensensitizationsandbyinducingallergen-specificimmunetolerance.(Adapted from Jutel M, Agache I et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015;136(3):556-68)

Barriers

TheapplicationofAITislimitedinmanyareasduetothelowawarenessofAITpotential

World-wideacceptanceandincreasedawarenessthatAITreduceslong-termcostsandburdenofallergiesandpotentiallychangesthenaturalcourseofthedisease.

RegulationsonAIT RegulationsonAIThaveprofoundeffectsonallergypractice,allergenmanufacturers,researchprograms.EspeciallyintheEUallergyvaccinesshouldundergoregistrationasallotherdrugs.Thereisaneedforastandardizedapproachbetweenregulatoryagenciesfromdifferentregionsoftheworld.

AdherencetoAIT Thedemandofprolongedtreatmentoverseveralyearsmayimpairpatients’adherence

Facilitators

Evidence-baseddocumentation

Standardization,validationandconsensusontheclinicaloutcomemeasuresforclinicaltrials.IdentificationandvalidationofbiomarkersforAITmonitoring.Environmentalexposurechambersassuitablesurrogatesfornaturalallergenexposure(59,60).ValidatedtoolsforassessingeffectivenessofAITinreallife–postmarketingstudies.

Guidelinesandrecommendations

Standardizationofguidelinesandrecommendationsattheglobalandnationalsocietylevelsisnecessary.

Betterselectionofpatients

Diagnostictoolsforbetteridentificationofclinicallyrelevantpatient’ssensitizationprofileforapropervaccineselection.Properuseofcomponent-resolveddiagnosistoidentifypotentialrespondersandnon-responders.

MoreconvenientAITregimens

Validationofdifferentregimens(preseasonal,perennial),modeofupdosing,durationoftherapy,maximaldose,cumulativedoseintermsofefficacyandsafety.

Novelapproaches Existingevidenceofefficacyandsafetyofnovelapproachesshouldbeconfirmedinindependentphase3DBPCtrials.

Pharmacoeconomics Moreevidenceontheoverallcost-savingeffectsofAITapplication.Limitthehighcostsofcurrenttreatmentandclinicaldevelopment.

Jointcommitment Coordinatedactionsamongregulators,industryandthescientificenvironmenttofindsolutionsthatproperlyanswerthehealthexpectationsoftheallergicpatients

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For allergic asthmaAIT canbedelivered ei-ther via the subcutaneous (SCIT) or sublin-gual(SLIT)route.Somealternativeroutesareunderinvestigation.However,theefficacyofneither SLIT nor SCIT has been establishedformanyallergens,especiallytherareones.

ThecurrentARIAguidelines (100)givebothSCITandSLITaconditionalrecommendationin allergic asthma due to moderate or lowquality of evidence.According to the GINAreportupdatedin2016(101)theefficacyofAITinasthmaislimited(levelAevidence)andcomparedtopharmacologicalandavoidanceoptions the benefit of both SCIT and SLITmustbeweighedagainsttheriskofsideef-fectsandtheinconvenienceandcostincurredbytheprolongedcoursetreatment,includingthe half on hourwait in the office for SCIT(levelDevidence).

Alimitednumberofstudieshasbeenspecif-icallydesignedtoevaluateAITinasthmaandonly onewith a formal sample size calcula-tion. Inadditionnoconsensusexistson theoptimal endpoints,with pulmonary functionorasthmaexacerbationsassessedasprimaryoutcomeonly sporadically.Yet, severaldou-ble-blind, placebo-controlled trials and me-ta-analysis(potentiallyhamperedbythehet-erogeneity of the trials included) confirmedthatbothSCITandSLITareofvalueinallergicasthmaassociatedwithallergicrhinitisbyre-ducingsymptomscoresandmedicationuse,improvingqualityoflifeandinducingfavora-blechangesinspecificimmunologicmarkers.

ConsideringtheunmetneedsinAITtheEu-ropeanAcademy ofAllergy and Clinical Im-munology is in the process of developingguidelinesforpublichealthusingtheAGREEIImethodologyfortheAITuse inallallergicdiseases. IoanaAgache is a member of theSteeringCommitteeoftheGuidelinesGroupandisleadingtheTaskForceonAITinasthma.The scope of the AIT Asthma Guidelines is to providerecommendationsforindicationsandcontraindicationsforAITinasthmabasedoneffectiveness,safetyandcost-economicanal-ysisand to identifygaps inknowledgeand/or implementation, unmetneeds and futureperspectives.TheAITasthmaTaskForce in-cludedawiderangeofcountries,profession-al background (allergy, pediatrics, internal

medicine, pediatric pulmonology, immunol-ogy, primary care, pharmacists) and patientrepresentatives.Representativesofimmuno-therapyproductmanufacturesweregiventheopportunity to review and comment on thedraftguidelines,and,whereappropriate,revi-sionsweremade.TheAITAsthmaGuidelinesaredevelopedusingtheAppraisalofGuide-linesforResearch&Evaluation(AGREEII)ap-proach(AgreeCollaboration2003;Brouwers2010), a structured approach to guidelinesfor public health.TheAGREE IImethodolo-gyincludesofacarefulsearchforandcriticalappraisal of the relevant literature followedbyasystematicapproachtotheformulationandpresentationof recommendationswhileensuringthattheriskofbiasisminimizedateach step of the process. Appropriate rep-resentationofthefullrangeofstakeholders,peer review and public comment and edi-torial independence, identifying gaps, bar-riers and facilitators are key features of theAGREE II approach.TheAITguidelinesTaskForce firstmet inApril 2015 and an agree-ment was reached on the search strategy,keyquestions,formulatingrecommendationsand the peer review process. Several otherface-to-face meetings and webconferencesfollowedincludingabroadrepresentationofallstakeholdersineachstepoftheguidelines.For a critical appraisal of theevidencepub-lishedsofarweperformedbothasystematicreview(SR)andanarrativereview.Theproto-colfortheSRwaspublishedatthebeginningof2016 (102)and the resultsof theSRarecurrentlyunderevaluation.Nineinternationaldatabaseswerescreenedagainstpredefinedeligibility criteria (Table 11). The populationof interestfortheSRwasallergicasthmaofanyagewithaphysicianconfirmeddiagnosisofasthmaandevidenceofclinicallyrelevantallergicsensitizationasassessedbyanobjec-tivebiomarker(e.g.,skinpricktestorspecif-ic-IgE)incombinationwithahistoryofasth-masymptomsduetoallergenexposure.Theintervention was AIT administered throughsubcutaneous (SCIT), or sublingual (SLIT)routes for the following allergens: pollens,housedustmites(HDM),animaldander,cock-roachandmouldwithcomparatorplacebooractive comparator. To assess effectivenesstheSRincludedprevioussystematicreviews+/-meta-analysisandrandomisedcontrolled

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trials (RCT).To assess health economicsweused cost-effectiveness or cost-utility anal-ysis. For assessing safety besides RCTs weincludedcaseseries(>300patients). Inviewoftheco-morbiditywithallergicrhinitis(AR),weincludedARstudiesintheasthmaSRifatleast80%ofparticipantshadasthmaand/orifseparateasthmaoutcomeswerereported.Dataweredescriptivelyand,wherepossibleand appropriate, quantitatively synthesisedusing random-effectsmeta-analyses.A sub-group analysis was conducted for children(<18)versus adults (≥18years), SCITversusSLIT; monosensitized/mono-allergic versuspolysensitized; mild/moderate versus mod-erate/severedisease,treatmentduration:≤3

yearsversus>3years.ForstudiesandreportsnotincludedintheSRanarrativereviewwasperformed covering the following aspects:pediatricagegroups(5-11versus12-18);rareallergens;theeffectofbackgroundtreatment(ICSvsno ICS); theeffectof co-morbidities(nasal polyps/chronic rhinosinusitis/aspirinexacerbatedrespiratorydisease,autoimmunediseases,foodallergy,atopicdermatitis);theeffect of smoking;AIT combinationwithbi-ologics;adjuvantsandalternativeroutes;re-combinantallergens;AITwithmultiplealler-gens;perennialversuspreseasonalschedules;biomarkersforefficacy;provocationtestsforpatientselection.

Table 11Primary and secondary outcomes considered in the SR for AIT in asthma.A limitednumberofstudieshavebeenspecificallydesignedtoevaluateAITinasthma.Inadditionnoconsensusexistsontheoptimalendpoints.Mostof thestudiesreportonsymptomandmedicationscores, thusthesewereconsideredasprimaryend-points,althoughsecondaryend-pointssuchasexacerba-tions,asthmacontrolandlungfunctionsaremorerelevanttoasthma.Unfortunatelyupuntilnowtheywereassessedonlysporadicallyandwithoutaproperpowercalculation.(Adapted from Dhami S, et al. Allergen immunotherapy for allergic asthma: protocol for a systematic review. Clin Transl Allergy. 2016;6:5)

Primaryoutcomes

1.Effectiveness Shortterm(duringtreatment) Symptomscore

Longterm(atleastoneyearafterdiscontinuationoftreatment)

Medicationscore

Symptomandmedicationscore

2.Cost-effectiveness

3.Safety

Secondaryoutcomes

1.Asthmacontrol

2.Asthmaspecificqualityoflife

3.Exacerbations

4.Lungfunction

5.Responsetoenvironmentalexposurechamberorbronchialallergenchallenge

6.Safetyasassessedbylocalandsystemicreactions

7.Healtheconomicanalysisfromtheperspectiveofthehealthsystem/payer

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Precision medicine represents a novel ap-proach,embracingfourkeyfeatures:person-alized carebasedonmolecular, immunolog-icand functionalendotypingof thedisease,withparticipationofthepatientinthedeci-sionmaking process of therapeutic actions,and considering predictive and preventiveaspectsofthetreatment (84,103-106).Theaudaciousgoalofprecisionmedicineistode-livertherighttreatment,totherightpatientattherighttime(Figure20).

Asthma,allergic rhinitis (AR),chronic rhinosi-nusitis(CRS),foodallergy(FA)andatopicder-matitis (AD) are ideally suited for precision

medicine,becausetheyrepresentanumbrellaofdifferentdiseasesthatpartiallysharebiolog-icalmechanisms(endotypes)andpresentsimi-larvisibleproperties(phenotypes)thatrequireanindividualizedapproachforabetterselec-tion of treatment responders, risk predictionanddesignofdisease-modifyingstrategies(81,84,106).Theprecisionintheclinicneedsfourmain components: an improved disease tax-onomyisacurrentunmetneedbecausenoneof the disease endotypes in allergic diseasesare included in the existing taxonomies; fullpatientmonitoringusingnoveldigitaltechnol-ogyandtheconceptofendotypesandnovelbiomarkersisamust;improvedunderstanding

1.4. PRECISION MEDICINE FOR ASTHMA

Figure 20The audacious goal of precision medicine.Understandingthecomplexnetworksofmolecular,ge-neticandenvironmentalincombinationwithstronghealtheconomicsdataandinalignmentwithpatientsparticipationwillopenthedoorforpreventionstrategiesandcurativetherapiesforaller-giesandasthma.(Reproduced from Agache I et al presentation at the European Rhinology Forum 2016)

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andcommonusageofdiseasephenotypes,en-dotypes and biomarkers preferentially at thepointofcare;andfinallybiomarkerandendo-type-linkedpatientcareandusageofprecisiontherapies(103).

ThePrecisionMedicineInitiativerecentlyan-nouncedtheneedtomovethefieldofpreci-sionmedicinemorerapidlyintoclinicalcare.Ascurrentlystructured,itwillprimarilyfundefforts in cancergenomicswith longer-termgoals of advancing precisionmedicine to allareasofhealth.Thisfocusedeffortprovidesscientists, clinicians, andpatientswithin theallergy community an opportunity to worktogetherboldly toadvanceclinical care; thecommunityneedstobeawareandengagedintheprocessasitprogresses(Figure21).

To emphasize the importance of precisionmedicineinrelationtoendotypingofdiseas-es, discovery of biomarkers, itwill be good

toquoteapioneerinprecisionmedicine,SirJohn Bell, Professor of Medicine at OxfordUniversity,andChairmanoftheOfficefortheStrategic Coordination of Health Research:“Thebestexampleofprecisionmedicineinmyopiniondoesnotcomefromcancer,itcomesfromasthma.Forthiscondition,wehavegonemorethan20yearswithoutanewdrug,be-causethediseasewasnotdefinedverywell.”(http://www.pharmafile.com/news/.)Assaid,successfulmanagementofpatientswith se-vere asthma and allergic diseases continuestobeamajorunmetneed.Oneofthebarrierstosuccessfulmanagementistheheterogene-ityofthediseaseswithdifferentphenotypesand endotypes. A revised paradigm for dis-easemanagement,thatentailscategorizationofpatientsviauseofendotypesandmultiom-icbiomarkersforprescribingtargetedthera-py,willreplacethe“onesizefitsall”approachtoallergicdiseases.Thesuccessofcytokine

Figure 21What we need to achieve the audacious goal of precision medicine.Harmonizationbetweenstake-holdersandtoolswithagreementonabroadresearchprogramencouragingcreativeapproachesandtestingthemrigorouslybothforrobustnessandforapplicabilityforreallifepersonalizedcareisneededtobringprecisionmedicinetotheclinic.(Reproduced from Agache I et al presentation at the European Rhinology Forum 2016)

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inhibitiondefiningthehierarchicalpositionofdistinctcytokines inallergicdiseasespatho-genesis with the description of meaningfulclinicalendotypesholdthepromisetotrans-formthetherapeuticlandscapeinallergicdis-easesinaprecisionbasedfashion.

To move beyond a select few genes/drugs,thesuccessfuladoptionofpharmacogenom-icsintoroutineclinicalcareanddevelopmentof computational approaches and tools toeffectively integratemultidomain data (suchas cognitive IT-systems) are urgently need-ed for the development of newly targetedtreatments.Real-timedatabasesformolecu-lar profiling data could become a pragmaticsolution to several knowledgemanagementproblemsinthepracticeandscienceofpre-cisionmedicine. “Interventional informatics”approach can substantially improve humanhealth andwellness through the use of da-ta-driven interventions at the point of careof broader population levels.The collabora-tivemedicineapproachwithopenaccesstoresearchdatabasesworldwidewillspeedthediscoveryofnewtargets.

Amajorchallengeforasthmaresearchersistodeveloppersonalisedapproachestotreatingpatientswithasthmabecauseonly thenwillwebeable to treatpatients asunique indi-viduals rather than as a group (an approachcalled‘personalisedmedicine’).Thisapproachwillfacilitatetoselecttheresponderstotar-geted treatment and to the implementationofajudiciouscost-effectivenessstrategyforthetreatmentofasthmapatients.Thefollow-inghealthindicatorsareexpectedtoimprove:numberofasthmaexacerbations,health-careutilisationincludingERvisitsandhospitalisa-tions, quality of life in parallel to decreased

costs for asthma management both for thesocietyandthepatient.

OnOctober 14, 2015, EAACI, ERS and theEuropeanMedicalAssociation (EMA)organ-izedasymposiumattheEuropeanParliamentinBrussels onPrecisionMedicine inAllergyandAirwaysDiseases,hostedbymemberofthe European Parliament (MEP) David Bor-relli andwith active participationof the EUCommissionerforHealthandFoodSafetyVy-tenisAndriukaitis, the InterestGrouponAl-lergyandAsthmaoftheEuropeanParliamentpresidedbyMEPSirpaPietikainen,ERS,theEuropeanFederationsofAllergyandAirwaysDiseases Patients Associations (EFA), theGlobalAllergyandAsthmaEuropeanNetwork(Ga2len),ARIA,theRespiratoryEffectivenessGroup (REG), and the European InnovationPartnership on Active and Healthy Ageing.Participants discussed how precision medi-cinewill increase theknowledgeonchronicairwaydiseases,theirprevention,earlydetec-tion,andappropriatemanagementinordertopropose innovative solutions for improvingthe socioeconomic challenge across the lifecycle and ultimately to promote active andhealthyaging.A consensusdocumentEuro-pean Symposium on Precision Medicine in Allergy and Airways Diseases: Report of the European Union Parliament Symposium (Oc-tober 14, 2015)waspublishedbothinAllergyand in Rhinology journals (105). The docu-menthighlightsthecurrentchallengesofal-lergiesandchronicrespiratorydiseasesinEu-rope(Figure22)andadvocatesforajointandinnovative action plan at the EU level,withprecisionmedicineatitscore(Figure23).Theconceptofprecisionmedicineisnotnew,astheanalysisofthesensitizationprofileofal-lergicpatientshasbeenthediagnosticbasisforthestartofpersonalized,allergen-specificimmunotherapyfordecades(107).Thepros-pect of broadly applying precisionmedicineinthefieldofallergyandchronicairwaysdis-easesis,however,novel.The4Psofprecisionmedicineandtheirapplicabilitytoallergyandasthmaarethoroughlydescribed:

• Personalized care is a medical practicethat proposes customization of healthcare, with medical decisions, practices,and/orproductsbeingtailoredtothe in-dividualpatient.

The application of precision medicine to asthma comes as a compelling continuation of the phenotypes, endotypes and biomark-ers field pioneered by Ioana Agache since 2009. In recognition of the achievements in the field the author was included in two prestigious Expert Panels reuniting the ma-jor scientific academies in the field of Asth-ma and Allergy – EAACI, ERS, European Rhi-nologic Society and AAAAI.

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Figure 22Current challenges in allergies and asthma.One-thirdofthepopulationinEuropeissufferingfromallergiesandasthma,withaprevalencereaching40%inthepopulationundertheageof60.Thesediseasesoftenbeginearlyinlifeandpersistthroughoutthelifecycle,affectingallagegroupsandhaveaheavyimpactonproductivity,qualityoflifeandschoolperformance.Modifiableriskfac-torsareknown,includingallergens,tobaccosmoke,andoutdoorandindoorpollution(air quality). Health promotion and prevention strategies should be better implemented across policy areas. (Repro-duced from Muraro A, et al. European Symposium on Precision Medicine in Allergy and Airways Diseases: Report of the European Union Parliament Symposium (October 14, 2015). Allergy. 2016 71(5):583-7)

Figure 23Top reasons for an action plan on precision medicine in allergy and asthma. (Reproduced from Mu-raro A, et al. European Symposium on Precision Medicine in Allergy and Airways Diseases: Report of the European Union Parliament Symposium (October 14, 2015). Allergy. 2016 71(5):583-7)

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• Prediction of the natural progress of disease and of the success of treatment allows themedicaldoctor aswell as thepatienttodecideonthebesttherapeuticstrategy.

• Prevention of disease should be distin-guished in primary, secondary, and ter-tiary prevention. Preventive measuresshouldbeadvisedtopreventthediseasefrom occurring (primary), to prevent thedisease from becoming symptomatic(secondary),andtopreventfromcausingdamageordisability(tertiary).

• Participation of the patient inthethera-peutic plan is crucial for achieving goodadherenceandhenceoptimalefficacyoftreatment.

Theactionplanproposedisbasedonemerg-ingnewscientificallowingpredictionandpre-vention,noveldiagnostic toolsareemerging,allowing better immunologic and functional

endotyping of the patient such as compo-nent-resolved diagnosis (CRD) allowing theevaluationofthe individualsensitizationpat-tern to environmental allergens (108), whilenovele-healthtoolsallowforbetterfollow-upofpatients.Inadditionnoveltherapeuticstrat-egies,suchasendotype-drivenapproach,areemergingallowingthedesignofnovel thera-peutic strategies, including allergen immuno-therapy and biologicals. Elaboration and im-plementation of optimal care pathways (22)followingtheprinciplesofprecisionmedicinein allergology and chronic airways diseasesmayleadtoarresttheepidemicandtoreducethe socioeconomic burden of allergies andchronicairwaysdiseases(Figure24).

Thesecondexpertpanelreunitedrepresenta-tivesofthetwotopAllergyAcademies,EAA-CIandAAAAI,underthePRACTALL(Practi-calAspectsofAllergy) initiativeonprecisionmedicineinallergyandasthma.IoanaAgacheisthelastauthoroftheconsensusdocument

Figure 24Aims of precision medicine in allergy and asthma.Withtheboostprovidedbynewdiagnosticandtherapeutictoolsthenewmodelofpatient-centeredmedicineintentstoreducethediseasebur-denandimprovesatisfactiononmultiplelevels:thehealthcaresystem,theregulatorsandpayersand thepatients. (Reproduced from Muraro A, et al. European Symposium on Precision Medicine in Allergy and Airways Diseases: Report of the European Union Parliament Symposium (October 14, 2015). Allergy. 2016 71(5):583-7)

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(110) “Precision medicine in patients with al-lergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the Euro-pean Academy of Allergy and Clinical Immu-nology and the American Academy of Allergy, Asthma & Immunology”, published in a highimpact journal (JACI) in 2016 and cited un-tilnow14times.Thepapersummarisesthecurrentknowledgeonasthma,rhinitisandat-opicdermatitisendotypes.Besides reinforc-ingthevalueofasthmaendotypesandsub-endotypes,developedbyIoanaAgacheinthelast decade into a strongvalidated concept,the paper describes innovative aspects onrhinitisandatopicdermatitis(AD)endotypes,buildingonthescaffoldofasthmaintroducedby Ioana Agache. For rhinitis the following

endotypes are being proposed (Figure 25):type2andtype1immuneresponserhinitis,neurogenic rhinitis and epithelial dysfunc-tion.Inclinicalpractice,effortscanbemadeinendotyping rhinitispatientsbymeasuringtotalandspecific IgE,bloodeosinophils,na-saleosinophilsandneutrophils.SeveralotherbiomarkersareusedinresearchsettingssuchasserumIL-5,nasaltotalandspecificIgE,eo-sinophil-derived neurotoxin (EDN), eosino-philcationicprotein(ECP), IL-5,substanceP(SP),neurokinin(NK)-1,IL-33,thymicstromallymphopoietin(TSLP)andstainingofmucosalbiopsies for vanilloid receptor–related tran-sient receptor potential (TRPV-1) channels,zonulla (ZO)-1 or occludin. These biomark-ersshould ideallybesupplementedbynasal

Figure 25Overview of rhinitis phenotypes and endotypes Similar to asthma a type 2 immune response and non-type 2 immune response endotype can be described for rhinitis.Neurogenicandepithelialbarrierdysfunctionendotypesareparticularlyrelevantforrhinitis.(Reproduced from Muraro A, et al. Precision medicine in patients with allergic diseases: airway diseases and atopic dermatitis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347-58)

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function measurements such as nasal flowmeasurement (to confirm nasal obstruction)andcolddryairprovocation(todeterminena-salhyperreactivity),nasalNO(tomeasurena-sal inflammation),nasalallergenprovocation(toconfirmtheclinicalrelevanceofallergens),evaluationofsmellperformance (inpatientsmentioningreducedsmellcapacity).Followingtheexampleofendotype-driventreatmentinasthma,anotherconceptpioneeredbyIoanaAgache,thepaperproposes increasedfocusonendotype-driventreatment inrhinitisex-emplifiedbyallergen-specificimmunotherapy(AIT)inpatientsinwhomanallergen-inducedtype2 immune responseendotype leads toclinicallyrelevantexposure-symptomrelationandbythehighlysuccessfulinterventionwithcapsaicin for theneurogenic endotype.Pre-cisionmedicineisofbroadrelevanceforthemanagementofAD,whichisknowntohavea

diversenaturalhistoryrangingfromcompleteremission,relapsingflarestoverysevereandpersistent forms, variably associated withcomorbidities such as asthma andAR. Bio-markerscouldbeuseful in themanagementofearly-onsetdiseaseatdifferenttimepointsthroughoutthenaturalhistoryofAD(Figure26).Thepaperintroducestheinnovativecon-cept of prognostic biomarkers, valuable forprimaryandsecondaryprevention.

The consensus document also provided es-sentialprecisionmedicinestepsfortheclini-cianandresearcher(Figures27and28).Afteracorrectdiagnosisandpropermanagementof co-morbidities a crucial step is to unrav-elwhich pathophysiologicalmechanism(s) isdrivingthedisease,therebydeterminingtheendotypeofthepatientandprovidevalidatedpathway-specificdiagnostictests.

Figure 26Biomarkers in the management of early-onset disease at different time points throughout the natural history of atopic dermatitis. (Reproduced from Muraro A, et al. Precision medicine in patients with allergic diseases: airway diseases and atopic dermatitis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunol-ogy. J Allergy Clin Immunol. 2016;137(5):1347-58)

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Figure 27Suggested approach to pre-cision medicine in asthma. First correct diagnosis ofasthma should be verifiedand co-morbidities treatedproperly. In a second stepphenotype is establishedbased on visible properties.Further characterization ofthepatients’endotypeiscru-cial to ensure the optimumresponse to treatment andriskprediction,especiallyforsevereanduncontrolleddis-ease. (Reproduced from Mura-ro A, et al. Precision medicine in patients with allergic diseas-es: airway diseases and atopic dermatitis—PRACTALL docu-ment of the European Acade-my of Allergy and Clinical Im-munology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016;137(5):1347-58)

Figure 28Suggested approach to pre-cision medicine in rhinitis. The 4Ps principle of pre-cision medicine is applied:personalisedapproachbasedon disease endotype andbiomarkers, preventive andpredictive aspects and par-ticipationofthepatient.(Re-produced from Muraro A, et al. Precision medicine in patients with allergic diseases: airway diseases and atopic dermati-tis—PRACTALL document of the European Academy of Al-lergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunol-ogy. J Allergy Clin Immunol. 2016;137(5):1347-58)

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Thetermcomorbidityisfrequentlymisappliedifoneacceptsthepreferreddefinition,thatis,acoexistentdiseaseorcondition.Inthiscon-text,comorbidconditionsoccurtogetherbutdo not necessarily influence one another. Incontrast,cliniciansfrequentlyusethetermco-morbiditytodescribeconditionsthatmutuallyaffect theother,assuch interactionscompli-catediagnosis,management,andassessmentmorethancoincidentdiseases.

Asthmacomorbidityreferstoaconditionthatinfluences asthma severity,management, orrecognitionorwhenreferringtoadiseaseaf-fectedbyasthma.Theserelationshipsincludeincreasedseverityofoneorbothdiseases,anincreasedprevalenceofonediseaseasaresultoftheother,asharedpathogenicprocessbe-tweenthetwo,andmisattributionofsharedsymptoms.Sinceasthmahasavariabletimeofonsetandclinicalcourseitscomorbiditieswillvarywithageandclinicalcontext.

Asthmacontrolisbasedpartiallyuponsymp-toms thataresharedor influencedbymanycomorbidconditions.Surveysshowinavari-etyofsettingsthatachievingoptimalasthmacontrolvariesfrom30to70%(111,112).In-dividualswhodonotrespondorrespondin-consistentlytoasthmatreatmentoftenhavecomorbidity.Thesecomorbiditiesmayresultin misdiagnosis, misinterpretation of symp-toms,aggravationofoneorbothdiseases,ordecreased adherence. Recognition of thesecomorbidities facilitates more appropriatetherapyorreductionofpotentiallyriskyther-apies,suchassystemiccorticosteroids(113,114).Comorbiditiesincreasethelikelihoodofpoorly controlled asthma as evidenced by arelativelysmallstudybytenBrinkeetal.Indi-vidualswithaconfirmeddiagnosisofasthmaand frequent exacerbations were surveyedforcoexistingconditions.Theassociationwascalculatedforaspecificcomorbidityandthelikelihoodofmorefrequentasthmaexacerba-tions.Onehundredandthirty-sixindividualscompletedthesurvey.Theoddsratio(OR)ofexperiencinganasthmaexacerbationwasin-

creased10.8-foldbydepression,4.9-foldbyGERD,3.7-foldbyseveresinusdisease,and3.4-foldbyobstructivesleepapnea(115).

Severalco-morbiditiesaredescribedforasth-ma,suchasallergic rhinitis, foodallergy,at-opicdermatitis,gatro-esophagealreflux,obe-sity. In addition, infections, particularly viralinfections, are the major trigger of asthmaexacerbations,bothinadultsandinchildren.Furthermore,lifestylewithdiet,exerciseandsmoking,isastronginfluencerofasthmacon-trolandiskeytoprimaryandsecondarypre-ventionofasthma.

A. ALLERGIC RHINITIS Allergicrhinitisisaglobalhealthproblemthatcausesmajorillnessanddisabilityworldwide.Patientsfromallcountries,allethnicgroupsandofallagessufferfromallergicrhinitis.Itaffectssociallife,sleep,schoolandwork.Theeconomic impact of allergic rhinitis is oftenunderestimatedbecausethediseasedoesnotinduceelevateddirectcosts.However,thein-directcostsaresubstantial.

Usingaconservativeestimate,ARoccurs inover 500 million people around the world.The prevalence of AR is increasing in mostcountriesoftheworld,andparticularlyinar-easwithlowormediumlevelsofprevalence.

Bothallergicrhinitisandasthmaaresystem-ic inflammatory conditions and are oftenco-morbidities.Theprevalenceof asthma inpatientswithrhinitisvariesfrom10%to40%,andupto98%ofasthmaticpatientshaverhi-nitis.The concept of united airways or oneairwaydiseaseissupportedbyexperimental,clinicalandepidemiologicaldata(116-118).

The links between rhinitis and asthma areseveralfolds:

1.5. ASTHMA CO-MORBIDITIES AND ENVIRONMENTAL INFLUENCES

Given the primary focus of Ioana Agache on pediatric and adult asthma research asth-ma comorbidities are an essential compo-nent of the scientific focus of the author.

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a. Bothallergic andnon-allergic rhinitisarerisk factors for asthma (119) and properrhinitis treatment could prevent the de-velopmentofasthma(primaryprevention)

b. The coexistence of rhinitis with asthmaimpairs significantlyasthmacontrol, thusrhinitis control prevents asthma wors-ening (120, 121) (secondary prevention)(Figure29).

A1. Authorship of International Guidelines for AR Afirstmajor achievementwas the inclusionintheauthorpaneloftheAllergicRhinitisanditsimpactonAsthma(ARIA).TheAllergicRhi-nitisand its ImpactonAsthma (ARIA)2008updatewaspublishedin2008intheAllergyjournal (19) and was cited until now 7012times.

TheARIAguidelinesprocessstartedin1999andwasintendedtobeastate-of-the-artforthespecialistaswellasforthegeneralprac-titioner and other healthcare professionals(HCP):

• Toupdatetheirknowledgeofallergicrhi-nitis;

• Tohighlighttheimpactofallergicrhinitisonasthma;

• Toprovideanevidence-baseddocument-edrevisionondiagnosticmethods;

Figure 29Links between asthma and rhinitis severity.Amodelhasbeenproposedtoillustratetherelation-shipbetweenallergicrhinitisandasthmaseverity.Thebasicprincipleisthatthetwoconditionsaremanifestationsofonesyndromeintwopartsoftherespiratorytractandthatthemoreseveretherhinitis,themoreseveretheasthma.(Reproduced from Bousquet J, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63 Suppl 86:8-160)

Thus, as a major co-morbidity of asthma, al-lergic rhinitis represented a special focus of the research of Ioana Agache, from interna-tional guidelines authorship to epidemiolo-gy of the disease and risk factors, new treat-ments for AR evaluated both in randomized control trials (RCT) and real-life scenarios and new models of care.

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• Toprovideanevidence-basedrevisionontreatmentsand

• Toproposeastepwiseapproachtoman-agement.

In 1999, during theARIAWorldHealthOr-ganization(WHO)workshop,thesuggestionsweremadebyapanelofexpertsandbasedonevidenceusinganextensivereviewoftheliterature available up to December 1999(122).Thestatementsofevidenceforthede-velopmentoftheseguidelinesfollowedWHOrulesandwerebasedonthoseofShekelleetal(123).

ARIA2008revisionaimedto:

• Develop an evidence-based global doc-ument (Figure 30) on a key problem ofrespiratorymedicine including diagnosis,epidemiology,commonriskfactors,man-agementandprevention;

• Propose educational materials for HCPandpatients

• Meet theobjectivesof theWHOGlobalAllianceagainstChronicRespiratoryDis-eases (GARD;29) in order tohelp coor-dinate theeffortsof thedifferentGARD

organizationstowardsabetterpreventionand management of chronic respiratorydiseases(CRDs),toincreaseCRDsaware-nessandalso tofill someof thegaps inknowledge;

• Focus on the prevention of chronic res-piratoryandallergicdiseases

• Highlightgaps inknowledge,particularlyindevelopingcountriesanddeprivedar-eas

• Prepareanexecutivesummaryandpock-etguidefordoctors,patientsandhealth-careprofessionals

Theauthorhada special focus indeliveringthe recommendations for evaluation andmanagementofasthma inpatientswithAR.Aneasytofollowalgorithmisprovided(Fig-ure31).

ARIA isaguidelineforpublichealth.Guide-lines are documents that synthesize currentevidenceonhowtomosteffectivelyorganizeanddeliverhealthservicesforagivencondi-tion.Theyinformhealthcaredecision-makingand can serve as the basis for policy, plan-ning, evaluation, and quality improvement.

Figure 30Development of guidelines.Clinicalrecommendationsonefficacyareevaluatedversussafetydata,healtheconomicsandreallifeinput(effectiveness)inordertoformulatethefinalrecommendationforanintervention.(ReproducedfromBousquetJ,etal.MACVIA-ARIASentinelNetworKforallergicrhinitis(MASK-rhinitis): the new generation guideline implementation. Allergy. 2015;70(11):1372-92)

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Whennewlydeveloped,orwhenevaluationidentifiessuboptimalcompliance,effortsareneeded to promote awareness, acceptance,adoption,andadherencetoguidelines.Suchefforts include dissemination (posting on aweb site, publishing in a journal, presentinginformation at a meeting) or implementa-tion (purposeful strategies that employ ed-ucational, social, organizational, financial ortechnologicalmeans of promoting guidelineuse.Many issues challenge guideline imple-mentation.Avarietyofcontextualfactorsatthe individual, institutional and system lev-el often co-exist and pose significant chal-lengestoguideline implementationanduse.Promotional efforts by guideline developersmay be constrained by lack of resources soimplementationisoftentheresponsibilityoftarget users. Regardless of whether imple-mentation is undertaken by developers orusers,implementationisfurthercomplicatedby two key factors. One,while instruments

exist to assess barriers of guideline use, ororganizationalcapacityorreadinesstoadoptguidelines, thesedonot reliably identifythemost appropriate implementation strategyfor a given guidelines.Two, implementationplanning most often occurs upon guidelinecompletion. Implementation could be moresuccessfulifplanningwereconcurrentratherthan consecutive to guideline developmentsothattherecommendationswereclearanduseable, targetuserswereprimedforadop-tion, and their needs and preferences, andinsightoncontextualfactorscouldinformim-plementationplanning.Thismayalsoreducethetimerequiredforguidelinestobeadoptedintopolicyorpracticebyavoidinga lengthywaitingperiodfromguidelinecompletiontoimplementation planning, and actual execu-tionof implementationactivities.Recentlyachecklist for guidelines implementationwaspublished(124).

Figure 31Diagnosis of asthma in patients with rhinitis.Twoclinicalscenarios(withorwithoutanasthmadiagnosis)areprovided inordertoassessthepresenceofasthmaorthecontrolofthediseaseimpactedbytherhinitisassociation.(ReproducedfromBousquetJ,etal.AllergicRhinitisanditsImpactonAsthma(ARIA)2008update(in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63 Suppl 86:8-160)

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After itspublicationARIAguidelinewas fol-lowedby tremendousefforts fordissemina-tion and implementation. Immediately afteritsrelease,alocaladaptationforRomaniawaspublished in 2009 by IoanaAgache as firstauthor (125).Aconsecutivepaperpublishedin Allergy in 2010 (126), cited 89 times topresent.Inthesepaperstheauthors,includ-ing IoanaAgache, thoroughly describe howARIA recommendations were formulated inorderto improveunderstandingandaccept-ancebyallstakeholders.Mostpatientswithrhinitisandasthmaconsultprimarycarephy-siciansandpharmacistsand therefore theseHCPareencouragedtounderstandanduseARIA guidelines. Patients should also be in-formedabout theseguidelines to raise theirawarenessofoptimalcareandincreasecon-trol of the two related diseases. To applytheseguidelines,cliniciansandpatientsneedtounderstandhowandwhytherecommen-dations were made. The goal of the ARIAguidelines is to provide recommendationsaboutthebestmanagementoptionsformostpatientsinmostsituations.Theserecommen-dationsshouldbebasedonthebestavailableevidence.Makingrecommendationsrequiresthe assessment of the quality of availableevidence, deciding on the balance betweenbenefitsanddownsides,considerationofpa-tients’ values and preferences, and, if appli-cable,resourceimplications.Guidelinesmustbeupdatedasnewmanagementoptionsbe-come available or important new evidenceemerges.Transparentreportingofguidelinesfacilitatesunderstandingandacceptance,butimplementation strategies need to be im-proved.

TheARIAguidelinewasreviewedin2010andin2016andonbothoccasionsIoanaAgachewaspartoftheExpertPanel.

The2010review (100)presentsrecommen-dationsabout thepreventionofallergicdis-eases,theuseoforalandtopicalmedications,allergen specific immunotherapy, and com-plementarytreatmentsinpatientswithaller-gicrhinitisaswellaspatientswithbothaller-gic rhinitis and asthma.The guideline paneldevelopedevidenceprofilesforeachrecom-mendation and considered health benefitsandharms,burden,patientpreferences,andresourceuse,whenappropriate,toformulate

recommendationsforpatients,clinicians,andotherhealthcareprofessionals.

BoththeExecutiveSummaryandthefulltextofthe2016revisionhavebeenrecentlysub-mitted(127).Theobjectiveofthe2016docu-mentistoprovideatargetedrevisionoftreat-mentoptionsinAR.TheARIAguidelinepanelidentifiednewclinicalquestionsandquestionsthat required an update: nasal and ocularsymptoms,qualityoflife,work/schoolperfor-mance, and adverse effects. We performedsystematic reviews of health effects and re-viewedtheevidenceaboutpatientvaluesandpreferences, and resource requirements (upto June 2016).We followed the Grading ofRecommendationsAssessment,DevelopmentandEvaluation(GRADE)evidencetodecisionframeworkstodeveloprecommendations.Welabeledtherecommendationsaseither“strong”or “conditional”according to theGRADEap-proach.Weusedthewords“werecommend”forstrongrecommendationsand“wesuggest”for conditional recommendations. Table 12provides suggested interpretation of strongand conditional recommendations.TheARIAguideline 2016 revision provides recommen-dationsabouttheuseof1)acombinationoforalH1-antihistamineandintranasalcorticos-teroidvs. intranasalcorticosteroidalone,2)acombination of intranasal H1-antihistamineand intranasal corticosteroid vs. intranasalcorticosteroid alone; 3) a combination of anintranasalH1-antihistamineandanintranasalcorticosteroidvs. intranasalH1-antihistaminealone,4)aleukotrienereceptorantagonistvs.oralH1-antihistamine,5)anintranasalH1-an-tihistamine vs. an intranasal corticosteroid,and 6) an intranasal H1-antihistamine vs. anoralH1-antihistamineintreatmentofallergicrhinitis.

TheimpactofARIAguidelineswasevaluatedin2012(20).TenyearsafterthepublicationoftheARIAWHOworkshop report theguide-lineisdisseminatedandimplementedinmorethan50countriesoftheworldanditsrecom-mendationsareincludedinseveralguidelinesrecommended by governments (e.g. BrazilandSingapore)orscientificsocieties.GlobalapplicabilityofARIAishighlightedintermsofmanagementinclinicalpractice,personalisedmedicine, usability by all stakeholders (pa-tients, primary care physicians, pharmacists,

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otherHCPs),inallcountries(includinginde-veloping countries), for research and clinicaltrials design, for public health planning, fordevelopingnewdrugsandforregistrationofmedicinesandreimbursement.Unmetneedsand future research arediscussed, includingdisease phenotyping and endotyping in thecontextofunitedairwaysdisease(rhinitisandasthma) and control of the disease. Controlandseverityarenotwelldelineatedinrhini-tisastheyareforasthma.Severaltoolsweresuch as symptom scores, visual analoguescale(VAS)andpatients’reportedoutcomessuchasquality-of-lifequestionnaires.Scoreswithseveralitemshavebeenproposed(128).It appears in rhinitis that a simple measuresuchasVASmaybesufficient toappreciatethe control of the disease (129) and is par-ticularlyrelevanttoprimary(130)orpharma-cycare(131)andtothefollowupofpatients.Thelevelofcontrolofallergicrhinitisisinde-pendentofthetreatmentstep(132).

Unifyingboththeneedtoassesdiseaseen-dotypes and severity/control assessmentthe author introduced in 2012 as part of aMeDALL–GA2LEN–ARIA consortium posi-tionpaper(15)theconceptofseverechronic

allergic(andrelated)diseases(SCUAD).Con-ceptsofdiseaseseverity,activity,controlandresponsiveness to treatment are linked butdifferent.Severityreferstothe lossoffunc-tionoftheorgansinducedbythediseasepro-cessortotheoccurrenceofsevereacuteex-acerbations.Severitymayvaryovertimeandneedsregularfollow-up.Controlisthedegreetowhichtherapygoalsarecurrentlymet.TheSCUADconceptgeneralizedtheapproachoftheuniformdefinitionofsevereasthmapre-sentedtoWHOforchronicallergicandasso-ciateddiseases (rhinitis, chronic rhinosinusi-tis,chronicurticariaandatopicdermatitis)inordertohaveauniformdefinitionofseverity,control and risk, usable in most situations.SCUAD concept is based on the appropri-atediagnosis,availabilityandaccessibilityoftreatments, treatment responsiveness andassociatedfactorssuchascomorbiditiesandrisk factors (Figure 32).This uniformdefini-tionallowedabetterdefinitionofthepheno-typesofsevereallergic(andrelated)diseasesfor clinical practice, research (including epi-demiology), public health purposes, educa-tionandthediscoveryofnoveltherapies.Thepaperforcited50timessinceitspublication.

Table 12Strength of recommendation. (Adapted from Brożek JL, Bousquet J, Agache I, Agarval A, Bachert C, Bosnic-Anticevich S et al. Allergic Rhinitis and its Impact on Asthma (ARIA) – 2016 Revision. Submitted)

Strong recommendation

For patients:mostindividualsinthissituationwouldwanttherecommendedcourseofaction,andonlyasmallproportionwouldnot.

For clinicians:mostindividualsshouldreceivetheintervention.Adherencetoastrongrecommendationcouldbeusedasaqualitycriterionorperformanceindicator.Formaldecisionaidsarenotlikelytobeneededtohelpindividualsmakedecisionsconsistentwiththeirvaluesandpreferences.

For health care policy makers:therecommendationcanbeadoptedaspolicyinmostsituations.

Conditional recommendation

For patients:themajorityofindividualsinthissituationwouldwantthesuggestedcourseofaction,butmanywouldnot.

For clinicians:recognizethatdifferentchoiceswillbeappropriateforindividualpatientsandthatyoumusthelpeachpatientarriveatamanagementdecisionconsistentwithhisorhervaluesandpreferences.Decisionaidsmaybeusefulinhelpingindividualstomakedecisionsconsistentwiththeirvaluesandpreferences.

For health care policy makers:policy-makingwillrequiresubstantialdebateandinvolvementofvariousstakeholders.

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A2. New models of care for AR EffectivestrategiesareneededtoreduceCRDburden.Nationalprogrammes(e.g.theFinn-ish, Czech or Portuguese asthma or COPDprogrammescanbecost-effective(133),buttheyareinsufficientlyimplementedintheEU.Integrated care pathways (ICPs) for COPDexist intheUnitedKingdom(UK)developedbytheNationalInstituteforHealthandCareExcellence(NICE)(134),inFrance(HauteAu-toritédeSanté)andintheNetherlands(135),butICPsforasthmaorasthmaandrhinitisco-morbiditydonotexist.Asthmaqualitystand-ardsforasthmahavebeenpublishedbyNICE.These are specific, concise statements thatactasmarkersofhigh-quality,cost-effectivepatient care.Moreover, some initiatives areaimedatalsoincentivisinggoodpracticeandimproving implementation(i.e.remunerationbasedonperformanceindicators).IntheUK,

the Quality and Outcomes Framework hasfourasthma-specificperformanceindicators,whichareexplicitlylinkedtothesubsequentremuneration of providers. In low-resourcesettings, some successful attempts to com-bine all non-communicable diseases (NCDs)into one single action plan have been de-veloped(136)fortheimplementationoftheWHONCDsactionplan.However,suchcom-binedplansarenotavailableforthemanage-mentofNCDsinhigh-resourcesettings.

The Polish Presidency of the EU Council(3051st Council Conclusions) has made theprevention, early diagnosis and treatmentof asthmaandallergicdiseases apriority toreduce health inequalities (137, 138). The3206th Cyprus Council Conclusions recom-mendedthatthediagnosisandtreatmentofchronic diseases should be initiated as ear-lyaspossible to improveactiveandhealthy

Figure 32Uniform approach to the definition of severe allergic (and related) diseases. Severeallergic(andrelated)diseasesinclude7groups(highlightedinyellow),eachcarryingdifferentpublichealthper-spectivesandchallenges.(ReproducedfromWHOCollaboratingCenterforAsthmaandRhinitis,BousquetJ,etal.Severechronicallergic (and related) diseases: a uniform approach--a MeDALL--GA-2LEN--ARIA position paper. Int Arch Allergy Immunol. 2012;158(3):216-31.)

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ageing(139).AdebateattheEuropeanPar-liament(CyprusPresidencyoftheEUCoun-cil,2012) recommendedearlydiagnosisandmanagementof chronic respiratorydiseasesin children in order to promote active andhealthyageing(140).

Ioana Agache is a member of Expert PanelTheEuropeanInnovationPartnershiponAc-tive andHealthyAgeing (EIP onAHA).Thisconsortium developed the concept of inte-grated care pathways for airway diseases(AIRWAYS-ICPs).Thepaper(22),publishedin2014intheEuropeanRespiratoryJournalwascited45timessinceitspublication.Thegen-eralobjectiveofAIRWAYS-ICPsistodevelopmulti-sectoralICPsforCRDsusedacrossEu-ropeancountriesandregionsinorderto1)re-ducetheburdenofthediseases,2)promoteactiveandhealthyageing,and3)createacarepathwayssimulatortoolwhichcanbeapplied

inolderadults.AIRWAYS-ICPswillnotdupli-cate existing EU prevention programmes inchronic respiratory diseases (e.g. anti-smok-ing) butwill strengthen themwhere appro-priate.The specificaimofAIRWAYS-ICPs isto propose central unifying themes and anoverallpotential togainpolitical leverage inthecurrentenvironmentandtobetterunder-stand andmanage the spectrumof care forpatients with CRDs in European countriesandregions.Itwillalsoaimtogeneralisetheapproachtotheuniformdefinitionofseveri-ty,controlandriskofsevereallergicdiseases(131),inordertodevelopuniformriskstrat-ificationusable forCRDs inmostsituations.AIRWAYS-ICPsproposedafeasible,achieva-bleandmanageableproject fromscience toguidelines(Figure33)usingexistingnetworksandpartnerscommittedtoActionPlanB3oftheEIPonAHA.

Figure 33From science to guidelines and best practices using ICPs.ICPsarestructuredmultidisciplinarycareplansfocusingonthequalityandco-ordinationofcarewhichdetailessentialstepsinthecareofpa-tientswithaspecificclinicalproblem.Theypromotethetranslationofguidelinesintolocalprotocolsandtheirsubsequentapplicationtoclinicalpracticeandempowerpatientsaswellastheirhealthandsocialcarers.Cliniciansarefreetoexerttheirownprofessionaljudgmentsasappropriate.However,anyalterationtothepracticeidentifiedwithintheICPmustbenotedasavariance.VarianceanalysismaybeusedtooptimisetheICPslinkedwithpay-for-performance,auditandfeedback,andinte-grationofrecommendationswithelectronicmedicalrecords.(Reproduced from European Innovation Partnership on Active and Healthy Ageing, Action Plan B3; Mechanisms of the Development of Allergy, WP 10; Global Alliance against Chronic Respiratory Diseases, Bousquet J, Addis A, Adcock I, Agache I, et al. Integrated care pathways for airway diseases (AIRWAYS-ICPs). Eur Respir J. 2014;44(2):304-23)

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SeveralunmetneedshavebeenidentifiedinAR:identificationofthetimeofonsetofthepollenseason,optimalcontrolofrhinitisandcomorbidities,patientstratification,multidis-ciplinary team for integratedcarepathways,innovationinclinicaltrialsand,aboveall,pa-tientempowerment.AnewconsortiumMASK(MACVIA-ARIASentinelNetworKforallergicrhinitis)studygroupwascreated(withIoanaAgacheasamemberoftheExpertPanel)totackletheseunmetneeds.Oneofthefirstde-liverables(21)oftheconsortium(MASK-rhi-nitis) is a simple systemcentredaround thepatient which was devised to fill many ofthesegapsusingInformationandCommuni-cationsTechnology (ICT) tools and a clinicaldecisionsupportsystem(CDSS)basedonthemostwidely used guideline in allergic rhini-tisanditsasthmacomorbidity(ARIA).Threetools areused for theelectronicmonitoringofallergicdiseases:acellphone-baseddailyVAS assessment of disease control, CARAT(ControlofAllergicRhinitisandAsthmaTest)and e-Allergy screening (premedical systemofearlydiagnosisofallergyandasthmabasedon online tools). These tools are combined

withCDSSandareavailableinmanylanguag-es.Ane-CRFandane-learningtoolcompleteMASK.MASKisflexibleandothertoolscanbeadded.Itappearstobeanadvanced,glob-alandintegratedICTanswerformanyunmetneedsinallergicdiseaseswhichwillimprovepoliciesandstandards.TheCDSSiscurrentlybeingtestedinclinicaltrials(141).

A3. New treatments for AR Ioana Agache’s interest in AR and asthmabroughtherresearchattheforefrontoftest-ingnewdrugsforthesediseases.

In2008anovel, selective long-actinghista-mine H1 receptor inverse agonistwith antiPAF activity, rupatadine, was evaluated inseveral clinical trials. The paper (142) pub-lished inAllergy in2008andcited 46 times sinceitsappearancereportsonarandomised,double-blind, parallel-group, placebo-con-trolled and multicenter study showing thatrupatadinesignificantlyrelievessymptomsofperennialAR,providinga rapidonsetof ac-tionandmaintainsitseffectsoveralongpe-riodof12-weeks(Figure34).Rupatadine10

Figure 34Serial time profile over 12 weeks of the instantaneous Total Nasal Symptom Score (iTNSS) mean change from baseline. Significant improvements at p < 0.05 level were seen in both treatments (x) and only with rupatadine alone (xx) in comparison with placebo. (Reproduced from Fantin S, et al; in-ternational Rupatadine study group. A 12-week placebo-controlled study of rupatadine 10 mg once daily compared with cetirizine 10 mg once daily, in the treatment of persistent allergic rhinitis. Allergy. 2008;63(7):924-31)

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mgpresentedahigherefficacycomparedtocetirizineinallcontrolscarriedout(4,8and12weeks),whichcouldbeexplainedby theadditional and sustained anti-inflammatoryeffect.Aclearimprovementinrupatadine10mgvsplacebowasobservedafter24hofthefirstdose,indicatingafastonsetofactionofthis drug in symptoms relief. This improve-mentwaspreviouslyreportedinpatientswithseasonalARwhere theauthors suggestedafastereffectthancetirizine inthecontrolofsymptoms(143).Inanotherrandomised,dou-ble-blind, parallel-group, placebo-controlledand multicenter study Ioana Agache alsoinvestigated the efficacy of rupatadine ver-sus desloratadine in seasonal AR (144) andshowedthatrupatadineisaverygoodchoiceforseasonalARduetoitscontributiontotheimprovement of nasal and non-nasal symp-tomstoasimilardegreeasdesloratadine.

Another novel antihistamine, bilastine, wastested versus cetirizine by IoanaAgache aspart of a randomized, double-blind, paral-lel-group study, in adults with seasonal AR(145).Bilastine20mgoncedailywassignif-icantly superior to placebo and comparabletocetirizine10mginrelievingsymptomsofseasonalAR,althoughitdemonstratedasig-nificantly better adverse events profile thancetirizine.Thepaperwascited 61 times sinceitsappearance.

Providing more effective pharmacologicaltherapies is needed to achieve AR control.Second generation anti-histamines with lit-tle or no sedative effects were evaluated,andnewintranasalcorticosteroids(INS)withlower systemic bioavailability (compared totheolderINS),butwithcomparableefficacy,provided.IncreasingthedoseofINSprovid-ednoadditionalsymptomaticbenefitduetotheflatnatureoftheirdoseresponsecurves.Indeed, an INS efficacy threshold has nowbeen established (146). Although, multipleAR therapyusage iswidespread throughoutEurope (147) adding oral antihistamines orleukotrienereceptorantagoniststoINSpro-vided little or no symptomatic benefit overINSmonotherapy(148,149).

The combination between an intranasal an-ti-histamine (azelastine hydrochloride) andanINS(fluticasonepropionate)deliveredasa

novelformulationinasinglespray(MP-AzeF-lu)isanewdrugforAR.Resultsfromwell-de-signedRCTsshowedthatpatientswithmod-erate-to-severe seasonal AR treated withMP-AzeFluexperienceda rapidonsetof re-lief (i.e.30mins)andtwicetheoverallnasalandocularsymptomreliefofanINSorintra-nasal anti-histamine (146). Moreover, moreMP-AzeFlu patients experienced complete/near to complete symptom relief andmanydays faster than thoseonfluticasonepropi-onate monotherapy (146, 150). In addition,MP-AzeFluhasasustainedeffect,supportingcontinuous usewith improved concordanceandhasestablisheditseffectivenessinalargemulticenter non-interventional study (151).As part of the European investigators teamIoanaAgache assessed the effectiveness ofMP-AzeFlu on achievingAR control in rou-tineclinicalpracticeacrossEurope(152).ARcontrolwasassessedusingaVAS,inlinewithMACVIA ARIA, REG and EAACI initiatives.2988patients(≥12years)withARIA-definedmoderate/severeARfromGermany,Sweden,Romania,UK,DenmarkandNorwaywerein-cluded. Patients assessed symptom severityusingaVASfrom0mm(notatallbothersome)to 100mm (very bothersome) onDays 0, 1,3,7,and lastvisit (~Day14) in themorningbefore MP-AzeFlu-use. Patients’ perceivedlevelofdiseasecontrolwasassessedonDay3.AVASscorecut-offonDay3for‘well-con-trolled’ARwasdeterminedand thepropor-tionofpatientswhoachieved this responsecalculated.MP-AzeFlutreatmentwasassoci-atedwithVASscorereductionfrom73.7mmat baseline to23.4mmby lastvisit.This re-ductionwas significant (p<0.001) comparedto baseline fromDay1 (fast relief of symp-toms),andsustaineduntillastday(Figure33).Byday3,50.3%ofpatientsconsideredtheirsymptoms ‘well-controlled’. 18.2%, 40.0%,66.6% and 75.9% of patients achieved the<38mm ‘well-controlled’ VAS score cut-offondays1,3,7and14,respectively.There-sults were consistent across countries, age,AR phenotype and severity (Figures 35 and36).Thesedataareavaluableadditiontothereal-lifeevidencebase,andconfirmtherap-idandsustainedeffectivenessofMP-AzeFluunderconditionsofroutinecarearoundEu-rope,complementingtheevidencegatheredin RCTs. The effectiveness observed in this

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real-life study was better than the efficacyreportedinRCTs,whereMP-AzeFluprovidedcomplete/nearcompletesymptomcontrolin1of6moderate/severeSARpatientsbyDay14andcompletereliefin7of10mild-to-mod-eratePARpatientsinthefirstmonth,achiev-ingtheseresponsesaboutaweekfasterthananINS.

The generalisability of MP-AzeFlu data de-rived from clinical studies to the Romani-an population is unknown. The aim of thenon-interventionalstudyconductedbyIoanaAgache(153)wastoassesstheeffectivenessofMP-AzeFlu inachievingARcontrol in re-al-lifeclinicalpractice inRomania,using theVAS, in linewithMACVIA-ARIA andEAACI

Figure 35Effect of MP-AzeFlu on visual analogue scale (VAS) score over time in (A) the total population (n=2656) and (B) according to baseline severity. Lesssevere:baselineVASscore50-74mm(n=1129),moresevere:baselineVASscore75-100mm(n=1398).Datapresentedasmeanandstandardde-viationforthepooleddata. (Reproduced from Klimek L, et al. MP-AzeFlu provides rapid and effective allergic rhinitis control in real life: A pan-European study. Allergy Asthma Proc. 2016;37(5):376-86)

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recommendations.Themulticenterstudy in-cluded253patients≥12yearsold.MP-Aze-Flu provided rapid, effective and sustainedAR symptomcontrol. Furthermore,8outof10 patients treatedwithMP-AzeFlu in rou-tine clinical practice crossed the well-con-trolled zone by end of treatment (i.e. VASscore≤38mm).Of note the results of this

study inRomaniashowedabettersymptomcontrolcomparedtotheotherreal-lifestud-ieswithMP-AzeFluconductedinScandinaviaandGermany.Forexample,themeanchangefrombaselineinVASscoreinourstudywas63.6mm,higher than that reported inSwe-den(36.1mm),Denmark(38.8mm),Norway(30.8mm)andGermany(54.1mm).

Figure 36Effect of MP-AzeFlu on visual analogue scale (VAS) score over time according to (A) allergic rhi-nitis phenotype and (B) age. Datapresentedasmeanandstandarddeviationforthepooleddata.(Reproduced from Klimek L, et al. MP-AzeFlu provides rapid and effective allergic rhinitis control in real life: A pan-European study. Allergy Asthma Proc. 2016;37(5):376-86)

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A4. Epidemiology of AR Data collected from patients during thePan-European real life study (152) prior toMP-AzeFluprescriptionhighlightedthehighburdenofAR aroundEurope, and the needfor a more effective pharmacological ther-apy.The societal burdenofARwas evidentfromthehighphysicianconsultationrate(2.2times/calendar year) and frequency of po-ly-pharmacy practices,with over two-thirdsof patients reporting use of multiple thera-pies,whichisneitherrecommendednorprov-en.Bothofthesepracticesinflatecostsasso-ciatedwiththeARmanagementandindicatedissatisfactionwiththerapy,acommonfind-ingfromotherARsurveys.ThesymptomaticburdenofARwasevidentnotonlyfromhighbaseline VAS scores reported despite mul-tiple therapyusebymanypatients,butalsothe high frequency of troublesome symp-toms,activityimpairment,sleepdisturbance,and incidenceofocularsymptoms reported,whichcanimpairpatients’qualityoflifetoagreater degree thannasal congestion.Nasalcongestionwasreportedby1inevery2pa-tients, and associated with a high reporteduseofdecongestants(oralorintranasal,bothof which carry significant adverse effects).Anothermedicationwithpotentsideeffects,systemiccorticosteroids,wasusedpreviouslyin1of8subjects,torelieveseveresymptomsandunblockthenose.

TheburdenofARwasalsohighlightedbytheRomanianMP-AzeFlustudy (153).Asa sec-ondary end-point the study collected dataontheprevalenceofmoderate/severeARinRomania(wherethelatestpublicationsonARepidemiologyarefrom1998)andtheuseofallergen specific immunotherapy (AIT). Themean VAS score at baseline was 78.4 mm,showingnotonlythehighsymptomaticbur-denexperiencedby thesepatients,but alsothe inadequate symptom relief provided bypreviously used AR treatments. The latterwasconfirmedbythehighdegreeofpolyp-harmacy noted (85.0%), higher that that re-ported in other countries, and the fact thatover three-quartersofphysiciansprescribedMP-AzeFlu as otherAR therapieswere notsufficient in the past. Interestingly, almost30%ofphysiciansprescribedMP-AzeFlufirstline,whentheyconsideredthatotherthera-

pieswouldbeinsufficienttotreatacutesymp-toms.Over60%ofpatientshadmademulti-plevisitstotheirphysicianduetoARinthecurrentcalendaryearemphasisingtheburdenuncontrolled disease has on healthcare sys-tems. The study also showed the very lowusageofAITformoderate/severeAR(n=30,11.9%)highlightingtheneedtoincreasetheknowledgeofthephysiciansontheAITdis-ease-modifyingbenefits

A5. AR as a risk factor for asthmaAsthmaandARarecomorbidconditions,withAR being amajor risk factor for the occur-renceof asthma and lackof asthma control(111,113,117).However,therearefewerandlessconvincingdataontheriskofdevelopingasthmainseasonalAR.Also,therearenodataontheclinicalphenotypesofasthmaassoci-atedwithSAR.Theseaspectswereevaluat-edbyIoanaAgacheinthepaperpublishedin2010 (39) and communicated at theAAAAIAnnualMeeting(154).Thestudyenrolled33children (meanage8.27±1.77years)and82adults (meanage34.12±10.59years)withseasonalAR. Study subjectswere evaluatedforasthma (history, reversibilityofbronchialobstruction, increasedFeNO).The followingasthma risk factors were considered in themultipleregressionanalysis:malesex,familyhistoryofasthma,breastfeeding<2months,passive/activesmoking,obesity,pets/mouldsexposure,hightotalserumIgE,polysensitised(sensitisedto3seasonalpollenswithdifferentstructure),mixed sensitisation (seasonal andperennialallergens),severerhinitis(ARIA)andlackofAIT for rhinitispreceding asthmadi-agnosis.Asthmaphenotypeswerecharacter-isedusingthek-meansclustering(silhouettemethod for cluster validation). Asthma wasdiagnosed in 22 (66.7%) children and in 57(69.5%) adultswith seasonalAR. Independ-ent risk factors forasthmawere lackofAITprecedingasthmadiagnosisbothforchildren(p=0.008132) and adults (p=0.000017) andmixedsensitisationforchildren(p=0.035694).Asthma phenotypes identified in children(Figure37A)accordingtotheassociatedriskfactorswere:breastfeeding<2monthsandsevererhinitis in16(63.6%)subjects;male,polysensitisedandsevererhinitisin8(36.4%)subjects.Asthma phenotypes in adults (Fig-

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ure37B)polysensitisedandsevererhinitisin30(52.6%)patients,male,exposuretopetsand severe rhinitis in 11 (19.3 %) patients,hightotalserumIgEandpolysensitisedin16(28.1%)patients.

Thisstudydemonstratedthatasthma is fre-quently associated with seasonal AR, withseasonal AR preceding the development ofasthma.The incidenceofasthma inpatientswith seasonal AR observed in this study ishighlysignificant(66.7%inchildrenand69.5%inadults)andveryclosetotheincidencecit-edforasthmainpatientswithpersistentAR(122). Inall thecasesseasonalARprecededasthma appearance. Being a cross-section-alstudywecannothoweverfirmlyconcludethatseasonalARisperseariskfactorforde-velopingasthma.Ourresultsclearly indicatelackofAITisariskfactorforasthmabothinadultsandinchildrenwithseasonalAR.Theseresultsareinconcordancewithaprospective10-yearstudy,whichprovedtheroleofAITinchildrenwith seasonalAR inpreventing theappearanceofasthma(155).Preventingasth-macouldbeanotherbenefitofAIT intreat-

ingARapartfromthepotentialforearlyandsignificant cost savingsby reducingmedica-tionandhealthcareresourceutilization(156).Until this study no data existed on the po-tentialofAITofpreventingasthmainadultswithARandourstudyprovedthatlackofAITwasanindependentriskfactorforasthmainadultswithseasonalAR.This isafirststudydescribingasthmaphenotypes inadultsandin childrenwith SAR according to the asso-ciated risk factors forasthma.Thepresenceofshortornobreastfeedingasaphenotypictraitofasthma inchildrenwithseasonalARis in concordancewith other studies identi-fyingbreastfeedingasaprotectivefactorforthe appearance of asthma (157, 158, 159,160,161).TheotherphenotypeofasthmainchildrenwithseasonalARassociatesmalesexand polysensitisation, both clearly demon-stratedasriskfactorsforasthmainchildren(122,158,162,163).Severerhinitis ispres-ent in both phenotypes and is also demon-stratedasariskfactorforasthma(122,134).Inadultssevererhinitisandpolysensitisationareencountered intwooutofthreeasthma

Figure 37Cluster means for seasonal AR and asthma in children (A) and adults (B). Asthmaphenotypesidentified inchildrenwere:breastfeeding<2monthsandsevererhinitis in63.6%subjectsandmale,polysensitisedandsevererhinitisin8(36.4%)subjects.Asthmaphenotypesinadultswerepolysensitisedandsevererhinitisin52.6%patients,male,exposuretopetsandsevererhinitisin19.3%patients,hightotalserumIgEandpolysensitisedin28.1%patients. (Reproduced from Agache I, Ciobanu C. Risk factors and asthma phenotypes in children and adults with seasonal allergic rhinitis. Phys Sportsmed. 2010;38(4):81-6)

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phenotypes. While severe rhinitis is clear-ly demonstrated as adefinite risk factor forasthmainadults,polysensitisationislessclearcutrelatedtotheriskofasthma,asitischil-dren,althoughastudyshowedthatincreasedtotal serum IgE is a risk factor for asthmaonlyinthepresenceofspecificsensitisation(164). In another study atopy increased theriskofnewlyonsetasthmainadultsby12to21%,with total serum IgE and sensitisationtocatbeingindependentpredictorsforasth-ma(165).Thepresenceofmalesexasariskfactordescribinganadultasthmaphenotypeis surprising since it isknown thatafterpu-bertyasthmaismorefrequentandmorese-vereinfemales.Howevernoneofthestudiesdemonstratingfemalesexasariskfactorforasthma included patients with seasonal ARandasthma.Exposuretopetsasaphenotyp-ictraitofasthmainadultswithseasonalARisalsosurprisingly.While inchildren therearemanycontroversies(166,167,168),noneofthe studiesevaluatedexposure topets as ariskfactorfordevelopingasthmainadults.

B. LIFESTYLE (DIET, OBESITY, EXERCISE) AND ASTHMAInthelastfewdecades,Europehaswitnessedadramaticincreaseintheburdenofasthma(bothmetabolicandallergy-inducedasthma),which has now reached pandemic propor-tions.Asthmacurrentlyaffects70millionciti-zensintheEuropeanUnion,ofwhom30mil-lionarechildrenoradultsaged lessthan45years.Theprevalenceofasthmahasparticu-larlysoaredinchildrenandyoungstersundertheageof15.Today,asthmarepresentstheleading chronic disease in childhood acrossEuropeandistheprincipalcauseofemergen-cyhospitalvisits andadmissionamongchil-dren(8).Thistrendhasbeenaccompaniedbynoticeablechangesinlifestyle.Improvedac-cesstotechnologyanddevelopmenthaveledtoamoresedentarylife.Easieraccesstofoodandashiftintheeatingpatternsfromnatu-rallysourcedtoprocessedfoodhavebeenac-companiedbyareducedintakeoffreshfruitsand vegetables, less fibre, and an increasedintakefoodsrichinrefinedsugar.

In parallel the proportion of children andyoungsterswho are overweight or obese in

Europe isworryinglyhighandconstantly in-creasing.AccordingtotheWorldHealthOr-ganization,around1 in3children in theEUaged6–9yearswere affectedbyobesityorexcessweightin20102comparedwith1in4childrenin2008.Globallyitisestimatedthatthenumberofchildrenagedunder5whoareoverweightwillrisefrom41milliontodayto70millionby2025.Thisconstitutesamajorpublichealthconcernasobesityisdirectlyas-sociatedwithan increasedriskofnumerouschronicdiseases(169).

Numerous epidemiological studies havedemonstratedtheassociationbetweenobe-sity and asthma. Obese children and adultsareatan increasedriskofasthmaandasth-ma-likesymptoms,withaproportionaterela-tionshipbetweenincreasingbodymassindex(BMI)and increasingasthmaincidence(170,171,174,175,176).Thefrequentassociationbetween the2diseaseshas led to thecon-cept of “twin epidemics”with interventionstargeting lifestyleaimingtoreduceboththeincidenceofobesityandasthmaandimproveasthmacontrol

Theconsensusdocument (177) “Weight loss interventions in asthma: EAACI evidence-based clinical practice guideline (part I)”publishedin2013andcited 42 timessinceitspublicationis the latest systematic review (SR) of threelargebiomedicaldatabasesonobesity,weightloss and asthma. Studies were scrutinizedand critically appraised according to agreedexclusion and inclusion criteria. Quality as-sessment of eligible papers was conductedusingtheGRADEmethod.Meta-analysesofcomparablestudieswerecarriedout.TheSRshowedthatweightincreasesabovetheobe-sitythresholdsignificantlyincreasetheriskofasthma:becomingobeseincreasedtheodds

As a significant risk factor and co-morbidity of asthma, life style (diet, obesity, exercise) represented a special focus of the research of Ioana Agache. As secretary of the EAACI Asthma Section Ioana Agache initiated and chaired a Task Force on life style and asth-ma that produced several consensus doc-uments and position papers based on sys-tematic reviews derived data.

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for incident asthma by 1.82 (95% CI 1.47,2.25) inadultsand1.98(95%CI0.71,5.52)inchildren (Figure38).Theavailablestudiesshowweakevidenceofbenefitsfromweightreduction on asthma outcomes:weight losswasassociatedwithsignificantimprovementinmeanscoresforsymptoms,rescuemedica-tionscore, andasthmaexacerbations in theonlyrandomizedcontrolledtrial.Similarly,ev-idence gathered fromobservational studies,withfollow-uprangingbetween8weeksto1year,andfromchanges1yearafterbariatricsurgery showed improvements inall asthmacontrol-related outcomes. Changes in lungfunction were reported in one randomizedcontrolledandeightobservationalstudiesofasthmatic subjects, with conflicting results.Eitherimprovementafterweightloss,declinewithweightgain,ornoeffectsatallwerere-ported.Changes inairway inflammationandresponsivenesswerereportedonlybyobser-vationalstudies.

It is known thatoxidative stress andairwayinflammationarecentralfeaturesintheman-ifestationofasthma,whichmightbeexacer-batedbythepoorerqualityofthediet(178).The possible effect of diet on asthma, par-ticularlyinrelationtotheroleofdietaryanti-oxidantsandpolyunsaturatedfattyacidshasbeeninvestigatedinnumerousobservationalstudies(179).CurrentevidencesuggeststhatantioxidantvitaminsCandEandahigherin-takeoffreshvegetablesandfruitsmighthaveaprotectiveeffectonasthma,butmostofthefindingsarestillconsideredweakduetothecross-sectionaldesignofthestudiesandtheheterogeneity in diet assessment betweenthem. Intervention trials have added littlesofartounderstandtheroleofnutrientsonasthma,whichopensthequestionofwheth-erthesourcesofnutrientsmatter(e.g.dietvssupplements).

Figure 38Forest plot showing meta-analysis of incident asthma risk comparing obese vs normal-weight subjects.Studiesareorderedbyyearofpublication,thecenterofeachsquarerepresentsstudyspecificORs,andhorizontallinesrepresent95%CIs;verticalvertexofthediamondrepresentstheORsummaryestimate,whereastheendsofthediamond(width)correspondtothe95%CI;verticallineindicatesanORof1(nodifference).(ReproducedfromMoreiraA,etal.“Weightlossinterven-tionsinasthma:EAACIevidence-basedclinicalpractice guideline (part I)”. Allergy 2013;68(4):425-39)

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A second position paper (180) of the TaskForce Asthma and dietary intake: an overview of systematic reviews published in 2016 fo-cusesonseveralcomponents found in foodshave proposed to have a protective effectagainstasthmariskthroughtheirantioxidant,anti-allergicandanti-inflammatoryproperties.In this overviewof SRondietary intake andasthmawefoundsevenSRthatmettheAM-STARscoreforhighquality.Theresultsshowevidence of a negative association betweenasthmaorwheezeanddietary intakeofvita-minsC,EandD,aswellasintakeoffruitsandadherencetoaMediterraneandiet.ObjectivemeasuresofasthmawereunrelatedtovariablelevelsofintakeofsaltinRCTs.Withtheexcep-tionoftheevidenceforvitaminD,theassoci-ationsobservedbetweenasthmaanddietaryintakeoffoodsandantioxidantnutrientscomemostly from cross-sectional studies.Most oftheevidenceofaprotectiveeffectofdietaryantioxidants and asthma was found in chil-dren,thustimeofexposurewouldseemtobeimportant.Thereareseveralstrengthsofthisoverview.First, itemployedacomprehensivesearchstrategy,developedandpilotedtocap-tureallavailableSRthatmettheeligibilitycri-teriaofthisTaskForce’sreview.WealsousedAMSTARasavalidated instrument toassessindetailthemethodologicalqualityofinclud-edreviews.Inspiteoftheabundantscientificliteratureonasthmaanddiet,fewsystematicreviewsmeettherecommendedcut-offscorefor high quality reviews. These are neededin order to produce adequate guidelines forhealthprofessionals,patientsandpatient-affil-iatedassociations.Thisevidencesupportsrec-ommendations inclinicalpracticeto increasethenetintakeoffruitsandvegetablesasawayofreducingtheriskofasthma,particularly inchildren.Thecurrentevidencecomesmostlyfromobservationalstudiesandhighlightstheneedforwell-designedRCTsto investigate ifsuch aneffecthas clinical benefits.Thehighprevalentratesofasthmainthegeneralpop-ulation,particularlyinchildren,justifytheim-plementationofsuchstudies.

FollowingthisoverviewofhighqualitySRtheTaskForcefollowedon itsownSRaimingtocomprehensivelyassesstheexistingscientificliteratureontherelationshipbetweentodie-tary intakeandtheriskofasthmainchildren

andadults,published inthe last5years.TheSR protocol (181) registered on PROSPEROon3March2016hasbeenpreparedfollowingthe newPRISMA-P guidelines.The scope oftheSRistoprovideevidenceondietaryintakeanddietaryhabits in relation to riskof asth-ma,wheeze(recurrentorpersistent),andAHR.Ourfindingswillserveasareferencetoinformguidelinesondietaryhabitsinsusceptibleandgeneral population to reduce the risk and/orseverityofasthmainchildrenandadults.TheSRwillseektoanswerthefollowingquestions:

• Doesexposuretodiet (asawholeor in-dividualfoods)duringchildhoodinfluencetheriskofasthma?

• Doesexposuretodiet(asawholeorindi-vidualfoods)inadultsinfluencetheirriskof asthma?

C. FOOD ALLERGY AND ASTHMAPrevalenceof both food allergy and asthmaisontherise,theyaresharingthesameriskfactors and food allergy is a risk factor forasthma later in life. Moreover the associa-tionbetweenfoodallergyandasthmaisquitefrequent:4-8%ofchildrenwithasthmahavefoodallergyandasthmaispresentin29–76%ofallfood-allergicpeople(182,183).Duetothe respiratory barrier defect in asthma theriskforbeingsensitizedtomilk,egg,peanut,shrimp,ormultiplefoodsishigherinasthmat-icpatients(184).

The first SR review andmeta-analyses thatassessedtheassociationbetweenfoodsen-sitizationandsubsequentallergicdiseasesin13birthcohortstudiesprovedthatfoodsen-sitizationinthefirst2yearsoflifecanidenti-fychildrenathighriskofsubsequentallergicdisease, including asthma,whomay benefitfromearlylifepreventivestrategies(185).

Bothinchildrenandinadultasthmaticsfoodsensitization increases asthma morbidity,withhighriskofhospitalisationsanduncon-trolledasthma(183,186,187).Foodallergyisariskfactorforlife-threateningasthma(188,189).Ontheotherhanduncontrolledasthmaisa risk factor for severe reactionandevendeath in food-inducedanaphylaxis:85–96%of fatal food anaphylaxis occurs in peoplewithasthma(190-192).

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The SR performed in 2014 (193) examinedwaystopreventthedevelopmentoffoodaller-gyinchildrenandadults.Sevenbibliographicdatabasesweresearchedfromtheirinceptionto September 30, 2012, for systematic re-views,randomizedcontrolledtrials,quasi-ran-domized controlled trials, controlled clinicaltrials, controlled before-and-after studies, in-terruptedtimeseriesstudies,andprospectivecohortstudies.Expertswereconsultedforad-ditionalstudies.Therewerenolanguageorge-ographicrestrictions.Tworeviewersappraisedthestudiesusingappropriatetools.Datawerenotsuitable formeta-analysisduetohetero-geneity,sowerenarrativelysynthesized.Sev-enty-four studies were included, one-thirdofwhichwereof highquality.Therewas nogood evidence to recommend that pregnantorbreastfeedingwomenshouldchange theirdietor takesupplements topreventallergiesin infants at highor normal risk.Thereweremixedfindingsabout thepreventivebenefitsofbreastfeedingforinfantsathighornormalrisk, but there was evidence to recommendavoidingcow’smilkandsubstitutingwithex-tensively or partially hydrolyzedwhey or ca-sein formulas for infants at high risk for thefirst4months.Soymilkanddelaying the in-troductionofsolidfoodsbeyond4monthsdidnothavepreventivebenefitsinthoseathighornormalrisk.Therewasvery littleevidenceaboutstrategiesforpreventingfoodallergyinolderchildrenoradults.

In2015theprimarypreventionLEAP(Learn-ingEarlyaboutPeanutAllergy)studyshowedthatearlyintroductionofpeanutssignificantlydecreasedthefrequencyofthedevelopmentofpeanutallergyamongchildrenathighriskfor this allergy and modulated immune re-sponsestopeanuts(194).Ofnote,sincechil-drenwithlesserriskfactorsforpeanutallergy

wereexcludedfromenrollmentinLEAP,therearenoprospective, randomizeddata investi-gatingthebenefitorriskofearlypeanutintro-ductioninthegeneraltolow-riskpopulations.Followingthisgroundbreakingstudythescien-tificcommunityreactedwithclearrecommen-dationonhow,whenandtowhomthisprima-ryprevention intervention isaimed to. IoanaAgachewasamemberoftheExpertPanelthatissuedtheConsensus communication on ear-ly peanut introduction and the prevention of peanut allergy in high-risk infants published(195)inallmajorjournalsoftheAcademiesin-volved(AmericanAcademyofAllergy,Asthma& Immunology; American Academy of Pedi-atrics,AmericanCollegeofAllergy;Asthma&Immunology, Australasian Society of ClinicalImmunology and Allergy; Canadian SocietyofAllergyandClinicalImmunology;EuropeanAcademyofAllergyandClinicalImmunology;IsraelAssociationofAllergyandClinicalImmu-nology;JapaneseSociety forAllergology;So-cietyforPediatricDermatology;WorldAllergyOrganization).BasedondatageneratedintheLEAPtrialandexistingguidelines,thefollow-inginterimguidanceissuggestedtoassisttheclinicaldecision-makingofhealthcareprovid-ers(Table13).

ThenextSRsystematicreview(196)summa-rizestheevidenceabouttheimmediateman-agement of reactions induced by food andlonger-termapproachestominimizeadverseimpacts. Eighty-four studies were included,buttwo-thirdswereathighriskofpotentialbias. There was little evidence about acutemanagement for non-life-threatening reac-tions. H1-antihistaminesmay be of benefit,but this evidencewas in part derived fromstudiesonthosewithcross-reactivebirchpol-lenallergy.Regardinglong-termmanagement,avoidingtheallergenicfoodorsubstitutinganalternativewascommonlyrecommended,butapartfromforinfantswithcow’smilkallergy,therewas littlehigh-quality researchonthismanagementapproach.Toreducesymptomsinchildrenwithcow’smilkallergy,therewasevidencetorecommendalternativessuchasextensivelyhydrolyzedformula.Supplementssuch as probiotics have not proved helpful,butallergen-specificimmunotherapymaybedisease modifying and therefore warrantsfurtherexploration.

As a member of the Expert Panel of EAACI Food Allergy and Anaphylaxis Guidelines Io-ana Agache brought her expertise on asth-ma in relation to food allergy and anaphy-laxis. Ioana Agache led the Task Force on Food Allergy and Anaphylaxis Management in the Community and was part of the Food Allergy Prevention and Epidemiology Task Forces.

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IoanaAgacheledtheEAACI Food Allergy and Anaphylaxis Guidelines for managing patients with food allergy in the community (197).Theseguidelines intendtoprovideguidancetoreducetheriskofaccidentalallergicreac-tions to foods in the community addressingearly-childhoodandschoolsettingsaswellasprovidersofnon-prepackagedfood(e.g.,res-taurants, bakeries, takeaway, deli counters,and fast-food outlets). Food allergy is themost common trigger of anaphylaxis in thecommunity.Providingchildrenandcaregiverswithcomprehensive informationonfoodal-lergenavoidanceandpromptrecognitionandmanagementof allergic reactions areof theutmost importance. Provision of adrenalineauto-injectordevicesandeducationonhow

andwhentousetheseareessentialcompo-nentsofacomprehensivemanagementplan.Managingpatientsatriskofanaphylaxisrais-esmanychallenges,whicharespecifictothecommunity.Thisincludestheneedtointeractwiththirdpartiesprovidingfood(e.g.,schoolteachers and restaurant staff) to avoid acci-dentalexposureandtohelpindividualswithfood allergy to make safe and appropriatefoodchoices.Educationofindividualsatriskandtheirfamilies, theirpeers,schoolnursesandteachersaswellasrestaurantandotherfoodretailstaffcanreducetheriskofsevere/fatal reactions. Increased awareness amongpolicymakers may improve decision-makingonlegislationatlocalandnationallevel.

Table 13Interim Guidance Regarding Early Peanut Introduction.Theevidenceforthebenefitofearlyin-troductionofpeanutsislimitedtothehigh-riskinfantsfromcountrieswithahighprevalenceofpeanutallergy.Thereiscurrentlynoevidencethatthisinterventionissuitableforlow-riskinfantsorforcountrieswithlowprevalenceofpeanutallergy.Themetabolicconsequencesofearlypea-nutconsumptionneedtobeevaluated.(Adapted from Fleischer DM, et al. Consensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants. J Allergy Clin Immunol. 2015;136(2):258-61)

ThereisnowLevel1evidencefromarandomizedcontrolledtrialthathealthcarepro-vidersshouldrecommendintroducingpeanut-containingproductsintothedietof“high-risk”infantsearlyoninlife(between4–11monthsofage)incountrieswherepeanutallergyisprevalent

Infantswithearly-onsetatopicdisease,suchassevereeczema,oreggallergyinthefirst4-6monthsoflife,maybenefitfromevaluationbyanallergistorphysiciantrainedinmanagementofallergicdiseasesinthisagegrouptodiagnoseanyfoodallergyandassistinimplementingthesesuggestionsregardingtheappropriatenessofearlypeanutintroduction.Evaluationofsuchpatientsmayconsistofperformingpeanutskintestingand/orin-of-ficeobservedpeanutingestion,asdeemedappropriatefollowingdiscussionwiththefamily.Theclinicianmayperformanobservedpeanutchallengeforthosewithevi-denceofapositivepeanutskintesttodetermineiftheyareclinicallyreactive,beforeinitiatingat-homepeanutintroduction.

TheLEAPstudydoesnotaddressuseofalternativedosesofpeanutprotein,minimallengthoftreatmentnecessarytoinducethetolerogeniceffect,orpotentialrisksofpre-maturediscontinuationorsporadicfeedingofpeanut.

TheLEAPtrialonlyincludedhigh-riskinfantswithaminimalornegativeSPTtopea-nut,andthereforedoesnotaddressastrategyforthosewithouttheseriskfactorsfordevelopingpeanutallergy

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D. INFECTIONS AND ASTHMA

Inrecentyears,agrowingnumberofobser-vations have highlighted the importance ofrespiratory infections in acute asthmaexac-erbations. Respiratory viruses have repeat-edly and consistently been associated withasthma exacerbations in different patientgroups, with detection frequencies rangingfrom40 to90%.Bacteria,mostlyMycoplas-ma and Chlamydophila pneumoniae, are fre-quentlyidentifiedinchronicasthmaandmayalsoprecipitateexacerbations.Takingintoac-countthatamajorproportionofasthma-re-lateddiseaseburden iscausedbyexacerba-tions (198),aswellasthat infectiousagentsare potential treatment targets, it becomesevident that the above associations requirefurtherattention.

As a member of the GA²LEN-DARE project-ed fundedbyEUunder the6thFrameworkProgramme IoanaAgacheevaluated in a SRtheevidenceforvirusesandbacteriainacuteasthmaexacerbations.

Thepaper (199), cited108timesuntilnow,reports on the prevalence of individual mi-crobialagentsinacuteasthmaexacerbationsininfants,childrenandadults(Table14)andper geographical region (Table 15). The in-volvement and preponderance of rhinovirus(RV)isclear,andtheplethoraofdata/studiesassociatingthisvirustypewithacuteasthmaexacerbations leaves little doubt about theimportanceofthispathogen,althoughtheki-neticsofRVinfectioninthecommunitystillrequiresattention,especiallyconsideringthenewly identifiedRV-C.Therelationshipwithdifferentwheezing illnesses is also clear for

Table 14Reported prevalence of individual microbial agents in acute asthma exacerbations.Percentagerangeandmedianvalue(inparentheses)areshown.Percentagesreferringtoviralspeciesarede-rivedpredominantlybyPCRtechniquesthatareappliedinthemajorityofstudiesforviraldetec-tion.Bacterial(CP/MP)detectionisusuallybyserologyand/orPCR.Remarksinthelastcolumnarebasedondatafromcase–controlstudies.?=Insufficientdata.AAE,acuteasthmaexacerbation;CP,Chlamydophilapneumoniae;MP,Mycoplasmapneumoniae. (Adapted from Papadopoulos NG, et al. Viruses and bacteria in acute asthma exacerbations-a GA²LEN-DARE systematic review. Allergy 2011;66(4):458-68)

Pathogen

Prevalence (%) in AAEHigher frequency

in AAE than control populations

Infants and pre-school-age

children

Children (6–17 years) Adults

Rhinovirus 17–78(33) 42–82(55) 8–65(29) Yes

Enterovirus 12–25(18) 5–16(7) ? ?

Coronavirus 0–5(2) 0–13(1) 4–21(12) No

Influenzavirus 1–20(3) 0–7(2.5) 8–25(23) Yes(adultsonly)

Parainfluenzavirus 4–12(7.5) 0–7(2) 0–18(0) No

RespiratorySyncytialvirus 2–68(19) 1.5–12(4) 0–39(3) Yes(infantsonly)

Metapneumovirus 1.5–9(4) 4–7.5(4.5) 7 ?

Adenovirus 1.5–8(4.5) 0–71(0) 1–3(2) No

Bocavirus 7.5–19(11) ? ? ?

ChlamydophilaPn 0–45(4) 4–23(11) 0–73(13) ?

MycoplasmaPn 1–10(2) 0–50(14) 0–8(4) Yes(childrenonly)

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respiratory syncytial virus, which is mostlyprevalentininfants.Theassociationwithoth-errespiratorypathogensisnotasclear,possi-blybecauseoftherelativelysmallproportionof cases for each, in addition to geographicand temporal variability. This is particularlytrue in regard to any possible involvementof bacteria in exacerbations, onwhich verylittle information isavailable.Thepaperalsohighlightsseveralunmetneedsthatshouldbeaddressedinfurtherresearchstudies.Takingintoaccountthatrespiratorypathogensmayinteractbetweenthemselvesandwithotherfactors, such as pollution, allergens, stress,nutrition,etc.,intheinductionofacuteasth-maexacerbations,largestudieswithcompre-

hensiveanalysisofinfectiousagentsandoth-er possible precipitants are among researchprioritiestoevaluatetherelativecontributionofrespiratorypathogensinasthmaexacerba-tions.Asbreakthroughsinmicroorganismde-tectionbecomeavailableforepidemiologicaluse,inparalleltobioinformaticstoolsfortheiranalysis,extensivevirologyandbacteriologyshouldbecomeavitalpartoflongitudinalco-hort studies, aimingatbetterunderstandingthe kinetics andnatural historyofmicrobialexposures, and reveal new targets for ther-apeutic intervention.Such interventionswillalso be needed to confirm causality behindthedescribedassociations.

Table 15Reported prevalence of microbial agents in acute asthma exacerbations sorted by geographical region.Percentagerangeandmedianvalue(inparentheses)areshown.Percentagesreferringtovi-ralspeciesarederivedpredominantlybyPCRtechniquesthatareappliedinthemajorityofstudiesforviraldetection.Bacterial(CP/MP)detectionisusuallybyserologyand/orPCR.?=Insufficientdata.AAE,acuteasthmaexacerbation;CP,Chlamydophilapneumoniae;MP,Mycoplasmapneu-monia. (Adapted from Papadopoulos NG, et al. Viruses and bacteria in acute asthma exacerbations-a GA²LEN-DARE systematic review. Allergy 2011;66(4):458-68)

Pathogen Prevalence (%) in AAE (by region)

Children Adults

Americas Europe Australasia Americas Europe Australasia

Rhinovirus 26–77(57) 17–82(40) 33–78(42) 29–36(33) 35 8–65(20)

Enterovirus 5 5–25(9) ? ? ? 3.5

Coronavirus 0–3(1.5) 0–13(2.5) 1.5–2(2) 12–21(17) ? 4

Influenzavirus 0–20(10) 0–7(3) 1–12(6.5) 8–13(11) ? 12–25(23)

Parainfluenzavirus 2–6(4) 0–7(4) 7.5–8(8) 0–18(9) ? 0

Respiratorysyncytialvirus 8–68(40) 1.5–61(12) 7.5–17

(16) 3 ? 0–39(2)

Metapneumovirus 7.5 2–8.5(4) 1.5–8(2.5) 7 ? 0

Adenovirus 0–4(2) 0–5(4) 1.5 1 ? 2.5–3(3)

Bocavirus ? 7.5–19(12.5) 11.5 ? ? ?

Chlamydophila Pn 4 0–45(6.5) 3–45(24) ? 0–73(18) 9–18(14)

Mycoplasma Pn 0 1–50(5) 3 ? 0–4(3.5) 8

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The burden of asthma around the world isofsufficientmagnitudetowarrantitsrecog-nition as a priority disorder in governmenthealth strategies.The prevalence of asthmahasbeenincreasingdramaticallymainlyinthelastdecadesbothinindustrializedanddevel-opingcountries.Therateofasthmaincreasesascommunitiesadoptwesternlifestylesandbecome urbanized. With the projected in-creaseintheproportionoftheworld’spopu-lationthatisurbanfrom45%to59%in2025,thereislikelytobeamarkedincreaseinthenumber of asthmatics worldwide over thenext twodecades. It isestimatedthat theremaybeanadditional100millionpersonswith

asthmaby2025,addingtotheexistingworldasthmapopulationof300millionpeople.

A. ASTHMA PREVENTION AND CONTROLAnimportantpartoftheintegratedmanage-mentprogrammeforasthmathisresearchdi-rectionwasapproachedinthechapter“Best buys for asthma prevention and control” fromtheGlobalAtlasofAsthma(23),whereIoanaAgacheisbothEditorinChiefandauthor.Theauthordescribes10keypointstobetackledbyanefficientasthmamanagementplan(Ta-ble 16).An example of an asthmamanage-mentplanfocusingonpreventionandcontrolisalsoprovided(Figure39).

1.6. ASTHMA MANAGEMENT PLANS AND NEW MODELS OF CARE

Figure 39Asthma “best-buys” management plan.Specialtargetsareadherencetotreatment; lowincomecountries/hard-to-reachpopulations;registries;efficientimplementationofguidelines;cost-effi-ciencystudiesandsmartinvestmentinasthmaresearch,increasedawareness;welldefinedshortandlong-termoutcomes;focusonspecialneeds:exacerbations/severeasthma/phenotypes-en-dotypes.(Reproduced from Agache I. Global Atlas of Asthma, EAACI 2013)

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Table 16Ten “best buys” for asthma prevention and control.Therearemanyeconomicandpoliticalfactorsconditioningtheefficiencyofasthmapreventionandcontrolstrategies.Examplesincludepover-ty,pooreducationandinfrastructure,lowpublichealthpriorityandthelackofgoodworldwidevaliddataonmorbidityandmortalityfromasthma.Guidelinesusedtopreventandcontrolasthmashouldbepracticalandrealisticintermsofdifferenthealthcaresystems.Usually,duetodiffer-encesacrossculturesandhealthcaresystemsmanagementinternationalguidelinesdevelopedinhigh-incomecountries aredifficult to implement in lowandmiddle-incomecountries. (Adapted from Agache I. Global Atlas of Asthma, EAACI 2013)

Identifyandaddressbarrierslimitingtheefficiencyofinterventionsaimingtopreventandcontrolasthma.

Positionasthmaasanimportantcauseofmorbidity,economiccost,andmortalityworldwide.

Well-controlledepidemiologicaldescriptionandsurveillanceofasthma.National,regionalandinternationalasthmaregistriesareurgentlyneededtocontinuouslymonitortheprevalence,morbidityandmortalityofasthmaataglobalscale.

Cost-efficientuseofavailableresources.Particularresourcesareneededforasthmaresearch,whichshouldprovideeffectiveprevention,accurateandrapiddiagnosisandacurativetreatmentofasthma.

Improveaccessibilitytoasthmadiagnosisandtoessentialdrugsforthemanagementofasthmainlow-andmiddle-incomecountriesandforhard-to-reachpopulations

Controlthepreventableenvironmentalfactorsincreasingasthmaprevalenceandmorbiditybyusingstandardiseddecisionsupporttools

Adaptinternationalasthmaguidelinesfordevelopingandlowincomecountriesanduserealisticdisseminationandimplementationstrategies

Promotecost-effectiveasthmamanagementapproacheswhichhavebeenproventoreducemorbidityandmortalityinparallelwithdisease-relatedcostsandinvestininnovativemodelsforchronicdiseases

Smartinvestmentinasthmaresearch-keypriorityareas• unveilingtheriskfactorsandmechanismsthatcauseasthma,includingdetailedphenotyping/endotyping

• novelbiotechnologicalinnovationsandpatient-orienteddiagnosticandtreatmentprotocols• welldesignedprimaryandsecondaryinterventionstrategiesforasthmapreventionandcontrol,withreproducibleshortandlong-termdeliverablesandfullyapplicableindevelopingandlowincomecountries

Specialfocusondifficult-to-manageandcostlyseverediseaseformsand/orexacerbationsofasthma.Amultidisciplinaryapproachwithinspecialistcenterswithexperienceandwideraccesstonationalandinternationalsevereasthmanetworksisneeded

involvementofallstakeholders,includingthePrimaryCareNetwork,PatientOrganizationsandpolicymakers

Thelowpublichealthpriorityofasthmaduetotheimportanceofotherillnessesandtothelackof awarenessof the general public andpolicymakersisanimportantbarriertoeffi-cientimplementationofasthmamanagementplans.Until asthma is recognisedas anovelmajorpublic healthproblemandpharmaco-

logicalmeasuresbecomeavailabletoreducetheprevalenceofasthma,resourcesneedtobeprioritisedtoaddressasthmapreventablerisk factors, suchasairpollutionor tobaccosmoke,toimprovethecareofdisadvantagedgroupswithhighmorbidity,includingcertainracialgroupsandthosewhoarepoorlyedu-

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cated, live in largecities,orarepoorandtoensure that cost-effective management ap-proacheswhichhavebeenproventoreducemorbidity and mortality are available to asmanypersonsaspossiblewithasthmaworld-wide.Evenifasthmacontrolisnotachieved,improvements in quality of life can still beobtainedwithappropriatetreatment.There-fore, treated patientswith partly controlledasthma,andevenuncontrolledasthma,couldcontributetolessenasthma-associateddisa-bility.

Currentinformationonthecosteffectivenessof interventions in asthma is limited to ran-domisedtrialsresultsconductedindevelopedcountries.Asectoralcosteffectivenessanal-ysisusingalifetimepopulationmodelevalu-atedasthmainterventionsintwoWHOepi-demiologicalsub-regions,inAfrica(countrieswithhighchildandveryhighadultmortality),andSouthEastAsia(countrieswithhighchildandadultmortality).Ifresourcesareavailable,theresultsindicatethatpolicymakersinbothregionsshouldprioritisefirst the implemen-tation of low dose inhaled corticosteroidsformildpersistentasthma.This interventionis relatively inexpensivebut averts a sizablenumber of DALYs, avoiding exacerbations,which are an important source of damageto quality of life and increasedmortality. Inthesub-SaharanAfricanregionpolicymakersshouldfocusontheprovisionoflowdosein-haledcorticosteroidspluslongactingβago-nists formoderatepersistent asthma as thenextmostcosteffectiveintervention.Medi-umdoseinhaledcorticosteroidsformoderatepersistentasthmacaseswouldmakeafurtherimportantcontributiontoasthmacontrolbutisalesscosteffectiveoption.

Most of the lifestyle-related risk factors forasthma (poor hygiene or diet, obesity andpsychosocial stress) are prevalent amongthepoor.Inmanyareasoftheworldasthmasufferersdonothaveaccesstodiagnosisorto basic asthmamedications. Increasing theeconomicwealthandimprovingthedistribu-tionof resourcesbetweenandwithincoun-triesrepresentimportantprioritiestoenablebetterhealthcaretobeprovided.

The“YesWeCanUrbanAsthmaPartnership”was created by local organisations in San

Francisco and reaches out to high-risk chil-drenfromunderservedurbanareasindiffer-entclinical settings:urgentvisits, thehospi-tal,acomprehensivespecialtyasthmaclinic,andthroughanexpandedcommunityhealthworker programme. Programme evaluationdemonstrated significant increases in pre-scribingcontrollermedications,useofactionplans, use of mattress covers and togetherwitha significantdecrease inasthmasymp-toms.Additionalchangesoccurredwithinthelocalsystemofasthmacaretosupportongo-ing efforts to improve asthmamanagement.Weconcludethatpediatricasthmaprogramscaneffectivelytarget thesocialandmedicalneedsofchildreninasustainablemanner.

TheLaRedinterventionintheselectedPuer-toRicancommunitiesexperiencingadispro-portionatelyhighlevelofasthmaburdencom-binedthekeycomponentsfromthe“YesWeCan”andtheInner-CityAsthmaStudyinter-ventions. The program significantly reducedasthma symptoms and exceeded reductionsoftheoriginalUSbasedinterventions.Asth-ma-related hospitalizations and emergencydepartment use, and their associated highcosts,werealsosignificantlyreduced.

Avarietyofdecisionsupporttools(DSTs)areused atvarious levels andbyvarious stake-holders,bothresearchersanddecisionmak-ers.Arecentsurveyshowedthatmorethan25%oftheDSTsaddressonlyonepollutionsource or only one environmental stressor,whilealmost50%oftheDSTsareonlyappliedtoonechronicdiseaseand41%oftheDSTscanonlybe applied toonedecisionmakingarea.Inthesamesurvey60%oftheDSTs’re-sultsareusedonlybynationalauthorityand/or municipality/urban level administrationandalmosthalfoftheDSTsareusedonlybyenvironmental professionals and research-ers.Thissurveyindicatestheneedtodevel-opstandardisedDSTscoveringanincreasingnumber of pollution sources, environmentalstressorsandhealthendpoints.

Telemanagement of asthma includes keycomponentsofasthmamanagement,suchaseducation,self-monitoring,goalsetting,writ-tenactionplansandregularmedical review.Anincreasingnumberofstudiesshowedthata comprehensive telemanagement approach

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is effective in improving quality of life andclinicaloutcomes,especiallyinadultpatientswithmoderate to severe asthma.The inter-vention is tailored to the individual patientneeds.However,moreresearchisneededonthe long-term effectiveness and cost-effec-tivenessunderreal-worldconditions.

Community pharmacies have the potentialto make a greater contribution to promot-ingpublichealth.Anewconcept, called theHealthyLivingPharmacy(HLP)wasdesignedtomeetpublichealthneedsthroughatieredcommissioning framework delivering healthand well being services through communi-ty pharmacy, tailored to local requirementsfor tackling health inequalities. Some goodevidence exists for the introduction of spe-cificcommunitypharmacyservices,targetedat customer groups, bothwith andwithoutpre-existing diseases, for interventions onasthma.

The Chronic Care Model advocates a mul-ti-componentremodellingofchronicdiseaseservices to improve patient outcomes. Inte-grated at the point of care in primary carepracticesisapromisinginnovationexpectedtoimprovepatientself-efficacyandempow-ermentintheshort-termandanimprovementinhealthbehaviour,functionalhealthstatus,qualityoflifeandpsychologicalwell-beinginthemid-term.Attheorganizationallevel,theproject should lead to coordinated servicedelivery, improvedpatientfollow-upmecha-nismsandenhancedinterprofessionalcollab-oration.

B. IMPROVED DIAGNOSIS OF ASTHMA

In most of the cases the standard diagno-sisofanallergicdisease isdonebasedona

detailed clinical history and demonstrationofsensitisation (eitherbyskin testor invit-ro testing) toa relevantallergenconcordantwith thehistory.Theallergenchallenge testisrarelyrequired.However,thehistoryofal-lergydiagnosisstartedwitha‘functionalskintest’,namedthepatchtestin1894,whichisessentially a provocation test. Systematical-ly applied provocation tests followed withthe introductionofconjunctivalprovocation(1907),followedbynasalandbronchialprov-ocationwithallergens(1914and1925).

Theallergenprovocationtestisalong-stand-ingmodelforstudyinganddiagnosingallergicdiseasessuchasrhinitis,conjunctivitis,asth-maorfoodallergy.Duetosafetyissuesandlack of standardisation in conjunction withincreasedavailabilityofhighqualityreagentsforskintestsorinvitrodiagnosistheallergenprovocationtestwasalmostabandonedfromdailypracticeandreservedforresearchpur-poses.

ThepositionpaperpublishedbyIoanaAgacheasfirstauthorprovidesacriticalappraisalofallergenchallengemethods(bronchial,nasal,conjunctival,food,venom)togetherwithrec-ommendationsonindications,procedureandsafety(200).Aspecialsubchapterisdedicat-ed to a novel diagnostic test – the allergenchallengechamber (ACC) - targeting severallocationswhereatypeIallergicreactionoc-curs(eyes,upper-andlowerrespiratorytractandevenskin).Theuseofastableandrepro-ducibleallergenloadleadstoanevensymp-tomscore.Challengesessionsarepossibleallover theyear,withno regard to seasons. Incontrasttofieldorparkstudiesitispossibleto report additionallyobjectiveassessmentssuchasslitlampinvestigation,rhinomanom-etry,spirometry,endoscopywiththeoppor-tunity tocrosscheck thevalidityof thesub-jectivescoring.Furthermore it ispossible totakebloodsamples,lavagesandscrapingsonseveraltimepointsof the challenge sessionfor pharmacodynamics and pharmacokinet-icinvestigation.TheACCisnotusuallyusedfor individual diagnosis and is indicated forassessing the efficacy of anti-allergic treat-ments,forstudiesinoccupationalallergyandbasic research.TheACCmodel is approvedandacceptedbytheFDAandEMAforphaseIItrials(proofofconceptordosefinding)and

Better asthma diagnosis is a prerequisite of an efficient management plan. Ioana Agache’s research focused on the in vivo and in vitro diagnosis of allergies and asth-ma, leading an EAACI Task Force focusing on provocation tests in asthma and allergic diseases and being an author of a guideline for in vitro molecular diagnosis.

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for further supporting phase III trials. EMAsuggestsACCtrialsforconductingdosefind-ing trials of immunotherapeutic products.Sincetheyrequiresignificantlylesstimethanfieldstudiesandsmallernumbersofindivid-ualspertrialthepotentialofACCtrialscouldbe extended to monitor AIT and to reducethe cost of drug development substantially.The paper highlights the value of challengetesting is the mainstay of allergy diagnosissince itdirectlyprovestheclinical relevanceofthetestedallergen.Oncearesearchtool,challenge tests are slowlymaking theirwayintodailypractice,mainlyduetoanincreasedsafetyprofileandbetterstandardisation.Theuse of recombinant allergens and moderntechniquestoobjectivelyquantifyandcom-pare the biological modifications inducedby allergen challenge are highly promising.However, properuseof clinical judgment inrecommendingachallenge test, selectionoftheappropriateallergenfortestingandinter-pretationofresults,asderivedofathoroughtrainingasanallergist,areessentialtoensurethedeservedvalueofallergenchallengetest.

The availability of allergenmolecules (‘com-ponents’) from several protein families hasadvancedourunderstandingofimmunoglob-ulinE(IgE)-mediatedresponsesandenabled‘component-resolveddiagnosis’ (CRD). IoanaAgachewas a co-author of the EAACIMo-lecular Allergology User’s Guide (MAUG), acomprehensive book that provides detailedinformation on important allergens and de-scribes the diagnostic options using CRD(108). IgE-mediated reactions and allergicdiseases, including allergic rhinoconjunctivi-tis, asthma, food reactions, and insect stingreactions, are discussed from a novel mo-lecular perspective.TheEAACIMAUGdoc-uments the rapid progression of molecularallergology from basic research to its inte-grationintoclinicalpractice,aquantumleapin themanagementofallergicpatients.PartA of the EAACI MAUG introduces allergenmolecules, families, compositionofextracts,databases,anddiagnosticIgE,skin,andbaso-philtests.SingleplexandmultiplexIgEassayswithcomponentsimprovebothsensitivityforlow-abundanceallergensandanalyticalspec-ificity; IgE to individual allergens can yieldinformation on clinical risks and distinguish

cross-reactivity from true primary sensiti-zation.PartBdiscussestheclinicalandmo-lecular aspects of IgE-mediated allergies tofoods (includingnuts,seeds, legumes, fruits,vegetables,cerealgrains,milk,egg,meat,fish,andshellfish), inhalants(pollen,moldspores,mites,andanimaldander),andHymenopteravenom.Diagnosticalgorithmsandshortcasehistories provide useful information for theclinicalworkupofallergic individuals target-ed for CRD. Part C covers protein familiescontaining ubiquitous, highly cross-reactivepanallergens from plant (lipid transfer pro-teins,polcalcins,PR-10,profilins)andanimalsources (lipocalins, parvalbumins, serum al-bumins, tropomyosins)andexplainstheirdi-agnostic and clinical utility. PartD lists 100importantallergenmolecules.

C. THE ROLE OF PRIMARY CARE IN ASTHMA

TheTaskForcestartedwithasurvey(201)incollaborationwith the International PrimaryCare Respiratory Group (IPCRG) aiming toevaluatetheactualstatusofcareforallergicdiseasesinprimarycare.Accesstoallergyandasthmaspecialisttreatmentwasidentifiedasthegreatest‘unmetneed’.Theaveragewait-ing time between a referral and being seeninapublichealthserviceisusually>6weeks.Referringthepatientstoan‘organ’specialistismucheasiercomparedwith referral toanallergist.Mostgeneralpractitionershaveac-cesstobloodtestsfortotalandspecificIgE.Skinprick testing is available inonlyhalf ofthe cases, while provocation tests, allergen

The standard of care for asthma and allergic diseases within a primary care setting has a strong influence on disease prevention and control, quality of life, and patient sat-isfaction. The level of knowledge of asthma and allergic diseases and the accessibility to regular follow-up are essential. Ioana Agache led an EAACI Task Force on Allergy and Asthma Management in Primary Care aiming to deliver the best care pathways for the general practioners as part of the inte-grated management of asthma and allergic diseases

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quantification inhomes,andadieticianser-viceareevenlessavailable.20.6%ofpractic-esdonothaveaccess toallergy testsatall.Other issues raised by the surveywere lowpoliticalorgeneralpublicawareness, lackofunderstandingbythepatientsoftheirallergicdisease, the need to invest in primary care,andtoachievesufficientcompetenceat theappropriatelevelofcare.

The dominant model of allergy care withinEurope is at the moment specialist-based.This model will become unsustainable andundeliverablewith increasingdiseasepreva-lence.One solution to increaseprovisionofallergy services is todiversify theproviders.Anewmodelfortheprovisionofallergycareinthecommunitywiththegeneralpractition-er at the forefront is proposed by the TaskForce lead by IoanaAgache (202). Pre- andpostgraduate allergyeducationand training,implementationof pathwaysof care, allergyspecializationandpoliticalwilltogeneratere-sourcesandsupportareessentialtoachievethis newmodel. In parallel the holisticviewofallergicdiseasesshouldbemaintained,in-cludingassessmentofseverityandrisk,psy-chological factors and health-care relatedcosts in thecontextof thepatient-centereddecisionmakingprocess.

Inmost of theEuropean countries, thema-jority of patients who seek medical adviceforallergicdiseasesarefirstseeninaprima-ry care setting, partly because relative easeofaccessbutalsobecauseofthepaucityoftrained allergists to meet the ever growingdemand. Correct diagnosis with identifica-tionofalloffendingallergens isanabsoluteprerequisite for appropriatemanagement ofallergic disease by the general practitioner.OneoftheaimsoftheEAACITaskForceforAllergyManagement inPrimaryCarewastocritically review the diagnostic tests and toprovidemanagementpathwaysforthemostcommonallergicdiseasesseenandtreatedinprimary care (203). Management pathwaysforasthmaandmajorallergicdiseaseswithintheprimarycarenetworkarerecommended(Figure40).Keyrecommendationsforallergymanagementinprimarycareareasfollows:

1. Specific IgE measurement can be per-formed in primary care or referred (de-

pendingon local conditions), butonly inlightofaprecisepatientshistory

2. Skin prick tests are not recommendedwithoutapropertrainingandtheriskofanaphylaxisshouldbeconsidered

3. Total IgEasasingleparametermeasure-mentisnotrecommended

4. IgGmeasurementisnotrecommended

5. Seasonal andeasily responsible to treat-ment allergic rhinitis should not be IgEtested

6. Use of management pathways adaptedforPCisstronglyrecommended

D. INCREASING AWARENESS ON ALLERGIES AND ASTHMASincemore than30%of the totalEuropeanpopulationsuffersfromairwaysallergiesandasthma,reachingahigherlevelofawarenessandelaborationofanactivepreventionplanismandatory.

Independent of incidence, age group or na-tionality, it is important to realize thatasth-ma and allergic diseases have a detrimentalimpacton thequalityof lifeofpatientsandtheir families,affectingtheirpersonaldevel-opment, career plans and lifestyle choices.These diseasesmay affect sleep andmood,schoolorworkcompetence,andsocialinter-action.Theimpactofasthmaandallergiesonqualityof lifecanbeashighorevenhigherthanthatofdiseasescommonlyperceivedasbeingmore‘serious’(8,204,205)

Atthesociety level, therisingprevalenceofallergicdiseasesposesamultifaceted,majorsocioeconomic burden on national and Eu-ropeanbudgets.Theincreaseduseofhealthservices, hospitalization and pharmaceuticalcosts,inadditiontothebillionsofdaysoflostproductivitythroughabsenteeismorpresen-teeism (peoplegoing toworkbutbeingun-abletoperform),revealaworryingprospectforpublichealthwhenitcomestoasthmaandallergies(8,206).Giventhenatureofcurrentlifestyles, theageingpopulationandcontin-uingenvironmentalchanges,thesecostsarelikelytoincrease,unlessaconcertedeffortisdevisedtounderstandthecausesandmech-

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Figure 40Pathway for asthma diagnosis and management in primary care.Objectiveteststomeasureair-way obstruction are recommended as the correlation between pulmonary symptoms and lungfunctionispoor.Measuringlungfunctioninprimarycareisneededforthediagnosisofasthmaandforguidingsubsequentmanagement.Patientswithinconclusivespirometricresultsshouldbere-ferredforadditionaltests,suchasnitricoxide(NO)measurementand/orbronchialprovocation.Af-tertherecentintroductionofsmall,portableanalyzers,NOmeasurementisalsofeasibleinprimarycare.Inhalermedicationisthecornerstoneofasthmatreatment.Thereareseveraltypesofinhalersthatvaryindosedelivery,depositionandparticlesize,flowdependencyandconvenience.Severalaspectsneedtobeconsideredwhenprescribinganinhaler:asthmaseverity,cooperation,inspira-toryflow,hand-mouthcoordination,typeofmedication(bronchodilators,anti-inflammatory)andlocationofthediseaseprocessandreceptorsinthelung.Teachingoptimalinhalertechniquere-quiresrepeatedvisitsandguidancebyexperiencedhealthcareworkers.(Reproduced from Jutel M, et al. Recommendations for the allergy management in the primary care. Allergy. 2014;69(6):708-18)

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anismsofallergyanddesigneffectivestrate-giesforpreventionand/ortreatment.

Thelowpublichealthpriorityofasthmaduetotheimportanceofotherillnessesandtothelackofawarenessof thegeneralpublicandpolicymakers isan importantbarriertoefficient im-plementationofasthmamanagementplans.

The paper Research needs in allergy: an EAACI position paper, in collaboration with The Eu-ropean Federation of Allergy and Airways Dis-eases Patients’ Associations (EFA), (207)cited85timessince itspublication,highlightsthemost important research needs in the fieldofallergyandasthmatoserveaskeyrecom-mendationsforfutureresearchfundingatthenationalandEuropeanlevels.

Thereareseveralcommonthemesthatneedtobeprioritizedinresearchefforts.

1. Asinmanyotherchronicdiseases,effec-tive prevention, curative treatment andaccurate,rapiddiagnosisrepresentmajorunmet needs. Detailed phenotyping/en-dotypingstandsoutaswidelyrequiredinorder to arrange or re-categorize clinicalsyndromes into more coherent, uniformand treatment-responsive groups. Re-search efforts to unveil the basic patho-physiologic pathways and mechanisms,thus leading to the comprehension andresolution of the pathophysiologic com-plexityof asthmaandallergieswill allowfor the design of novel patient-orienteddiagnosticandtreatmentprotocols.

2. Asthma and allergic diseases requirewell-controlled epidemiological descrip-tion and surveillance, using disease reg-istries, pharmacoeconomicevaluation, aswellaslargebiobanks.

3. There is a need for extensive studies tobringpromisingnewbiotechnological in-

novations,suchasbiologicalagents,vac-cinesofmodifiedallergenmoleculesandengineered components for allergy diag-nosis,closertoclinicalpractice.

4. Particularattentionshouldbepaidtothedifficult-to-manage,precariousandcostlysevere disease forms and/or exacerba-tions.Nonetheless,currentlyarisingtreat-ments,mainlyinthefieldsofimmunother-apyandbiologicals,holdgreatpromisefortargetedandcausalmanagementofasth-maandallergicconditions.

5. Activeinvolvementofallstakeholders,in-cluding PatientOrganizations and policymakersarenecessarytoachievetheaimsemphasizedherein.

From26th to28thofApril2016,anallergyawarenesscampaignwasorganizedbyEAA-CI and EFA in the European Parliament inBrussels,with supportof theEuropeanPar-liament’sInterestgrouponAllergyandAsth-maandwasco-hostedbytheMembersoftheEuropeanParliamentDavidBorrelli,SirpaPi-etikainenandNessaChilders.Skinpricktestswereperformedtogainattentionforthein-creasingprevalenceofallergicairwaysdiseas-esinEurope.Theresultsoftheinterventionwererecentlypublished(208):ofthe406in-dividuals tested intheEuropeanParliament,211participants(52%)reportedtohavesuf-feredfromanallergyinthepast,withallergicsymptomsbeingpresentinthenoseandeyes(40%and36%respectively), the skin (27%),lower airways (14%) and the gut (8%). Ofthe381skinpricktestswithreliableresults,sensitizationtoatleastoneaeroallergenwasfound in 201 (53%) participants. Of those,70 participants (35%) were monosensitizedwhile131participants(65%)werepolysensi-tized.Thepositiveskinreactionswerefoundmostly forgrasspollen (n=108), followedbyDermatophagoides pteronyssinus (n=105),Dermatophagoides farina (n=96) and birchpollen (n=85).This paper provides evidencethatchronicrespiratorydiseasesareamajorand growing health problem in Europe andhighlightstheneedforajointpreventiveac-tionplanneedstobedevelopedforabetterhealthstatusofEuropeancitizens.

Two recently published papers highlight Ioa-na Agache’s activity in increasing awareness on asthma and allergic diseases in order to ensure proper funding for research and effi-cient management of these diseases.

Professional developments

Chapter 2

B-iScientific and


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Profesional developmentsScientific and professional achievements

Thefoundationofacareerplanneedstobedrivenbyyourprofessionalgoals,alwaysbal-ancing short-termwith long-term consider-ations, creative research with self-develop-ment,beingbothanefficientproblem-solverand problem-creator by asking interestingnewquestions, poseoldproblems in a newway,orbydemonstratingasimplebutfruitfulconnection that no-one previously realizedexisted.

Igraduatedin1994CarolDavila”UniversityinBucharestasaMedicalDoctor, in1998 Istartedmy residency inAllergy and ClinicalImmunology and became in 2000 Specialistand in2004SeniorSpecialist inAllergyandClinicalImmunologyatthe“CarolDavila”Uni-versity,Bucharest.

Ifinalisedin2005myPhDThesisinInternalMedicineMagna cum laude.The thesiseval-uatedaveryoriginal facetof thepathogen-esis of atherosclerosis with the hypothesisthat the immune-inflammatory mechanismsprecedeandpotentiatethewell-knownmet-abolicpathwaysthatleadtoatheromalesionsformationandprogression.At thattime theresearch theme was considered absolutelyleading-edgeandwasappreciatedviapubli-cationsandoralcommunications,includingalectureastheguestspeakerattheprestigiousSwissAllergyandClinicalImmunologySocie-tyAnnualMeeting.

Myresearchpathwaywasalwaysatthefore-frontoftheinnovativeandcutting-edgesci-encefocusingonasthma,allergicrhinitisandfood allergy.As an appreciation Iwas invit-

edtobeamemberoftheExpertPanelsforseveralinternationalguidelinessuchasARIA(AllergicRhinitis and its Impact onAsthma),a famousWHO project referenced all overtheworld,theFoodAllergyandAnaphylaxisGuidelinesrecentlypublishedbytheEurope-anAcademyofAllergyandClinicalImmunol-ogy(EAACI)andtheAllergenImmunotherapyGuidelinescurrentlydevelopedbyEAACI.

I published 58 papers with 2567 citations and h-index 18 in ISI Web of Science. In Google Scholar my activity is reflected by 8590 ci-tations (4644 since 2012). My h-index is 20 and i10-index 32 (figure 41).IeditedrecentlythreeverysuccessfulGlobalAtlases,onasthma,allergicdiseasesandrhi-nitis/chronic rhinusinusitisandwas involvedinseveralExpertPanelsoftheWorldAllergyOrganisation.

I am a highly appreciated reviewer of highimpact scientific journals such as Journal ofAllergyandClinical ImmunologyandAllergyandtheAssociateEditoroftheopen-journalClinicalandTranslationalAllergy.

I was a member of several Scientific Com-mitteesorganizing internationalconferenceswith>8000participantsforseveralyearsinarowandIamatpresenttheVice-PresidentandPresidentElectoftheEuropeanAcademyofAllergyandClinicalImmunology(EAACI).

In the last five years my research focusedon the area of asthma and allergic diseasesphenotypes and endotypeswith the aim toidentifynewtreatmenttargetsandbetterse-lecttheresponderstothetreatmentoptionsavailable for these diseases. I am the first/last authorof6original papers and reviewspublished inhighly ranked ISI journalshigh-lightingtheneedandthemodalityofendo-type-drivenapproachesforthemanagementof asthma. The research on asthma and al-lergic disease endotypes is performed since2010incooperationwiththeSwissInstituteforAllergyandAsthma(SIAF),Davos,whereIwasVisitingProfessor.

2.1. CAREER OVERVIEW

Developing a unique combination of abili-ties such as being a compassionate medical doctor, a good teacher and top researcher was the main goal of my career develop-ment. Developing a unique combination of abilities such as being a compassionate medical doctor, a good teacher and top re-searcher was the main goal of my career de-velopment.

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Profesional developments Scientific and professional achievements

Figure 41Scientific and professional achievements achievements – Web of science and Google scholar ci-tation index.

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A. PhD THESISIdefendedin2005myPhDThesisinInternalMedicine“3 Years Evolution in Patients with Acute Coronary Syndromes and Chlamydia Pneumoniae Infection”andIgraduatedMag-na cum laude.Thebackgroundofmyresearchwas based on several novel publications atthat time underlining the association, how-ever controversial, between increased titresofantiChlamydia Pneumoniae(CP)antibodiesand coronary heart disease, stroke and pe-ripheralobstructivearterydisease(209,210),while endovascular CP markers expressiondemonstrated through immunohistochemis-try, electronicmicroscopy, in situ hybridisa-tionandcultivationofthebacteriafromtheatheroscleroticplaquesupportedtherelationbetweentheCPinfectionandcoronaryath-erosclerosisbyariskratioof20(211).Animalmodelsand invitroexperimentshave impli-catedCPpathogenicallyintheinitiationandacceleratedprogressionoftheatherosclerot-iclesionsandinplaqueactivation(212).Theimpact ofmacrolide or chinolone treatmenton the incidence of cardiovascular eventsin patientswith coronary heart diseasewaslargelycontroversial(213).

ThePhDresearchwaspartofmyengagementbetween 2000-2003 in the CNCSIS pro-gramme, contract 3993/14.06.2000, “Chla-mydia Pneumoniae infection as a risk factorforacutecoronarysyndromes,strokeandpe-ripheralarterydisease“,coordinatedbyProf.Dr.Mariana Radoi.My specific assignmentswereCPdetectionviaimmunohistochemistryandserologyandtheimmunologicevaluationofacutecoronarysyndromesandstroke.

The main aim of the PhD researchwas theevaluation of the incidence of major cardio-vascularevents(MACE)-cardiovasculardeath,non-fatalmyocardialinfarction,unstableangi-nawithreadmission–after30days,6month,1year,2yearsand3yearsofevolutioninpa-tientswith acute coronary syndromes (ACS),with orwithoutCP infection, as appreciatedserologically.Secondaryaimswere:1)Evalua-

tionoftherelationbetweenCPinfectionandsystemic inflammation (fibrinogen,Creactiveprotein, IL6, TGF-β), serum concentration ofTtroponin,thetitreofantioxLDLantibodiesandoftherelationbetweenCPinfectionandtraditionalatheroscleroticriskfactors;2)studyoftheCPinfectionincidenceinunstableath-eroscleroticlesionsandthecorrelationofCPinfectionwith the severity of atheroscleroticlesionsandwiththecellulareventsimplicatedinplaque instability; 3) evaluationof the im-pactofmacrolidetreatmentassociationtotheconventionaltreatmentofACSonMACEinci-denceafter3months,6monthsand4yearsofevolutioninpatientswithACS.Severalmajorfindingsdeservetobehighlighted:1)Thein-cidenceofCP infection inpatientswithACSwassignificantlyincreased,bothbyserologicalevaluationandbyimmunohistochemistryeval-uation;2)ThepresenceandthepersistenceofantiCPantibodiesat30dedaysandtheIgGantiCPtitre>1/1024UI/mlattheinitialmo-menthavethehighestprognosticvaluefortheshort,medium and long term evolutionwithMACE3)HistologicalmarkersofCPinfectionareimplicatedinthepromotionofatheroscle-rotic lesions instability, independent of theexpressionofhistologicalmarkers forcellularactivation,andindirectrelationwithmyocar-dialnecrosis;4)TreatmentwithRovamycine®12or24dedaysadded to theconventionaltherapyofacutecoronarysyndromesisbene-ficialforthemediumandlongtermevolutionbyreducingtheMACEincidenceat6monthsandat4years.

Thereare several strengths in the resultsofmyPhDresearch:whileserologicandimmu-nohistologicaldatasupportingthe increasedincidence of CP infection inACSwere per-fectlyalignedwithotherstudiespublishedatthesametime,thusshowingconsistencyandreproducibility of the research, I found andpublishednewdatasupportingtheprognos-ticvalueofCP serologyand its relation thewithdislipidemiaasanindirectmechanismbywhich CP promotes systemic inflammation.ThesignificantlyincreasedincidenceofCD14

2.2. PhD THESIS AND PROJECTS

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expression ingradeVandVIatheroscleroticlesionswas reported for the first time hereand then confirmed by numerous successorstudies.Theresearchalsoaddedhighqualityevidence for the long-term beneficial effectofmacrolidetreatmentinACS.

Besides being appreciated “Magna cum lau-dae” thePhDthesis thevalueof the resultswas acknowledged by several publicationsandlecturesdeliveredbyIoanaAgache(Table17).

Table 17Scientific accomplishments during my PhD thesis.

Full text articles in ISI/BDI journals

• Ioana Agache, Mariana Rădoi, T. Leaşu; “Infecţia cu Chlamydia Pneumoniae -implicaţiiînpatogeniaaterosclerozei“;RevistaMedicalăNaţională,2001,vol.V,nr.1-2,ISSN1453-2506;pg.49-54,6pagini;

• Mariana Rădoi, Ioana Agache, Alina Pascu; “Reacția imun-inflamatorie înateroscleroză“;BritishMedicalJournal2002-ediţiaînlimbaromâna,http://www.bmj.ro/revista/martie-2002-nr-2

• MarianaRădoi,ElenaBobescu,Ioana Agache;“Rovamycineasadd-ontreatmentinunstableanginaand4yearevolutionwithmajorcardiovascularevents”;RomanianJournalofInternalMedicine2003,41,3;pg.237-246;2003

Book chapters

• MarianaRădoi,Ioana Agache.“Reacţiainflamatorieînateroscleroză–dateactuale“.Progreseincardiologie”subredactiaL.Gherasim,2002,EdituraInfomedica,ISBN973-9394-89-2;pg.377-399;2002

• Mariana Rădoi, Ioana Agache, Mariana Anghel, Marius Penciu, Florin Leasu;“ExpressionofCD14receptorandChlamydiaPneumoniaemembraneantigensincoronaryatheroscleroticlesionsgradeVandVI–studyon46patients“;„FrontiersinCoronaryArteryDisease”editedbyB.L.Lewis,DAHalon,MYFlugelman,GFGensini;2003,MonduziEditore,ISBN88–323-3161-6;pg.215-217;2003

Oral communications at international conferences

• ElenaBobescu,MarianaRădoi,Ioana Agache,A.Burducea;“Correlationbetweenoxidative stress, inflammatory syndrome and prognosis in patients with acutecoronarysyndromes”;11thInternationalConferenceonAdvancesinProstaglandinandLeukotrieneResearch:BasicScienceandNewClinicalApplication,Florence,Italy,June4–8,2000

• Ioana Agache, Mariana Rădoi; “Infection with Chlamydia Pneumoniae andatherosclerosis–istherealink?”;EAACISummerSchool,Rome-Cagliari,2000

• MarianaRădoi,ElenaBobescu, Ioana Agache,ClaudiaTimu; “Serological statusforChlamydiaPneumoniae,systemic inflammationandonemonthevolutionofpatientswith unstable angina”; First International Symposium on PPARs: frombasicsciencetoclinicalapplications.Florence,April4-7,2001

• Mariana Rădoi, Elena Bobescu, Ioana Agache,MarianaAnghel; “TGF β plasmalevelandevolutionofpatientswithunstableanginaatoneandsixmonths.”Heart,vol.87,suppl.1,pg.A11;2002

• Mariana Rădoi, Ioana Agache, Elena Bobescu, Mariana Anghel; SerologicalstatusforChlamydiaPneumoniaeinpatientswithacutecoronarysyndromesincorrelationwith IL6andTGFbetaserumlevel;1st InternationalConferenceonCytokineMedicine,Manchester;pg.16;2003

• MarianaRădoi,ElenaBobescu,Ioana Agache,FlorinLeasu;Rovamycineasadd-ontreatment inunstableanginaand4yearevolutionwithmajorcardiovascularevents”; 12th International Congress on Cardiovascular Pharmacotheraphy;AbstractBook,pg.4;2003

• Mariana Rădoi, Ioana Agache,MarianaAnghel,Marius Penciu, Elena Bobescu,FlorinLeasu;ExpressionofCD14receptorandChlamydiaPneumoniaemembraneantigensincoronaryatheroscleroticlesionsgradeVandVI–studyon46patients“;TheJournalofCoronaryArteryDisease,5;1:pg118;2003

• MarianaRădoi,ElenaBobescu,Ioana Agache,MarianaAnghel;AntibodiesagainstoxLDL,CRPandIL6serumlevelsanoneandsixmonthsevolutionof54patientswithacutecoronarysyndromes;ClinicalandExperimentalRheumathology22;pg.21,2004

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• Mariana Rădoi, Ioana Agache, Mariana Anghel, Marius Penciu, Elena Bobescu,Claudia Timu, Diana Tant; “CD 14 receptor expression in unstable coronaryatheroscleroticlesions”;ClinicalandExperimentalRheumathology22;pg.21;2004

Oral communications at national conferences

• MarianaRădoi,Ioana Agache;“Immune-inflammatorymechanismsinatheroslerosis”,AnnualConferenceoftheRomanianSocietyofAllergologyandClinicalImmunologywithinternationalparticipation,Bucharest2002,vol.rez.pg.53;2002

• Mariana Rădoi, Elena Bobescu, Ioana Agache, MarianaAnghel, Liliana Eftimie;“Antibodies against ox LDL in correlation with IgG and IgA anti ChlamydiaPneumoniae serumtiters in 54patientswith acute coronary syndromes”; FirstRomanianSymposiumwithInternationalParticipation-Inflammation2004.April20-23,2004,SâmbatadeSusAcademy,BraşovCounty,Romania;pg.53;2004

• Mariana Rădoi, Elena Bobescu, Diana Ţânţ, Mirela Şerbănoiu, Ioana Agache,Claudia Timu, T. Alexandru, Maria Anghel, Ioana Rusu; “Incidenţa infecţiei cuChlamydiaPneumoniaeînsindroamelecoronarieneacute”;RevistaNaţionalădeCardiologie,2000

• Mariana Rădoi, Elena Bobescu, Ioana Agache, ClaudiaTimu,Mirela Serbanoiu;“Status-ulserologicpentruChlamydiapneumoniae,inflamaţiasistemicăşievoluţialao lunăapacienţilorcuanginăinstabilă”RevistaRomânădeCardiologie,2001,vol.XIV,nr.3,pg.54-55

• ElenaBobescu,Ioana Agache,MarianaRădoi,ClaudiaTimu,DianaTînţ.“PersistenţainfecţieicuChlamydiaPneumoniaeşivalorileplasmaticealecolesterolului,PCR,fibrinogen, IL6,TGFbeta,status-ulantioxidant totalşisindroamelecoronarieneacute“;RevistaRomânădeCardiologie,vol.XVII,nr.3;pg.69;2002

• Elena Bobescu,Mariana Rădoi, Ioana Agache,MarianaAnghel, Gabriela Ifteni;“TitrulanticorpilorantioxLDL,nivelelesericealePCRsiIL6sievolutiala1si6lunia54pacienticusindroamecoronarieneacute“;RevistaRomânădeCardiologie,vol.XVII,nr.3;pg.75;2002

• Elena Bobescu, Mariana Rădoi, Ioana Agache, Alina Tudose, A. Burducea.“Corelatiile dintre status-ul antioxidant total si prognosticul pacientilor cusindroame coronariene acute“; Revista Română deCardiologie, vol. XVII, nr.3 ;pg.132;2002

• Mariana Rădoi, Ioana Agache,MarianaAnghel,Marius Penciu, Elena Bobescu,Claudia Timu, Diana Tânţ; “Aterotromboza coronariană în relaţie cu activareacelulară evaluată imunohistochimic prin expresia receptorului CD14“; RevistaRomânădeCardiologie,vol.XVIII,nr.3;pg.110;2003

Invited lectures

• Ioana Agache,MarianaRădoi;Immuneinflammatorymechanismsinatherosclerosis.5thCourse:AllergyandImmunologyUpdate(AIU),SwissSocietyofAllergologyandImmunology;2003

• Ioana Agache; „Mecanisme imun-inflamatorii în ateroscleroză”; al VII-leaSimpozionNaţional“Prof.Dr.DimitrieGerota”,27-29oct.2004

FollowingthePhDThesistheexperienceac-cumulatedwiththeimmunologicalevaluationofcardio-vasculardiseaseswasengagedintoanother research programme” the IMPACTprogram, CERICARD project 908/13 June2007–Researchandintegratedmanagementinheartfailure,ProjectCoordinatorProf.Dr.MarianaRădoi.Myspecificappointmentwasto coordinate the fundamental research inheartfailure.

B. PROJECTS

Leadership of national research programmes

(PN-II-RU-TE-2014-4-2303 – Endotypes ofNon-Eosinophilic Asthma - ENDANA), andpartnerships in EU projects: COST actions(COSTBM1201:EarlyOriginsofChronicLungDisease)andGA2LENprogram,DARE–diarycardpilotingandvalidationaredetailedbelow.

B1. PN-II-RU-TE-2014-4-2303 – Endotypes of Non-Eosinophilic Asthma - ENDANA Non-eosinophilic asthma representsapprox-imately 50% of the adult asthma cases andischaracterizedbyamodestresponsetothetherapeutic intervention with inhaled ster-oids(70,214,215),whichisthemainstayof

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asthmatreatmentasreflectedbythecurrentguidelines. Thus, profiling the non-eosino-philic(Th2low)andtheresidentcellcompart-mentofasthmaaremajorunmetneedsinthefieldofasthmaendotyping.

In the PN-II-RU-TE-2014-4-2303 projectlead by Ioana Agache we hypothesise thatnon-eosinophilic asthma is not a single dis-ease,buta syndrome resulting fromseveraldistinct underlying pathological processesknown as endotypes. Since non-eosinophil-ic asthma represent in adults approximately50%of all casesmany novel investigationaltherapiesdirectedagainstTh2targets (IL-5/IL-13/CRTH2), are likely to have efficacy inonly 50% of subjects with severe disease.There is currently a lack of hypothesisedspecific novel therapeutic targets for nonTh2-mechanismsandthefocusofthisprojectistocharacterisethesealternativedriversofasthmapathophysiology.Weanticipate thattheseapproacheswillidentifypotentialther-apeutictargetsinsubsetsofnon-eosinophilicasthmapatients,leadingtoendotype-specificpersonalisedtherapies.

The main objective of the ongoing researchprojectaretodescribeandvalidatenon-eosin-ophilic asthma endotypes using complemen-taryapproachessuchasdetailedimmunolog-icalandmolecularanalysisofinducedsputumcellsandofsputumandserumcytokinesandchemokinesinextensivelycharacterised(visi-bleproperties)adultnon-eosinophilicasthmapatients(mild/moderate/severe)togetherwithunbiased bio-statistical tools such as clusteranalysistoidentifyputativeimmunopatholog-icalnon-eosinophilicasthmaendotypes.Sec-ondaryobjectivesarealignedwiththeprofes-sionalandacademicdevelopmentand targetcapacitybuildingwithnewskillsorqualifica-tionsgainsbystaffinvolvedintheprojectinthefieldofbioinformatics,molecularbiologyandsputumcellflow-citometrywithFACS-analy-sis,acquirementofleadership,managerialandcommunication skills by young researchers,theprojectaimingtodevelopastableteamofyoungresearchers,whichisanchoredinspe-cific organisational needs and standards. Inadditionweaimtosetupaninterdisciplinaryframeworkforbasic,translationalandclinicalresearch, benefiting from pooled knowledgeandresources leading tonewproductdevel-

opmentinthefieldofasthmabiomarkersandother diagnostic techniques and new treat-ments for asthma andmore resources (bothfundingandhighqualifiedresearchers)forthepersonalizedapproachtoasthmamanagement

Thereareseveralelementsoforiginalityandinnovationinthisproject,relatedtothestateoftheartinthefieldandtothepreviouspro-jectsdevelopedby theproject leader, IoanaAgache. Non-eosinophilic asthma was notendotypedpreviouslysothisisafirsteverat-tempttodelineatethemechanisticpathway,theirbiomarkersandthepotentialtherapeutictargets.Innovativediagnostictechniqueswillbeemployedsuchassputumdialysisandul-trafiltrationforcytokineconcentration,whiletheincorporationoflongitudinaldatasuchasasthmaexacerbationsandlungfunctionintotheclusterswilladdtothevalidityofthecon-struct. The project aims to improve clinicalguidelines and clinical practicebymodellingthebehaviourofhealthcareprofessionalsorprovidersby reinforcing theconceptofper-sonalized medicine and is likely to identifypotential novel targets and biomarkers fornon-eosinophilic asthma. This pathway wassuccessfulforthedevelopmentofbiomarkersof eosinophilic asthma and subsequent se-lectionofresponderstotargetedtreatment.Thisprojectwillthussupportproductdevel-opmentsuchasnewtreatmentsandnewdi-agnostictechniques

The impactexpectedfor thisprojectcanbesystematizedasfollows:

• Knowledge production, such as journalarticlesandpresentations that add toorconfirmexistingknowledgetotheareaofresearch of asthma endotypes and per-sonalizedtreatment

• Capacity building, such as new skills orqualificationsgainsbystaffinvolvedintheproject in thefieldofbioinformaticsandsputumcellFACS-analysis

• Healthsectorbenefits,suchas improvedhealth economics via reduced costs andimprovedasthmacarewithreducedmor-bidityandbetterqualityoflife

Theprojectwillbefinalisedin2017.Prelim-inaryresultsreported inDecember2016onthein-depthcharacterizationonthepatientsbasedonvisibleproperties(phenotype)show

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specifictraitsfornon-eosinophilicasthmaincomparison with eosinophilic asthma suchas increased frequency of nocturnal symp-toms,increasedAHRbothoflargeandsmallairways, increasedresistanceoftheairways,decreaseddiffusioncoefficient,prominentre-modelingandparenchymalabnormalities.Asfor thebiomarkersevaluateduntilnow,half(57.14%)ofthepatientshadincreasedserumlevelsof total IgEprovidingevidence for an“allergic” sub-endotype of non-eosinophilicasthmathatmightberesponsivetotargetedantiIgEtreatment.ThisobservationisinlinewiththedatareportedontheserumIgE in-ducedairwaysmoothmusclecellremodelingindependent of allergens and prevented byomalizumab(216).

B2. COST BM 1201: Early Origins of Chronic Lung DiseaseRecentstudies indicatedthattherisktode-velopchronic lungdisease(CLD)ismodifiedby early exposures during critical develop-mentalwindows.Thisconceptopensuniqueopportunities for thepre-orearlypostnatalmodificationoflaterdiseaserisks,buttheun-derlyingmolecularmechanismsarelargelyun-explored.Toclosethisgap,ahighlycross-dis-ciplinary approach involving scientists frombasic and clinical research is required. Sev-eralEuropeaninstitutionsstudyearlyoriginsofCLDwith adequatenational funding, butthese efforts are not integrated and lack acomprehensive platform for synergistic col-laboration. This COSTAction created a co-ordinated and highly translational researchprogramandbroughtforwardanovelunder-standingofCLDpathogenesiswhilebuildingtheprerequisitesforthesuccessfuldevelop-mentofearlyinterventionsand/orinnovativetherapies.TheCOSTActionBM1201onEar-lyOriginsofChronic LungDisease involvedpartnersfrom21EuropeancountriesandtwopartnersfromtheUnitedStatestopooltheirresourcesandexpertisetoinvestigateeffectsofearlylifeexposuresonchroniclungdiseas-esinlaterlife.Theconsortiumincludedinter-nationallyacknowledgedleadersinkeyareasof epidemiology, lung morphogenesis, lungphysiologyandbiology,immunology,cellsig-naling,lungbiology,stemcellbiology,genet-ics,andclinicalresearchfrommajorresearch

centresacrossEuropeandtheUnitedStates.Manypartnershaveaproventrackrecordincollaborativeresearchandhaveparticipatedinother largescaleEUprojectse.g. suchasEU IMI,UBIOPREDonSevereAsthma,FP7iFAAM Programming food allergy, FP7 RE-SOLVE, FP7MeDaLL or ECRHS III,MedicalResearch Council and others. IoanaAgachewasamemberoftheManagementCommit-tee,thecoordinatoroftheShortTermScien-tificMissionsprogrammeandmemberoftheWorkingGroup1 InfantLungDevelopment.ActivitiesofWG1included

• Censusofexistingbirthcohortswithbothearly life exposure data and respiratoryoutcomes.Expert assessmentofexistingcohortswithinfant lungfunctiondatatoestablish thevalidityof poolingdatabe-tweencohorts.

• Metaanalysisofrelationshipbetweenan-thropometricmeasuresatbirthandadultlung function and lung function decline.Whileobservationshavebeenpreviouslymade in individual cohorts regarding therelationship between fetal growth andrespiratoryoutcomesinadultlife,combin-inganalysesacrosscohortswillstrength-en the evidence. Furthermore, this alsoallowstheinvestigationofpre-andearlypost-natalriskfactorsforpooradultlungfunction

• MetaanalysisoftheeffectofSNPsidenti-fiedingenome-widestudiesofadultlungfunction on their associationwith infantlungfunctionmeasurements

B3. GA2LEN Working Package 2.2.3 on virus-induced exacerbations of respiratory allergyTheDARECohort(‘DefinitionAndRiskfactorsofacuteExacerbationsofrespiratoryallergy:a longitudinalcohort’)hasbeendesigned toassessthedefinitionandriskfactorsofacuteexacerbationsofrespiratoryallergy.Itwillusediarycards,focusingoncommoncoldsand/or asthma exacerbations. Similar cards havebeenusedinseveralstudiesbeforebutmostof them have not been formally validated.IoanaAgacheparticipated in thepilot studyincludingfewselectedcentersthatvalidatedthediary cards tobeused in theDAREco-hort.Diarycardsallowpatientstoreporttheir

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symptomsandthemedicationtheytookdayafterday.IntheDAREstudy,diarieswillbeanessentialtooltohelpdescribewhathappensduringanasthmaexacerbationandcomparewithclinicaldefinitionsfromboththepatientandphysicianperspectives.Theobservationsinthediarycardsincombinationwithforin-stance peak flow rates, bronchial inflamma-tionmeasures,willbethebasisofanoptimaldefinition of an asthma exacerbation. TheDARE study will also evaluate the relativecontributionofexacerbationriskfactorsandcomparesymptomvariabilitybetweenupperandlowerairwaydisease-rhinitisandasth-ma–inthecontextofrespiratoryallergy.TheWorkingPackedalsodeliveredahighlycitedsystematicreview(199)ontheroleofvirusesand bacteria in acute asthma exacerbationswhereIoanaAgacheisco-author.

B4. European Asthma Research and Innovation Partnership (EARIP)TheEuropeanAsthmaResearchandInnova-tionPartnership(EARIP),supportedbyEuro-peanCommissionsFP7programme,aims toidentify the investment required indifferentareas to bring about significant improve-ments inasthmaoutcomes inEurope. IoanaAgachewasinvolvedEARIPWorkPackage4ExpertWorkshoporganisedbytheEuropeanFederation ofAllergy andAirways DiseasesPatients’ Associations (EFA) in close collab-orationwithAsthmaUK. The key objectiveof this workshop was to evaluate existingnational,regionalandEuropeanasthmapro-gramsandtodeveloprecommendationsandgapsforresearchinhealthcaresystemchangeinasthma.Thereportwasrecentlypublished(217)andprovidedthefollowingrecommen-dations:developmentofpreventiveinterven-tions;adoptionofminimumasthmastandardsacrossEurope; theestablishmentofmecha-nismstomeasurepublichealthperformance;booststructuralchanges,focusmoreonper-sonalisedmedicineandextendeducationofbothhealthcareprofessionalandpatients.

B5. INTEGRATED CARE PATHWAYS FOR AIRWAY DISEASES (AIRWAYS-ICPS) (22)WorkingPackage10oftheEuropeanInnova-tionPartnershiponActiveandHealthyAge-

ing,ActionPlanB3;MechanismsoftheDe-velopmentofAllergy

The objective of Integrated Care Pathwaysfor Airway Diseases (AIRWAYS-ICPs) is tolaunchacollaborationtodevelopmulti-sec-toral care pathways for chronic respiratorydiseases in European countries and regions.AIRWAYS-ICPshasstrategicrelevancetotheEuropeanUnionHealthStrategyandwilladdvaluetoexistingpublichealthknowledgeby:

1. proposing a common framework of carepathways for chronic respiratory diseas-es,whichwillfacilitatecomparabilityandtrans-nationalinitiatives;

2. informing cost-effective policy develop-ment,strengtheninginparticularthoseonsmokingandenvironmentalexposure;

3. aidingriskstratificationinchronicdiseasepatients,usingacommonstrategy;

4. havingasignificant impactonthehealthofcitizensintheshortterm(reductionofmorbidity, improvement of education inchildrenandofworkinadults)andinthelong-term(healthyageing);

5. proposing a common simulation tool toassistphysicians;and

6. ultimatelyreducingthehealthcareburden(emergency visits, avoidable hospitalisa-tions,disabilityandcosts)whileimprovingqualityoflife.

In the longer term, the incidence of diseasemay be reduced by innovative preventionstrategies. AIRWAYS ICPs was initiated byArea 5 of the Action Plan B3 of the Euro-pean Innovation Partnership on Active andHealthy Ageing (AHA). All stakeholders areinvolved(healthandsocialcare,patients,andpolicymakers). Eight proposals for synergieshave been approved by theTask Force: Fivecross-cuttingsynergieswhichcanbeusedforall current and future synergies as they con-sideroverarchingdomains(appropriatepolyp-harmacy,citizenempowerment,teachingandcoachingonAHA,deploymentofsynergiestoEUregions,ResponsibleResearchandInnova-tion),andthreecross-cuttingsynergiesfocus-singoncurrentActionGroupactivities (falls,frailty,integratedcareandchronicrespiratorydiseases). Ioana Agache is a member of theAIRWAYS ICPs consortium and co-author oftwopapersinhighlyrankedjournals(22,218).

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2.3. PROFESSIONAL DEVELOPMENT AND NATIONAL AND INTERNATIONAL RECOGNITIONA. MEMBERSHIP IN STEERING COMMITTEES AND EDITORIAL BOARDS FOR THE DEVELOPMENT OF INTERNATIONAL GUIDELINES, CONSENSUSES AND STATEMENTS1. ARIA (Allergic Rhinitis and its Impact on

Asthma) guidelines(19,20)-MemberoftheScientificAdvisoryBoard

The ARIA guidelines process started in1999andwasintendedtobeastate-of-the-artforthespecialistaswellasforthegeneralpractitionerandotherhealthcareprofessionals.IoanaAgacheisco-authorof the 2008, 2010 and 2016 revisionsandfirstauthoroftheARIA2008adap-tation forRomania (125).Unifyingboththe need to asses asthma and allergicrhinitis endotypes and severity/controlassessment Ioana Agache co-authoredthe MeDALL–GA2LEN–ARIA consorti-um position paper (15) introducing theconcept of severe chronic allergic (andrelated)diseases(SCUAD).

2. MASK (MACVIA-ARIA Sentinel Net-worK for allergic rhinitis) (21)SeveralunmetneedshavebeenidentifiedinAR:identificationofthetimeofonsetofthepollenseason,optimalcontrolof rhi-nitisandcomorbidities,patient stratifica-tion,multidisciplinaryteamfor integratedcarepathways, innovationinclinicaltrialsand, above all, patient empowerment. Anew consortium MASK (MACVIA-ARIASentinelNetworKforallergicrhinitis)studygroupwascreated (with IoanaAgacheasamember of the Expert Panel) to tackletheseunmetneeds.Oneofthefirstdeliv-erables(21)oftheconsortium(MASK-rhi-nitis)isasimplesystemcentredaroundthepatientwhichwasdevisedtofillmanyofthese gaps using Information and Com-munications Technology (ICT) tools andaclinicaldecision support system (CDSS)basedonthemostwidelyusedguidelinein allergic rhinitis and its asthma comor-bidity(ARIA).Threetoolsareusedforthe

electronicmonitoringofallergicdiseases:acellphone-baseddailyVASassessmentofdisease control, CARAT (Control ofAller-gicRhinitisandAsthmaTest)ande-Allergyscreening(premedicalsystemofearlydiag-nosisofallergyandasthmabasedonon-linetools).ThesetoolsarecombinedwithCDSSandareavailable inmany languag-es.Ane-CRFandane-learningtoolcom-pleteMASK.MASK is flexible and othertoolscanbeadded.Itappearstobeanad-vanced,globalandintegratedICTanswerformanyunmetneedsinallergicdiseaseswhichwillimprovepoliciesandstandards.TheCDSSiscurrentlybeingtestedinclin-icaltrials(141).

3. EAACI International Guidelines for Clini-cal Practice for Allergen Specific Immu-notherapy (AIT)–MemberoftheSteer-ingCommitteeandChairTaskForceforAITinasthma

Considering the unmet needs in AITthe European Academy of Allergy andClinicalImmunologyis intheprocessofdeveloping guidelines for public healthusing the AGREE II methodology fortheAIT use in all allergic diseases. Ioa-naAgache is amemberof theSteeringCommitteeoftheGuidelinesGroupandisleadingtheTaskForceonAITinasth-ma.ThescopeoftheAITAsthmaGuide-lines istoproviderecommendationsforindicationsandcontraindicationsforAITinasthmabasedoneffectiveness,safetyandcost-economicanalysisandtoiden-tifygapsinknowledgeand/orimplemen-tation,unmetneedsandfutureperspec-tives.TheAITasthmaTaskForceincludeda wide range of countries, professionalbackground (allergy, pediatrics, internalmedicine,pediatricpulmonology, immu-nology, primary care, pharmacists) andpatientrepresentatives.Foracriticalap-praisalof theevidencepublishedso farweperformedbothasystematicreview(SR)andanarrativereview.Theprotocol

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for the SRwas published at the begin-ningof2016(102)andtheresultsoftheSRarecurrentlyunderevaluation.

4. EAACI International Guidelines for Food Allergy and Anaphylaxis – Member oftheSteeringCommitteeandTaskForceChaironManagingpatientswithfoodal-lergyinthecommunity.

The EAACI Food Allergy and Anaphy-laxis Guidelines Group has undertakenthisunprecedentedprojectover2years.Within the group, six task forces havecomprehensively reviewed food allergyand anaphylaxis in children, adolescentsandadults.Theactivityhasbeenground-ed in evidencewith the use of compre-hensive systematic reviews and, whereappropriate,meta-analyses of the litera-ture.Theworkwascarriedoutbyawiderange of health care professionals andscientists alongwith the involvement ofbothpatientgroupsandregulators.IoanaAgachewasamemberoftheTaskForc-es on Epidemiology and Prevention andledtheTaskForceonManagingpatientswith foodallergy in thecommunity. Ioa-naAgacheisfirstauthorandco-authorofseveralpapersonguidelines recommen-dations(197)andsystematicreviewssup-portingtherecommendations(193,196).

5. Member of the expert panel of the iCAALL collaboration.Fourof themostinfluential allergy/immunology profes-sional organizations have joined forcesto launch the International Collabora-tioninAsthma,AllergyandImmunology(iCAALL).ParticipatinginiCAALLaretheAmericanAcademyofAllergy,Asthma&Immunology(AAAAI),theAmericanCol-lege of Allergy, Asthma & Immunology(ACAAI),theEuropeanAcademyofAller-gyandClinicalImmunology(EAACI)andtheWorldAllergy Organization (WAO).iCAALL is designed to collect and dis-seminate consensus-driven informationaboutallergies,asthmaandimmunolog-icaldiseases.Communicatingthisknowl-edgecanpositivelyimpactdiagnosisandtreatment, as well as cost containmentand policy decisions. A major focus ofthis initiative is theproductionof a se-

ries of International Consensus (ICON)reports.These documents offer generalrecommendationsbasedonglobalchal-lengesincaringforpatientswithallergicandimmunologicdiseases.

IoanaAgachewasmemberoftheICONon Allergen Immunotherapy. Two con-sensus documents were published inJACI(97,98)

6. Member of the expert panel of the PRACTALL collaboration. The PRAC-TALL program is a common initiativeofEAACIand theAAAAI. It focusesonpracticalaspectsofallergytodeliverup-datedandevidencebasedrecommenda-tionsforclinicians.

IoanaAgachewasmemberofthePRAC-TALLonPrecisionMedicine.Theconsen-susdocumentwasrecentlypublishedinJACIwiththeIoanaAgacheaslastauthor

7. Chair of the EAACI-European Respirato-ry Society Task Force “Understanding of and Adherence to International Guide-lines in the Management of Stable Asth-ma by Non-Specialists. Indications for Specialist Referral”.Thistaskforceintendsto:

1. Systematicallyreviewtheliteratureinordertoidentify:

a. Previous studies and audits as-sessingtheunderstandingofandadherence to the internationalasthma guidelines and whetherany interventionswere suggest-edinordertoimprovethequalityofcare;

b. Studiesassessingwhetherdiffer-ent thresholds of referral to therespiratory team improved thequalityofcare.

2. Develop, validate and distribute ashortonlinequestionnaire to assesstheunderstandingofandadherencetointernationalguidelinesamongthedifferentspecialtiesacrossEurope.

Multiple-choicequestionswillbeusedtoassesstheapproachtosimpleandfrequentclinicalscenarios inpatientswithasthma.Theapproachtothediagnosis,assessment

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andmanagementofstableasthma,aswellasthemanagementofacuteasthmaexac-erbationswillbeassessed.

All datawill be combined and analysedandifsignificantdiversityishighlighted,itwillbedecidedwhetherthesedifferenc-escouldbenarrowedbyfurthertrainingorwhetheranearlierinputbyrespiratoryphysiciansmaybeconsidered.

OutcomesoftheTaskForcewillbepub-lished as an official ERS/EAACI State-ment.

8. ChairofEAACITaskForceon“Lifestyle Interventions in Allergy and Asthma”The focusof thisTaskForcewasa sys-tematicreviewoftheeffectsofnutrition,physical activity andobesity on asthmaand allergies related outcomes both inchildren and adults. One SR onweightgain and losswas published, one over-viewondietwaspublished aswell, to-getherwiththeprotocolforthesecondSRondiet,whichisongoing.

9. SecretaryoftheEAACITaskForceon“Al-lergy Management in Primary Care”This Task Force outlined and proposedthe optimalwork up and diagnostics tobeperformedinpatientsvisitingprimarycare, including standardization of tests,suggested health economy considera-tions of available tests and provided anup-to-date guideline on what to do inprimary care, interpretation of the testsandwhentoreferallergypatientstosec-ondarycare.Thefinalaimwastoensurethat allergy patients are investigated atthelowestappropriateeconomiclevelattheminimumappropriatecost forsocie-ty.ThreepaperswerepublishedinAllergywithIoanaAgacheasfirstorlastauthor.

10. SecretaryoftheEAACITaskForceon“In vivo allergy diagnosis”Theallergenchallengetesthasbeenthemainstayofdiagnosisofallergicdiseas-esforalongtimesinceitoffersadirectproof of the clinical relevanceof a par-ticular allergen for the allergic diseasesymptoms and severity. Standardisationandavailabilityfordailypractice(includ-

ing safety issues) are still to be refinedbut most of the challenge tests havesafelycrossedtheborderfromresearchtoolstodiagnostictestsavailablefordai-lypracticeforawelltrainedclinicalstaff.The use of recombinant allergens andmoderntechniquestoobjectivelyquan-tifyandcomparethebiologicalmodifica-tions induced by allergen challenge arehighly promising. Proper use of clinicaljudgementinrecommendingachallengetest,selectionoftheappropriateallergenfor testingand interpretationof results,as derived of a thorough training as anallergist,areessential toensurethede-served value of allergen challenge test.The EAACITF on “In vivo allergy diag-nosis”providedacriticalappraisalofal-lergenchallengemethods,togetherwithrecommendationsonindications,proce-dureandsafety.ThepaperwaspublishedinAllergybyIoanaAgacheasfirstauthor.

11. Secretary of the EAACI Task Force for“Allergy Nomenclature”The aims of this TF are to develop anupdatedof allergy, to include themiss-ing new diseases, such as eosinophilicosephagitis and new concepts such asendotypes, immune tolerance, to coverhypersensitivityreactionsundertheum-brella of our specialty, to have interna-tionaldisseminationandacceptanceandaligned veterinary terminology. BesidestherevisedterminologyanEncyclopediaofAllergywillbepublished

12. Member of the EAACI Task Force on“Guidelines on Pediatric Clinical Trials”.TheBelmontReportjustifiedresearchin-volvingchildren,asitwouldhelpfindbet-terways of treating childhood illnessesandpromotetheirhealthydevelopment.(6).TheReportcategorizedchildrenasavulnerable population with diminishedautonomy and hence entitled for addi-tional protection from undue influenceand coercion.The protective approach-essuchasrequirementofcarefulscruti-nyofpediatricresearchprotocolforthelevelof risk,entrustingtheresponsibili-tyofpermitting thechild toenrollwithparentsanddemandingstepsforminimi-

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zationofriskaresomeoftheprotectiveapproachesdescribedinthatreport.

Consideringtheimportanceofdrugtrialsinchildren, theUSandEuropeancoun-triesenactedseveral legalprovisions toencourage, entice or compel pharma-ceutical companies to undertake pedi-atric trials. The European Regulation ofPediatricMedicineshasthreemajor ini-tiativesforensuringthatchildrenwillre-ceivedrugsthataresafeandefficacious:the adoption of incentives for industry,theimplementationofamandatoryPedi-atric Investigation Plan considering allagerangesandthecreationofaPediatricCommittee.

Respondingtotheneedstoaddressasth-maandallergyinchildrenEAACIstartedthisTask Force aiming to offer regularyagenciesthescientificrecommendationsensuringboththeefectivenessofthetri-alsandthesafetyofthesubjectsinclud-ed.

13. MemberoftheEAACITaskForceon“Di-agnosis and Management of NSAIDs-Ex-acerbated Respiratory Disease”. This TFaimstocollectandanalyseavailabledataontheclinicalfeaturesandheterogeneityofasthma/CRSphenotypeassociatedwithhypersensitivitytoNSAIDs,tosummarizenovelinformationonthepathomechanismofNSAIDs-inducedhypersensitivity reac-tionsaswellasonthepathophysiologyoftheunderlyingeosinophilictissue inflam-mation (endotype, biomarkers), to assessperformance and propose recommenda-tions for diagnostic methods to confirmNSAID hypersensitivity (oral , bronchialchallengesandinvitrotests),toreviewtheeffectiveness of currently available, phe-notype-specific treatmentmodalities andtoagreeonalgorithm(s)fordiagnosisandmanagementandunmetneeds

14. Member of the EAACI Task Force on“The role of nutritional factors in immu-nomodulation”.Optimalfunctioningoftheimmunesystemiscrucialtohumanhealth,and nutrition is one of themajor exoge-nousfactorsmodulatingdifferentaspectsof immune function. Currently, no singlemarkerisavailabletopredicttheeffectof

adietaryinterventionondifferentaspectsofimmunefunction.Nutritionmaymodu-latetheimmunesystemofbothhealthandcompromisedpeople.Anumberoffactorsmay play a role, including, milk, breast-feeding, enteral feeding, prebiotics, andprobiotics.Thegoalofthistaskforceistocollectivelydevelopandpublishupdated,authoritativeandevidencebasedpositionpapersinthisimportantfield.

15. Member of the EAACI Task Force on“Standardization of nasal allergen chal-lenges.The laststandardization ismorethanadecadeago,withthelastpositionpaperpublishedin2004.TheaimofthisTask Force is to evaluate and critical-ly discuss all subsequent technical im-provements and scientific findings thatweremadeduringthelast12years.

16. MemberoftheEAACITaskForceon“The Harm Of Long-term Use Of Systemic Steroids In Rhinitis And Rhinosinusitis”.This TFwill gather evidence to demon-stratethatuseofsystemiccorticosteroidsordepot-steroidinjectionsisharmfulbothshort term and long term and providesupportfortherecommendationthattheuseofsystemiccorticosteroidsshouldbeabandoned as standard long term treat-mentforrhinitisandrhinosinusitis.

B. EDITORIAL ACTIVITY

• Associate Editor of Clinical and Transla-tionalAllergysince2014

• EditorialboardPolishJournalofAllergol-ogy

• EditorialboardoftheRomanianSocietyofAllergyJournal

• CoordinatingEditorforEAACIGlobalAt-lasofAsthma(2013)(23),GlobalAtlasofAllergy(2014)(24(2015)(25)

• EditorialboardofFoodAllergyandAna-phylaxisGuidelines(2014)(213)

• Coordinating Editor for ImplementingPrecisionMedicine In Best Practices OfChronicAirway Disease due to be pub-lishedbyElsevierinNovember2017

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C. BOOKS, MONOGRAPHS • Ioana Agache.Phenotypesandendotypesofallergicrhinitis.GlobalAtlasofAllergicRhinitisandChronicRhinosinusitis2015,publishedbyEAACI,pg.268-270

• Ioana Agache,CezmiAkdis.Endotypesofallergic diseases. Global Atlas of Allergy2014,publishedbyEAACI,pg.104-107

• Muraro A, Agache I, Clark A, Sheikh A,Roberts G, Akdis CA, et al; EuropeanAcademyofAllergyandClinicalImmunol-ogy(EAACI)foodallergyandanaphylaxisguidelines: managing patients with foodallergy in the community, published byEAACI,pg.239-259(219)

• Ioana Agache.Bestbuysforasthmapre-ventionandcontrol.GlobalAtlasofAsth-ma 2013, published by EAACI, pg. 132-134

• Ioana Agache. Astmul-de la noi mecan-isme patogenice până la noi metode deterapie,2008,EdituraLuxLibris,Braşov,

• MarianaRădoi,Ioana Agache,DianaŢînţ,PatologiaTrombotică.Dateactuale,2007,EdituraLuxLibris,Braşov,209pag

• MarianaRădoi,Ioana Agache,Reacţiain-flamatorieînateroscleroză–dateactuale,în”Progreseincardiologie”subredactiaL.Gherasim, 2002, Editura Infomedica, pg.337-399

• Mariana Rădoi, Ioana Agache, Astmul în“PneumologieClinică”subredacţiaM.Ră-doi,VolI,1999,Ed.Concordia,pg.75-138

• Ioana Agache, Mariana Rădoi Boli pul-monareinterstiţialeîn“PneumologieClin-ică” sub redacţia M. Rădoi, Vol I, 1999,EdituraConcordia,pg.139-200

• MarianaRădoi,Ioana Agache,T.Alexand-ru,PneumologieVol I, 1999,ReprografiaUniversităţii “Transilvania” Braşov, 200pag

• EmanoilGheorghiţă,Ioana Brumaru,Imu-nologie.VolI,1998,ReprografiaUniversi-tăţii“Transilvania”Braşov,105pag

D. REVIEWER ACTIVITY • Reviewer board of Journal of Allergy

and Clinical Immunology (impact factor12.485)since2010

• ReviewerboardofJournalofAllergyandClinical Immunology in Practice (impactfactor6.335)since2014

• ReviewerboardofAllergy (impact factor5.429)since2009

• Reviewer for the European Commission,DGResearch&Innovation,E4Non-com-municableDiseasesandtheChallengeofHealthyAgeing

• Reviewer for Asthma UK

• ReviewerforNationalScienceCenter,Po-land

• Reviewer for Respiratory Research (im-pactfactor3.751),PlosOne(impactfactor3.234), International Archives of Allergyand Clinical Immunology (impact factor2.677),RespiratoryMedicine(impactfac-tor3.036)

E. LECTURER AT INTERNATIONAL MEETINGS IN ASTHMA AND CO-MORBIDITIES (SELECTED LIST)• MicrobiomeandAsthma:AnObviousbutOften Overlooked Parameter – March2017,AAAAIAnnualMeeting

• Precisionmedicineinasthma–November2016,EuropeanRhinologyForum

• Precisionmedicineinallergyandasthma-October2016,JointCongressofAPAAA-CI&APAPARI2016

• Appraising the Evidence: Is PrecisionMedicineReadyfortheClinic?–October2016,9thHongKongAllergyConvention

• TheComplexityofType2AsthmaEndo-type-October2016,9thHongKongAl-lergyConvention

• Serum IL-5 and IL-13 consistently serveas the best predictors for the blood eo-sinophilia phenotype in adult asthmatics–September2016,EuropeanRespiratorySocietyAnnualMeeting

• Food allergy and asthma – September2016,XLIIICongressoBrasileirodeAler-giaeImunologia

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• Useofbiomarkers inpersonalizedmedi-cine–June2016,EAACIAnnualCongress

• Canweaffordasystemchangetopreventdiseaseprogression?–January2016,Al-lergyThinkTank

• Type2asthmaendotype–October2015,WorldAllergyCongress

• Theasthmaepidemic:Howdidwecometoworldwide300Millionpatients?–Oc-tober2015,GlobalRiskForum

• Asthmaphenotypesandendotypes–im-plicationsforAIT–October2015,PolishAllergySocietyAnnualmeeting

• Newtools in asthma:biomarkers–June2014,EAACIAnnualMeeting

• Lessons from the lower airways – June2014,EuropeanRhinologySocietyAnnu-alMeeting

• Induced sputum cytokines and chemok-ines and mechanistic pathways in adultasthma phenotypes – September 2014,European Respiratory Society AnnualMeeting

• Mechanism-guidedtreatmentforasthma–June2013,EAACIAnnualMeetingandWorldAllergyCongress

• Molecularmarkersofasthmaphenotypesandendotypes–December2011,WorldAllergyCongress

• Immune pathogenesis of asthma exac-erbations – June 2011, EAACI AnnualMeeting

• Isanti-microbialtherapyanoptiontotreatasthma/allergy?–November2008,WorldCongressofAsthma

• AsthmamanagementinEasternEurope–November2008,WorldCongressofAsth-ma

F. INTERNATIONAL RECOGNITION Iamcurrently involved inseveral leadershipboardsandcommitteesof internationalpro-fessionalorganisations

• 2017-2019–Presidentof theEuropeanAcademyofAllergyandClinicalImmunol-ogy(EAACI)

• 2017-2019-WAO(WorldAllergyOrgan-isation)NominatingCommittee

• 2013-2017-Vice-PresidentCommunica-tion&MembershipofEAACI

• 2009-2013 - EAACI Executive Commit-teeMemberatLarge

• Since2008-WHOprojectARIA(AllergicRhinitisand ImpactonAsthma)AdvisoryCommitteeMember

• 2005-2009 - Secretary of the EAACIAsthmaSection

• 2005-2009 - EAACI Scientific ProgramCommittee

• 2009-2011-WAOAsthmaSpecialCom-mittee

• 2008-2009 - WAO CommunicationCouncil

• 2009-2011-WAOCongressCouncil

• 2008-2009-WAOAllergyDiagnosisSpe-cialCommittee

• 2000-2005-EAACIJuniorMembersandAffiliatesWorkingGroup

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2.4. LEADERSHIP AND MANAGERIAL SKILLS

Between 2004-2007 IwasHead of theAl-lergy and Clinical Immunology Department,BrasovCountyHospitalandsince2006IamtheMedicalManagerandHeadofAllergyandClinical Immunology Department, Nation-al Centre of Allergy and Asthma TheramedHealthCareBrasov

Since 2003 I am leading the ImmunologyDiscipline atTransylvaniaUniversity Brasov,FacultyofMedicineandsince2010IamalsoleadingthePhysiologyDiscipline

On the international side since 2013 I amleadingtheCommunicationandMembershipDepartmentoftheEuropeanAcademyofAl-lergyandClinicalImmunology,aprofessionalorganization with 10.000 members world-wide

I am also leading the PN-II-RU-TE-2014-4-2303 project, Endotypes ofNon-EosinophilicAsthma(ENDANA)

Academic development

Chapter 3

B-iScientific and


111


Academic developmentScientific and professional achievements

Myacademicdevelopmentcombinedteach-ingactivitieswithcreativeresearchasanex-tensionoftheself-developmentprocess.

Teachinginvolvesanopened-mindedplanforhelpingstudentsandyoungdoctorstomeetandexceededucationalgoals.Teachingstylesmay differ from teacher to teacher, class toclassandschool to school.Yetevery teach-ing objectivemust include a structured butflexibleprocessforstudentadvancement.Myacademiccareer started in1996asaJuniorAssistantProfessoratTransylvaniaUniversityfromBrasov,whereIamatpresentanAsso-ciateProfessor.ThroughmyacademiccareerIfocusedonengagingstudentsinthelearn-ingprocessandmotivatingthemtopracticehigher-levelcriticalthinkingskills,whilepro-motingmeaningfullearningexperiences.

A. 1996-2000, Junior Assistant Professor, TransylvaniaUniversityfromBrasov,Fac-ulty of Medicine, Internal Medicine De-partment,ClinicalImmunologyDiscipline

As JuniorAssistant Professor I deliveredpracticallessonsinthefieldofclinicalim-munologytothemedicalstudents in the4thyearandlecturesininternalmedicineto the students in the 4th and the 5thyear.To achieve these tasks I developedthecurriculumforpracticallessonsinclin-ical immunologyandrespiratorydiseasesformedical students (alsopublishedasareferenceguides,seebelow)andthecur-riculumforlecturesinasthma,chronicob-structivelungdiseases(COPD),interstitiallungdiseasesandanaphylaxis.

I supervised together with the Head ofthe Discipline 5 dissertation thesis andwrote twopractical reference guides forstudentsuse:

1. Emanoil Gheorghiţă, Ioana Brumaru, Imunologie. Vol I, 1998, ReprografiaUniversităţii“Transilvania”Braşov,105pages

2. MarianaRădoi,Ioana Agache,T.Alex-andru, Pneumologie Vol I, 1999, Re-prografia Universităţii “Transilvania”Braşov,200pag

B. 2000-2006, Assistant Professor,Transyl-vania University from Brasov, Faculty ofMedicine,InternalMedicineDepartment,ClinicalImmunologyDiscipline.

C. AsAssistantProfessorIcontinuedtheprac-ticallessonsinthefieldofclinicalimmunol-ogytothemedicalstudentsinthe4thyearandtothestudentsattendingthe2ndyearat the General Nursing specialization to-getherwithlecturesininternalmedicinetothestudentsinthe4thandthe5thyear.Toaccomplish these tasks Idevelopedanewcurriculuminallergyandclinicalimmunolo-gyadaptedtotheneedsofGeneralNurs-ing focusing on practical aspects such asrecognition and treatment of emergencies(anaphylaxis,severedruginducedreactions,severe asthma attack, acute hemolysis,acuterespiratoryfailure,etc)togetherwithpreventivemeasures(anaphylaxisandana-phylactoidreactions,drughypersensitivity,immune induced tissue and blood incom-patibility,latexandfoodallergy,etc)

In2003IbecameHeadofClinicalImmu-nologyDisciplineandstarted the lectureprogramme in clinical immunology forthemedicalstudentsinthe4thgrade.Toachieve thisassignment I implementedanew teaching approach based on the in-teractive teaching styles incorporating amultitudeofgoalsbeneatha single roof.Interactiveclassesweredesignedaroundasimpleprinciple:withoutpracticalappli-cation,studentsoftenfailtocomprehendthe depths of the study material. Inter-active training stylesprovided fourbasicformsoffeedback:

• Measurablestudentaccomplishments:severalstudentschooseaftergradua-tiontospecialiseinAllergyandClinicalImmunologyandonejoinedthedisci-plineasJuniorAssistantProfessor. Inadditionthegradesatthefinalexami-nationimprovedconsiderably

• Flexibility in teaching: applying train-ing methods that involve two-waycommunications enabled quick ad-justmentsinhowtheinformationwasdeliveredandthelecturesweremod-ifiedeachyearaccordingtotheinputreceivedfromstudents

Teachers are integral portions of a student’s ability to succeed in life.

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• Practicemakesperfect:interactivein-struction enhanced the learning pro-cesswithstudentsacquiringpracticalskillsvaluable for their further careerdevelopment.

• Studentmotivation:two-wayteachingand constructive feedback dispelledstudentpassivityandengagedtheminlectures and practical lessons design,researchprojects and involunteeringactivitiesatthehospital(nightroundsintheemergencydepartmentorinthegeneral department, home visits tocheckoncriticallyillpatients,etc)

Variabilityinteachingmethodsandmate-rials,learningaidsandmultiplelevelques-tionswerealsoused.

Icontinuedtosupervisedissertationthe-sis while implementing a new approachfor creative scientific research to improve students’perceptionofacademicsuccess.Thestudentswerestimulatedtoapproacha task-oriented behavior, exactness andconsistency in the scientific quest whilerespectingtheethicprinciplesofresearch.Proactivity,personalresponsibility,vision,anddisciplinewereenforcedasbasicprin-ciplesofcreativescientificresearch.Ahighqualityresearchenvironmentwasensuredinordertodevelopresearchstrengthsofthestudentwiththedissertationasakeyopenerforfuturecareerdevelopment.

2006-2007, Lecturer, Transylvania Uni-versityfromBrasov,FacultyofMedicine,Internal Medicine Department, ClinicalImmunologyDiscipline.

Between 2006 and 2007 I continued tolecture inclinical immunology to the4thyear medical students and to 2nd yearstudents inGeneralNursing. Inparallel IcoordinatedtheactivityofresidentsinAl-lergyandClinicalImmunologyfromdiffer-entyearsoftheirresidency.

2007-present, Associate Professor,Tran-sylvaniaUniversityfromBrasov,FacultyofMedicine, InternalMedicineDepartmentand since 2008 Fundamental ScienceDepartment, Immunology Discipline andsince2010bothPhysiologyandImmunol-ogyDisciplines.

In2008theprofileoftheDisciplinethatIleadchangedfromClinicalImmunologytoImmunologyandIstartedanewcurricu-lumforthe3rdyearmedicalstudentswithextendedfocusonbasicimmunology.

In 2010 I was assigned the Physiolo-gyDiscipline formedical students in the2nd year. I developed a new curriculumwhilekeepingthenewteachingapproachbasedon the interactive teaching styles.The new curriculum implemented nov-el concepts such as physiologic systemstemporal behaviors and structural pat-ternsinhealthanddiseasetogetherwiththe application of biomedical researchwith concepts and computational toolsderived from the contemporary study ofcomplex systems suchas the respiratoryor the cardiovascular system. In parallelthenewcurriculaincorporatedcross-sec-tionalinformationfromrelateddisciplinessuchasfunctionalgenomicsandgene-en-vironment interactions,cell signalingandthe role of cytoskeleton, lung and heartstressors,etc.Athoroughpracticallessoncurricula teachingmethods for exploringlung, heart, circulation, endocrine andnervoussystemwasdeveloped

In 2014 I was appointed the Physiolo-gy Discipline for 1st year students fromPhysical-Kinetic-Therapy specialisation.Idevelopedanewcurriculumaddressingthe special needs of their specialisationsuchasbiomechanics,respirationinexer-cise,orcardiopulmonaryexercisetesting

Addressing the needs of early career re-searchesandyoungdoctorswasalsopartofmyAcademicdevelopment.

In2008Iwasalecturerinthemasterpro-gramme for Emergency Medicine withlecturesonasthmaandanaphylaxisman-agement and since 2014 I am a lecturerin researchmethodologyandscience forthemasterprogrammeofPalliativeCareStrategiesandforthemasterprogrammeManagementofpreventivestrategiesandhealthpolicies.

THE EVOLUTION AND DEVELOPMENT PLANS FOR

CAREER DEVELOPMENT

B-ii

My career achievements in the last decade offer me a position at the forefront in translating bench-to-bedside innovations while offering the best education and research training.

The modern research and learning environment, much more complex and challenging than before, new models of care, a sufficient pipeline for our clinical and academic workforce, international recognition through strong partnerships are “key-shapers” of the changing landscape to which my future career needs to adapt. The challenge is to develop relevant and practical deliverables and to grow steadily in a sustainable way

My career focus is personalized medicine in asthma from endotypes and biomarkers to new patient centered models of care. “Team care” is the center of my practice. Medicine requires passionate, supportive, collaborative providers. In my clinic and at the university we embrace an interdisciplinary model that capitalizes on patients and students’ engagement while delivering high-level education. I’m proud to have trained graduate students, and

undergraduates, many of whom have attained academic positions or reached the level of independent investigator.

Based on the SWOT analysis of my career development the following aspects should be considered to pursue further achievements my scientific, professional and academic development

Strenghts: professional, scientific and didactic abilities developed in the last 12 years of my career; strong partnerships and the national and international level; interdisciplinary joint effort to develop curricular activities

Weaknesses: small research team that can be developed by incorporating PhD students as their coordinator

Opportunities: improved collaboration with professional and allergy networks from the perspective of the EAACI 2017-2019 Presidency

Threats: incoherency in legislation and declining human and economic resources

Scientific development future plans

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Scientific development future plans The evolution and development plans for career development

A. ASTHMA ENDOTYPESBuilding on the results from the PN-II-RU-TE-2014-4-2303 project, Endotypes ofNon-EosinophilicAsthma (ENDANA)projectmyfutureresearchplansfornon-eosinophil-ic asthma focusonvalidationof the suben-dotypes both through therapeutic targetedintervention and by longitudinal evaluationofthestabilityoftheclustersdescribed.Thesame approachwill be undertaken for type2 asthma subendotypesusing andunbiasedapproach such as topological data analysis,Bayesian network analysis and longitudinalevaluation. Expansion of endotype researchinto the pediatric asthma population is alsoanticipated.

Expected benefit is translation of endotyperesearch into bedside, clinically meaningfuldecisionprotocolsforselectingatargetedin-terventionintoagivenasthmapatientandforabetterprognosisofdiseaseevolution.

B. BIOMARKERS AND ENDOTYPES FOR ALLERGEN IMMUNOTHERAPYAnewprojectthatisabouttostartincoop-eration with the Swiss Institute for AllergyandAsthmaResearch(SIAF)willevaluatethebiomarkersfortheefficacyofallergenimmu-notherapyinadultandpediatricpatientswithallergicrhinitisandasthma.

Objectives

1. tovalidate thebiomarkersacrossclinicalefficacy end-points such as decrease inthe symptom andmedication score, de-creaseinasthmaexacerbations,improvedlungfunction,decreasedsteroid loadforrhinitis and asthma control, decrease inthenasalprovocationtestscore,improvedqualityoflife,improveddiseasecontrol

2. tolinkbiomarkerstotheendotypesofre-sponderstoAIT

ThestudywillevaluatetheAITbiomarkersintwodatasets:

1. Aretrospectiveanalysiswillcorrelatetheresponder statuswith biomarkersmeas-uredfrombloodandnasalsamplesfromadultsandchildrenafter2-3yearsofAIT

2. Aprospectiveanalysiswilluseserialblood

and nasal samples from adults and chil-drenatthebeginning,afteronemonthofAIT,afterreachingthestablemaintenancedoseofAITandattheendofAIT.Thesec-ondsetwillallowtheidentificationofear-lypredictorsofresponsetoAIT.

Expectedbenefitsaretheidentificationofre-sponderstoAITbasedontheirendotypeandreshapingtheallergyvaccineadaptedtotar-gettheresponderpathways.

C. INTERNATIONAL GUIDELINES AND CONSENSUS DOCUMENTS DEVELOPMENT AND IMPLEMENTATION SeveralitemsareinpreparationfollowingtheARIAguidelines in2016and theAITguide-lines in2017.FoodAllergyandAnaphylaxisguidelines launched in 2014 are in the pro-cess of dissemination and implementationwithin the primary care network across Eu-rope. EAACIwill engage startingwith 2017intheAtopicDermatitisInternationalGuide-linesandconsensusdocumentsincollabora-tionwithAAAAI andERS are envisaged forbiologicsandexposomeinasthma.

D. MOBILE HEALTH/ALLERGY 2.0 AND 3.0Rapid advances in health information tech-nology(HIT)havecreatedunprecedentedop-portunitiestocollect,analyzeandlearnfromvast amounts of “real-world” data that cur-rentlyarelockedawayinunconnectedserv-ersandfilecabinets.Whileclinicaltrialswilllikely remain the gold standardof evidence,crowdsourcing backed up by HIT advanc-espromises toovercomethecurrent limita-tionsofobservational data.By analyzing animmense body of observational data in realtimephysiciansandresearcherscan identifytrendsandassociationsbetweenmyriadvari-ablesandgeneratenewhypothesesanddrawimmediatepractice-changingconclusion.

The project will develop an IT-based sys-temforasthmaclinics thatsecurelycompileand analyze information from the individualelectronichealthrecords(majorclinicalend-points, comorbidities, symptom scores, ob-jective measurements, treatments, side ef-fects,molecular profiles, quality of life, etc).Thedatacollectedwillnotbebiasedbyany

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pre-selection criteria. Advanced HIT tools,suchasrapidlearningsystems,willstructurethehugebodyof unbiaseddata bynormal-ising similar information even if provided indifferentformats,correctingforthewidevar-iationindatastandards.Thendatawillberunthroughcorrelationandtrendanalysistools,revealing connections that can be used todrawstatisticallyvalidconclusionsanddevel-oprobusthypotheses

Inadditionthesystemwillprovidereal-time,robustandtrulyinformativeclinicaldecisionsupportatthepointofcare.Decisionsupportat thepointof care is amust in theadventof precisionmedicine in the clinic.As a re-sultof this real-timeguidance,mostasthmacarewillharmonisedandbasedonguidelines,practiceparametersandqualitycriteria.Oth-erproviderswillplaya larger role in routineasthma care. For less complex cases and infollow-upcareprimarycarephysicians,com-munity pharmacists and allied health work-erswill be equipped to provide care basedon the IT-system feedbackandconsultationwith specialists. The increased involvementofnon-specialistswillcounteracttheasthmaspecialists’ shortage that isprojectedas thepopulationagesandallergyandasthmainci-denceincreases.Specialistsfreedupfromac-tivitiesthatdonotcapitalizeontheiruniqueexpertisewillbeabletoguideoroverseecareforlargernumbersofpatientsandcanfocuson developing better prevention and treat-ment plans and highly qualified managingcare teams.

Through personalized, patient-friendly HITtools, patientswill have amuchgreaterop-portunitytoserveaswell-informedadvocatesfortheirowncareandtostayconnectedwiththehealthcareproviderinrealtime.Asignif-icant shift in thedoctor-patient relationshipisexpectedwiththepatientbetterinformedonallergyandasthmawhenhearrivesattheconsultation and the doctor provided withpersonalized information from patient por-tals.Thepatientsareexpectedtocontributeto all important decisions about their carewith increased confidence that treatmentplanswillwork since they truly reflect theirpatients’wishes.Theywilltakeanactiverole

intheircarebyreportingtheirhealthstatus,side effects and other experiences as theyhappenandthusthemajorityofpatientswillparticipate in clinical research with greaterunderstanding and appreciation of clinicalresearchasapartof routineallergycare, inpartbecauseenrollmentprocedureswillbe-comesimplerandmorepatient-andprovid-er-friendly.

GlobalHITsystemswillallowphysiciansandpatients anywhere in the world to benefitfrom the latest, best available knowledge,helping to reduce today’s noticeable globaldisparitiesinallergyandasthmacare.Low-re-sourcecountrieswillcontributeto,andben-efit from, global cooperation networks.Thebenefits of clinical decision support will begreatest incountriesor regionswherealler-gists are in short supply.At the same time,collecting the experiences of patients inthesecountrieswillleadtothedevelopmentofmeaningfulinternationalclinicalguidelinesforallergyandasthmacare.Allergyresearchgoglobal,asHITsystemslinkresearchers,pa-tients,biobanks,registriesandresearchpro-cedures,even in themost remote locations,soendotyping—acentralelementofprecisionmedicine—becomesaffordableanduniversal.

E. DEVELOPMENT OF PROTOCOLS FOR EDUCATIONAL INTERVENTION IN THE COMMUNITY FOR ASTHMA MANAGEMENTThecommunitypharmacyisanewmilieuforasthmacare.Theprojectwilldevelopacareprotocol with the important ingredients ofasthma education on medications, triggers,self-monitoring and an asthma plan, withpharmacists taking responsibility for out-comes,assessmentofapatient’sreadinesstochangeandtailoringeducationtothatread-iness, compliance monitoring and physicianconsultation to achieve asthma prescribingguidelines.

Expected benefits while using the pharma-ceutical care-based protocol are significantimprovements in clinical, economic and hu-manistic outcome measures in asthma pa-tientsasanincentiveforthehealthcaresys-temtosupportsuchcare.

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Wehaveamoraldutytopromotehighstand-ardsofbothmedicalundergraduateandpost-graduatemedicaleducation.Iwillcontinuetooffermedicalstudentsandhealthcareprofes-sionals (HCPs) purposeful training to reflectchangesinpractice,changesintheneedsofpatientsandtheservice,andchangesinsoci-ety’sexpectationsofthewayHCPswork.

Both as clinician, researcher and teacherI will continue to develop a wide-rangingcompetencies encompassing clinical update,research and scientificwriting,multidiscipli-narycontextofpatientcare,ethicalpractice,communication,managementandbehavioralskills,teambuilding,informationtechnology,audit, and appropriate attitudinal change toensure improved outcomes and satisfactionfor my patients, my students and my col-leagues

In2017IwilltakeoverthePresidencyoftheEuropeanAcademyofAllergyandClinicalIm-munology (EAACI), with a 2-year mandate.EAACI, is an association including over 50NationalAllergy Societies,more than 9,500academicians, research investigatorsandcli-nicians, from121different countries, aimedat:

• Promotingbasicandclinicalresearch

• Collecting, assessing and disseminatingscientificinformation

• Functioningasascientificreferencebodyforotherscientific,healthandpoliticalor-ganisations

• Encouraging and providing training andcontinuouseducation

• Promoting good patient care in this im-portantareaofmedicine

MyvisionformyPresidencyisforEAACItoinspire the way towards sustainable healthpoliciesforallergyandasthmaensuringhigherqualitycareataffordablecosts.TheAcademyshould continue its journey as internationalleader in allergy, asthma and clinical immu-nology.Clinicians,researchers,andeducatorschooseEAACIastheirprofessionalhome.Wemustcontinuetotrain,mentorandenrollthenextgenerationofleadersbydemonstratingthevalueofmembership.Andweneedtoun-derstandwhoweareandwhatourmembersneed.

Besides the international recognition I aimto facilitate the cooperation between inter-national and national societies as a scaffoldfor local adaptation and implementation ofguidelines and cutting-edge research, bestpractices and efficient health policies andadvocacy for promoting asthma as a majorhealthproblem.

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Iplan todevelop in thenext4yearsaneweducationalportfolioforstudentsandyoungHCPsthatfacilitatebothprofessionalandca-reerdevelopmentwithaclinicalandaresearchtrack. The concept of purposeful educationincluding key-concepts such as work-expe-rience and social servicewill be introduced.New tools facilitating interactive learningare envisaged, such as tutorials for the fac-ultymasterprogrammesandforthedoctoralschool,multidisciplinarylearnerprogrammes,interactive brainstorming, buzz-sessions,Think-Pairshare,incidentprocess,etc.Beingcertified formyEnglish literacy for teachingpurposes Iwillactivelysupport thecreationof a newDepartmentwith English teachingforforeignstudents.

InadditionIwillsupporttheinceptionofin-terdisciplinary teams inouruniversity inco-operation with the coordinators of licenceand master programmes in ensure that themajorityof our students engage in researchduringoraftermedicalschool.Awidechoiceof subjects for research should be encour-aged.Studentsmaychoosebasic laboratoryprojectsormayinvestigateclinical,epidemi-ologic or sociologic (includingmedicine andhumanities)topics.

Building thecommunity feeling for studentsand teacherswith increased engagement in

shapingtheacademic landscapeandtheor-ganizationalcultureisalsoapriority.Acloseworking relationship between the studentand faculty researchmentor is amajor goalandisstronglyencouraged.Whenlaboratoryresearchisperformed,itistheresponsibilityofthefacultyadvisortoprovideallnecessaryspace,equipmentandsupplies.Iftheprojectisconcernedwithclinicalorepidemiologicalinvestigation,thesamecommitmenttoguid-anceandsupportisexpected.Weeklyconfer-ences between student and advisor are en-couragedduring thecourseof the research.The researchmust bedesigned and specifi-callyperformedbythestudentwiththead-viceofthefacultymentor.

BothPhDcoordinationandachievingfullpro-fessorshipareenvisagedinordertoprogresswithmyacademicactivityinthenext2years.Throughmy involvement in coordination ofdoctoralthesisIwillcontinuetosupporttheyoungdoctorstoperformtheirownresearch-esandtocommunicatetheresultsoftheirre-search in the national and international sci-entific environment. Early career researchesshouldbestronglysupported inpreparationof their doctoral thesis through cooperativeprojectsdevelopedwithcolleagues fromre-lateddisciplines.

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