Revista SRAIC Nr. 2 (aprilie-iunie 2016)

www.sraic.eu

Vol. XIII - No. 2 / April - June 2016

JOURNAL OF THE ROMANIAN

SOCIETY OF ALLERGOLOGY AND CLINICAL IMMUNOLOGY Revista societății române de alergologie și Imunologie clinică

SUMMARY Envisioning allergy care in the next decades

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Agache I

Risk factors for severe asthma in children

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Kalayci Ö

Online microblogging and asthma

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Popescu FD

RSACI Annual Conference

Patterns of sensitization to ragweed species in Western Romania

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Panaitescu Bunu C et al

May 13-15, 2016 Bucharest

SRAIC

Societatea Română de

Alergologie și Imunologie Clinică

Intra-anaesthetic severe immediate type hypersensitivity to cefoperazone.

Case Report

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Onitiu-Gherman N et al

Minireview on molecular pharmacology of intranasal azelastine and fluticasone propionate

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Popescu FD, Popescu F

ISSN 1584-7330

Abstracts Annual Conference 2016 SRAIC

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JOURNAL OF THE ROMANIAN

SOCIETY OF ALLERGOLOGY AND CLINICAL IMMUNOLOGY Revista societății române de alergologie și Imunologie clinică

Vol. XIII, No. 2, April - June 2016

E-mail: secretariat@sraic.eu Web: www.sraic.eu

173-177 Gheorghe Titeica street, fl 1, ap 4, district 2, Bucharest, postal code 20296

ISSN 1584-7330 SRAIC

Societatea Română de

Alergologie și Imunologie Clinică

Copyright © 2016 RSACI. Copyright for published articles and photos belong exclusively to the Romanian Society of Allergology and Clinical Immunology. Reproduction, in full or partial, or any other form, in printed or electronic format, or distribution of the published materials is done only with the Romanian Society of Allergology and Clinical Immunology ‘s written agreement. The responsibility for materials’ original content belongs entirely to the authors. Interviewed individuals are responsible for the content of their statements and advertising space users for the information included in their layouts.

Copyright © 2016 SRAIC. Drepturile de autor pentru articolele și fotografiile publicate aparțin exclusiv Revistei Societății Române de Alergologie și Imunologie Clinică. Reproducerea, totală sau parțială, și sub orice formă, tipărită sau electronică, sau distribuția materialelor publicate se face numai cu acordul scris al Revistei Societății Române de Alergologie și Imunologie Clinică. Responsabilitatea asupra conținutului original al materialelor aparține în întregime autorilor. Persoanele intervievate răspund de conținutul declarațiilor lor, iar utilizatorii spațiului publicitar, de informațiile incluse în machete.

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Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 2, April - June 2016

Editorial Board

Editor-in-Chief

Florin-Dan Popescu Bucharest, Romania

Adjunct Editor-in-Chief Diana Deleanu Cluj-Napoca, Romania

Associate Editor Adelaida Marinescu Bucharest, Romania

Editorial Board

Ioana Agache, Brașov, Romania Ludmila Baxan, Republic of Moldova Camelia Berghea, Bucharest, Romania Ioana Corina Bocșan, Cluj-Napoca, Romania Roxana Silvia Bumbăcea, Bucharest, Romania Diana Church, UK Martin Church, UK Alexis Cochino, Bucharest, Romania Ioana Gabriela Crișan, Cluj-Napoca, Romania Oana Mariana Cristea, Craiova, Romania Victor Cristea, Cluj-Napoca, Romania Diana Gârniță, USA Cristian Gheonea, Craiova, Romania Liviu Nicolae Ghilencea, Bucharest, Romania Stela Goția, Iași, Romania Ioan Bradu Iamandescu, Bucharest, Romania Ömer Kalayci, Turkey Poliana Mihaela Leru, Bucharest, Romania Dumitru Moldovan, Târgu Mureș, Romania Adriana Muntean, Cluj-Napoca, Romania Carmen Panaitescu Bunu, Timișoara, Romania Nikolaos Papadopoulos, Greece Florica Popescu, Craiova, Romania Sanda Mihaela Popescu, Craiova, Romania Todor Popov, Bulgaria Caius Radu, USA Roxana Radu, USA Gabriel Samașca, Cluj-Napoca, Romania Codruț Sarafoleanu, Bucharest, Romania Roxana Sfrent-Cornățeanu, Bucharest, Romania Georgeta Sinițchi, Iași, Romania Celina Stafie, Iași, Romania Luminița Aurelia Stanciu, UK Michel Thibaudon, France Adriana Mihaela Tudose, Bucharest, Romania Corina Ureche, Târgu-Mureș, Romania Liliana Vereș, Iași, Romania Mariana Vieru, Bucharest, Romania

English Language Editor Cornelia Talida Ioniță

Editorial Office:

173-177 Gheorghe Titeica street, fl 1, ap 4, district 2, Bucharest, postal code 20296

Publishing House:

4 WORK INTERNATIONAL 20-24, Aleea Someșul Rece, district 1, Bucharest, Tel.: +40 732 155 157 Email: office@4work.ro

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Print: MM&LM WORK TECH

Număr semnificativ mai mare de cazuri de folosire corectă comparativ cu Turbuhaler® I (p<0,00 1)

Contraindicaţii. Hipersensibilitate la substanțele active sau la oricare dintre excipienți (lactoza monohidrat).

Atenţionări şi precauţii speciale pentru utilizare. Seretide Diskus nu se utilizează pentru tratamentul crizelor de astm bronşic, în acest caz fiind necesară administrara unui bronhodilatator cu acțiune rapidă şi de scurtă durată. Pacienții trebuie sfătuiți să păstreze tot timpul asupra lor un inhalator necesar pentru tratamentul crizei. Tratamentul cu Seretide Diskus nu trebuie inițiat în timpul unei exacerbări sau dacă pacienții prezintă o agravare semnificativă sau o deteriorare acută a astmului bronşic. În timpul tratamentului cu Seretide Diskus pot să apară reacții adverse grave legate de astmul bronşic şi exacerbarea acestuia. Pacienții trebuie sfătuiți să continue tratamentul, dar să ceară sfatul medicului dacă nu se mai realizează controlul astmului bronşic sau simptomele se agravează după inițierea tratamentului cu Seretide Diskus. Tratamentul cu Seretide Diskus nu trebuie întrerupt brusc la pacienții cu astm bronşic, datorită riscului de exacerbare a afecțiunii. Dozele trebuie scăzute treptat sub supravegherea medicului. La pacienții cu BPOC, oprirea tratamentului se poate asocia cu decompensări simptomatice şi de aceea trebuie făcută sub supravegherea medicului.

Similar altor corticosteroizi inhalatori, Seretide Diskus trebuie administrat cu precauție în cazul pacienților cu tuberculoză pulmonară activă sau pasivă, infecții fungice, virale sau altfel de infecții ale căilor respiratorii. Seretide Diskus trebuie utilizat cu precauție la pacienții cu tulburări cardiovasculare severe sau aritmii cardiace şi la pacienți cu diabet zaharat, tireotoxicoză, hipokaliemie netratată sau pacienți predispuşi a avea concentrații scăzute de potasiu în sânge. A fost raportată o incidență crescută a infecțiilor de tract respirator inferior (în special pneumonii şi bronşite) în studiul TORC. Doza de corticosteroid inhalată trebuie redusă la cea mai mică doză cu care se menține un control eficient asupra astmului.

Reacţii adverse. Foarte frecvente: Cefalee, rinofaringite. Frecvente: Candidoză orală şi faringiană, pneumonie, bronşite,hipokaliemie, iritație faringiană, răguşeală/disfonie, sinuzită, contuzii, crampe musculare, fracture traumatice, artralgii, mialgii. Pentru informații complete privind reacțiile adverse, atenționările şi precauțiile speciale privind utilizarea Seretide Diskus vă rugăm consultați Rezumatul Caracteristicilor Produsului.

*Aerolizer nu este înregistrat in România

salmeterol/propionat de fluticazonă

Decembrie 2015, Cod zinc: RO/SFC/0018/15(1)

*

INFORMAȚII DE PRESCRIPȚIE ABREVIATE 1. DENUMIREA COMERCIALĂ A MEDICAMENTULUI Seretide Diskus 50 micrograme/100 micrograme pulbere de inhalat. Seretide Diskus 50 micrograme/250 micrograme pulbere de inhalat.

Seretide Diskus 50 micrograme/500 micrograme pulbere de inhalat. 2. COMPOZIȚIA CALITATIVĂ ŞI CANTITATIVĂ Seretide Diskus 50 micrograme/100 micrograme pulbere de inhalat. Fiecare doză de pulbere de inhalat conține salmeterol 50 micrograme sub formă de xinafoat de salmeterol micronizat 72,5 micrograme şi propionat de fluticazonă 100 micrograme. Seretide Diskus 50 micrograme/250 micrograme pulbere de inhalat. Fiecare doză de pulbere de inhalat conține salmeterol 50 micrograme sub formă de xinafoat de salmeterol micronizat 72,5 micrograme şi propionat de fluticazonă 250 micrograme. Seretide Diskus 50 micrograme/500 micrograme pulbere de inhalat Fiecare doză de pulbere de inhalat conține salmeterol 50 micrograme sub formă de xinafoat de salmeterol micronizat 72,5 micrograme şi propionat de fluticazonă 500 micrograme. 3. FORMA FARMACEUTICĂ Pulbere de inhalat. Pulbere de inhalat de culoare albă. 4. DATE CLINICE 4.1.Indicații terapeutice: Astm bronşic. Seretide Diskus este indicat în tratamentul de fond al astmului bronşic, în cazurile în care este adecvată utilizarea unei asocieri (corticosteroid şi β2-agonist cu durată lungă de acțiune, cu administrare pe cale inhalatorie): - pacienți care nu sunt controlați în mod adecvat cu corticosteroizi inhalatori asociați la nevoie cu β2-agonişti inhalatori cu durată scurtă de acțiune; sau - pacienți care sunt deja controlați adecvat prin utilizarea atât a corticosteroizilor cât şi a β2- agoniştilor cu durată lungă de acțiune.Notă: Seretide Diskus 50 micrograme/100 micrograme, pulbere de inhalat nu este adecvat pentru tratamentul astmului bronşic sever la adulți şi copii. Bronhopneumopatie obstructivă cronică (BPOC). Seretide este indicat pentru tratamentul simptomatic al pacienților cu BPOC cu un VEMS < 60% din valoarea prezisă normală (pre-bronhodilatator) şi un istoric de exacerbări repetate, care au simptome semnificative în ciuda terapiei bronhodilatatoare constante. 4.2 Doze şi mod de administrare Doze Cale de administrare: inhalatorie. Pacienții trebuie atenționați că, pentru a obține rezultate optime, Seretide Diskus trebuie utilizat regulat, chiar atunci când sunt asimptomatici. Pacienții trebuie să fie reevaluați în mod regulat de către medic, pentru a se asigura că doza de Seretide pe care o primesc este cea optimă; doza va fi modificată numai la recomandarea medicului. Doza trebuie ajustată până la cea mai mică doză la care se menține controlul simptomatologiei. În cazul în care controlul simptomatologiei este menținut prin două administrări zilnice de salmeterol-propionat de fluticazonă în cea mai mică concentrație disponibilă, următoarea etapă poate include încercarea de a administra un corticosteroid inhalator în monoterapie. Ca alternativă, pacienții care necesită un β2-agonist cu acțiune lungă pot fi trecuți la Seretide administrat în priză unică zilnică dacă, în opinia medicului care prescrie tratamentul, ar fi adecvat pentru menținerea controlului asupra boli . În eventualitatea administrării unei singure prize zilnice atunci când pacientul are un istoric de simptome nocturne, doza trebuie administrată seara, iar atunci când pacientul are un istoric de simptome în principal diurne doza trebuie administrată dimineața. Pacienții trebuie tratați cu doza de Seretide ce conține cantitatea de propionat de fluticazonă corespunzătoare severității boli lor. Dacă un anume pacient necesită doze în afara schemei recomandate, trebuie prescrise doze adecvate de β2-agonist şi/sau corticosteroid. Doze recomandate: Astm bronşic Adulți şi adolescenți cu vârsta peste 12 ani: Este recomandată o doză de 50 micrograme salmeterol şi 100 micrograme propionat de fluticazonă administrată pe cale inhalatorie de două ori pe zi sau o doză de 50 micrograme salmeterol şi 250 micrograme propionat de fluticazonă administrată pe cale inhalatorie de două ori pe zi sau o doză de 50 micrograme salmeterol şi 500 micrograme propionat de fluticazonă administrată pe cale inhalatorie de două ori pe zi. Administrarea Seretide Diskus ca tratament de întreținere inițial, poate fi avută în vedere pentru o perioadă scurtă de timp, la adulți sau adolescenți cu forme moderate de astm bronşic persistent (definite ca simptome zilnice, utilizare zilnică de medicație bronhodilatatoare cu acțiune rapidă şi obstrucție bronşică moderată până la severă), la care este esențială obținerea unui control rapid asupra simptomatologiei. În aceste situații doza inițială recomandată este de o doză de 50 micrograme salmeterol şi 100 micrograme propionat de fluticazonă pe cale inhalatorie de două ori pe zi. Când se ajunge la menținerea controlului asupra astmului bronşic, tratamentul trebuie reevaluat înainte de a recomanda pacienților reducerea treptată până la utilizarea unui corticosteroid inhalator în monoterapie. Este necesară monitorizarea regulată a pacienților atunci când schema de tratament este redusă. Nu a fost stabilit un beneficiu terapeutic clar privind utilizarea Seretide Diskus comparativ cu propionatul de fluticazonă în monoterapie în tratamentul de întreținere inițial, dacă lipsesc unul sau două criterii de severitate. În general, corticosteroizi inhalatori reprezintă tratamentul de primă intenție pentru majoritatea pacienților. Seretide Diskus nu este recomandat în tratamentul inițial al astmului bronşic uşor. Seretide în concentrația 50 micrograme/100 micrograme nu este adecvat adulților şi copiilor cu astm bronşic sever; se recomandă stabilirea dozelor adecvate de corticosteroid inhalator înainte de a putea utiliza orice combinație fixă la pacienții cu astm bronşic sever. Populația pediatrică Copii cu vârsta de 4 ani şi peste: Este recomandată o doză de 50 micrograme salmeterol şi 100 micrograme propionat de fluticazonă administrată pe cale inhalatorie de două ori pe zi. Doza maximă recomandată de propionat de fluticazonă este 100 micrograme de două ori pe zi. Nu există date privind utilizarea Seretide Diskus la copii cu vârsta sub 4 ani. Bronhopneumopatie obstructivă cronică (BPOC) Adulți: Doza recomandată este o doză de 50 micrograme salmeterol şi 500 micrograme propionat de fluticazonă administrată pe cale inhalatorie de două ori pe zi. Grupe speciale de pacienți Nu este necesară ajustarea dozei la pacienții vârstnici sau la cei cu insuficiență renală. Nu sunt disponibile date cu privire la utilizarea Seretide la pacienți cu insuficiență hepatică. Folosirea dispozitivului Diskus: Dispozitivul se deschide şi se încarcă prin glisarea manetei. Piesa bucală este introdusă apoi în gură cu buzele strânse în jurul ei. Doza poate fi inhalată în acest moment şi dispozitivul poate fi închis.

4.3 Contraindicații Hipersensibilitate la substanțele active sau la oricare dintre excipienții enumerați la pct. 6.1. 4.4 Atenționări şi precauții speciale pentru utilizare Seretide Diskus nu se utilizează pentru tratamentul crizelor de astm bronşic, în acest caz fi nd necesară administrarea unui bronhodilatator cu acțiune rapidă şi de scurtă durată. Pacienții trebuie sfătuiți să păstreze tot timpul asupra lor un inhalator necesar pentru tratamentul crizei. Tratamentul cu Seretide Diskus nu trebuie inițiat în timpul unei exacerbări sau dacă pacienții prezintă o agravare semnificativă sau o deteriorare acută a astmului bronşic. În timpul tratamentului cu Seretide Diskus pot să apară reacții adverse grave legate de astmul bronşic şi exacerbarea acestuia. Pacienții trebuie sfătuiți să continue tratamentul, dar să ceară sfatul medicului dacă nu se mai realizează controlul astmului bronşic sau simptomele se agravează după inițierea tratamentului cu Seretide Diskus. Creşterea necesității de utilizare a medicației de calmare a crizei (bronhodilatatoarelor cu durată scurtă de acțiune) sau diminuarea răspunsului la aceasta, indică deteriorarea controlului astmului bronşic şi pacienții trebuie reexaminați de către medic. Agravarea bruscă şi progresivă a stării pacientului cu astm bronşic poate pune în pericol viața acestuia şi necesită consult medical imediat. Trebuie luată în considerare creşterea dozelor de corticosteroid. Odată ce se realizează controlul astmului bronşic, trebuie luată în considerare reducerea gradată a dozei de Seretide. Este importantă evaluarea periodică a pacienților pe măsura derulării tratamentului. Trebuie utilizată cea mai mică doză eficace (vezi pct. 4.2). Pacienții cu BPOC care prezintă exacerbări au asociat de obicei tratament sistemic cu corticosteroizi, prin urmare aceşti pacienți trebuie sfătuiți sa ceară sfat medical dacă prezintă simptome de deterioare a stării sub tratament cu Seretide. Tratamentul cu Seretide Diskus nu trebuie întrerupt brusc la pacienții cu astm bronşic, datorită riscului de exacerbare a afecțiunii. Dozele trebuie scăzute treptat sub supravegherea medicului. La pacienții cu BPOC, oprirea tratamentului se poate asocia cu decompensări simptomatice şi de aceea trebuie făcută sub supravegherea medicului. Similar altor corticosteroizi inhalatori, Seretide Diskus trebuie administrat cu precauție în cazul pacienților cu tuberculoză pulmonară activă sau pasivă, infecții fungice, virale sau altfel de infecții ale căilor respiratorii. Dacă este necesar, trebuie administrat imediat tratament corespunzător. Seretide Diskus poate determina, rareori, aritmii cardiace, de exemplu tahicardie supraventriculară, extrasistole şi fibrilație atrială şi o uşoară scădere, trecătoare, a concentrației plasmatice de potasiu la administrarea de doze terapeutice mari. De aceea, Seretide Diskus trebuie utilizat cu precauție la pacienții cu tulburări cardiovasculare severe sau aritmii cardiace şi la pacienți cu diabet zaharat, tireotoxicoză, hipokaliemie netratată sau pacienți predispuşi a avea concentrații scăzute de potasiu în sânge. Au fost raportate foarte rar cazuri de creştere a glicemiei (vezi pct. 4.8) şi acest lucru trebuie avut în vedere în cazul prescrierii medicamentului la pacienții cu diagnostic de diabet zaharat. Similar celorlalte terapii administrate inhalator, este posibilă apariția bronhospasmului paradoxal, cu intensificarea imediată a wheezing-ului şi scurtarea respirației după administrarea dozei. Bronhospasmul paradoxal cedează la administrarea unui bronhodilatator cu durată rapidă de acțiune şi trebuie administrat imediat. În acest caz, administrarea Seretide Diskus trebuie imediat întreruptă, pacientul trebuie reevaluat şi dacă este necesar, se instituie o terapie alternativă. Au fost raportate efecte ale β2-agonistilor precum tremor, palpitații şi cefalee, dar acestea tind să fie tranzitorii şi să se reducă pe parcursul administrării regulate. Seretide Diskus conține lactoză până la 12,5 miligrame/doză. Această cantitate nu determină, de obicei, probleme la persoanele cu intoleranță la lactoză. Efectele sistemice pot să apară în cazul oricărui corticosteroid inhalator, în special la doze mari prescrise pentru perioade lungi de timp. Aceste efecte apar mai puțin decât în cazul utilizării corticosteroizilor administrați oral. Reacțiile adverse sistemice care pot să apară includ sindromul Cushing, caracteristici cushingoide, supresia glandei suprarenale, scăderea densității osoase, cataractă, glaucom şi mai rar, un palier de efecte psihologice şi de comportament, inclusiv hiperactivitate psihomotorie, tulburări de somn, anxietate, depresie sau agresivitate (mai ales la copii şi adolescenți) (a se vedea sub-titlul Populația pediatrică de mai jos pentru informații legate de efectele sistemice ale corticosteroizilor administrați inhalator la copii şi adolescenți). De aceea, este important ca pacientul să fie reevaluat în mod periodic şi să se folosească doza minimă de corticosteroid inhalator la care este menținut controlul eficient al astmului bronşic. Administrarea îndelungată de doze mari de corticosteroizi inhalatori poate determina supresia funcției corticosuprarenalei şi insuficiență corticosuprarenală acută. De asemenea, au fost descrise cazuri foarte rare de apariție a supresiei funcției corticosuprarenalei şi insuficiență corticosuprarenală acută în timpul tratamentului cu propionat de fluticazonă în doze cuprinse între 500-1000 micrograme pe zi. Insuficiența corticosuprarenală acută poate fi declanşată de anumite situații, incluzând: traumatisme, intervenții chirurgicale, infecții sau orice scădere rapidă a dozei. Tabloul clinic este în general atipic şi poate să includă: anorexie, dureri abdominale, scădere în greutate, fatigabilitate, cefalee, greață, vărsături, hipotensiune arterială, reducerea stării de conştiență, hipoglicemie şi convulsi . În perioadele de stres sau în timpul intervențiilor chirurgicale trebuie avut în vedere tratament suplimentar cu corticosteroizi. Benefici le terapiei inhalatorii cu propionat de fluticazonă ar trebui să reducă necesitatea administrării steroizilor orali, însă pacienții care sunt trecuți de la tratament cu steroizi orali pot rămâne cu riscul insuficienței corticosuprarenaliene pentru o periodă considerabilă de timp. Prin urmare, aceşti pacienți trebuie tratați cu precauție, iar funcția corticosuprarenalei trebuie să le fie monitorizată regulat. Pacienții care au necesitat în trecut terapie de urgență cu corticosteroizi în doze mari pot, de asemenea, prezenta un risc crescut. Posibilitatea unui răspuns corticosuprarenalian insuficient trebuie avută întotdeauna în vedere în situațiile de urgență şi în situații care pot declanşa o stare de stres, fi nd necesară luarea în considerare a instituiri unui tratament adecvat cu corticosterozi. Gradul afectării corticosuprarenaliene poate face necesară recomandarea medicului specialist înaintea intervențiilor programate. Ritonavirul poate creşte mult concentrațiile plasmatice ale propionatului de fluticazonă. Ca urmare, administrarea concomitentă de propionat de fluticazonă şi ritonavir trebuie evitată, cu excepția cazului când beneficiul potențial depăşeşte riscul de reacții adverse sistemice corticosteroidiene. Există, de asemenea, un risc crescut de reacții adverse sistemice la administrarea concomitentă de propionat de fluticazonă cu alți inhibitori puternici ai izoenzimei 3A4 a citocromului P450 (vezi pct. 4.5). A fost raportată o incidență crescută a infecțiilor de tract respirator inferior (în special pneumonii şi bronşite) în studiul TORCH efectuat la pacienți cu bronhopneumopatie obstructivă cronică (BPOC) cărora li s-a administrat de două ori pe zi Seretide 50 micrograme/500 micrograme comparativ cu placebo, precum şi în studiile SCO40043 şi SCO 100250, care au comparat doza mai mică de Seretide (50 micrograme/250 micrograme, de două ori pe zi - doză neaprobată în indicația de BPOC) cu salmeterol 50 micrograme administrat de două ori pe zi în monoterapie (vezi pct. 4.8 şi 5.1). În toate studiile a fost observată o incidență similară a pneumoniei în grupul la care s-a administrat Seretide. În studiul TORCH, pacienții în vârstă, pacienții cu un index mic de masă corporală (<25 kg/m2) şi pacienții cu afecțiune foarte severă (VEMS <30% din valoarea prezisă), au prezentat un risc crescut de apariție a pneumoniei indiferent de tratament. Medici trebuie să fie atenți în ce priveşte posibila apariție a pneumoniei sau infecțiilor de tract respirator inferior la pacienții cu BPOC, deoarece simptomele acestor infecții şi exacerbările se suprapun frecvent. În cazul apariției pneumoniei la un pacient cu BPOC sever tratamentul cu Seretide Diskus trebuie reevaluat. Date provenite dintr-un studiu clinic de amploare (The Salmeterol Multi-Center Asthma Research Trial, SMART) au arătat că

Acest medicament se elibereaza doar pe baza de prescriptie medicala, tipul de prescriptie P6L.

pacienții afro-americani prezintă un risc crescut de evenimente respiratorii grave sau finalizate cu deces în cazul utilizării de salmeterol comparativ cu placebo (vezi pct. 5.1). Nu se cunoaşte dacă acest lucru se datorează factorilor farmacogenetici sau altor factori. De aceea, pacienții cu strămoşi de rasă neagră de origine africană sau afro-caraibiană trebuie sfătuiți să continue tratamentul, dar să ceară sfatul medicului dacă nu se mai realizează controlul astmului bronşic sau simptomele se agravează în timpul tratamentului cu Seretide. Utilizarea concomitentă de ketoconazol sistemic a crescut semnificativ expunerea sistemică la salmeterol. Acest lucru poate duce la creşterea incidenței reacțiilor adverse sistemice (de exemplu, prelungirea intervalului QTc şi palpitații). Tratamentul concomitent cu ketoconazol sau alți inhibitori puternici ai izoenzimei 3A4 a citocromului P450 trebuie evitat, cu excepția cazurilor în care beneficiul potențial depăşeşte riscul de reacții adverse sistemice ale tratamentului cu salmeterol (vezi pct. 4.5).

Populație pediatrică Copii şi adolescenții cu vârsta sub 16 ani tratați cu doze mari de propionat de fluticazonă (≥1000 micrograme pe zi) pot prezenta risc crescut de efecte sistemice. Efectele sistemice pot apărea în special la doze mari în tratament prelungit. Efectele sistemice posibile includ sindromul Cushing, caracteristici de tip cushingoid, supresie corticosuprarenală, insuficiență corticosuprarenală acută şi întârzierea creşterii la copii şi adolescenți şi mai rar un palier de efecte psihologice şi de comportament, inclusiv hiperactivitate psihomotorie, tulburări de somn, anxietate, depresie sau agresivitate. Se recomandă consult la un medic pediatru specialist în boli respiratorii în cazul copii lor sau adolescenților. Se recomandă monitorizarea periodică a creşterii în înățime a copiilor cărora li se administrează tratament îndelungat cu corticosteroizi inhalatori. Doza de corticosteroid inhalată trebuie redusă la cea mai mică doză cu care se menține un control eficient asupra astmului. 4.5 Interacțiuni cu alte medicamente şi alte forme de interacțiune β-blocantele adrenergice pot reduce sau antagoniza efectul salmeterolului.Atât blocantele β-adrenergice neselective, cât şi cele selective trebuie evitate, cu excepția cazurilor în care utilizarea lor este absolut necesară. Terapia cu β2 agonişti are un potențial efect de apariție a unei hipokaliemii grave. Deoarece acest efect poate fi potențat de tratamentul concomitent cu derivați xantinici, steroizi şi diuretice, este necesară precauție în tratamentul astmului sever acut. Utilizarea concomitentă a altor medicamente β-adrenergice poate avea un efect aditiv potențial. Propionat de fluticazonă În condiți normale, după administrarea inhalatorie sunt atinse concentrații plasmatice mici de propionat de fluticazonă, datorită metabolizării marcate la primul pasaj hepatic şi clearance-ului sistemic mare, mediat prin intermediul izoenzimei 3A4 a citocromului P450, la nivel intestinal şi hepatic. Ca urmare, sunt improbabile interacțiuni medicamentoase semnificative clinic datorate propionatului de fluticazonă. Un studiu privind interacțiunile medicamentelor efectuat la voluntari, administrarea de propionat de fluticazonă intranazal şi ritonavir (un inhibitor foarte puternic al izoenzimei 3A4 a citocromului P450) în doze de 100 mg de două ori pe zi, a crescut concentrația plasmatică a propionatului de fluticazonă de câteva sute de ori, determinând scăderea marcată a cortizolemiei. Pentru propionatul de fluticazonă administrat inhalator, datele privind aceste interacțiuni sunt insuficiente, dar este de aşteptat creşterea concentrației plasmatice a acestuia. Au fost raportate cazuri de sindrom Cushing şi supresie corticosuprarenaliană. Această asociere trebuie evitată cu excepția cazurilor în care beneficiul potențial depăşeşte riscul de reacții adverse sistemice corticosteroidiene. Într-un studiu restrâns efectuat la voluntari sănătoşi, ketoconazolul, un inhibitor mai puțin potent al CYP 3A4 a crescut cu 150% expunerea la propionat de fluticazonă după o singură administrare inhalatorie. Aceasta a determinat o scădere marcată a cortizolemiei comparativ cu administrarea propionatului de fluticazonă în monoterapie. Tratamentul concomitent cu alți inhibitori potenți ai CYP 3A4, cum este itraconazolul şi cu inhibitori moderați ai CYP3A, cum este eritromicina, este de asemenea de aşteptat să crească expunerea sistemică la propionat de fluticazonă şi riscul reacțiilor adverse sistemice. Se recomandă precauție şi trebuie evitat, dacă este posibil, tratamentul prelungit cu aceste medicamente. Salmeterol Inhibitori puternici ai izoenzimei 3A4 a citocromului P450 Administrarea concomitentă de ketoconazol 400 mg (administrat oral, o dată pe zi) şi salmeterol (50 micrograme administrat inhalator, de două ori pe zi) la 15 voluntari sănătoşi, timp de 7 zile, a condus la o creştere semnificativă a expunerii plasmatice la salmeterol (de 1,4 ori a Cmax şi de 15 ori a ASC). Acest lucru a condus la creşterea incidenței celorlalte reacții adverse sistemice ale tratamentului cu salmeterol (de exemplu, prelungirea intervalului QTc şi palpitații), comparativ cu tratamentul numai cu salmeterol sau ketoconazol (vezi pct.4.4). Nu au fost observate efecte semnificative clinic asupra tensiunii arteriale, ritmului cardiac, concentrației de glucoză din sânge şi concentrației de potasiu din sânge. Administrarea concomitentă de ketoconazol nu a crescut timpul de înjumătățire plasmatică prin eliminare al salmeterolului sau acumularea de salmeterol după doze repetate. Administrarea concomitentă de ketoconazol trebuie evitată, cu excepția cazurilor în care beneficiul potențial depăşeşte riscul de reacții adverse sistemice ale tratamentului cu salmeterol. Este posibil să existe un risc similar de interacțiune cu alți inhibitori potenți ai CYP 3A4 (cum sunt itraconazolul, telitromicina, ritonavirul). Inhibitori moderați ai izoenzimei 3A4 a citocromului P450 Administrarea concomitentă de eritromicină (500 mg administrată oral, de trei ori pe zi) şi salmeterol (50 micrograme administrat inhalator, de două ori pe zi) la 15 voluntari sănătoşi, timp de 6 zile, a condus la o creştere mică, dar nu semnificativă statistic, a expunerii la salmeterol (de 1,4 ori a Cmax şi de 1,2 ori a ASC). Administrarea concomitentă de eritromicină nu a fost asociată cu reacții adverse grave. 4.6 Fertilitatea, sarcina şi alăptarea. Fertilitatea Nu există date pentru oameni. Oricum, studiile pe animale nu au arătat niciun efect al salmeterolului sau al propionatului de fluticazonă asupra fertilității. Sarcina O cantitate moderată de date de la femeile gravide (de la 300 la 1000 rezultate de sarcină) nu a indicat malformații sau toxicitate fetală/neonatală în cazul salmeterolului sau al propionatului de fluticazonă. Studiile la animale au arătat o toxicitate a reproducerii după administrarea de agonişti β2-adrenergici şi de glucocorticosteroizi (vezi pct. 5.3). Administrarea Seretide Diskus în timpul sarcini trebuie luată în considerare numai dacă beneficiul terapeutic matern depăşeşte orice risc potențial la făt. La gravide trebuie utilizată cea mai mică doză eficace de propionat de fluticazonă pentru a obține controlul adecvat al astmului bronşic. Alăptarea Nu se ştie dacă salmeterolul şi propionatul de fluticazonă/ metaboliți sunt excretați în laptele matern. Studiile au arătat că salmeterolul şi propionatul de fluticazonă şi metaboliți lor sunt excretați în laptele şobolanilor. Un risc la nou-născuți/sugari alăptați la sân nu poate fi exclus. Trebuie luată decizia fie de a întrerupe alăptarea, fie de a întrerupe tratamentul cu Seretide, având în vedere beneficiul alăptării pentru copil şi beneficiul tratamentului pentru femeie. 4.7 Efecte asupra capacității de a conduce vehicule sau de a folosi utilaje Seretide Diskus nu are nicio influență sau are influență neglijabilă asupra capacității de a conduce vehicule şi de a folosi utilaje. 4.8 Reacții adverse Deoarece Seretide Diskus conține salmeterol şi propionat de fluticazonă, sunt de aşteptat să apară aceleaşi reacții adverse ca tip şi severitate ca pentru fiecare substanță în parte. Nu au apărut reacții adverse suplimentare după administrarea simultană a celor două substanțe active. Evenimentele adverse au fost enumerate mai jos, clasificate pe aparate, sisteme, organe şi în funcție de frecvență. Frecvențele sunt definite în felul următor: foarte frecvente (≥1/10), frecvente (≥1/100 şi <1/10), mai puțin frecvente (≥1/1000 şi <1/100), rare (≥1/10000 şi <1/1000) şi cu frecvență necunoscută (care nu poate fi estimată din datele disponibile). Frecvențele au fost obținute din datele studiilor clinice. Incidența în grupul placebo nu a fost luată în considerare. Infecții şi infestări: candidoză orală şi faringiană - frecvente; pneumonie – frecvente1,3,5; bronşite - frecvente1,3, candidoză esofagiană - rare. Tulburări ale sistemului imunitar. Au fost raportate reacții de hipersensibilitate cu următoarele manifestări: reacții de hipersensibilitate cutanată şi sisteme respiratorii (dispnee) - mai puțin frecvente, edem angioneurotic,în principal edem facial şi orofaringian – rare, simptome respiratorii (bronhospasm) – rare, reacții anafilactice, incluzând şocul anafilactic – rare. Tulburări endocrine: sindrom Cushing, caracteristici de tip cushinoid, supresie corticosuprarenală, întârziere a creşterii la copii şi adolescenți, scădere a densității minerale osoase – rare4. Tulburări metabolice şi de nutriție: hipokalemie – frecvente3, hiperglicemie – mai puțim frecvente4. Tulburari psihice: anxietate, tulburări de somn, modificări de comportament, incluzând hiperactivitate psihomotorie şi iritabilitate (mai ales la copii) – mai puțin frecvente, depresie, anxietate (mai ales la copii) – cu frecvență necunoscută. Tulburări ale sistemului nervos: cefalee – foarte frecvente1, tremor – mai puțin frecvente. Tulburări oculare: cataractă - mai puțin frecvente, glaucom – rare4. Tulburări cardiace: palpitații, tahicardie, fibrilație atrială şi angină pectorala – mai puțin frecvente, aritmii cardiace (incluzând tahicardie supraventriculară şi extrasistole – rare. Tulburări respiratorii, toracice şi mediastinale: rinofaringite – foarte frecvente2,3, iritație faringiană şi raguşeală/disfonie – frecvente, sinuzită –frecvente1,3, bronhospasm paradoxal – rare. Afecțiuni cutanate şi ale țesutului subcutanat: contuzii – frecvente1,3. Tulburări muculoscheletice şi ale țesutului conjunctiv: crampe musculare, artralgi , mialgi – frecvente, fracture traumatice – frecvente1,3. 1. Reacții adverse raportate frecvent cu placebo. 2. Reacții adverse raportate foarte frecvent cu placebo. 3. Raportate pe o perioadă de 3 ani într-un studiu cu BPOC. 4. Vezi pct. 4.4. 5. Vezi pct. 5.1. Descrierea reacțiilor adverse selectate. Au fost raportate reacții adverse asociate tratamentului cu β2-agonişti, cum sunt tremor, palpitații şi cefalee, dar acestea tind să fie tranzitorii şi să se reducă pe parcursul administrării constante. Similar celorlalte terapii administrate inhalator, este posibilă apariția bronhospasmului paradoxal, cu intensificarea imediată a wheezing-ului şi scurtarea respirației după administrarea dozei. Bronhospasmul paradoxal cedează la administrarea unui bronhodilatator cu durată rapidă de acțiune şi trebuie administrat imediat. În acest caz, administrarea Seretide Diskus trebuie imediat întreruptă, pacientul trebuie reevaluat şi dacă este necesar, se instituie o terapie alternativă. Datorită propionatului de fluticazonă, la unii pacienți poate să apară disfonie şi candidoză orofaringiană şi, rareori, candidoză esofagiană. La aceşti pacienți, atât răguşeala cât şi incidența candidozei orofaringiene pot fi reduse prin clătirea cu apă a cavității bucale şi/sau periajul dinților după inhalarea medicamentului. În timpul tratamentului cu Seretide Diskus, candidoza orofaringiană simptomatică poate fi tratată cu antifungice topice. Populația pediatrică. Efectele sistemice posibile includ sindrom Cushing, caracteristici de tip cushingoid, supresia corticosuprarenalei şi întârziere în creştere la copii şi adolescenți (vezi pct. 4.4). Copii pot prezenta, de asemenea, anxietate, tulburări de somn şi tulburări de comportament, inclusiv hiperactivitate şi iritabilitate. Raportarea reacțiilor adverse suspectate. Raportarea reacțiilor adverse suspectate după autorizarea medicamentului este importantă. Acest lucru permite monitorizarea continuă a raportului beneficiu/risc al medicamentului. Profesioniştii din domeniul sănătății sunt rugați să raporteze orice reacție adversă suspectată prin intermediul sistemului național de raportare, ale cărui detali sunt publicate pe web-site-ul Agenției Naționale a Medicamentului şi a Dispozitivelor Medicale http://www.anm.ro.

4.9 Supradozaj. Nu sunt disponibile date din studii clinice despre supradozajul cu Seretide Diskus, cu toate acestea, date despre supradozajul cu fiecare substanță în parte sunt prezentate mai jos: Semnele şi simptomele în supradozajul cu salmeterol sunt amețeală, creşterea tensiunii sistolice, tremor, cefalee şi tahicardie. Dacă terapia cu Seretide Diskus trebuie întreruptă datorită supradozajului componentei β-agoniste a medicamentului, trebuie avută în vedere administrarea de corticoterapie de substituție adecvată. În plus, poate apărea hipokalemia şi, prin urmare, trebuie monitorizate valorile potasiului seric.

Trebuie luată în considerare refacerea rezervei de potasiu. Supradozaj acut cu propionat de fluticazonă: Inhalarea acută a unor doze mai mari de propionat de fluticazonă decât cele recomandate poate determina inhibarea temporară a funcției corticosuprarenalei. Aceasta nu necesită intervenție de urgență, având în vedere că funcția corticosuprarenalei revine la nivelul normal în câteva zile, lucru demonstrat prin măsurarea cortizolemiei. Supradozaj cronic cu propionat de fluticazonă: Trebuie monitorizată funcția la nivel suprarenal şi poate fi necesar tratament cu un corticosteroid sistemic. După stabilizare, tratamentul trebuie continuat cu un corticosteroid inhalator, în dozele recomandate. Vezi pct. 4.4: risc de inhibare la nivel suprarenal. În cazul supradozajului cronic cât şi acut cu propionat de fluticazonă, tratamentul cu Seretide Diskus ar trebui continuat cu doze adecvate pentru controlul simptomatologiei. 6. PROPRIETĂȚI FARMACEUTICE. 6.1 Lista excipienților. Lactoză monohidrat. 6.2 Incompatibilități. Nu este cazul. 6.3 Perioada de valabilitate 2 ani. 6.4 Precauții speciale pentru păstrare. La temperaturi sub 30ºC, în ambalajul original. 6.5 Natura şi conținutul ambalajului. Cutie cu un dispozitiv de inhalat din plastic prevăzut cu indicator ce arată numărul dozelor rămase; conține 60 doze pulbere de inhalat. 6.6 Precauții speciale pentru eliminarea reziduurilor şi alte instrucțiuni de manipulare. Seretide Diskus eliberează o pulbere care este inhalată în plămâni. Numărul de doze rămase este afişat de indicatorul special de pe Diskus. Pentru informații detaliate privind administrarea a se vedea Prospectul pentru pacient. 7. DEȚINĂTORUL AUTORIZAȚIEI DE PUNERE PE PIAȚĂ. GLAXO WELLCOME UK LIMITED. 980 Great West Road, Brentford, Middlesex, TW8 9GS, Marea Britanie. 8. NUMĂRUL (ELE) AUTORIZAȚIEI DE PUNERE PE PIAȚĂ Seretide Diskus 50 micrograme/100 micrograme pulbere de inhalat. 5797/2013/01. Seretide Diskus 50 micrograme/250 micrograme pulbere de inhalat. 5798/2013/01. Seretide Diskus 50 micrograme/500 micrograme pulbere de inhalat. 5799/2013/01. 9. DATA PRIMEI AUTORIZĂRI SAU A REÎNNOIRII AUTORIZAȚIEI Reînnoire - Septembrie 2013. 10. DATA REVIZUIRII TEXTULUI. Octombrie 2015

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 2, April - June 2016

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JOURNAL OF THE ROMANIAN

SOCIETY OF ALLERGOLOGY AND CLINICAL IMMUNOLOGY Revista societății române de alergologie și Imunologie clinică

Journal of the Romanian Society of Allergology and Clinical Immunology is published 4 times a year. The magazine is distributed free of charge to all subscribing members of the Romanian Society of Allergology and Clinical Immunology (RSACI). With the exception of subscriptions, RSACI reserves its right to choose the area of distribution for the journal. 2016’ s yearly subscription cost for institutions, national and abroad, as well as for interested individuals is of 180 Euros.

Revista Societății Române de Alergologie și Imunologie Clinică este o publicație cu apariție de 4 ori pe an.

Revista se distribuie gratuit membrilor cotizanți ai SRAIC. În afara abonamentelor, SRAIC își rezervă dreptul de a alege aria de distribuție a revistei. Costul unui abonament pe anul 2016, pentru instituții din țară și străinătate și pentru persoanele fizice interesate, este de 180 euro.

“Journal of the Romanian Society of Allergology and Clinical Immunology” is included in Romanian Medical College (RMC) Medical Publications Index for 2016. This Journal is credited by RMC with 5 CME credit points.

Revista Societâții Române de Alergologie și Imunologie Clinică a fost introdusă în Nomenclatorul Publicaţiilor Medicale al Colegiului Medicilor din România (CMR) pentru anul 2016. Revista a fost creditată cu 5 puncte de EMC.

Our journal may publish with permission World Allergy Organisation Journal articles.

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European Academy of Allergy and Clinical Immunology 11 â&#x20AC;&#x201C; 15 June 2016 Vienna, Austria

EAACI Congress 2016

e Visit the websit e r for mo ion at inform

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Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 2, April - June 2016

CONTENTS

Editorial Florin-Dan Popescu

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EAACI Speakers Session Envisioning allergy care in the next decades

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Ioana Agache

Risk factors for severe asthma in children

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Ă&#x2013;mer Kalayci

Awareness, Training and Education Online microblogging and asthma

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Florin-Dan Popescu

Original articles and brief communications Patterns of sensitization to ragweed species in Western Romania

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Carmen Panaitescu, Laura Marusciac, Tudor-Paul Tamas, Inmaculada Perez, Fernando Pineda

Intra-anaesthetic severe immediate type hypersensitivity to cefoperazone. Case Report

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Nadia Onitiu-Gherman, Mihaela Cocis, Cristina Laura Petrisor, Natalia Hagau

News and Current Perspectives Minireview on molecular pharmacology of intranasal azelastine and fluticasone propionate

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Florin-Dan Popescu, Florica Popescu

Instructions for authors

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Abstracts Annual Conference 2016 SRAIC

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Advances in Allergology / Interdisciplinary approaches

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Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 2, April - June 2016

EDITORIAL

I

n 2016, the European Academy of Allergy and Clinical Immunology (EAACI) is celebrating 60 years of excellence in research and education in allergy science and patient care. EAACI congresses and meetings held over time in various European cities, provided substantial progress in the knowledge of allergic diseases and asthma, and an opportunity for exchanging ideas, friendship and collaborations. Allergies and asthma are major public health concerns, requiring priority and concerted actions. In order to mark its 60th anniversary, EAACI is rolling out an important informational campaign to its members, national and international health stakeholders and policymakers, with the aim of reframing the current conversation: from disease burden to prevention and health promotion. As allergy specialists and Romanian national allergy society members, we need to engage in this process. Thus, we all will be dedicated to allergy science in favor of a continuous commitment to patients’ health. Moreover, EAACI campaign underlines that modern control of allergies and asthma and cost-efficient prevention are available, discussing more research needs for relevant medical advice in clinical practice. As the leading European medical society focusing on allergy, EAACI aims to have consistent interaction with European Union Institutions, in order to promote allergy awareness. The European Parliament (EP) Interest Group on Allergy and Asthma will organize in April the exhibition Test Your Allergies 2016 “Test, Inform, Prevent”, an important event at the EP in Brussels, and will present “Allergy at the forefront of EU Chronic Diseases Policy: The road towards better prevention and management of Allergy in Europe”.

The launch of this special issue of the Journal of the Romanian Society of Allergology and Clinical

Immunology (RSACI) is related to the RSACI Conference 2016, organized in partnership with the Romanian Hereditary Angioedema Network. This annual meeting is an important scientific event for the community of allergists in our country, due to the interdisciplinary approach in the focused fields of angioedema, asthma and allergy, and the participation of prestigious speakers, internationally recognized in the medical fields of interest, from Europe, United States of America and Israel. A multidisciplinary approach is important because it makes use of the skills and experience from different specialties, with each discipline approaching the patient from their own perspective, while an interdisciplinary approach brings the various disciplines together into a coherent whole which is favorable for a more patient-centred approach.

Allergists and immunologists, along with other specialists in otorhinolaryngology, pediatrics, dermatology, pulmonology, emergency medicine, internal medicine and laboratory medicine, are interested in these areas of clinical practice because their patients may often present diseases or conditions in which different types of hypersensitivities are suspected or confirmed. Besides recent advances in the diagnosis and treatment of these disorders, the members of such a large professional and scientific community are interested to use a common language and to disseminate updated international guidelines, in order to provide medical care to the highest quality standards and to improve the health of people affected.

RSACI Conference 2016 is organized in partnership with the Romanian Hereditary Angioedema Network, a foundation committed to ensure that hereditary angioedema patients in this country have access to care that reflects current guidelines, to coordinate the initiatives for fighting against isolation of these patients, HAE reg-

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EDITORIAL

istry, patients education, participation in clinical trials and international cooperation. On behalf of RSACI, I would like to warmly thank Associate Professor Dumitru Moldovan (Tîrgu Mureș, Romania), the founder of the Romanian Hereditary Angioedema Network, for his great support and very active involvement as a co-president of this conference.

Highly valued speakers, Professors and top international experts Ioana Agache (Brașov, Romania), Sladjana Andrejevic (Belgrade, Serbia), Jonathan A. Bernstein (Cincinnati, OH, USA), Konrad Bork (Mainz, Germany), Sandra Corinne Christiansen (San Diego, CA, USA), Marco Cicardi (Milan, Italy), Enrico Compalati (Genoa, Italy), Timothy J. Craig (Hershey, PA, USA), Henriette Farkas (Budapest, Hungary), Ömer Kalayci (Ankara, Turkey), Todor Popov (Sofia, Bulgaria), Avner Reshef (Tel-Hashomer, Israel), Peter J. Späth (Berne, Switzerland), Daniel Suez (Irving, TX, USA), Anna Dimitrova Valerieva (Sofia, Bulgaria), Lilian Varga (Budapest, Hungary) and Bruce L. Zuraw (San Diego, CA, USA) are invited to our conference to share their expertise.

In the first part of the Journal of RSACI current issue, in the EAACI Speakers Session, Professor Ioana Agache, from the ‘’Transilvania’’ University, Brașov, Romania, presents an original envisioning of allergy care in the next decades, identifying key drivers of change that will have the biggest impact: endotypes and precision medicine, health information technology and delivering value in health care. Allergists must embrace and adapt such changes in order to implement a new system of care for their patients. In the same session, Professor Ömer Kalayci, from the Hacettepe University School of Medicine, Ankara, Turkey, presents recent data on the risk factors for severe asthma in children, with very interesting discussions on the definition of severe asthma, its prevalence, aspects related to asthma phenotypes and the risk factors associated with specific phenotypes, genetic variants associated with asthma, oxidant stress due to environmental tobacco smoke, obesity and vitamin D status.

One of the articles in the current journal, under the heading of awareness, training and education, is dedi-

cated to online microblogging and asthma. Such online media used in a responsible manner provide concise information dissemination, social networking, and realtime communication, might be practically relevant for scientists analyzing big data and for online users interested in asthma care. In the original articles and brief communications section of the journal, Professor Carmen Panaitescu Bunu, from the University of Medicine and Pharmacy “Victor Babeș” Timișoara, and co-workers reveal the results of a study on the patterns of sensitization to ragweed species in Western Romania. Original results are useful to understand cross-reactivity and co-sensitization aspects, being of importance in the selection of allergy immunotherapy. In the same section, Nadia OnitiuGherman, from Cluj-Napoca, and co-authors present a case of intra-anaesthetic severe immediate-type hypersensitivity to cefoperazone. Under the news and current perspectives heading, a minireview on molecular pharmacology brings into focus a novel intranasal formulation of azelastine and fluticasone propionate.

Finally, I want to thank, on behalf of RSACI, the EAACI Executive Committee which has kindly accepted the request for EAACI speakers support for our RSACI Conference 2016: Professor Ioana Agache, EAACI VicePresident Communications & Membership, and Professor Ömer Kalayci, EAACI Asthma Section Chairperson. It is a great honor to mention the acknowledgement of the EAACI sponsorship in this editorial, and that the EAACI Executive Committee representatives will be given the opportunity to make their statements on behalf of EAACI at the opening ceremony.

I wish our RSACI Conference 2016 to be as dynamic and energetic as it is the host city of Bucharest, the capital of Romania. We hope this conference to be an event that everyone will enjoy and remember.

Florin-Dan Popescu President of the Romanian Society of Allergology and Clinical Immunology

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Contact EAACI Headquarters Hagenholzstrasse 111, 3rd Floor 8050 Zurich - Switzerland Tel: + 41 44 205 55 32 Mobile: +41 79 892 82 25 communications@eaaci.org www.eaaci.org/campaign2016

EAACI’s 60 years celebration – Dedicated to allergy science, committed to your health

ON THE ROAD TO PREVENTION AND HEALTHY LIVING 

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European Academy of Allergy and Clinical Immunology (EAACI) celebrates 60 years at the forefront of allergy science and patient care Allergies and asthma constitute a public health concern of pandemic proportions that requires immediate and concerted actions. Prevention and control is the best cost-efficient way to decrease the disease burden Healthcare professionals, National Allergy Societies, patients and policy makers need to engage in reframing the conversation from disease burden to prevention and health promotion

Zurich, 15 March 2016 – The European Academy of Allergy and Clinical Immunology (EAACI) is celebrating its 60th anniversarry this year. EAACI has dedicated all its resources to improving the health of people affected by allergic diseases and asthma.

Reframing the conversation from disease burden to prevention and health promotion Allergic diseases and asthma constitute a public health concern of pandemic proportions that requires immediate and concerted actions. By 2025, more than 50 percent of all Europeans will suffer from allergy. Asthma and allergic rhinitis alone are estimated to result in more than 100 million lost workdays and missed school days in Europe every year.

Disease prevention is vital to controlling this growing public health burden. As the primary source of expertise in Europe for all aspects of allergic diseases and asthma, EAACI calls on all healthcare professionals, patients, National Allergy Societies and EU and national policy makers to engage and act to coordinate actions to improve prevention and allergy and asthma care, as well as support the allocation of resources and the development of Allergy Speciality.

Cost-efficient prevention and control of allergies and asthma are available If patients in Europe were treated appropriately with available cost-effective treatments, savings of €142 billion each year could be made. A number of specific interventions can lead to prevention of allergy, especially of atopic dermatitis and food allergy. Two randomized open-label trials and a real-world setting trial indicated that allergy immunotherapy prevents the onset of asthma in patients with allergic rhinitis. However, more research needs to be carried out before advice can be given in clinical practice.

About EAACI The European Academy of Allergy and Clinical Immunology (EAACI) is a non-profit organisation active in the field of allergic and immunologic diseases such as asthma, rhinitis, eczema, occupational allergy, food and drug allergy, and anaphylaxis. EAACI was founded in 1956 in Florence and has become the largest medical association in Europe in the field of allergy and clinical immunology. It includes over 9,000 members from 121 countries, as well as 52 National Allergy Societies.

Journal of the Romanian Society of Allergology and Clinical Immunology

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EAACI Speakers Session

Envisioning Allergy Care in the next decades Ioana Agache

Faculty of Medicine, Transilvania University, Brasov, Romania

ABSTRACT On the verge of a new age of allergy care we must embrace and adapt to the key drivers of change likely to impact significantly our work in order to implement a new system of care for our patients. Disease endotypes and precision medicine represent a new model of patient care building on large-scale biologic databases, omics and diverse cellular assays, health information technology and computational tools for analyzing large sets of data, health information technology (HIT). Advances in HIT create unprecedented opportunities to collect, analyze and learn from vast amounts of “real-world” data that will advance allergy research and care at a global level. Last but not least unsustainable cost increases and improvements in quality metrics are leading to a growing focus on cost effectiveness and “value” in health care.

KEYWORDS: allergy, asthma, cost-effectiveness, endotypes, health information technology, precision medicine, quality criteria, system of care

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of molecular pathways and characteristics of the allergy endotypes that interact to drive inflammation and remodelling and will need to be targeted, in combination, to develop prevention strategies and curative therapies for allergies and asthma (1,2).

This subtle and highly complex architecture of disease-specific pathways (endotypes) steadily provides new targets for more efficient and tailored interventions(3,4,5).

A major critical step for this tailored, mechanistic approach will be the identification, validation and qualification of pathways specific biomarkers as companion diagnostics, which will ultimately enable the clinician to select ‘the right patient at the right time (5,6,7).

Therefore, the ultimate goal of the endotype-driven approach is to develop the “magic bullet” linking drug

ver the last years Allergy and Clinical Immunology Speciality has delivered scientific advances and improved outcomes for patients, significantly increasing both quality of care and quality of life. However, we are now on the verge of a new age of allergy care, in which emerging scientific, technical and economic trends are likely to significantly impact our work. As a speciality, we must embrace and adapt these changes if we aim to implement a new system of care for our patients.

We can identify three key drivers of change that will have the biggest impact on allergy and asthma care over the coming decades: 1. Endotypes and Precision medicine We are coming to understand the complex networks

Corresponding Author: Ioana Agache Faculty of Medicine, “Transilvania” University, Brasov, 56 Nicolae Bălcescu street Phone: +40 268 412 185; E-mail: ibrumaru@unitbv.ro Submission date: 05/04/2016; Acceptance date: 17/04/2016; Publication date: 10/05/2016

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worldâ&#x20AC;? data that currently are locked away in unconnected servers and file cabinets. While clinical trials will likely remain the gold standard of evidence, crowdsourcing backed up by HIT advances promises to overcome the current limitations of observational data. By analyzing an immense body of observational data in real time, physicians and researchers can identify trends and associations between myriad variables and generate new hypotheses and draw immediate practicechanging conclusions(12,13,14,15).

In the near future, allergy practices will participate in IT-based systems that securely compile and analyze information from the individual electronic health records (major clinical end-points, comorbidities, symptom scores, objective measurements, treatments, side effects, molecular profiles, quality of life, etc). The data collected will not be biased by any pre-selection criteria. Advanced HIT tools, such as rapid learning systems, will structure the huge body of unbiased data by normalising similar information even if provided in different formats, correcting for the wide variation in data standards. Then, data will be run through correlation and trend analysis tools, revealing connections that can be used to draw statistically valid conclusions and develop robust hypotheses(14,16,17, 18,19).

In addition, the system will provide real-time, robust and truly informative clinical decision support at the point of care (15,16,20). Decision support at the point of care is a must in the advent of precision medicine in the clinic. As a result of this real-time guidance, most allergy care will be harmonised and based on guidelines, practice parameters and quality criteria. Other providers will play a larger role in routine allergy care. For less complex allergy cases and in follow-up care primary care physicians, community pharmacists and allied health workers will be equipped to provide care based on the IT-system feedback and consultation with specialists. The increased involvement of non-specialists will counteract the allergy specialistsâ&#x20AC;&#x2122; shortage that is projected as the population ages and allergy and asthma incidence increases. Specialists freed up from activities that do not capitalize on their unique expertise will be able to guide or oversee care for larger numbers of patients and can focus on developing better prevention and treatment plans and highly qualified managing care teams.

Through personalized, patient-friendly HIT tools, patients will have a much greater opportunity to serve as well-informed advocates for their own care and to stay connected with the healthcare provider in real time (18,19). A significant shift in the doctor-patient re-

response with the biological profile and to provide a safe and efficacious drug for a selected patient population. Besides the therapeutic purpose the endotypedriven approach should be able to open new avenues for prevention in high-risk individuals, early diagnosis and intervention and disease modifying strategies(5).

Precision Medicine (PM) represents a novel approach in patient care, embracing 4 key features: personalized care based on endotyping of the disease, with participation of the patient in the decision making process of therapeutic actions, and taking into account predictive and preventive aspects of the treatment (8,9).

The concept of PM that takes individual variability into account is not new: anemia treatment is guided by its mechanism, transfusion by blood typing, allergen immunotherapy is driven by the relevant sensitizing allergen. The prospect of applying this concept broadly has been dramatically improved by the recent development of large-scale biologic databases, powerful methods for characterizing patients (such as proteomics, metabolomics, genomics, diverse cellular assays, and health information technology), and computational tools for analyzing large sets of data(5,8,9).

This path also generated on one side a variety of stakeholders: Academia, patients, ethics committees, regulators and policy makers, diagnostic and pharmaceutical industry, and a variety of tools such as omics, biobanks and registries, bioinformatics and health information technology, that all need to be accounted for.

In addition, although the progress in understanding the mechanisms of allergies and asthma has been so significant during the last decade, it does not yet mirror the number of submitted dossiers for new medicinal products in the EMA and US FDA. Instead, it seems as the pipeline in successful drug development is rather slowing down(10.11). The reasons for this declining trend could be the sluggish translational implementation of these discoveries and the uncertainty experienced by pharmaceutical companies due to the lack of guidance, which should be provided by the regulators.

What is needed now is harmonization between stakeholders with agreement on a broad research program encouraging creative approaches and testing them rigorously both for robustness and for applicability for real life personalized care.

2. Health information technology Rapid advances in health information technology (HIT) have created unprecedented opportunities to collect, analyze and learn from vast amounts of â&#x20AC;&#x153;real-

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lationship is expected with the patient better informed on allergy and asthma when he arrives at the consultation and the doctor provided with personalized information from patient portals. The patients are expected to contribute to all important decisions about their care with increased confidence that treatment plans will work since they truly reflect their patients’ wishes.

They will take an active role in their care by reporting their health status, side effects and other experiences as they happen and thus the majority of patients will participate in clinical research with greater understanding and appreciation of clinical research as a part of routine allergy care, in part because enrollment procedures will become simpler and more patient- and provider-friendly.

Global HIT systems (21) will allow physicians and patients anywhere in the world to benefit from the latest, best available knowledge, helping to reduce today’s noticeable global disparities in allergy and asthma care.

Low-resource countries will contribute to, and benefit from, global cooperation networks. The benefits of clinical decision support will be greatest in countries or regions where allergists are in short supply. At the same time, collecting the experiences of patients in these countries will lead to the development of meaningful international clinical guidelines for allergy and asthma care. Allergy research go global, as HIT systems link researchers, patients, biobanks, registries and research procedures, even in the most remote locations, so endotyping—a central element of precision medicine— becomes affordable and universal.

There are several obstacles to be overcome for the widespread use of HIT including inconsistency in IT development, variation between countries in resources and infrastructure and limits of patient involvement and expertise in population subgroups.

public reporting of practices and compensation quality care for medical services upon certification of value and quality.

Conflict of interests: The authors declare no conflict of interests.

References 1. Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355-60 2. Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012;67(7):835-46.

3. Agache I. From phenotypes to endotypes to asthma treatment.

Curr Opin Allergy Clin Immunol. 2013;13(3):249-56 4. Agache I, Sugita K, Morita H, Akdis M, Akdis CA. The Complex Type 2 Endotype in Allergy and Asthma: From Laboratory to Bedside. Curr Allergy Asthma Rep. 2015;15(6):29.

5. Muraro A, Lemanske RF, Hellings PW, Akdis CA, Bieber T, Casale TB, 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, in press 6. Wagner JA. Overview of biomarkers and surrogate endpoints in drug development. Disease Markers. 2002;18(2):41–6.

7. Goodsaid FM, Frueh FW, Mattes W. Strategic paths for biomarker qualification. Toxicology. 2008;245(3):219–23 8. Muraro A, Fokkens WJ, Pietikainen S, Borrelli D, Agache I, Bousquet J, Costigliola V, Joos G, Lund VJ, Poulsen LK, Price D, Rolland C, Zuberbier T, Hellings PW. European Symposium on Precision Medicine in Allergy and Airways Diseases: Report of the European Union Parliament Symposium (October 14, 2015).

Allergy. 2015 Dec 10. doi: 10.1111/all.12819. [Epub ahead of print] 9. Jameson JL, Longo DL. Precision medicine – personalized, problematic, and promising. N Engl J Med 2015; 372:2229–2234 10. European Medicines Agency/Committee for Medicinal Products for Human Use. Zelboraf, Summary of opinion (2011).

11. Krishan M. New drug approvals FDA/EMA in 2010: declining R&D productivity? Guild (KPG), Knol Publishing 12. Chaudhry B1, Wang J, Wu S, Maglione M, Mojica W, Roth E, Morton SC, Shekelle PG. Systematic review: impact of health information technology on quality, efficiency, and costs of medical care Ann Intern Med. 2006;144(10):742-52.

13. Blumenthal D. Stimulating the Adoption of Health Information Technology. N Engl J Med 2009; 360:1477-1479 14. Gibson CJ, Dixon BE, Abrams K. Convergent Evolution of Health Information Management and Health Informatics: A Perspective on the Future of Information Professionals in Health Care. Appl Clin Inform. 2015; 6(1): 163–184

3. Delivering value Unsustainable cost increases and improvements in quality metrics are leading to a growing focus on cost effectiveness and “value” in health care. Two major challenges can be foreseen: healthcare professionals will need to adapt to demands for greater quality, efficiency and transparency and the society will need to address the spiraling costs of new diagnostic procedures and therapeutic interventions.

In order to implement value as a driver for allergy services several prerequisites need to be tackled such as routine quality measurement and improvement embedded firmly in daily practice, training programs focused on skills needed to ensure high-value care, routine

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15. Milgrom H, Tran ZV. The rise of health information technology.

Curr Opin Allergy Clin Immunol. 2010;10(3):178-80 16. Jensen RE, Rothrock NE, DeWitt EM, Spiegel B, Tucker CA, Crane HM, Forrest CB, Patrick DL, Fredericksen R, Shulman LM, Cella D, Crane PK. The role of technical advances in the adoption and integration of patient-reported outcomes in clinical care. Med Care. 2015;53(2):153-9 17. Custovic A, Ainsworth J, Arshad H, Bishop C, Buchan I, Cullinan P, Devereux G, Henderson J, Holloway J, Roberts G, Turner S, Woodcock A, Simpson A. The Study Team for Early Life Asthma Research (STELAR) consortium ‘Asthma e-lab’: team science bringing data, methods and investigators together. Thorax.

2015;70(8):799-801

18. Matui P, Wyatt JC, Pinnock H, Sheikh A, McLean S. Computer decision support systems for asthma: a systematic review. NPJ Prim Care Respir Med. 2014;24:14005.

19. Morrison D, Wyke S, Agur K, Cameron EJ, Docking RI, Mackenzie AM, McConnachie A, Raghuvir V, Thomson NC, Mair FS. Digital asthma self-management interventions: a systematic review. J Med Internet Res. 2014;16(2):e51.

20. Lyman JA, Cohn WF, Bloomrosen M, Detmer DE. Clinical decision support: progress and opportunities. J Am Med Inform Assoc. 2010 17(5):487-92.

21. Haux R. Health information systems – past, present, future. Int J Med Inform. 2006;75(3-4):268-81.

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Risk factors for severe asthma in children Ă&#x2013;mer Kalayci

Pediatric Allergy & Asthma Hacettepe University School of Medicine, Ankara, Turkey

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count. More importantly they have a higher median number of aeroallergen sensitivity. These results suggest that it is not only atopy but kind of quantitative atopy that may be a more significant factor in contributing to the severity.

This is further supported by the results obtained from the Royal Brompton cohort that compared children with difficult asthma (DA) and severe treatment resistant asthma (STRA)(7). Again, even compared to those with DA, children with STRA had more atopy.

he challenge of defining severe asthma resulted in many different definitions for severe asthma which has caused considerable difficulty in evaluating the results of different studies. In order to overcome these difficulties ATS and ERS have convened a workshop and come up with a definition. According to this document(1) a patient has severe asthma if the patient needs GINA steps 4â&#x20AC;&#x201C;5 treatment with high dose inhaled corticosteroids and LABA or LTRA or teophyllin the previous year or systemic corticosteroids for 50% of the previous year to prevent asthma from becoming uncontrolled or still remains uncontrolled despite this treatment.

Another problem hampering the progress in severe asthma research was its low prevalence. Recently, a survey in the Netherlands has shown that the prevalence among adult asthmatics is 3.6%(2). In our cohort of asthmatic children aged 6-18 years the prevalence was 1.8%(3). In addition to low prevalence, another problem with severe asthma in childhood is the question of phenotype stability. Melbourne study has shown that even those children classified as severe asthma had a 15% remission rate(4). What is classified as severe today may not even have asthma in the future.

Therefore the important question that still remains to be answered is: whether severe asthma develops early in the course of the disease, or whether it develops over time.

In recent years unbiased hierarchical cluster analysis has improved our understanding of asthma phenotypes and the risk factors associated with specific phenotypes. In the Severe Asthma Research Program (SARP) study(5) atopy and the longer duration of asthma were associated with more severe disease outcome. The results of the Paris cohort also support this notion(6). Cluster analysis of this cohort have produced three clusters. The first cluster has the highest rate of hospitalizations and the highest rate of steroid unresponsiveness as well as the highest atopic indices including family history, high IgE and high eosinophils

Even though genetic studies in asthma have found many genetic variants associated with asthma, data on severe asthma are scarce. In one of the few studies(8), white blood cells were isolated and the global transcriptome profile was characterised using the Affymetrix Human Gene ST 1.0 chip in children with severe, therapy-resistant asthma (n=17), controlled asthma (n=19) and healthy controls (n=18). Receptor expression was studied in separated leukocyte fractions from asthmatic adults (n=12). Overall, 1378 genes were differentially expressed between children with severe/controlled asthma and controls. Quantitative PCR experiments confirmed upregulation of bitter taste transduction receptors (TAS2Rs) in severe asthmatics.

In a more recent study(9), gene expression was analyzed

by Cap Analysis of Gene Expression -which detects the transcription start sites of known and novel mRNAs and noncoding RNAs- in children with severe asthma (n=13), children with controlled persistent asthma (n=15), and agematched healthy control subjects (n=9). Expression of RAR-related orphan receptor A (RORA), which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with severe asthma.

We have also been interested in the genetic determinants of asthma severity. In one of our studies we screened for genetic variants in the promoter region of AMCase gene(10).

Corresponding Author: Ă&#x2013;mer Kalayci, MD Professor of Pediatrics Pediatric Allergy & Asthma Hacettepe University School of Medicine, Ankara, Turkey E-mail: okalayci@hacettepe.edu.tr Submission date: 22/03/2016; Acceptance date: 26/03/2016; Publication date: 10/05/2016

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2. Hekking PP, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015;135:896-902.

3. Prosperi MC, Sahiner UM, Belgrave D, Sackesen C, Buchan IE, Simpson A, Yavuz TS, Kalayci O, Custovic A. Challenges in identifying asthma subgroups using unsupervised statistical learning techniques. Am J Respir Crit Care Med. 2013;188:1303-12.

4. Tai A, Tran H, Roberts M, Clarke N, Gibson AM, Vidmar S, Wilson J, Robertson CF. Outcomes of childhood asthma to the age of 50 years. J Allergy Clin Immunol. 2014;133(6):1572-8 5. Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, et al.

National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung and Blood Institute Severe Asthma Research Program. J Allergy Clin Immunol.

2011;127:382-389.

6. Just J, Gouvis-Echraghi R, Rouve S, Wanin S, Moreau D, AnnesiMaesano I. Two novel, severe asthma phenotypes identified during childhood using a clustering approach. Eur Respir J. 2012 Jul;40(1):55-60.

7. Sharples J, Gupta A, Fleming L, Bossley CJ, Bracken-King M, et al.

Long-term effectiveness of a staged assessment for paediatric problematic severe asthma. Eur Respir J. 2012 Jul;40(1):264-7.

8. Orsmark-Pietras C, James A, Konradsen JR, Nordlund B, Söderhäll C, et al. Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics. Eur Respir J. 2013 Jul;42(1):65-78 9. Persson H, Kwon AT, Ramilowski JA, Silberberg G, Söderhäll C, et al.

Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles. J Allergy Clin Immunol. 2015;136:638-48 10. Birben E, Sackesen C, Kazani S, Tincer G, Karaaslan C, Durgunsu B, Gürsel I,Wechsler ME, Israel E, Kalayci O. The effects of an insertion in the 5’UTR of the AMCase on gene expression and pulmonary functions. Respir Med. 2011;105:1160-9.

11. Ercan H, Birben E, Dizdar EA, Keskin O, Karaaslan C, Soyer OU, Dut R, Sackesen C, Besler T, Kalayci O. Oxidative stress and genetic and epidemiologic determinants of oxidant injury in childhood asthma. J Allergy Clin Immunol. 2006;118:1097-104.

12. Brown SD, Baxter KM, Stephenson ST, Esper AM, Brown LA, Fitzpatrick AM. Airway TGF-β1 and oxidant stress in children with severe asthma: association with airflow limitation. J Allergy Clin Immunol. 2012 ;129:388-96 13. McCarville M, Sohn MW, Oh E, Weiss K, Gupta R. Environmental tobacco smoke and asthma exacerbations and severity: the difference between measured and reported exposure. Arch Dis Child. 2013 Jul;98:510-4 14. Hacihamdioglu B, Arslan M, Yeşilkaya E, Gok F, Yavuz ST. Wider neck circumference is related to severe asthma in children. Pediatr Allergy Immunol.2015 May 8. doi: 10.1111/pai.12402.

15. Gupta A, Sjoukes A, Richards D, Banya W, Hawrylowicz C, Bush A, Saglani S. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med. 2011;184:1342-9

In this study we discovered a 10 bp insertion in the promoter region that modifies gene expression. This mutation was associated with a lower FEV1 in the pediatric population suggesting that it may modify the severity of the disease. Therefore, we wanted to ascertain our findings in an adult population with asthma and compared the frequency of the insertion in a population of mild asthma and severe asthma. The insertion was not only different between the mild and severe asthmatic populations but also showed an opposite relationship with FEV1. These findings suggest that the genetic factors regulating the severity of asthma may be different in adults and children Some of the genetic studies have also been backed up by physiologic measurements. For example, we investigated the effect of genetic variants in the anti-oxidant enzymes on asthma severity in children. For this purpose we had a population composed of mild and moderate-severe asthmatics and two control populations. Of the various mutations that we studied we found that a specific mutation in the coding region of the Glutathion S Transferase P isoenzyme is associated with the severity of asthma(11). More recently, the physiologic support for the role of oxidant stress in severe asthma was also published and increasing oxidant stress was found to be associated with more severe disease(12) One major source of oxidant stress is environmental tobacco smoke (ETS). Even though the association of ETS exposure with asthma is generally well appreciated, its effect on asthma severity is less well studied. Investigators from “Chicago Initiative to Raise Asthma Health Equity study” have looked into this question(13). Their results suggest that although ETS may predict asthma exacerbations, it is not a significant predictor of severity. This study has also shown that obesity may significantly predict severity.

In connection with obesity a recent study has found that the neck circumference is associated with asthma severity in children(14). Obese individuals have low vitamin D status, and Sejal Saglani and colleagues have reported lower vit D levels in children with severe asthma(15).

Conflict of interests: The authors declare no conflict of interests.

References 1. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, et al.

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343-73.

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Awareness, training and education

Online microblogging and asthma Florin-Dan Popescu

Department of Allergology, „Nicolae Malaxa” Clinical Hospital, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

ABSTRACT Free popular microblogging services include Twitter, Tumblr (Latin-based alphabet characters) and Sina Weibo (Chinese characters). Such online media used in a responsible manner provide concise information dissemination, social networking, and real-time communication, and have a potential increasing relevance of application for users interesed in asthma care, such as patients and their families, clinicians, academic physicians, scientific and health organisations, professional medical societies, patient-support organizations and public health institutions. More research is needed to evaluate the impact of microblogging as a form of continuous medical education for physicians, as a tool for improving asthma patient education and medication compliance or in prediction models for asthma.

KEYWORDS: social media, microblogging, asthma

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sthma management requires information and education of both care providers and patients. New GINA documents are remarkable educational tools, and their applicability in real life needs to be further demonstrated (Bousquet and Humbert, 2015). Next generation guidelines should incorporate integrated care pathways, with structured multidisciplinary care plans, e-health, using mobile operating systems applications and online tools, and clinical decision support systems, identifying the most suitable patients for whom an intervention is appropriate, in order to propose a manageable and personalised medicine easily accessible to the patients, health and social care providers (Bousquet et al, 2015).

In the last five years it began to be increasingly discussed the role of social media networks in asthma management for patients and care givers as a novel way to

improve asthma care (Baptist et al, 2011; Barczok, 2012). Developments in information technology may influence asthma management. Online social media and mobile technology could address some of the problems associated with increasing asthma prevalence, but internet-based interventions for this chronic respiratory disease are often designed without the use of any documented behavioral change theory, clinical guidelines, and/or assessment tools (Al-Durra et al, 2015).

Regarding asthma online, pro and cons of social media and networks were recently discussed. In some asthmatic patients, the excessive use of social networks can induce depression, and psychological stress due to socializing online media login may represent a trigger of asthma exacerbations in depressed asthmatic individuals, in which hyperventilation might play a key role, whereas in others their rational use can induce

Corresponding Author: Florin-Dan Popescu Clinical Hospital ”Nicolae Malaxa”, 12 Soseaua Vergului, postal code 022441, Bucharest; E-mail: florindanpopescu@allergist.com Submission date: 06/04/2016; Acceptance date: 08/04/2016; Publication date: 10/05/2016

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beneficial effects in terms of asthma management, with enhancing communication, social connection and selfesteem (D’Amato et al, 2010; D’Amato et al, 2013; Yaqub, 2014).

Asthma self-management may be supported by smartphone applications with reminder functions and easy access to online social media, as adherence-enhancing interventions, because forgetting is one major reason for not using medication as prescribed, and patients may be positive about sharing of experiences with others, especially adolescents (Koster et al, 2015; Incorvaia et al, 2016). Digital media products able to track conditions, triggers and related asthma activities may be useful to improve asthma control in teens and helpful to decrease school absenteeism (Panzera et al, 2013).

In scientific publishing, altmetrics are non-traditional metrics proposed as alternative to traditional citation impact metrics, such as the impact factor.

There is evidence that some altmetrics such as Tweets and Facebook wall posts, associate with citation counts, at least in medical and biological sciences.

Google+ posts might possibly have little or insignificant association with citations, and too little data is available to be confident about whether other metrics, such as LinkedIn posts, Pinners and Reddits, associate with citation counts. The coverage of all the altmetrics, except for Twitter, seems to be low, and so it is not clear if they are prevalent enough to be useful in practice (Thelwall et al, 2013).

For the members of the European Academy of Allergy and Clinical Immunology (EAACI) the Code of Ethics strongly recommended to check and adjust the privacy settings of social media accounts, to discriminate private from professional presence on social media, to be conscious and cautious of the image presented online, to be respectful, polite, responsible and considerate, and to preserve the doctor-patient relationship with caution (Dörries et al, Annexe II to the EAACI Ethics Code: Using social media Internet platforms as an EAACI member).

Social media represent dynamic computer-mediated communication tools based currently on mobile and Web 2.0 internet-based technologies to generate highly interactive platforms, in which individuals or groups create user-specific profiles for a site or application software, designed and maintained by a social media service, connected in online social networks or virtual communities, in which user-generated content is created or co-created, accessed, shared or exchanged, discussed or modified. The backbone of the social media service is the user-specific profile, while the user-generated content is the lifeblood of the social media (Obar and Wildman, 2015).

Online social media can be classified (Grajales et al, 2014) in: publishing social media, such as wikis (e.g.

Wikipedia) and blogs (e.g. WordPress), location-based social networks (e.g. Foursquare), collaborative filtering sites (e.g. Digg, Reddit), virtual worlds (e.g.

SecondLife), social networks used for complex socializing, networking and sharing (e.g. Facebook, Google+) or for professional networking (e.g. LinkedIn, Sermo), thematic networking sites (e.g. PatientsLikeMe), social networks for media sharing (e.g. Flickr, Instagram, Meerkat, Periscope, Pinterest, SlideShare, Vimeo, YouTube) and microblogs for concise information dissemination, social networking, and real-time communication (e.g. Twitter, Tumblr).

The main uses of social media in health communication among the general public, patients, their families and health professionals focus on increased interactions with others, more available and tailored information, increased accessibility and widening access to health information, peer/social/emotional support, public health surveillance and potential to influence health policy (Moorhead et al, 2013).

Microblogging social networks are very popular social media services that allow users to update brief content called “microblogs” in the form of short sentences, individual images, web page links, or video links (Jiang et al, 2015). Microblogging social media can be considered as “social sensors”, while content from its platforms can provide real-time updates of social activities and collective human behaviors (Sasahara et al, 2013; Wang et al, 2015). Free popular microblogging services include Twitter, Tumblr (Latin-based alphabet characters) and Sina Weibo (Chinese characters) (Jiang et al, 2015).

At first glance, it probably seems counterintuitive that an application limiting the exchange of textbased messages to a number of characters should be of great interest. Yet still, microblogs are growing fast and represent an established category within the general group of social media. The success of microblogging has some characteristics: condensed information, creation of ambient awareness, unique form of push-pushpull communication, and ability to serve as an online informative platform (Kaplan and Haenlein, 2011).

Twitter is a free popular microblogging social network, launched in 2006, with headquarters in San

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of Twitter by allergy and asthma specialists increased rapidly in the last five years. Twitter is used to expand the reach and engagement of allergists. Some individual specialist accounts have thousands of followers.

Twitter campaigns and chats hosted by profesional allergy, asthma and clinical immunology organizations and specialized magazines may reach a huge number of accounts and make important impressions during discussions. Professional use of Twitter peaks during the international scientific meetings (tweeting a meeting is supported by professional organizations by promoting meeting-specific hashtags). Symplur is an online resource that provides analytics for specific hashtags (Dimov and Eidelman, 2015; Stukus, 2016).

Moreover, Twitter discussions posted by specialists regarding published articles in respiratory medicine may determine further comments as author’s reply (Martineau and Hooper, 2015), allowing to reach a larger audience, suggesting new ideas and presenting personal opinions. Health discussions occur regularly on Twitter, with content sharing among a variety of groups, including health care professionals, patients and their caregivers (Hamad et al, 2016).

Twitter can also promote allergy practice, with sharing daily pollen counts, work hours, provided medical services, including immunotherapy, physician on call information (Joshi and Dimov, 2014). An interesting US study compared weekly Twitter trends with weekly pollen counts, and found a high correlation of the sum of the total pollen counts from each pollen counting stations with tweets reporting allergic rhinoconjunctivitis symptoms and with tweets reporting H 1 antihistamine drug names (Gesualdo et al, 2015). Adolescents with asthma positive attitude toward the use of social media or mobile technology opens the possibility for future studies to explore some potential benefits of social media interventions in asthma control (Nickels and Dimov, 2012).

In a study assessing a novel method using multiple data sources for predicting the number of asthma-related emergency department visits in a specific area, Twitter data, Google search interests, and environmental sensor data were collected. Findings revealed that the model can predict the number of asthma emergency department visits based on near-real-time environmental and social mediadata with approximately 70% precision. Further research is requested to evaluate how combining real-time/near-realtime social media and environmental data with more traditional data might affect the prediction models for asthma (Ram et al, 2015).

Francisco USA. It is based on the sharing of short messages of up to 140 characters, called Tweets.

Twitter has currently 320 million monthly active users, 80% active users on mobile, and more than 35 languages supported. Twitter profiles can display a picture as well as personal and/or professional affiliations. Messages from Twitter accounts a user choose to follow will show up on the personal home page, called “Timeline”. A Tweet format with a maximum of 140 characters forces users to be concise, and thus condensed information is easy to read, easy to follow, and easy to statistically analyze. Many users contribute with their own content to Twitter, a process called “tweeting”, retweet messages they consider interesting or @reply with their reaction to selected Tweets, mention other users by their Twitter username (preceded by the @ sign) in their Tweets. Some users explore more advanced features: lists, direct messages, and likes, include images or videos in their Tweets, or consider connecting personal Twitter account to other social media. The # symbol, called a hashtag, is used to mark keywords or topics in a Tweet. People use the hashtag symbol # before a relevant keyword or phrase (no spaces) in their Tweets to categorize messages and help them appear more easily in Twitter Search.

Hashtags should be kept short as the characters count toward the limit for each tweet. Hashtagged words that become very popular are often Trending Topics (https://about.twitter.com/company ; https://support. twitter.com).

There are multiple current and potential uses for Twitter in asthma practices. With regards to allergy and asthma specialists, Twitter facilitates the availability, rapid spread and discussions of up-to-date scientific information on latest news and journal articles, latest guidelines, position papers and educational materials, congresses, conferences and focused meetings, as a form of continuing medical education, as well as exchange of opinions and collaboration with other colleagues. There are tweets containing information on updated asthma guidelines and reports, including the GINA global strategy for asthma management and prevention. Moreover, physicians treating patients with asthma have the opportunity to connect on Twitter with other specialists, academic physicians and recognized experts, scientific and health organisations, professional medical societies, patient-support organizations, public accounts interested in health issues, and other entities, some with verified accounts. Many asthma organizations have Twitter accounts, and this microblooging service is widely used by junior members. The use

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Online microblogging and asthma

Tumblr is another free, easily modifiable, featurerich microblogging platform, founded in 2007, which allows users to post multimedia and other content to a short-form blog. As of April 2016, Tumblr hosts more than 288 million blogs, 132 billion posts. The company’s headquarters is in New York City, USA (www.tumblr.com/about). Users can follow other users’ blogs, as well as make their blogs private. Much of the website’s features are accessed from the “dashboard” interface, where the option to post content and posts of followed blogs is. The ease of content dissemination via Tumblr is due to the simplicity with which it enables the posting and sharing of text, quotes, links, photos, audio and video content, from mobile phone, email, desktop or web browser (Correnti et al, 2014; Elliot et al, 2015).

Tumblr is a social media domain insufficiently explored as a resource for information dissemination and interaction with the public for asthma specialists, professional groups, journals and organizations. For instance, international guidelines recommend smoking cessation in all patients with asthma. In the context of young adult Tumblr-based health interventions, a recent publication described a proof-of-concept social media strategy to reach and engage young adult smokers on this social media site. The engagement included creating content, conducting proactive outreach to current and former smokers, and fostering user engagement and support within Tumblr. It was underlined that steady online community growth and positive qualitative feedback constitute early indicators of impact (Jacobs et al, 2016).

people communicate about a topic concerning asthmatics. Although influenza virus continues to be an important contributor to morbidity and mortality in at-risk populations, including those with underlying pulmonary diseases, and the administration of influenza vaccine is recommended to patients with asthma (Hanania et al, 2006), on Pinterest, many vaccine-related pins are anti-vaccination, with concerns about vaccine safety and side effects, while pro-vaccination pins elicit consistently more engagement than antivaccine pins (Guidry et al, 2015).

Sina Weibo is a massive microblogging social network in China, launched in 2009 by Sina Corporation, and available in Simplified Chinese and Traditional Chinese. Sina Weibo is the largest microblog platform with Chinese characteristics, currently having more than 500 million users. Active users can number 4.6 million daily, with about 100 million messages posted every day. This Twitter-like social media appealing features include real-time availability of information, message compactness and wide publicity. All users can see posts, called Weibos in Chinese, published by users.

There is a limited number of characters per posting.

Sina Weibo functions are similar to Twitter, such as forwarding (retweeting), mentioning (@), and hashtags (#). Hashtags differ slightly, using a double-hashtag “#HashName#”, since the lack of spacing between Chinese characters necessitates a closing tag. The major differences between Sina Weibo and Twitter are in the content available from user profiles. Sina Weibo collects more optional personal information, such as gender, birthdays, and blood type in user profiles.

Weibo users may be categorized into four primary groups: celebrities and grassroots stars, organizations/ media accounts and ordinary individuals (Guo et al, 2014; Jiang et al, 2015; Wang et al, 2014; Li et al, 2016).

Air pollution is a major public health concern affecting the great majority of people living in urban areas worldwide (Kurt et al, 2016). Although the global rise in asthma prevalence and severity could be also considered an effect of air pollution and climate changes, it is not easy to evaluate their impact on the prevalence of asthma in general and on the timing of asthma exacerbations (D’Amato et al, 2015). There are recent evidences that short-term exposures to air pollutants account for increased risks of asthma-related emergency room visits and hospitalizations, an important healthcare utilization and socioeconomic burden (Zheng et al, 2015).

A recent study extracted Sina Weibo data content about the dynamics of air quality in the real world, by assess-

Although besides Tumblr, Pinterest is considered by some health profesionals as a microblogging tool (Duffy, 2013), it is in fact more of a visual social bookmarking online service, which can be used to promote active and engaged learning in medical education (Shellenbarger and Robb, 2013). Pinterest is a social media internet service utilized by individuals and organizations to collect and share ideas related to projects or interests (Whitsitt et al, 2015). Free registered users can upload, save, sort, and manage images, known as pins, and other media content through collections known as pinboards. There are currently more than 50 billion Pins to explore (www.pinterest.com), but not many asthma and allergy specialists and organizations are very actively present on this social media. Health educators and public health organizations should be aware of some online social media risky dynamics, since efficient health communication campaigns should start with an understanding of what and how

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Journal of the Romanian Society of Allergology and Clinical Immunology

ing three types of microblogs (retweet messages, mobile app messages, original individual messages). The vocabulary concerning air pollution that occurred in the microblog texts was analyzed. Based on correlation analysis, it was concluded that individual messages may be used to monitor the air quality dynamics to some extent (Jiang et al, 2015).

Vol. XIII, No. 2, April - June 2016

7. D’Amato G, Liccardi G, Cecchi L, Pellegrino F, D’Amato M. Facebook: a new trigger for asthma? Lancet. 2010 Nov 20; 376(9754): 1740. doi: 10.1016/S0140-6736(10)62135-6. PubMed PMID: 21093651.

8. D’Amato G, Cecchi L, Liccardi G, D’Amato M, Stanghellini G. Social networks and bronchial asthma. Curr Opin Allergy Clin Immunol. 2013 Feb; 13(1): 87-91. doi: 10.1097/ ACI.0b013e32835af1c6. Review. PubMed PMID: 23222071.

9. D’Amato G, Vitale C, De Martino A, Viegi G, Lanza M, Molino A, Sanduzzi A, Vatrella A, Annesi-Maesano I, D’Amato M. Effects on asthma and respiratory allergy of Climate change and air pollution. Multidiscip Respir Med. 2015 Dec 22; 10: 39. doi: 10.1186/s40248-015-0036-x. eCollection 2015. Review. PubMed PMID: 26697186; PubMed Central PMCID: PMC4687168.

10. Dimov V, Eidelman F. Utilizing social networks, blogging and YouTube in allergy and immunology practices. Expert Rev Clin Immunol.

2015; 11(10): 1065-8. doi: 10.1586/1744666X.2015.1065731. Epub 2015 Jul 10. PubMed PMID: 26163316.

11. Dörries A, Krones T, Espesson B, Scadding G, Tsilochristou O, Skevaki C, Porz R, Pauli G, Rosado Pinto J, Spranger O, Gayraud J. The European Academy of Allergy and Clinical Immunology (EAACI) Code of Ethics. Annexe II to the EAACI Ethics Code: Using social media Internet platforms as an EAACI member. http://www.eaaci.org/images/committee_ethics/New-EAACICode-of-Ethics-and-annexes.pdf 12. Duffy M. Microblogging: tumblr and pinterest. Am J Nurs. 2013 Jun;113(6):61-4. doi: 10.1097/01.NAJ.0000431274.68030.90.

Review. PubMed PMID: 23702769.

13. Elliot D, Rohlman D, Parish M. Focus Groups Move Online: Feasibility of Tumblr Use for eHealth Curriculum Development.

JMIR Res Protoc. 2015 Mar 27; 4(1): e34. doi: 10.2196/resprot.3432. PubMed PMID: 25831197; PubMed Central PMCID: PMC4393503.

14. Gesualdo F, Stilo G, D’Ambrosio A, Carloni E, Pandolfi E, Velardi P, Fiocchi A, Tozzi AE. Can Twitter Be a Source of Information on Allergy? Correlation of Pollen Counts with Tweets Reporting Symptoms of Allergic Rhinoconjunctivitis and Names of Antihistamine Drugs. PLoS One. 2015 Jul 21; 10(7): e0133706. doi: 10.1371/journal.pone.0133706. eCollection 2015. PubMed PMID: 26197474; PubMed Central PMCID: PMC4510127.

15. Grajales FJ 3rd, Sheps S, Ho K, Novak-Lauscher H, Eysenbach G. Social media: a review and tutorial of applications in medicine and health care. J Med Internet Res. 2014 Feb 11; 16(2): e13. doi: 10.2196/jmir.2912. Review. PubMed PMID: 24518354; PubMed Central PMCID: PMC3936280.

16. Guidry JP, Carlyle K, Messner M, Jin Y. On pins and needles: how vaccines are portrayed on Pinterest. Vaccine. 2015 Sep 22; 33(39): 5051-6. doi: 10.1016/j.vaccine.2015.08.064. Epub 2015 Aug 28. PubMed PMID: 26319742.

17. Guo L, Wang W, Cheng S, Que X. Event-based user classification in Weibo media. ScientificWorldJournal. 2014; 2014: 479872. doi: 10.1155/2014/479872. Epub 2014 Jul 16. PubMed PMID: 25133235; PubMed Central PMCID: PMC4124743.

18. Hamad EO, Savundranayagam MY, Holmes JD, Kinsella EA, Johnson AM. Toward a Mixed-Methods Research Approach to

In conclusion, microblogging social media used in a responsible manner provide concise information dissemination, social networking, and real-time communication, and have a potential increasing relevance of application for users interesed in asthma care, such as patients and their families, clinicians, academic physicians, scientific and health organisations, professional medical societies, patient-support organizations, public health institutions. Further studies are needed to assess the impact of microblogging as a form of continuous medical education for physicians, as a tool for improving asthma patient education and medication compliance or in prediction models for asthma.

Conflict of interests: The authors declare no conflict of interests.

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Vol. XIII, No. 2, April - June 2016

Original articles and brief communications

Patterns of sensitization to ragweed species in Western Romania Carmen Panaitescu Bunu1, Laura Marusciac1, Tudor-Paul Tamas1, Inmaculada Perez2, Fernando Pineda2

Department of Functional Sciences, University of Medicine and Pharmacy Victor Babes Timisoara, Romania 2 DIATER Laboratorios, Madrid, Spain

1

ABSTRACT Introduction: The Asteraceae family is one of the largest families of flowering plants. Among Ambrosia species, A. artemisiifolia and A. trifida have high allergenic potential. This study aimed to evaluate whether there is concurrent hypersensitivity to multiple Ambrosia species as a result of co-sensitization or cross-reactivity, and to perform the biological standardization of ragweed pollen extract.

Materials and methods: Standardization of ragweed pollen extract for skin prick tests was performed on patients with confirmed ragweed pollen allergy. The allergenic activity of A. artemisiifolia and A. trifida pollen extracts was evaluated in vitro, by specific serum IgE, immunoblotting and IgE inhibition.

Results: 76% of the patients had intermittent, and 24% had persistent moderate-severe allergic rhinoconjunctivitis. Sensitivity to Amb a 1 based on specific IgE levels was moderate in most patients (84%). IgE ELISA inhibition revealed different patterns of recognition to A. artemisiifolia and A. trifida extracts, with a greater response for A. artemisiifolia vs A. trifida (Ag50 = 0.65 and 13.92 mg/mL respectively). Histamine equivalent prick to ragweed pollen corresponded to 0.07 mg/mL. Conclusion: Understanding the specific cross-reactivity pattern between A. artemisiifolia and A. trifida pollens is of great importance for appropriate selection of allergen-specific immunotherapy, and for prevention measures. Specific IgE is an important diagnosis tool to identify the primary cause of weed pollen allergy. A. artemisiifolia is the major allergenic ragweed species in Western Romania. Most ragweed allergic patients are sensitized specifically to A. artemisiifolia allergens. There is no significant cross- or co-sensitization between A. artemisiifolia and A. trifida.

KEYWORDS: ragweed allergy, allergic rhinoconjunctivitis, skin prick test, specific IgE, IgE inhibition.

Introduction

allergenic sources, the most important being Ambrosia (ragweed) and Artemisia (mugwort). Other, less allergenic members, are Parthenium (feverfew) and Helianthus (sunflower). The Ambrosia genus includes approximately 40 species, most of them native to North

The Asteraceae or Compositae family is one of the largest families of flowering plants, including more than 23,000 species(1). Only a few genera are relevant as

Corresponding Author: Laura Marusciac E-mail: laura.marusciac@umft.ro Submission date: 05/04/2016; Acceptance date: 07/04/2016; Publication date: 10/05/2016

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Patterns of sensitization to ragweed species in Western Romania

sensitized patients showed positive reactions to purified natural Amb t 5 in SPTs. Amb t 5 was produced as a recombinant protein in E. coli and compared with Amb a 1, and no major structural differences between the molecules have been found. However, conclusive data on human IgE cross-reactivity between Amb a 1 and Amb t 5 is not yet available(14).

America (1). Among ragweed species, A. artemisiifolia (short ragweed) and A. trifida (giant ragweed) are of special interest, due to their high allergenic potential.

A. artemisiifolia was imported into Europe at the beginning of the XXth century, together with grain, and in the past decades it has rapidly spread into many areas from Central and South Eastern Europe.

Nowadays the prevalence of ragweed pollen allergy has an increasing trend (2) , particularly in Romania (3) , Hungary (4), Austria (5), Croatia (6), Serbia (7), Bulgaria (8), France (9) , and Italy (10) . In Romania, only in the Timisoara area, ragweed pollen represents approximately 20% out of the total pollen in the atmosphere, and it is the most allergenic in this climate zone. Most of the ragweed from the Western part of Romania is A. artemisiifolia, but A. trifida is also encountered(11).

Skin prick tests (SPTs) are the most commonly used in vivo diagnostic procedure that induces an immediate IgE-mediated allergic reaction and establishes the allergic nature of the disease. However, in order to achieve representative results, the quality of the allergen extract is of key importance, as there are wide variations in the potency and/or quality of commercially available inhaled allergen extracts. In order to avoid these variations, the extracts used for SPTs need to be standardized.

The aim of this study was to evaluate whether there is a concurrent hypersensitivity to multiple Ambrosia species as a result of co-sensitization or cross-reactivity, and to carry out the biological standardization of allergenic ragweed pollen extract.

Methods 1. Design The standardization of the ragweed pollen extract for SPTs was performed on patients with confirmed allergy to ragweed pollen, and in accordance with the biological standardization guidelines of the Nordic Council on Medicine, using SPTs. Further, the allergenic activity of A. artemisiifolia and A. trifida pollen extracts, was evaluated in vitro, by immunoblotting and IgE inhibition experiments. The study was approved by the local ethics committee and all subjects gave written informed consent before entering the study.

2. Subjects The study group included 25 patients screened for positive skin prick test to Ambrosia pollen extract (DIATER Laboratories, Madrid, Spain), a positive test being a wheal of â&#x2030;Ľ3 mm on the largest diameter, who were symptomatic during ragweed pollen season (August-October), with a diagnosis of allergic rhinoconjunctivitis, according to ARIA criteria(15). Blood was collected from these patients, and sera were stored at -20ÂşC. In the in vitro experiments, the patientsâ&#x20AC;&#x2122; sera were tested for specific immunoglobulin E (IgE) to Amb a 1 by ImmunoCAP and further for specific IgE reactivity to A. artemisiifolia vs A. trifida pollen extracts containing allergenic fragments, by immunoblotting and ELISA inhibition. All subjects avoided antihistamines or intranasal corticosteroids for 7 days and oral corticosteroids for 3 months before undergoing in vivo and in vitro tests.

Ragweed pollen allergens Amb a 1 Amb a 1 is the major allergen from A. artemisiifolia pollen, as the great majority of ragweed pollen allergic patients are sensitized to it. Amb a 1 is a member of the pectate lyase protein family, it has a molecular weight of 38 kDa, and it constitutes approximately 15% of the total protein content of ragweed pollen (12). Several isoallergens have been described, which exhibit sequence similarities between 59% and 86%(13), and which have not been characterized biochemically and immunologically in depth, due to the fact that the production of heterologous recombinant full-length pollen pectate lyases is still difficult, and cannot be achieved in sufficient quality and quantity.

3. Skin prick tests The test consisted of applying different concentrations (0.01; 0.1; 1; and 10 mg/mL) of ragweed pollen extract (DIATER Laboratories, Madrid, Spain) to select the lowest concentration of allergen extract which produces a wheal that is similar to the wheal of histamine dihydrochloride 10 mg/mL (histamine equivalent prick, HEP). The dose-response relationship of the allergen was estimated by regression line analysis,

Amb t 5 A molecule that is homologous with Amb a 5 has been identified in Ambrosia trifida (giant ragweed) and designated Amb t 5. Approximately 5% of ragweed

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a

Vol. XIII, No. 2, April - June 2016

b

c

Figure 1. Patient characteristics: a) patient gender; b) patient mono- or polysensitization; c) patient diagnosis

using the geometric mean of the four wheal areas obtained with each concentration, in a double logarithm system. The concentration of allergen estimated to provoke a response with the same wheal area as the histamine reaction was then calculated from the regression line formula.

with PBS buffer. Then the membrane was incubated with serum diluted in PBS Tween 0.1%, overnight.

After incubation with serum, unbound antibodies were removed by washes with PBS buffer. The membrane was then incubated with the conjugate, which was peroxidase-conjugated rabbit immunoglobulins to human IgE (DakoPatts, Denmark), which was diluted in PBS Tween buffer at a ratio of 1:5000. To remove unbound conjugate, the samples were then washed with PBS buffer. For the development of the reaction, the PerkinElmer Immune Complex method was used, according to the manufacturer’s protocol.

4. Immunoblotting Immunoblotting was performed according to Shen et al(16). Briefly, crude extracts of ragweed pollen were mixed with equal volume of double-concentration sample buffer (2% SDS, 5% 2-mercaptoethanol), boiled for 5 min and separated on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), as described by Laemmli(17). When the electrophoresis was completed, the gel was balanced with transfer buffer (Bio-Rad, Berkeley, CA, USA). 0.45 μm hydrophobic immobilon-P PVDF transfer membranes (Millipore, Billerica, MA, USA) and filter paper, Miniblot size, extra-thick blotting paper (Bio-Rad, Berkeley, CA, USA) were used. Proteins transferred to PVDF membrane was detected according to Shen et al.(16), with modifications. The membrane was incubated for 1 hour with 0.1% PBS-Tween buffer and then washed

5. Specific serum IgE Sera from all 25 patients were screened for the detection of specific IgE using a commercial allergen microarray immunoassay (ISAC; Phadia, Uppsala, Sweden), according to the manufacturer’s recommendations. Briefly, reactions sites were incubated with 20 µgL of patients’ serum for 2 hours. After rinsing, washing, and drying, allergen specific IgE complexes were stained with fluorescence-labeled anti-human IgE for 1 hour. After further washings, a laser scanner was used to take fluorescence readings and results were trans-

28

Patterns of sensitization to ragweed species in Western Romania

of 29.68±5.55 years) presented with moderate-severe allergic rhino-conjunctivitis (intermittent in 19 cases, persistent in 6 cases) and 4 patients were additionally diagnosed with mild asthma. The onset of allergic symptoms occurred less than 5 years ago in most cases (76%). From the whole group, 9 patients were monosensitized to A. artemisiifolia pollen, and 16 were polysensitized (3 to indoor, 5 to outdoor and 8 to both indoor and outdoor allergens)(Fig. 1).

2. D etermination of the histamine equivalent prick concentration The HEP to Ambrosia pollen corresponded to 0.07 mg/mL, after calculating the median of the 23 patients who fulfilled the final inclusion criteria.

Figure 2. Specific serum IgE levels to Amb a 1

3. Specific serum IgE levels The degree of sensitivity to Amb a 1 based on specific IgE levels was moderate (class 3-4) in most patients (84%), and mild (class 1-2) or severe (class 5-6) in 8% each (Fig. 2).

formed into numerical data by comparison with a reference serum standardized against ImmunoCAP IgE. Levels higher than 0.3 ISU/L (ISAC Standardized Units) were regarded as positive, following the manufacturer’s recommendations.

4. Identification of the most prevalent ragweed pollen allergens in allergic rhinoconjunctivitis Major allergens of an allergic source are defined as those recognized by more than 50% of allergic patients.

In order to assess the prevalence of specific IgE to electrophoretically separated ragweed pollen proteins, we analyzed the 25 individual patient’s atopic sera.

Individual sera showed a considerable variation in the reaction intensity, as well as in the different number of proteins it had reacted to. Several ragweed pollen proteins, in the range of 10 to 75 kDa, appeared reactive with specific IgE. Bands at the molecular weight of 38, 37, 17, 14 and 12 kDa were recognized by several of the tested sera. The specific IgE band around 38 kDa was visible in 23 out of the 25 positive sera (i.e. in 92% of the cases), thus being the most prominent ragweed protein that induces IgE production in the tested population (Amb a 1). In addition, there was specific IgE reactivity present in 24 out of the 25 sera connected to a protein band around 37 kDa (Amb a 11), in 9 out of the 25 sera there was a band at 14 kDa, and in 4 out of the 25 sera there was a band at 12 kDa (minor allergens, such as Amb a 6, 7, 8 (profilin), 9, and 10). Other specific IgE binding related to a minor antigenic protein component of approximately 45 kDa (1/25 patients)(Fig. 3).

6. IgE Inhibition To evaluate cross-reactivity between Amb a 1 and Amb t 5, fluorometric ELISA inhibition for Amb a 1 and Amb t 5 with human IgE was performed. Briefly, Amb a 1 or Amb t 5 (0.5 mg/ml) were immobilized in the wells of a Fluotrac™ 600 microplate (Sigma-Aldrich, St. Louis, MO, USA) overnight at 4 ºC. Amb a 1 or Amb t 5 inhibitors (final concentrations, 0 - 10 μg/ml) were incubated with equal volumes of human sera, for a final dilution of 1:50, for 3 h at room temperature. The microplate was then washed with PBS Tween buffer and incubated with diluted (1:10) serum samples for 3 h at room temperature.

7. Statistical analysis Data analysis was performed using the SPSS software package, version 13.0 for Windows (SPSS Inc., Chicago, IL, USA). Multiple regression analysis by the stepwise method was used to study the contribution of A. artemisiifolia and A. trifida IgE responses individually.

Results

IgE reactivity to A. trifida allergens is much more decreased, and only in 9 of the patients (36%) specific bands are recognizable (Fig. 4).

1. Clinical data The patients (14 men and 11 women, with mean age

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5. IgE inhibition The IgE of patientâ&#x20AC;&#x2122;s sera revealed different patterns of recognition to A. artemisiifolia and A. trifida allergenic extracts, leading to a greater response for A. artemisiifolia vs A. trifida (Ag50= 0,65 and 13,92 mg/ mL respectively) by ELISA inhibition, meaning that the inhibition for A. artemisiifolia allergens is approximately 20 times more potent than for A. trifida allergens (Fig. 5).

Discussion Understanding the specific IgE cross-reactivity pattern between A. artemisiifolia and A. trifida pollen is of great importance for appropriate selection of allergen-specific immunotherapy, as well as for measures of prevention.

The present study shows that specific IgE is an important differential diagnosis tool to identify the primary cause of weed pollen allergy. The 25 patients in this study were all diagnosed as having weed polleninduced allergic rhinoconjunctivitis, based on nasal symptoms, clinical history, and SPT results. Specific IgE testing demonstrated that all patients had specific IgE against A. artemisiifolia pollen allergens, and only 9 of them were positive for specific IgE to A. trifida pollen allergens. None of the 25 patients were monosensitized to only one ragweed pollen allergen. The present study demonstrates a strong correlation between the specific IgE levels of Amb a 1 in allergic patientsâ&#x20AC;&#x2122; sera and the results of the skin prick tests.

However, we found that there was no significant crosssensitization or co-sensitization between the two studied species of ragweed, which indicates that there are major allergenic differences between the two species, unlike other studies(18, 19), which found substantial allergenic cross-reactivity among A. artemisiifolia, A. psilostachya, and A. trifida.

Several studies have shown that profilin is an important panallergen (20, 21). Specific IgE to profilin (Cor a 2) is found in 40â&#x20AC;&#x201C;45% of patients allergic to hazelnut (22), and 52.7% of patients with IgE to Parietaria pollen extract had specific IgE to profilin (Phl p 12) (23), while 34% of peach-allergic patients showed a positive IgE response to birch profilin (Bet v 2) (24). In ragweed, previous studies identified two isoforms of Amb a 8, which were expressed in Escherichia coli, purified to homogeneity and characterized by biochemical and immunological means(25). In our study, specific IgE against profilin was detected in 7 out of the 25 patients (28%),

Figure 3. Immunoblotting for A. artemisiifolia allergens

Figure 4. Immunoblotting for A. trifida allergens

Figure 4. Immunoblotting for A. trifida allergens

30

Patterns of sensitization to ragweed species in Western Romania

zation between A. artemisiifolia and A. trifida. There are currently no detailed studies regarding the distribution within the pollen grain of the major allergens of ragweed pollen. There are no current data regarding ragweed pollen concentration in the atmosphere, in Romania.

which confirms the previous results.

Allergic rhinoconjunctivitis is estimated to affect 25% of the population in Europe, and its prevalence is increasing(26). In the United States, ragweed pollen represents the major seasonal source of allergenic protein compared to other pollen sources, with a prevalence of about 50% in atopic human individuals (27,28). In Europe, ragweed allergy is rapidly increasing, particularly in the Pannonian valley of the Balkan region(29). Therefore, characterization of A. atremisiifolia pollen components, in terms of defining major and minor allergens that may induce a clinically manifest allergic reaction in humans, is important for valid diagnosis and efficient therapy, including component-resolved diagnosis and allergenspecific immunotherapy. Among several allergens described in ragweed pollen, Amb a 1 has been identified as its major allergen. Amb a 1 actually consists of several isoforms that are acidic, single-chain proteins with a molecular weight of approximately 38 kDa determined

by SDS-PAGE (30). Confirmation and determination of their identities is expected from further Matrix-assisted laser desorption/ionization Time-of-Flight (MALDITOF) mass spectrometry peptide fingerprint analyses.

In the present study, we aimed to identify the dominant, most abundant proteins in A. artemisiifolia and A. trifida pollens and to focus on the major immunoreactive proteins with regard to human IgE. It is of great importance to define major and minor allergens in humans, because skin prick testing could be performed only with the specific allergen (or group of allergens). This would increase the diagnostic value of skin prick tests in terms of increasing its specificity and sensitivity, and it would also enable a personalized approach for allergen-specific immunotherapy, which would increase its efficacy and safety. In recent years, component-resolved allergy diagnosis has increased in use, but its costs are still too high for a great part of the population in some countries, therefore the in vivo diagnostic procedures, such as the skin prick tests, still remain in use. However, in order to have a reliable skin prick test, it is necessary to use a standardized allergen extract.

Conflict of interests: The authors declare no conflict of interests.

References 1. Bremer K, Anderberg AA. Asteraceae: cladistics and classification. 1994.

2. Smith M, Cecchi L, Skjøth CA, Karrer G, Šikoparija B. Common ragweed: A threat to environmental health in Europe.

Environment international. 2013 Nov 30;61:115-26.

3. Ianovici N, Bunu C, Marusciac L Ambrosia artemisiifolia in Romania. Journal of Romanian Society of Alergology and Clinical Immunology 2009 May 1;6(4):146 4. Vitányi B, Makra L, Juhász M, Borsos E, Béczi R, Szentpéteri M. Ragweed pollen concentration in the function of meteorological elements in the south-eastern part of Hungary. Acta Climatologica Chorologica, 36. 2003;37:121-30.

5. Jäger S. Ragweed (Ambrosia) sensitisation rates correlate withthe amount of inhaled airborne pollen. A 14-year studyin Vienna, Austria. Aerobiologia. 2000 Mar 1;16(1):149-53.

6. Peternel R, Culig J, Srnec L, Mitić B, Vukusić I, Hrga I. Variation in ragweed (Ambrosia artemisiifolia L.) pollen concentration in central Croatia, 2002-2003. Annals of agricultural and environmental medicine: AAEM. 2004 Dec;12(1):11-6.

7. Šikoparija B, Smith M, Skjøth CA, Radišić P, Milkovska S, Šimić S, et al. The Pannonian Plain as a source of Ambrosia pollen in the Balkans. Int J Biometeorol 2009;53:263–72.

8. Yankova R, Zlatev V, Baltadjieva D, Mustakov T, Mustakov B. Quantitative dynamics of Ambrosia pollen grains in Bulgaria.

Aerobiologia. 2000 Jun 1;16(2):299-301.

9. Thibaudon M, Elias K, Besancenot JP. Ambroisie et allergie Le cas de la France. Environnement, Risques & Santé. 2004 Nov 1;3(6):353-67.

10. Asero R. The changing pattern of ragweed allergy in the area of Milan, Italy. Allergy. 2007 Sep 1;62(9):1097-9.

11. Ianovici N, Panaitescu CB, Brudiu I. Analysis of airborne allergenic pollen spectrum for 2009 in Timişoara, Romania.

Aerobiologia. 2013 Mar 1;29(1):95-111.

12. Gadermaier G, Hauser M, Ferreira F. Allergens of weed pollen: an overview on recombinant and natural molecules. Methods.

2014 Mar 1;66(1):55-66.

13. Bordas-Le Floch V, Le Mignon M, Bouley J, Groeme R, Jain K, Baron-Bodo V, Nony E, Mascarell L, Moingeon P. Identification of novel short ragweed pollen allergens using combined transcriptomic and immunoproteomic approaches. PloS one. 2015 Aug 28;10(8):e0136258.

Conclusion The clinical data, correlated with the laboratory results, validate that A. artemisiifolia is the major allergenic ragweed species in the western part of Romania, and the vast majority of patients allergic to ragweed pollen are sensitized specifically to A. artemisiifolia allergens, and there is no significant cross- or co-sensiti-

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Patterns of sensitization to ragweed species in Western Romania

14. ‑http://www.whiar.org/docs/ARIAReport_2010.pdf, last accessed on 31.03.2016 15. Shen HD, Wang SR, Tang RB, Chang ZN, Su SN, Han SH. Identification of allergens and antigens of Bermuda grass (Cynodon dactylon) pollen by immunoblot analysis. Clinical & Experimental Allergy. 1988 Jul 1;18(4):401-9.

16. Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug;227:680-5.

17. Christensen LH, Ipsen H, Nolte H, Maloney J, Nelson HS, Weber R, Lund K. Short ragweeds is highly cross-reactive with other ragweeds.

Annals of Allergy, Asthma & Immunology. 2015 Dec 31;115(6):490-5.

18. Zhu X, Greenstein JL, Rogers BL, Kuo MC. T cell epitope mapping of ragweed pollen allergen Ambrosia artemisiifolia (Amb a 5) and Ambrosia trifida (Amb t 5) and the role of free sulfhydryl groups in T cell recognition. The Journal of Immunology. 1995 Nov 15;155(10):5064-73.

19. Ferreira F, Hawranek T, Gruber P, Wopfner N, Mari A. Allergic cross‐reactivity: from gene to the clinic. Allergy. 2004 Mar 1;59(3):243-67.

20. Ebo DG, Hagendorens MM, Bridts CH, Stevens WJ. Sensitization to cross‐reactive carbohydrate determinants and the ubiquitous protein profilin: mimickers of allergy. Clinical & Experimental Allergy. 2004 Jan 1;34(1):137-44.

21. Hansen KS, Ballmer-Weber BK, Sastre J, Lidholm J, Andersson K, Oberhofer H, Lluch-Bernal M, Östling J, Mattsson L, Schocker F, Vieths S. Component-resolved in vitro diagnosis of hazelnut allergy in Europe. Journal of Allergy and Clinical Immunology.

2009 May 31;123(5):1134-41.

22. Rossi RE, Monasterolo G, Coco G, Operti D. Possible relationship between systemic side effects and sensitization to rPar j 2 in

allergic patients submitted to an ultra-rush (20 min) sublingual immunotherapy and selected by component resolved diagnosis.

International archives of allergy and immunology. 2005 Oct 31;138(2):105-10.

23. Movérare R, Larsson H, Carlsson R, Holmquist I. Mugwortsensitized individuals from North Europe, South Europe and North America show different IgE reactivity patterns.

International archives of allergy and immunology. 2010 Aug 24;154(2):164-72.

24. Wopfner N, Gruber P, Wallner M, Briza P, Ebner C, Mari A, Richter K, Vogel L, Ferreira F. Molecular and immunological characterization of novel weed pollen pan‐allergens. Allergy.

2008 Jul 1;63(7):872-81.

25. http://www.worldallergy.org/UserFiles/file/WAO-White-Bookon-Allergy_web.pdf, last accessed on 31.03.2016 26. Boulet LP, Turcotte H, Laprise C, Lavertu C, BEDARD PM, Lavoie A, Hebert J. Comparative degree and type of sensitization to common indoor and outdoor allergens in subjects with allergic rhinitis and/or asthma. Clinical & Experimental Allergy.

1997 Jan 1;27(1):52-9.

27. Wopfner N, Gadermaier G, Egger M, Asero R, Ebner C, JahnSchmid B, Ferreira F. The spectrum of allergens in ragweed and mugwort pollen. International archives of allergy and immunology. 2005 Nov 18;138(4):337-46.

28. Csontos P, Vitalos M, Barina Z, Kiss L. Early distribution and spread of Ambrosia artemisiifolia in Central and Eastern Europe.

Botanica Helvetica. 2010 Jul 1;120(1):75-8.

29. Pilyavskaya, Anna, et al. Isolation and characterization of a new basic antigen from short ragweed pollen (Ambrosia artemisiifolia). Molecular immunology 32.7 (1995): 523-529.

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Vol. XIII, No. 2, April - June 2016

Intra-anaesthetic severe immediate type hypersensitivity to cefoperazone.

Case Report Nadia Onitiu-Gherman, Mihaela Cocis, Cristina Laura Petrisor, Natalia Hagau “Iuliu Hatieganu”, University of Medicine and Pharmacy Cluj-Napoca, Romania

ABSTRACT Intra-anaesthetic anaphylactic reactions’ diagnosis is mainly retrospective based on clinical history, skin prick, intradermal and in vitro tests. We bring up the case of a 67 years old male patient who presented a lifethreatening immediate-type hypersensitivity reaction during general anaesthesia performed for the surgical treatment of benign prostate hypertrophy. The initial diagnostic tests revealed an intense positive skin prick test for cefoperazone. The basophil activation test was initially negative and only the second test had positive results, showing a delay in comparison with the skin test. When re-testing after 6 years, the skin prick test was positive for cefoperazone, demonstrating that the skin test reactivity was maintained during this period. For rocuronium, the basophil activation test had an initial positive result, with a negative skin test. This test may confirm an immediate-type sensitization to a neuromuscular blocking agent, even when the skin tests are negative. These findings highlight the fact that each patient needs to be tested for all culprit drugs, both in vivo and in vitro, as multiple drug hypersensitivity might occur.

KEYWORDS: anaphylaxis, perianaesthetic, cefoperazone, skin tests, basophil activation

Introduction

sporins, have allergic side effects more common than drugs from other antibiotic families(3).

Intra-anaesthetic anaphylactic reactions’ diagnosis is mainly retrospective based on clinical history, skin prick, intradermal and in vitro tests (detection of drug specific IgE and cellular tests: basophil activation by flow cytometry, histamine release test and leukotriene release test). Drug challenge, the gold standard diagnostic test, is potentially dangerous and has ethical consequences in case of anaesthetic drugs. Drug challenge can

The exposure of the patient during general anaesthesia to a mixture of drugs that alter physiological functions in a short period of time, may put the patient at risk of hypersensitivity reactions and side effects (1).

One of the most important drug class responsible for intra-anaesthetic anaphylaxis remains the neuromuscular blocking agents(2), followed by latex and antibiotics. Beta-lactam drugs, such as penicillins and cephalo-

Corresponding Author: Nadia Onitiu-Gherman Emergency County Clinical Hospital Cluj-Napoca, Surgery Clinic I, 3-5 Clinicilor street, Cluj-Napoca postal code 400006, Tel: +40264592771/1388; Fax: +40264599438; E-mail: nadiaghermanionica@yahoo.com Submission date: 08/04/2016; Acceptance date: 10/04/2016; Publication date: 10/05/2016

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Vol. XIII, No. 2, April - June 2016

SPT concentration

SPT result

IDT concentration

IDT result

Rocuronium

10 mg/ml

negative

100 µg/ml

ND

Fentanyl

0.05 mg/ml

negative

5 µg/ml

ND

Midazolam

5 mg/ml

negative

200 µg/ml

negative

Propofol

10 mg/ml

negative

1 mg/ml

negative

Cefoperazone

2,5 mg/ml

positive

2.5 mg/ml

ND

Latex

Stallergenes

negative

-

ND

Iodine/betadine

100 mg/ml

negative

-

ND

Atracurium

1 mg/ml

negative

10 µg/ml

negative

Suxamethonium

10 mg/ml

negative

100 µg/ml

negative

Etomidate

2 mg/ml

negative

200 µg/ml

negative

Pethidine

25 mg/ml

negative

2.5 µg/ml

negative

Reagent Culprit

Alternative

Tramadol

50 mg/ml

positive

500 µg/ml

ND

Negative control- NaCl

9 mg/ml

negative

9 mg/ml

negative

Positive control histamine

10 mg/ml

positive

-

ND

ND-not done Table 1. Skin prick test (SPT), intradermal test (IDT) 6 weeks after the incident.

normal. 2000 ml of crystalloids were infused with transient response and an anaphylactic reaction was suspected. 50 mcg iv adrenaline repeated at 5 min distance injected together with 250 mg iv hydrocortisone and 50 mg iv ranitidine. After 20 minutes, vital signs returned to normal. Surgery was cancelled and the patient was awakened and admitted to ICU for further monitoring.

only be performed for local anaesthetics, antibiotics, nonsteroidal anti-inflammatory drugs and latex(1).

Case report A 67 years old male patient was admitted for surgical treatment of benign prostate hypertrophy. The patient had a history of anaphylactic shock caused by iodinated contrast media and the preoperative physical examination was unremarkable. General anaesthesia was planned. Induction of general anaesthesia was performed with 0.2 mg of Fentanyl, 2 mg of Midazolam, 160 mg of Propofol, 50 mg of Rocuronium. Antibiotic prophylaxis was performed with 1 g of cefoperazone immediately after induction. At 10 minutes after the induction the patient became hemodynamically unstable with severe hypotension (BP 60/40 mmHg), and tachycardic (160 bpm, sinus rhythm). No skin eruptions were observed and the chest auscultation was

After 6 weeks, the patient presented for an allergoanaesthesia survey at our Allergo - Anaesthesia Outpatient Department. Skin tests were performed for the culprit and alternative drugs in accordance with the published guidelines(4,5) on the volar surface of the forearm (Table No.1). From the culprit drugs, the patient had a positive skin prick test to cefoperazone. From the alternative drugs, the patient showed a positive skin prick test for tramadol. After 7 weeks from the perioperative anaphylactic shock the patient was tested for alternative antibiotics and local anaesthetics. He had a negative skin test for chlaritromycin and levofloxacin.

34

Intra-anaesthetic severe immediate - type hypersensitivity to cefoperazone. Case Report

SPT concentration

SPT result

IDT concentration

IDT result

Rocuronium

10 mg/ml

negative

50 µg/ml

negative

Fentanyl

0.05 mg/ml

negative

5 µg/ml

Propofol

10 mg/ml

negative

Reagent Culprit

Cefoperazone

2 mg/ml

positive

negative

1 mg/ml

negative

2 mg/ml

ND

Alternative Atracurium

1 mg/ml

negative

10 µg/ml

negative

Suxamethonium

10 mg/ml

negative

100 µg/ml

negative

Etomidate

2 mg/ml

negative

200 µg/ml

negative

Levofloxacin

5 mg/ml

negative

50 µg/ml

negative

Negative control- NaCl

9 mg/ml

negative

9 mg/ml

negative

Positive controlhistamine

10 mg/ml

positive

-

ND

ND-not done

Table 2. Skin prick test (SPT), intradermal test (IDT) 6 years and a half after the incident (1,6)

Discussion

Drug challenge was also negative for these drugs. Local anaesthetics (bupivacaine and articaine) showed negative skin and challenge tests.

Basophil activation test using flow cytometry (Flow2CAST) was performed for the culprit drug except cefoperazone at 6 weeks after the anaphylactic event and the test showed positivity for rocuronium at a concentration of 500 µg/ml (stimulation index-2.17).

Basophil activation test for cefoperazone was first performed at 20 weeks after the allergic reaction and the test was negative. At 32 weeks, cefoperazone was retested using basophil activation test. The results were positive for all the tested concentrations - 1.25 mg/ml, 0.125 mg/ml, 0.0125 mg/ml with a stimulation index of 5.64, 4.71 and 3.39, respectively. Specific IgE tests are not commercially available for many drugs.

Any drug administered during the perioperative period may potentially induce life-threatening anaphylactic reactions. The diagnosis is established retrospectively based on the clinical history, skin tests and in vitro tests. In vitro tests are not substitutes for the skin tests (1).

Skin tests are the current reference tests for the diagnosis of antibiotic-induced hypersensitivity reactions, for β lactams having 97-99% specificity and a lower sensitivity (2). Basophil activation tests present only moderate sensitivity and good specificity for β lactams (7).

In our patient, who presented a severe intra-anaesthetic anaphylactic reaction, the allergo-anaesthetic survey comprised the clinical history, the skin tests and the basophil activation test using CD63 activation marker in flow-cytometry.

From the culprit drugs, cefoperazone showed strong positivity in the skin prick test. Sensitivity of skin tests might decrease over time(1), especially in case of antibiotics (8). In our patient, at re-testing, after 6 years, the skin prick test was positive for cefoperazone. Thus, the

6 years and a half after, the patient was scheduled for urological surgery and another general anaesthesia was planned. He was re-tested with skin tests for the culprit and alternative drugs taking into consideration the anaphylactic reaction to the previous general anaesthesia (Table No.2) (1,6). The positive skin prick test for cefoperazone was present.

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Intra-anaesthetic severe immediate - type hypersensitivity to cefoperazone. Case Report

skin test reactivity was maintained during this period for cefoperazone. For the basophil activation test, initialy, for cefoperazone the test was negative and only the second test had positive results, showing a delay in comparison with the skin test.

For rocuronium, the basophil activation test had a positive result with a negative skin test. This test may confirm an immediate-type sensitization to a neuromuscular blocking agent, even when the skin tests are negative (1). These findings highlight the fact that each patient needs to be tested for all culprit drugs, both in vivo and in vitro, as multiple drug hypersensitivity might occur. In fact, a positive history of hypersensitivity caused by antibiotics might constitute a risk factor for having positive skin tests for neuromuscular blocking agents(9).

In our case, we recommend to avoid cefoperazone. If a penicillin is needed, and the skin tests with the penicillin reagents are negative, a penicillin with dissimilar side chains (R) as the culprit cephalosporin is chosen.

If a cephalosporin is needed, and the skin test is negative, the challenge test is mandatory. If cefoperazone is required, a desensitization protocol should be performed (10). Rocuronium should also be avoided, and cross-reactivity with other neuromuscular blocking agents should be assessed by skin and basophil activation tests.

We emphasize the fact that in case of negative diagnostic tests for the suspected drugs causing anaphylaxis, re-testing several weeks after the initial survey is mandatory in order to avoid a false negative result.

References 1. Mertes PM, Malinovsky JM, Jouffroy L; Working Group of the SFAR and SFA, Aberer W, Terreehorst I, Brockow K, Demoly P; ENDA; EAACI Interest Group on Drug Allergy. Reducing the risk of anaphylaxis during anesthesia: 2011updated guidelines for clinical practice.

J Investig Allergol Clin Immunol. 2011;21(6):442-53.

2. Mertes PM, Tajima K, Regnier-Kimmoun MA, Lambert M, Iohom G, Gueant-Rodriguez R, et al. Perioperative anaphylaxis. Med Clin N Am. 2010; 94:761-789.

3. Petrişor C, Gherman-Ionică N, Bologa R, Sfichi M, Hagău N. Basophil activation test versus radio-immunoassay in the diagnosis of β-lactam immediate-type hypersensitivity reactions. Rev Romana Med Lab. 2013; 21: 415-422.

4. Mertes PM, Laxenaire MC, Lienhart A et al. Reducing the risk of anaphylaxis during anaesthesia: guidelines for clinical practice. J Invest Allergol Clin Immunol. 2005; 15(2):91-101.

5. Torres MJ, Blanca M, Fernandez J et al. Diagnosis of immediate allergic reactions to beta-lactam antibiotics. Allergy. 2003; 58:961–72.

6. Brockow K, Garvey LH, Aberer W, et al. Skin test concentrations for systemically administered drugs-an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2013;68(6):702-12 7. Torres MJ, Padial A, Mayorga C, Fernandez T, Sanchez-Sabate E, Cornejo-Garcia J, et al. The diagnostic interpretation of basophil activation test in immediate allergic reactions to betalactams. Clin Exp Allergy. 2004;34:1768-1775.

8. Blanca M, Torres MI, Garcia JJ, et al. Natural evolution of skin test sensitivity in patients allergic to beta-lactam antibiotics. J Allergy Clin Immunol. 1999; 103:918-924.

9. Hagău N, Gherman N, Cociş M, Petrişor C. Antibiotic-induced immediate type hypersensitivity is a risk factor for positive allergy skin tests for neuromuscular blocking agents. Allergol Int. 2016;65: 52-55.

10. Kim MH, Lee JM. Diagnosis and management of immediate hypersensitivity reactions to cephalosporins. Allergy Asthma Immunol Res. 2014;6(6):485-95.

Conflict of interests: The authors declare no conflict of interests.

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Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 2, April - June 2016

News and Current Perspectives

Minireview on molecular pharmacology of intranasal azelastine and fluticasone propionate Florin-Dan Popescu1, Florica Popescu2

Department of Allergology, ”Nicolae Malaxa” Clinical Hospital, ”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2 Department of Pharmacology, University of Medicine and Pharmacy of Craiova, Romania 1

ABSTRACT MP-AzeFlu, a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate, delivered in a single nasal spray, is a modern approach of pharmacological treatment in allergic rhinitis. This new formulation provides an optimal spray volume and viscosity, uniform distribution of the two drug components.

Its molecular mechanisms of action are complex and involve the actions of pharmacological components on H1 receptors (azelastine), blocking these widely nasal cellular distributed receptors and antagonizing the histamine actions at nasal mucosa level, and on some important transcription factors, especially glucocorticoid receptors (fluticasone), with downregulation of the production of important cytokines and other inflammatory molecules. MP-AzeFlu efficacy is due to significant anti-inflammatory and H1 antihistamine actions, but also to anti-leukotriene and mast-cell stabilizing properties, and could involve actions on sensory receptors, such as some bitter taste receptors. Molecular characterization of complex interactions between intracellular signaling cascades triggered by binding H1 receptors and GR-mediated transcriptional activity must be mentioned. The biopharmaceutical and molecular pharmacological characteristics represent a pharmacological rationale for the efficacy and safety of MP-AzeFlu in allergic rhinitis.

KEYWORDS: MP-AzeFlu, azelastine, fluticasone, molecular pharmacology, allergic rhinitis.

M

P-AzeFlu is a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate delivered in a single spray, and has surpassed available therapies in terms of symptom control and treatment response. This azelastine hydrochloride with fluticasone

propionate nasal spray delivers intranasally 137 µg of azelastine hydrochloride (125 µg azelastine) and 50 µg of fluticasone propionate per actuation (0.14 g suspension). It is indicated for the relief of symptoms of moderate to severe seasonal and perennial allergic rhinitis, if monotherapy with either intranasal H 1 antihistamine

Corresponding Author: Florin-Dan Popescu Clinical Hospital ”Nicolae Malaxa”, 12 Soseaua Vergului, postal code 022441, Bucharest; E-mail: florindanpopescu@allergist.com Submission date: 06/04/2016; Acceptance date: 08/04/2016; Publication date: 10/05/2016

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via transactivation (positive regulation of transcription) and transrepression (negative regulation of transcription). Transactivation is mediated by binding of the ligand-activated GR as homodimer to a DNA sequence called glucocorticoid response element (GRE), and this process may result in some pharmacological benefits. But other multiple transrepression mechanisms, such as those described in the tethering, protein-protein interaction and cofactor competition models, are mainly involved in the inhibition of expression of various proinflammatory proteins. Proteinprotein interaction mechanism of transrepression with mutual masking of active domains between GR as monomer and other transcription factors, such as activator protein-1 (AP-1) and nuclear factor-kappa B (NFkB), is important because negative GRE are not generally found in the promoters of inflammatory genes.

Cofactor competition mechanism is also critical because various TFs (GR, NF-kB, AP-1, STATs) converge to CREB-binding protein (CBP)/p300 with limited availability, and via its intrinsic histone acetyltransferase activity, the access of important TFs to promoter regions of inflammatory genes is restricted thus regulating transcription (Newton, 2000; Vanden Berghe et al, 2002; Popescu, 2003; Vandevyver et al, 2013).

Fluticasone propionate is a new generation intranasal glucocorticosteroid with potent topical anti-inflammatory effects, used in patients with allergic rhinitis. It has an optimal pharmacokinetic and pharmacodynamic profile, possessing a high degree of GR affinity, potency, and specificity, with high lipophilicity, low systemic availability, high rate of hepatic first-pass clearance and rapid systemic elimination. Binding to intracellular GR results in conformational changes that allows dissociation of the GR from chaperone complex and translocation into the nucleus (Derendorf and Meltzer, 2008). Suppression of GATA-3 nuclear import and phosphorylation is a novel aspect of the molecular mechanisms of action. Fluticasone-activated GR impairs GATA-3 interaction with importin-alpha and GATA-3 nuclear localization. Fluticasone propionate induces the expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), the endogenous inhibitor of p38 MAPK, which is necessary for GATA-3 nuclear translocation, and these inhibitory actions are rapid, potent, and prolonged (Maneechotesuwan et al, 2009). In allergic rhinitis, intranasal fluticasone acts significantly by a GATA3mediated inhibitory effect, it attenuates the allergic inflammation by reducing the number of Th 2 cells, not increasing the number of Treg cells and not modifying

or glucocorticoid is not considered sufficient. The posology for adults and adolescents (12 years and older) is one actuation in each nostril twice daily (b.d.), in the morning and evening. It is suitable for long-term use, and the duration of treatment should be established according to the period of allergenic exposure (Carr et al, 2012; Klimek, Mullol et al, 2016).

MP-AzeFlu modern intranasal formulation has an optimal spray volume (137 mL) and viscosity (41 cP), and droplet size distribution (DSD, distribution of surface/volume of generated droplets) reflected in a finer DSD profile. These biopharmaceutical characteristics result in improved nasal-mucosal distribution with a larger surface contact area (Derendorf et al, 2012). A study performed in an anatomical model of the human nasal cavity revealed that there is an improved retention in the targeted areas compared to sequential administration of marketed intranasal monoproducts (single actuation of MP-AzeFlu 0.137 mL vs single sequential actuations of azelastine 0.137 mL followed 1 min later by fluticasone propionate actuation 0.100 mL, manually actuated into the nasal cast model, away from the septum). If the two components would be administered separately in a sequential manner, then there will be an anterior nasal run-off from the nostril, which diminish efficacy, and also posterior drip toward the back of nasal cavity, which would be swallowed in vivo (Dâ&#x20AC;&#x2122;Addio, Ruiz et al, 2015). MP-AzeFlu single spray provides a more uniform distribution of the two drug components, targeting the nose/nostril and anterior portion of turbinates, with no loss of drug through dripping (Dâ&#x20AC;&#x2122;Addio, Karafilidis et al, 2015).

The review of the currently available literature regarding the molecular pharmacology of MP-AzeFlu intranasal formulation reveals complex pharmacological properties and mechanisms of action of both fluticasone propionate (topical glucocorticosteroid) and azelastine (topical H 1-antihistamine) components and benefits due to their combination, which all explain its good efficacy profile.

The beneficial effects of glucocorticoids are mediated by activation of the glucocorticod receptor (GR), after passing the cell membrane. The GR is a ligandactivated Cys4 zinc finger transcription factor (TF) belonging to the nuclear receptor superfamily. In its inactive state, GR resides predominantly in the cytoplasm, where it is sequestered in a chaperone complex consisting of heat shock proteins, immunophilins and other partner proteins to prevent its degradation and to assist in maturation. Upon ligand binding, the GR translocates to the nucleus, where it modifies gene expression

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Minireview on molecular pharmacology of intranasal azelastine and fluticasone propionate

(Schumacher et al, 2014).

Molecular characterization of the interactions between intracellular signaling cascades triggered by binding histamine H1 receptors and GR-mediated transcriptional activity provides a starting point for understanding the use of H 1-antihistamines combined with glucocorticosteroids. H 1 receptor signaling is capable to affect GR-mediated activity, impacting on its transcriptional activity, in complex dual regulatory manner: Gαq has an inhibitory effect via a PLC-RACmediated pathway, while Gβγ enhances GR activity via JNK. Inactivation of the Gαq-PLC pathway by H 1antihistamines acting as inverse agonists results in a potentiation of GR activity, thus a clinically relevant H1-antihistamine is able to synergize with a corticosteroid acting as GR agonist to induce gene transrepression (Zappia et al, 2015).

Moreover, in allergic rhinitis, azelastine enhances the clinical efficacy of topical glucocorticoid also by modulating MKP-1 expression. Azelastine and glucocoticosteroid additively increase mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and inhibit cytokine-induced intercellular adhesion molecule 1 (ICAM-1) upregulation in respiratory epithelial cells in vitro (Luo et al, 2015).

the number of Th1 cells (Malmhäll et al, 2007).

Fluticasone propionate bound to GR exerts its antiinflammatory actions mainly through transrepression of pro-inflammatory TFs, such as AP-1 and NF-kB. This glucocorticosteroid has a great relative transrepression potency (Jaffuel et al, 2000). The complex transrepression mechanisms mentioned previously act together for producing the most important anti-inflammatory actions of fluticasone propionate, by downregulation of the production of important cytokines and other inflammatory molecules (Derendorf and Meltzer, 2008).

In an in vitro model of eosinophilic inflammation using the interaction between cultured nasal mucosa epithelial cells and isolated peripheral blood eosinophils, it revealed that fluticasone propionate reduces eosinophil survival (assessed by Trypan blue dye exclusion) induced by epithelial cell secretions from nasal mucosa, but this inhibitory effect on eosinophil survival induced by MP-AzeFlu is significantly stronger than that induced by fluticasone alone at similar dilutions (Roca-Ferrer et al, 2015).

Azelastine is primarly a potent antihistamine drug selectively acting at the human histamine H 1 receptor, and it is used intranasally for the treatment of allergic rhinitis. This phthalazinone derivative blocks H 1 receptors with wide nasal cellular distribution, and antagonize the histamine actions at nasal mucosa level.

Azelastine hydrochloride in MP-AzeFlu nasal formulation is administered as a racemic mixture with no difference in pharmacologic activity noted between the enantiomers in in vitro studies. Its major metabolite, desmethylazelastine, is also active on H1 receptors. In other pharmacological in vitro studies, azelastine, a highly lipophilic molecule, reaches rapidly a steady state at the H₁ receptor, and exhibits a slower dissociation rate constant from this receptor comparative to a first generation antihistamine, diphenhydramine, antagonizing the effects of histamine at the H₁ receptor level for at least 18 h (Slack et al, 2011). Preclinical evidence of azelastine hydrochloride activity revealed in addition to having H 1-blocking activity, it has additional actions such as suppression of leukotriene synthesis, prevention of mast cell and basophil degranulation, down-regulation of adhesion molecules, suppression of eosinophil chemotaxis, and some anti-inflammatory properties (Lieberman, 2002). Moreover, azelastine decreases in vitro the lipopolysaccharide-induced TNF-alpha and IL-12 secretion from bone marrow-derived dendritic cells, independent of histamine receptors, this being linked probably to the inhibition of TF NF-kB pathway

Several leukotriene modifiers were assessed in the treatment of upper airway inflammatory diseases (Cingi et al, 2015), either CysLT1 receptor antagonists, such as montelukast, approved for the treatment of allergic rhinitis and asthma, or leukotriene synthesis inhibitors acting as arachidonate 5-lipoxygenase (5-LO) inhibitors such as zileuton, marketed for the treatment of asthma. Although the integral membrane protein 5-LO-activating protein (FLAP) is an essential partner of 5-LO for the synthesis of leukotrienes, and FLAP inhibitors showed efficacy in early clinical trials, these class of drugs was not developed commercially (Evans et al, 2008).

Interestingly, MP-AzeFlu antileukotriene properties are due to the fact that azelastine is a potent and specific inhibitor of allergen-induced generation of leukotrienes in the nose, being suggested that it may be an inhibitor of Ca2+-dependent translocation of 5-lipoxygenase (5-LO) from cytosol to the nuclear envelope or a FLAP inhibitor, rather than a direct 5-LO inhibitor (Chand and Sofia, 1995).

Regarding mast-cell stabilizing properties, azelastine inhibits the human cultured mast cells secretion of IL-6, TNF-alpha and IL-8, by inhibiting intracellular Ca 2+ ions and NF-kappaB activation, therefore, being

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helpful in treating allergic inflammation in rhinitis patients (Kempuraj et al, 2003).

MP-AzeFlu mechanisms of actions could involve also effects on sensory receptors, such as some bitter taste receptors and transient receptor potential channels sensitive to vanilloids (Singh et al, 2014; Ekstedt et al, 2015; Bernstein and Singh, 2015).

The role of bitter taste receptors (T2Rs) in the pathophysiology of various diseases including chronic rhinosinusitis, asthma, cystic fibrosis, and cancer have been recently discussed (Shaik et al, 2016). It is known the role of oral and extraoral T2R38 bitter taste receptors in epithelial innate immunity (Gil et al, 2015; Douglas et al, 2016). Moreover, oral T2R38 functionality correlates with nasal symptoms in healthy individuals (Farquhar et al, 2015), and T2R38 represents a potential therapeutic target in the management of chronic rhinosinusitis (Douglas et al, 2016).

Another interesting possible mechanism of action of azelastine and MP-AzeFlu is related to bitter taste, sometimes looked upon as a disadvantage. In fact, azelastine induces some of its beneficial effect through activation of bitter taste receptors (Ekstedt et al, 2015).

Chemosensory G protein-coupled receptors (GPCRs) include about 400 odorant receptors, 25 bitter taste receptors (TAS2Rs), which are thought to guard the organism from consuming poisons, and sweet and umami TAS1R heteromers, which indicate nutritive value of food (Di Pizio et al, 2016). Extraoral chemosensory GPCRs originally identified as taste receptors, present in human airway mucosa, in regions associated with high airflow and particulate deposition, have potential roles in upper innate immunity. The T2R38 bitter taste receptor in human upper airway cilia detects bacterial quorum-sensing molecules and stimulates nitric oxide production, while solitary chemosensory cells use both T2R bitter and T1R sweet taste receptors to regulate upper respiratory innate immunity through antimicrobial peptide secretion. Prospective clinical studies of T2R38 genotype and chronic rhinosinusitis susceptibility, including patient outcomes, are currently ongoing (Lee and Cohen, 2015). A recent in vitro pharmacology study investigated bitter taste receptor activation in isolated murine airways, Balb/c mice being used because they have a weak histamine receptor system. In addition, primary human nasal epithelial cell were cultured with different concentrations of MP-AzeFlu, azelastine and chloroquine (a bitter taste TAS2R agonist), and evaluated in relation to activation marker VCAM-1. The mechanisms of bitter taste receptor mediated action are not clearly

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understood, but involvement of prostaglandins, cAMP and cGMP (known to be common pathways for airway dilation) were ruled out. MP-AzeFlu has the ability to trigger nasal epithelia cells in a way that resembles of the effects induced by chloroquine (Ekstedt et al, 2015).

The role of transient receptor potential vanilloid receptors must also be mentioned. TRPV1, transient receptor potential cation channel subfamily V member 1, is an ion channel activated by heat, capsaicin and other exogenous vanilloids, a variety of endogenous lipids called endovanilloids, and other endogenous chemicals, including ATP, ammonia and polyamines, such as putrescine, as well as protons and alcohol. Exogenous vanilloids include capsaicin from chili pepper, gingerol from ginger and eugenol from cloves. TRPV1 may be be activated by nonvanilloid plant-derived molecules like camphor, and by piperine from black pepper.

TRPV1 has role in the thermal sensation, nociception and salty/metallic taste sensation. It is involved in the pathophysiology of neurogenic inflammation and chronic inflammatory pain conditions, asthma and chronic obstructive pulmonary disease, diabetic peripheral neuropathy, neurogenic detrusor overactivity and cystitis, ototoxicity of cisplatin and aminoglycosides (Riera et al, 2007; Green et al, 2013; Brito et al, 2014; Grace et al, 2014).

TRPV1 was reported to regulate the signaling and activation of CD4+ T cells. The number of TRPV1+/ CD4+ inflammatory cells is increased in the nasal mucosa of patients with allergic rhinitis, compared with that of control subjects. TRPV1 activation on CD4+ T cells is involved in T cell receptor signaling pathways, including NF-kappaB, MAP kinase, and NF-AT (Samivel et al, 2016).

It is interesting to mention that, in nonallergic rhinitis, sensory nerve endings within the airway epithelial cells and the solitary chemoreceptor cells, synapsing with sensory nerves, respond to airborne irritants.

Transient receptor potential (TRP) channels on these nerve endings initiate local antidromic reflexes resulting in the release of neuropeptides, such as substance P, which dilate epithelial submucosal blood vessels and increase transudation, involved in submucosal edema and congestion (Bernstein and Singh, 2015). Azelastine in vitro modulates the cytosolic Ca 2+ signaling, and thus desensitize transient receptor potential vanilloid 1 (TRPV1) channels in neuronal cells, and regulate cellular homeostasis in nasal epithelial cells (Singh et al, 2014), while fluticasone do not demonstrate specific activity on TRPV1 (Bernstein and Singh, 2015).

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Minireview on molecular pharmacology of intranasal azelastine and fluticasone propionate

Azelastine administered topically intranasal on a regular basis reduces substance P neuropeptide release into nasal lavage fluid, immediately after hypertonic nasal saline challenge, assessed by enzyme immunoassay (Gawlik et al, 2013).

Moreover, the azelastine effect in modulating the brain response to odorants must be discussed.

Functional MRI examining neurogenic response to unpleasant (hickory smoke) and pleasant (vanilla) odorants in patients with nonallergic rhinitis revealed that intranasal azelastine attenuates blood flow to relevant areas of the brain relevant to olfactory sensation or sensory processing of irritant stimuli (Bernstein et al, 2011). Whether this effect can be applied to other H 1 antihistamines is not mentioned.

Finally, the good safety profile of MP-AzeFlu has been confirmed in short term and long term studies, as well as in real life (Klimek, Bousquet et al, 2015). The very low systemic fluticasone propionate bioavailability (about 1%) from the nasal spray at therapeutical doses is attributed to poor aqueous solubility and high first pass metabolism of the swallowed fraction of dose. No interactions of azelastine and fluticasone propionate were found with the MP-AzeFlu formulation.

Azelastine bioavailability is similar for MP-AzeFlu and azelastine monotherapy (Derendorf et al, 2012). Nasal examinations reveal no evidence of mucosal ulcerations or septal perforations with MP-AzeFlu treatment (Berger et al, 2014). Azelastine intranasal treatment for one month has no significant effect on the nasal and nasopharyngeal microflora, being safe from a microbiological point of view (Aksoy et al, 2016).

In conclusion, all the molecular pharmacology and biopharmaceutical characteristics discussed represent an important pharmacological basis for the efficacy and safety of MP-AzeFlu in allergic rhinitis. By analyzing clinical pharmacology data from placebocontrolled studies, the most recent addition to intranasal therapy for the maintenance therapy of allergic rhinitis, MP-AzeFlu, a single formulation nasal spray of azelastine hydrochloride and fluticasone propionate in an advanced delivery system, provides significantly greater symptom relief than either azelastine or fluticasone propionate alone (Berger and Meltzer, 2015). The choice for such a new pharmacotherapeutical option is supported by its consistently symptomatic relief regardless of season, symptom or severity (Bachert et al, 2015). In addition, it effectively and rapidly reduces nasal congestion and eye pruritus in patients suffering predominantly from these symptoms (Fokkens et al, 2015). The consistent and rapid effect in alleviating all

nasal and ocular symptoms is significant, and contributes to its superiority over intranasal monotherapies, MP-AzeFlu being considered a new standard of care in allergic rhinitis (Hellings et al, 2015). This novel intranasal formulation shows great promise (Klimek, Mullol et al, 2016). Besides adults and adolescents, in which MP-AzeFlu is already registered, new published research data revealed that it is also efficaceous and safe in children (4-11 years) with moderate/severe seasonal allergic rhinitis (Berger, Meltzer et al, 2016), and more effective than intranasal fluticasone propionate (Berger, Bousquet et al, 2016).

Conflict of interests: The authors declare no conflict of interests.

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39. Riera CE, Vogel H, Simon SA, le Coutre J. Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors. Am J Physiol Regul Integr Comp Physiol. 2007 Aug; 293(2): R626-34. Epub 2007 Jun 13. PubMed PMID: 17567713.

40. Roca-Ferrer J, Pujols L, Pérez-Gonzalez M, Alobid I, Valero A, Picado C, Murray R, Mullol J. MP29-02* reduces eosinophil survival induced by epithelial cell secretions from nasal mucosa. Clinical and Translational Allergy, 2015; 5(Suppl 4): P9. doi:10.1186/2045-7022-5-S4-P9.

41. Samivel R, Kim DW, Son HR, Rhee YH, Kim EH, Kim JH, Bae JS, Chung YJ, Chung PS, Raz E, Mo JH. The role of TRPV1 in the CD4+ T cell-mediated inflammatory response of allergic rhinitis. Oncotarget. 2016 Jan 5; 7(1): 148-60. doi: 10.18632/oncotarget.6653. PubMed PMID: 26700618.

42. Schumacher S, Kietzmann M, Stark H, Bäumer W. Unique immunomodulatory effects of azelastine on dendritic cells in vitro. Naunyn Schmiedebergs Arch Pharmacol. 2014 Nov; 387(11): 1091-9. doi: 10.1007/s00210-014-1033-x. Epub 2014 Aug 15. PubMed PMID: 25119779.

43. Shaik FA, Singh N, Arakawa M, Duan K, Bhullar RP, Chelikani P. Bitter taste receptors: Extraoral roles in pathophysiology. Int J Biochem Cell Biol. 2016 Mar 23. pii: S1357-2725(16)30065-6. doi: 10.1016/j.biocel.2016.03.011. [Epub ahead of print] PubMed PMID: 27032752.

44. Singh U, Bernstein JA, Haar L, Luther K, Jones WK. Azelastine desensitization of transient receptor potential vanilloid 1: a potential mechanism explaining its therapeutic effect in nonallergic rhinitis. Am J Rhinol Allergy. 2014 May-Jun; 28(3): 215-24. doi: 10.2500/ajra.2014.28.4059. PubMed PMID: 24980233.

45. Slack RJ, Hart AD, Luttmann MA, Clark KL, Begg M. In vitro characterisation of the duration of action of the histamine-1 receptor antagonist azelastine. Eur J Pharmacol. 2011 Nov 30; 670(2-3): 586-92. doi: 10.1016/j.ejphar.2011.09.017. Epub 2011 Sep 21. PubMed PMID: 21946109.

46. Vanden Berghe W, De Bosscher K, Vermeulen L, De Wilde G, Haegeman G. Induction and repression of NF-kappa B-driven inflammatory genes. Ernst Schering Res Found Workshop. 2002; (40): 233-78. Review. PubMed PMID: 12355719.

47. Vandevyver S, Dejager L, Tuckermann J, Libert C. New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology. 2013 Mar; 154(3): 993-1007. doi: 10.1210/ en.2012-2045. Epub 2013 Feb 5. Review. PubMed PMID: 23384835.

48. Zappia CD, Granja-Galeano G, Fernández N, Shayo C, Davio C, Fitzsimons CP, Monczor F. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Sci Rep. 2015 Dec 4; 5: 17476. doi: 10.1038/srep17476. PubMed PMID: 26635083; PubMed Central PMCID: PMC4669453.

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Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 2, April - June 2016

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Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 2, April - June 2016

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Alergologie și Imunologie Clinică The Romanian Society of Allergology and Clinical Immunology Board President: Vice-Presidents: Treasurer: Secretary:

Florin-Dan Popescu, MD, PhD, Associate Professor, Bucharest Roxana Bumbăcea, MD, PhD, Associate Professor , Bucharest Diana Deleanu, MD, PhD, Professor, Cluj-Napoca Elena Camelia Berghea, MD, PhD, Bucharest Adriana Muntean, MD, PhD, Cluj-Napoca

The Association „Romanian Society of Allergology and Clinical Immunology” was established under the Romanian Government Decision No: 8/31.12.1989 and recognized as scientific association with legal personality by the District 1 Bucharest Court sentence No 1731/18.06.1990 in dossier 1775/PJ/1990 Asociația „Societatea Română de Alergologie și Imunologie Clinică” s-a înființat în baza legii nr. 8/31.12.1989 și a fost recunoscută ca asociație cu personalitate juridică de Judecătoria Sectorului 1, București, prin sentința judecătorească nr. 1731/18.6.1990 în dosar 1775/PJ/1990.

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46

Advances in Allergology Interdisciplinary approaches

Abstracts Annual Conference 2016 RSACI Annual Conference

Romanian Society of Allergology and Clinical Immunology

May 13-15, 2016 Bucharest

May 13-15, 2016, Bucharest

SRAIC

Societatea Română de

Alergologie și Imunologie Clinică

Rețeaua Română de

Angioedem Ereditar

Abstracts

Oral Presentations SCIENTIFIC SESSION

-1-

EAACI support speakers session Precision medicine in asthma

Ioana Agache Faculty of Medicine, Transilvania University, Brasov, Romania

According to the National Institutes of Health, precision medicine (PM) is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. PM is of broad relevance for the management of asthma in the context of a better selection of treatment responders, design of clinical trials, risk prediction, and design of disease-modifying strategies.

Improved knowledge of asthma pathogenesis together with defining validated and qualified biomarkers are key approaches to PM.

Risk factors for severe asthma in children Ă&#x2013;mer Kalayci Hacettepe University School of Medicine, Ankara, Turkey

SCIENTIFIC SESSION

-2-

Challenges in diagnosis and treatment of angioedema without wheals Chairpersons: Dumitru Moldovan, Florin-Dan Popescu

Angioedema phenotypes: disease expression and classification Marco Cicardi University of Milan, Italy Angioedema depends on increased endothelial permeability, which can be caused either by histamine or bradykinin, binding H1 and B2 receptors respectively. In a patient presenting without wheals both histamine and non-histamine (probably bradykinin)-mediated angioedema should be considered. In absence of other evidence, a course of high dose antihistamine may be the first approach. The second major point is to separate 50

Oral Presentations

hereditary from acquired forms. Among hereditary angioedema, it is possible to identify a form due to a genetic C1 inhibitor (C1-INH) deficiency (autosomal dominant, with almost 100% clinical penetrance and approximately 25% of de novo mutants), a form due to FXII mutations (with low penetrance, affecting almost only women especially during hyperestrogenemia) and a form of unknown origin (which might be linked to deficiency of plasminogen activator inhibitor 2). In absence of family history and genetic/biochemical markers of inheritance, angioedema should be diagnosed as acquired (AAE). AAE are more often histaminergic, while among those AAE that do not respond to anti-histamine the most common form relates to the use of angiotensin converting enzyme inhibitors (often with oral and perioral location). AAE can also be due to C1INH consumption, as occurs in forms usually associated with B cell disorders. These AAE show significantly decreased C4 and often low C1q values as well as anti-C1-INH antibodies. Idiopathic acquired angioedema has no identified etiology or pathogenesis, although some case series suggest that these patients may benefit from treatment with tranexamic acid.

Hereditary Angioedema: What does the future hold in store?

Bruce L. Zuraw University of California, San Diego, CA, USA There has been a tremendous increase in knowledge about the underlying pathophysiology of hereditary angioedema (HAE) as well as in the options for effectively treating HAE. Despite these advances, patients continue to experience significant morbidity and even mortality from HAE. Fortunately, there is every reason to believe that the future will bring continued advances in the diagnosis and treatment of HAE. The key to effective treatment of HAE is early and accurate diagnosis. International efforts to organize HAE centers of excellence together with continuing efforts to reach out to patients and health care providers are expected to decrease the delay in HAE diagnosis. While the diagnosis of HAE due to C1 inhibitor (C1INH) deficiency (HAE-C1INH) is generally straightforward, the diagnosis of HAE with normal C1INH (HAE-nl-C1INH) or bradykinin-mediated angioedema without a positive family history remain problematic. Ongoing efforts to define biomarkers should improve the ability of clinicians to diagnose HAE-nl-C1INH. The currently available on-demand HAE medicines are an enormous improvement relative to the earlier situation. Prophylactic treatment of HAE, however, remains more problematic due to various combinations of insufficient efficacy, inconvenience, or lack of tolerability. A range of new molecules are being studied that may lead to dramatic improvements in prophylactic treatment. In addition, basic studies of HAE pathophysiology should allow treatment programs to be more precise and better targeted to the affected individuals. Considered together, these changes are expected to lead to substantial improvements quality of life for HAE patients.

SCIENTIFIC SESSION

-3State-of-the-art

SLIT with monomeric allergoid towards the needs of patients and doctors Enrico Compalati University of Genoa, Italy Allergen immunotherapy (AIT) can be proud of more than one century of historical step forwards in the research of the underlying mechanism of action and more advantageous clinical set-up. However, some unmet needs remain a challenge, mainly the issues of tolerability and adherence to the treatment courses. The introduction of the sublingual route of administration has partially filled these gaps; nevertheless, data on compliance from the literature are not reassuring also for this route and sometimes the lack of tolerability and occurrence of side effects appear as some of the most impacting events on this outcome, as remarked by international consensus documents.

For these reasons, the most recent strategic approaches to AIT were targeted to improve the safety and the real rife efficiency of AIT. In order to increase the risk/benefit profile of AIT, the efforts were directed to enhance the immunological allergen stimulation from one side and decreasing the IgE-binding ability of allergen extracts from the other side. The first goal could be achieved by the use of adjuvants (i.e. TLR4-TLR7-TLR9 agonists) and the identification of alternative routes of administration (i.e. intralymphatic, intradermic), with the aim of increasing the biological 51

Abstracts

active dose of the extract reaching the immune system; the second goal could be reached by altering the allergen structure of the extract by means of chemically modified allergens and the recombinant technology to obtain hypoallergenic variants and peptides.

Monomeric allergoids are chemically modified extracts in which the allergen molecule undergoes a reaction of carbamylation that selectively modifies only the aminoacids lysines. Very interestingly this reaction does not induce polymerization, thus monomeric allergoids maintain the same molecular size of the native allergen; for this reason they are the exclusive allergoids that can be used for sublingual administration. The transformation results in: 1) a reduced IgE-binding activity (low allergenicity), responsible for an appreciable safety profile documented by many clinical trials and post-marketing experiences; 2) a particular resistance to enzymatic degradation of the extract, responsible for an increased bioavailability, as documented in pharmacokinetics studies.

In summary, monomeric allergoids represent a modern tool that provides both the perspectives mentioned above for improving the risk/benefit profile of AIT: sublingual administration, reduced allergenicity, easy handling, efficient dose, tolerability, all contribute to patients’ acceptance of AIT and satisfy doctors’ need for patients’ compliance.

SCIENTIFIC SESSION

-4State-of-the-art

Intracellular signaling mechanisms in allergic immune response to house dust mites - the point of no return: allergic rhinitis Carmen Panaitescu Bunu, Gabriela Tănăsie, Laura Marusciac, Luminița-Daniela Cernescu, Milena Opran University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania 1.a. Background: GATA transcription factors are a family of transcription factors which can bind to the DNA sequence GATA. GATA-3 is one of the most important transcription factors involved in the differentiation and transcription control of Th2 type cytokines, promoting the secretion of interleukin-4 (IL-4) and interleukin-13 (IL-13) from Th2 cells. The aim of this study was to evaluate the relation between GATA-3 expression, IL-4 and IL-13 serum levels, and the influence of inflammatory interleukins on total and specific serum IgE synthesis.

Material and methods: Serum IL-4, IL-13, and total and Der p 1 – specific serum IgE levels were determined from 39 allergic patients and 10 healthy individuals, using an enzyme-linked immunosorbent assay (ELISA). GATA-3 expression was determined semiquantitatively using mRNA obtained from the blood of 20 out of the 39 allergic patients. CD4+ T lymphocytes were isolated from whole blood using a CD4+ T cell isolation kit for human cells. RNA was isolated from CD4+ T cells using an RNA purification kit. RNA reverse transcription and cDNA amplification was performed with a one-step RT-PCR system, using forward/reverse primers specific for the GATA-3 sequence.

Results: GATA-3 expression is highly variable, ranging from overexpression to complete lack of expression. IL-4 serum levels are significantly higher in allergic patients compared to healthy individuals, and are very significantly correlated with GATA-3 expression (r = 0.660, p = 0.002), but IL-13 serum levels do not show any significant differences between allergic and non-allergic individuals, and they do not correlate with 52

Oral Presentations

GATA-3 expression (r = 0.061, p > 0.05). Total serum IgE levels do not correlate with GATA-3 expression (r = 0.053, p > 0.05), nor with IL-4 levels (p > 0.05), but it correlates with IL-13 serum levels (r = 0.3116, p = 0.0002). Der p 1 – specific IgE serum levels correlate with IL-4 serum levels (r = 0.7553, p < 0.05).

Conclusions: The results confirm that GATA-3 expression is IL-4-dependent, but not IL-13-dependent. Both IL-4 and IL-13 are involved in the development of an allergic immune response in house dust mite allergic patients, but their importance in the inflammatory process differs. The data suggests that IL-4 is more important than IL-13 for specific IgE production, whereas IL-13 seems to be the main cytokine that stimulates total IgE synthesis.

Exposure to house dust mites - what really counts for the development of the allergic immune response Luminița-Daniela Cernescu, Florina-Maria Bojin, Laura Marusciac, Carmen Panaitescu Bunu University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania 1.b. Background: Respiratory allergic diseases are heterogeneous disorders characterized by chronic inflammation. The modulation of the immune response is closely dependent of the costimulatory molecules expressed by dendritic cells (DCs) and the polarizing cytokines environment during DC-T cell interaction. The aim of the study was to evaluate the in vitro effect of Der p1, the major allergen of Dermatophagoides pteronyssinus (Der p), on Th2 cytokines production by monocyte-derived DCs and naive CD4+ T cells cocultured with autologous DCs from Der p allergic patients comparison with healthy donors.

Method: CD14+ monocytes isolated from the venous peripheral blood of house dust mite allergic patients and healthy donors were differentiated into DCs. Generated antigen presenting cells were pulsed for 24 hours with Der p1 and then cocultured with the autologous naive CD4+ T cells.

Supernatants were harvested and assayed for IL-10, IL-12, IL-4 and IFN-γ presence.

Results: Der p1 is associated with an increased expression of CD86 and CD83 on DCs from house dust mite allergic patients and a higher production of IL-10. In the same group, stimulated naive T cells by autologous Der p1 pulsed DCs preferentially produced IL-4.

Conclusions: Th2-oriented immune response is dependent on many factors, but the immune status of the individual has the main role in the establishment of the balance between allergy and tolerance.

SCIENTIFIC SESSION

-5-

National Agency for Medicines and Medical Devices (NAMMD) session The regulatory framework for clinical trials in Romania Marius Tănasă - Vicepresident NAMMD Bucharest, Romania Clinical trials represent an important step in the development of the innovative medicines. They ensure the development of new indications, and on the other hand, comparison with standard of care treatments. In Romania, clinical trials have been conducted in accordance with European Directives and Regulation (EU) 536/2014. These legal provisions are transposed into national legislation by Law 95/2006 and by Orders of the Minister of Health. Now, the priorities regarding clinical trials are: simplification and harmonization of administrative requirements, shortening the evaluation/authorization process, cost reduction of multi-centric clinical trials. Besides simplifying authorization procedures we are looking forward to increase transparency and risk-based approach regarding clinical trials.

53

Abstracts

SCIENTIFIC SESSION

-6-

Short session on drug allergy A positive history of non-anaesthetic drug allergy is a risk factor for positive allergological skin tests for neuromuscular blocking agents Nadia Oniţiu-Gherman, Cristina Petrișor, Natalia Hagău Cluj-Napoca, Romania Background: We have previously reported a high incidence of positive in vivo and in vitro allergy tests for neuromuscular blocking agents (NMBAs) in patients with a positive history of non-anaesthetic immediate-type drug hypersensitivity reactions. Larger studies are required to investigate the link between non-anaesthetic drug hypersensitivity and the results of the skin tests for NMBAs. The objective of our prospective, observational study was to evaluate the rates of positive skin tests for NMBAs in patients with a positive history of non-anaesthetic drug hypersensitivity (including antibiotics and non-steroidal anti-inflammatory drugs) and those of healthy controls (patients with no history of drug-induced immediate-type hypersensitivity.

Methods: We included a total number of 180 patients with a positive history of non-anaesthetic drug allergy and 72 controls*. Skin tests were performed according to international recommendations for atracurium, pancuronium, rocuronium, and suxamethonium.

Results: We found 100 positive skin tests from the 720 tests performed in patients with a positive history of non-anaesthetic drug allergy (13.88%) and 23 positive skin tests from the 288 performed in controls (7.98%), the two incidences showing significant statistical difference (p=0.013). The relative risk for having a positive skin test for NMBAs for patients versus controls was 1.74 (1.13-2.68). When each NMBA was considered, for atracurium, skin tests were more often positive in patients with a positive history of drug allergy when compared to controls (p=0.02). For pancuronium, rocuronium and suxamethonium the statistical difference was not attained (p-values 0.19 for pancuronium, 0.21 for rocuronium, and 0.32 for suxamethonium).

Conclusions: A positive history of non-anaesthetic drug allergy might constitute a risk factor for having positive skin tests for NMBAs. This positive skin tests results might highlight latent sensitization in this patient category. Whether patients with previous non-anaesthetic drug hypersensitivity are at higher risk for developing intraoperative anaphylaxis needs further investigations. * From these, 98 patients with previous antibiotic hypersensitivity and 72 controls were included in a published article on drug hypersensitivity: Hagău N, Gherman N, Cociș M, Petrișor C. Antibiotic-induced immediate type hypersensitivity is a risk factor for positive allergy skin tests for neuromuscular blocking agents. Allergology International 2016;65(1):52-55.

SCIENTIFIC SESSION

-7-

Diagnostic approach in hand eczema Chairpersons: Roxana Silvia Bumbacea, Calin Giurcaneanu

General considerations on the etiology and diagnosis of hand eczema Liliana Popa “Carol Davila“ University of Medicine and Pharmacy, Bucharest, Romania Hand eczema (HE) is a common skin disease with complex, multifactorial pathogenesis. Individual factors such as age, gender, genetic predisposition, atopic background, in association with environmental factors including occupational and recreational exposure to contact allergens and other work-related triggers, greatly influence the onset, course, and prognosis of HE. Chronic HE interferes with daily activities and work productivity and has a significant impact on the patient’s well-being and quality of life.

We discuss the classification, diagnostic work-up, as well as the differential diagnosis of hand eczema.

54

Oral Presentations

Hand eczema allergy work-up Ileana Ghiordanescu Bucharest, Romania Introduction / Background: Hand eczema (HE), the most frequent skin disease of the hand has a 1 year prevalence of 10 %, that raises up to 30 % in risk population (exposure to humid environment, irritants and allergens). The pathogenesis of hand eczema, a highly discussed subject, is multifactorial, with contribution of endogenous factors (e.g. atopy) and exogenous factors, (e.g. allergens and irritants exposure). Some of these factors can be evaluated during the diagnostic work-up. Atopy is considered a risk factor for HE for both children and adults. One third of patients with HE are atopic.

Materials and Method: The presentation discusses modern diagnostic techniques of HE emphasising the allergy work up methods with secondary impact on future therapeutic measures. Many reviews and position papers have been analysed in order to present updated data regarding HE diagnostic, correlation to clinical type, most important contact allergens, discussing risk factors that can be evaluated through questionnaires, particular situations, etc.

Results: Positive diagnostic of HE includes evaluation of personal and family history of atopy, personal history of eczema, clinical examination, allergological work-up (patch, open patch test, atopy patch test, prick, prick to prick, specific IgE dosage, challenge test, etc). Cutaneous biopsy is not usually indicated. Also, there are modern methods, used in clinical studies, that could determine different etiological factors for HE. Conclusions: In conclusion this review analyses different diagnostic methods for HE, a frequent, highly prevalent cutaneous condition with enormous impact on the quality of life.

Severe dyshidrotic eczema (pompholyx) - case report Roxana Silvia BumbÄ&#x192;cea â&#x20AC;&#x153;Carol Davilaâ&#x20AC;? University of Medicine and Pharmacy, Bucharest, Romania Introduction: Hand eczema is a morphological and etiological heterogeneous disorder with significant impact on the quality of life. One of the morphological forms, acute dyshidrotic eczema (pompholyx) is characterized by a recurrent, vesicular eruption, localized on palms and lateral sides of fingers. Most commonly, it affects teenagers and young adults with a prevalence of approximately 3% in the general population.

Case presentation: A 15 years old male patient was sent to our clinic presenting palmar localized cutaneous lesions like blisters and tense bullae, sudden onset, in the absence of an identifiable trigger. Local (antiseptic) and systemic (AH1 oral route) pretreatment did not provide the expected benefit. Significant personal medical history shows episodes of bronchospasm in childhood and recurring palmar eczematous lesions, exacerbated during winter; Additional clinical examination reveals moderate to severe dry skin, hyperkeratosis pilaris, hyperlinear palms. Complex clinical and investigational assessment allowed framing dyshidrotic eczema as a manifestation of the non-IgE mediated atopic dermatitis.

Treatment consisted in following some general measures regarding the prevention of skin exposure to irritants, restoring the skin barrier, suppressing inflammation and itching control. To prevent future exacerbations, pro-active use of topical calcineurin inhibitors has been recommended.

Conclusions: Hand eczema exists in multiple morphological forms, but there are no morphological-etiology type correlations.

Etiologic diagnosis is essential for the therapeutic option. Our case can be considered a particular form of atopic eczema.

55

Abstracts

SCIENTIFIC SESSION

-8-

Exposure to food allergens and food oral immunotherapy Chairperson: Diana Deleanu

Food allergy – avoidance or exposure?

Irena Manea, Diana Deleanu “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Understanding the epidemic proportions of food allergy as well as the effective strategies to promote immunological tolerance to foods is currently an unanswered task.

Food allergy has a significant social and economic impact worldwide. Reportedly, over 220 million people suffer from food allergy.

Food hypersensitivity mainly affects the paediatric population, with an estimated worldwide prevalence of 3-8%. Some food allergies, such as allergy to peanuts and nuts, are rarely outgrown. Moreover, an increasing number of severe life-threatening reactions in children have been linked to food allergy. Avoidance of the culprit food allergen and carrying epinephrine auto injectors are the current management strategies.

The success of specific immunotherapy to inhalant allergens has prompted an increased interest to search for similar curative treatment in food allergic individuals.

This paper aims to highlight the international efforts to identify new therapeutic strategies in food allergy, as proved by the results of different clinical trials. Among these, several studies bring data that favours the shift from avoidance to early-life introduction of food allergens.

Conclusions: novel therapeutic approaches in food allergy may bring the necessary answers regarding future primary prevention strategies.

Oral immunotherapy for food allergies Diana Deleanu “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Food allergies are a major problem for children, due to the importance of food for the growth. Unfortunately, until today, there is no therapy, except avoidance, for food allergy. In the last years, oral immunotherapy (OIT) with foods has been introduced having good results. IgE-mediated food allergy may be controlled with OIT which induces tolerance in T cells. OIT was performed for peanuts, cow-milk proteins, wheat. Both OIT and anti-IgE therapy can be associated for very sensitive patients. For patients with oral allergy syndrome, immunotherapy with birch pollen was also effective for food cross-reactivity to fruits.

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SCIENTIFIC SESSION

-9-

Emergencies in allergology Chairpersons: Henriette Farkas, Dumitru Moldovan

Laryngeal attacks and asphyxiation in patients with hereditary angioedema Konrad Bork ”Johannes Gutenberg” University Mainz, Germany Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency (HAE-C1-INH) is caused by mutations in the gene encoding C1-INH (SERPING1) leading to a low plasma level of functionally active C1-INH. In 2000, a new type of hereditary angioedema was described, which was not associated with a deficiency of C1-INH. It was termed HAE with normal C1-INH (HAEnCI) or HAE type III. HAEnCI comprises two subtypes, HAE with an HAE-specific mutation in the FXII gene (HAE-FXII) and HAE with a still unknown genetic background (HAE-unknown). In all the types of HAE potentially life-threatening upper airway obstruction may occur, mainly due to a supraglottic edema, simply termed “laryngeal attack”. In HAE-C1-INH, about 1% of attacks are laryngeal attacks. They may occur spontaneously or after being elicited by various triggering factors. In undiagnosed patients with HAE-C1-INH mortality is about 30%.

There were some patients reported who died although the diagnosis of HAE-C1-INH was known. Death cases due to upper airway obstruction have been reported in some patients with HAE-FXII as well as with HAE-unknown. The main goal of treatment is to avoid asphyxiation in HAE patients. Comprehensive information of patients and their relatives about the recognition of symptoms of laryngeal attacks and the measures which have to be taken in all stages of laryngeal attacks are mandatory. In patients with HAE-C1-INH the available drugs for treating laryngeal attacks include plasma-derived C1-INH, icatibant and recombinant C1-INH, among others. In progressed laryngeal attacks measures for keeping the upper airways open may become necessary.

The ENT non-pharmacological intervention in upper respiratory angioedema Codrut Sarafoleanu “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Acute upper respiratory insufficiency due to angioedema can be a life-threatening situation that may require immediate response from doctors from any specialty. In particular situations in which the rapid pharmacological treatment is not available or not effective, tracheostomy is a mandatory life-saving gesture. This paper presents the indications and some surgical aspects needed in this situation.

Emergency Treatment Of Acute Urticaria And Anaphylaxis Jonathan A. Bernstein Cincinnati, USA Acute urticaria/angioedema is defined as being less than 6 weeks in duration. When the urticaria/angioedema is generalized, a patient should seek immediate emergency treatment with epinephrine to manage the risk of disease progression to anaphylaxis and laryngeal obstruction. In such instances a detailed history and physical examination for anaphylaxis should follow administration of treatment in57

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cluding other possible factors that might explain the development of urticaria/angioedema. Exposures leading to acute urticaria that can progress to anaphylaxis include foods, drugs, infections, insect stings, and physical factors and their temporal relationship to urticaria/ angioedema should be documented. Initial treatment involves avoiding factors that induce urticaria/angioedema. First line treatment with antihistamines for persistent symptoms is recommended. Epinephrine should be prescribed if the diagnosis of anaphylaxis has not been excluded in a patient presenting with urticaria/angioedema.

SCIENTIFIC SESSION

- 10 -

Actual aspects and difficulties in clinical evaluation of rare diseases in allergist practice Chairpersons: Almudena Matito, Polliana Leru

Multidisciplinary approach of hypereosinophilic syndromes Lessons from clinical practice Polliana Mihaela Leru “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Diseases accompanied by peripheral blood hypereosinophilia are relatively frequent in medical practice and may rise difficult diagnosis problems, needing multidisciplinary approach. Significant hypereosinophilia may be only in peripheral blood and clinically silent or accompanied by tissue eosinophilia and end organ damage, most frequent in skin, heart, lung and nervous system. From ethiopathogenic point of view, hypereosinophilia may be reactive to other diseases, generally to allergies or parasitic infections or primary, included in the heterogeneous group of hypereosinophilic syndromes (HES).These are diagnosed based on criteria defined by actual international guidelines. Etiologic diagnosis of high hypereosinophilia is sometimes very difficult or delayed, leading to severe evolution, multiorgan involvement and fatal outcome. Some cases remain idiopatic, despite exhaustive investigation and can not be included in one of the well defined subtypes. HES prognosis depends on the severity of hypereosinophilia, cardiac involvement, response to initial therapy, complications such as infections or thromboembolism, associated cancers.

Acute cases are rare, but frequently with severe evolution and high risk of death. Despite important progress in understanding mechanisms, diagnosis and new treatment options, clinical approach of hypereosinophilic disorders may be difficult, needing multidisciplinary collaboration between many experienced specialists, with allergists having an important role.

Diagnosis and treatment of clonal mast cell disorders and indolent systemic mastocytosis Almudena Matito Toledo, Spain Clonal mast cell disorders (c-MCD) comprise a heterogeneous group of disorders characterized by the presence of gain of function KIT mutations and a constitutively altered activation-associated mast cell immunophenotype frequently associated with clinical manifestations related to the release of mast cells mediators –e.g. anaphylaxis-.

The use of highly sensitive and specific methodological approaches is essential to detect the clonal KIT mutated, morphologically atypical and phenotypically aberrant bone marrow (BM) mast cells (MC), since these disorders frequently have a very low BM MC burden and do not fulfill the major proposed criteria for systemic mastocytosis (SM).

These patients present symptoms due to the release of MC mediators; showing a remarkable predominance of males, as well as anaphylactic symptoms primarily involving the cardiovascular system in the absence of urticaria and/or angioedema, which makes such clinical presentation highly suspicious of an underlying c-MCD, particularly when occurring after a hymenoptera sting.

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Treatment strategies are focused to control the frequency and intensity of symptoms secondary to MC mediators release including the strict avoidance of triggers and antimediator therapy carefully selected on the basis of the intensity and/or severity of the signs and symptoms; whereas cytoreductive therapy must be used only in a few selected cases of severely affected indolent SM patients because of potential secondary effects concerns.

Symptomatic selective immunoglobulin A deficiency – diagnosis pitfall and therapeutic issues Aurica Rugina1, Mihaela Bataneant2, Monica Alexoae1, Ileana Ioniuc1 1 ”Grigore T. Popa” University, Iaşi, Romania 2 ”Victor Babes” University, Timisoara, Romania Selective immunoglobulin A deficiency is defined as decreased serum level of IgA in the presence of normal levels of other immunoglobulin serotypes. Most individuals with IgA deficiency are asymptomatic and identified coincidentally. However, some patients may present recurrent infections of respiratory and gastrointestinal tracts, allergic disorders and autoimmune manifestation. The authors present a clinical case of selective immunoglobulin A deficiency associated with sinopulmonary chronic infections, gastrointestinal disorders, inflammatory bowel disease and allergic pathology. The investigation of subclasses of immunoglobulin have described the association with IgG4 deficiency, cellular immunity being normal, there is a possibility of evolution toward commune variable immunodeficiency. Treatment with immunoglobulin was recommended. Conclusions: recurrent sinopulmonary infections, gastrointestinal infections, allergic and autoimmune disorders require the determination of IgA levels. The genetic basis of IgA deficiency remains to be clarified. Better understanding of the production and function of IgA is essential in elucidating the disease mechanism of selective IgA deficiency.

SCIENTIFIC SESSION

- 11 State-of-the-art

Human exhaled breath biomarkers in airway inflammatory diseases Todor Popov Medical University Sofia, Bulgaria Exhaled breath constitutes of over 3500 components, the bulk of which are volatile organic compounds in miniature quantities. Many of these characterize the functioning of the organism as a whole (systemic biomarkers), but some are related to processes taking place in the respiratory system and the airways in particular (lung biomarkers). Assessment of lung biomarkers has been proven useful in airway inflammatory diseases. It involves direct measurement of gases like nitric oxide and inflammatory indicators in exhaled breath condensate like oxidative stress markers (hydrogen peroxide, isoprostanes), nitric oxide derivatives (nitrate and nitrates), arachidonic acid metabolites (prostonoids, leukotirenes, epoxides), adenosine, cytokines. Integral approaches have been also suggested like exhaled breath temperature measurement and devices of the type “electronic nose” capturing exhaled molecular fingerprints (breathprints). Examination of exhaled breath combined with analytical technologies has the potential to change the existing routine approaches and open the way for precision medicine in to the field of respiratory and internal medicine. The advances of modern technology can render the examination of the exhaled breath with personalized devices at the patients’ homes common practice, thus introducing also telemedicine in respiratory care.

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SCIENTIFIC SESSION

- 12 -

Particularities of the infections immunoprophylaxis to allergic child Chairperson: Camelia Elena Berghea

Characteristics of vaccination in children with allergies Camelia Berghea Bucharest, Romania Vaccination is an important method of reducing the risk of developing a number of infectious diseases. An allergy to any component of vaccine (antigenic component or the additional components, especially food allergens) is not uncommon in childhood and in this case, the subsequent immunization will be a reason of concern for parents and for most primary care specialists. The incidence of severe allergic reactions is reported to be very low, the causes of allergic reactions to vaccines are residual protein components of the manufacturing process such as gelatin or egg, and less commonly yeasts or latex. If an immediate-type allergic reaction is suspected at vaccination, the culprit allergen should be determined in order to make the proper recommendations regarding future vaccination, to avoid or reduce reactions to vaccine components in allergic children.

Infection - cause or effect in childhood asthma

Alina Murgu University of Medicine ”Grigore T. Popa” Iasi, Romania

Asthma in children now recognizes a multitude of triggers that can induce disease or initiate asthmatic crisis. Viral infection has been most commonly associated with asthma exacerbations, but in a percentage of cases has been shown viral and bacterial co-infection or bacterial infection and in particular only with atypical bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae). Although hygiene theory attributed a protective role for the infection against the onset of the “allergic march” today, it has been proved the major impact of viral and / or bacterial infection in the phenotype induction in atopic asthma in certain immunogenic circumstances in relation with: the type and duration of the infection, the precocity and intensity of exposure to bacterial LPS, the efficiency of binding to toll-like receptors (TLR 2,3,4) of the bronchial epithelium, TH1 cytokine response failure caused by deficiency IFNу, polymorphisms of genes encoding crs.5 TH2 cytokine response of asthmatic type, thymic stromal limfophoietin system intervention, the changes in relation to the particularities of the epithelial cell response to oxidative stress and cell apoptosis, the onset and maintenance of the bronchial remodeling and fibrosis process by proinflammatory cytokines and profibrogenic cytokines (VEGF, FGF2, TGF β).

In conclusion, the viral and / or bacterial infection creates the pathogenic premises for failure airways in asthmatic patient manifested as an exacerbation or in the intercritical period, that increases susceptibility of the airways to the non-specific triggers (smoke cigarette, cold air, etc.) and consequently increases resistance to the bronchodilators and alters respiratory functional parameters worse and more durable than non-asthmatics.

Keywords: child, asthma, infection

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Children vaccination mandatory / optional Mirela Luminita Pavelescu Bucharest, Romania Children antibacterial immunization is responsible for the significant decrease of the incidence of some infectious diseases included in the vaccination program, by their eradication. Given that, in a modern way, parents have the tendency of refusing children vaccination, even when it comes to mandatory vaccines, questions occur: what is the risk for these children and also for those vaccinated, to develop severe infectious diseases, potentially disabling or life threatening? Which diseases are covered by the national vaccination plan and which diseases can be prevented through optional vaccines? Do mandatory vaccines have a dramatic immunologic impact on the children’ s health status? These are righteous questions given that the percentage of those refusing children vaccination has seriously increased, questions to which the entire pediatric medical community makes efforts to respond. The present work proposes to set straight all current data regarding this topic.

SCIENTIFIC SESSION

- 13 State-of-the-art

Holistic approach to early sensitization and allergies benefits for prevention

Stela Gotia ”Grigore T. Popa” University, Iasi, Romania

Allergy belongs to “fetal programmed” diseases, the genetic transmission is complex, hereditary gene polymorphisms are accompanied by the acquired ones through epigenetic resets under the pressure of the pre, intra and postnatal factors.

The rapid growth in the period of organogenesis is accompanied by an increased sensitization of the relationships gene-gene and geneenvironment. Cord blood markers may prove intrauterine sensitization or immunological features favoring early allergy. Epigenomemicrobiome-environment relationship evolves with age, favoring allergy. The implication of non-genetic factors has been proven: pregnant woman obesity, poor diet, genetically modified foods, smoking, air and chemical pollutants, stress, infections, antibiotics and other medicines, obstetric complications.

Early systematically applied allergy investigation allows for recording and treatment of allergic pregnant women, detection of those at risk, introduction of preventive measures and preparedness for natural childbirth and breastfeeding.

Newborns from pregnancy with risk, apparently nonsymptomatic, have immunologic resets that favor the early onset of allergy when the risk factors are present (cesarean delivery, formula feeding, antibiotics, air pollutants, viral infections etc).

Children (newborns, infants, toddlers) with increased familial risk and / or exposed to epigenetic risk may benefit from primary preventive measures. Evolution of early onset allergic manifestations (which must be recognized!) can be improved by secondary prevention.

The involved team includes family physicians, obstetricians, pediatricians, allergists, dermatologists, nutritionists, psychologists.

A guideline for pre, intra and postnatal allergy would serve as a binder for the team engaged in prevention and treatment of early allergy.

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- 14 -

SCIENTIFIC SESSION

Scientific partnership session Chairpersons: Doina Anca Pleşca, Codrut Sarafoleanu

Primary prevention of food allergy in children 1,2 Doina Anca Plesca, 2Luminita Spatariu, Prof. Dr. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 2 Pediatrics and Pediatric Neurology Clinic, “Victor Gomoiu” Clinical Hospital for Children, Bucharest 1

Allergies are a frequent cause for morbidity affecting over 60 million people in Europe and approximately a billion worldwide (EAACI 2012). 1 in 3 European children suffer from allergy and the increasing figures give a forecast of 1 in 2 children presenting allergies by 2025.

Clinical manifestations in allergy are different for each patient depending on age. If clinical manifestations in infants are represented by atopic dermatitis and food allergies, in preschool and school children, allergic rhinitis and/or bronchial asthma (the ‘Allergic March’) add up to the clinical picture.

Food allergies have a maximum of prevalence in childhood. These occur in 6 – 8 % of children, with a prevalence in adults of only 3%.

The large majority of food allergies (60%) are IgE – mediated. They appear more often through exposure to one food only and in 35% of cases multiple food allergies are determined.

Food allergies can have a significant effect on morbidity and on patients’ quality of life, being costly in terms of medical visits and treatments.

Cows’ milk protein allergy (CMPA) is the most common food allergy in children aged up to 3. This disease is most encountered in infants (1 - 3 %). CMPA can occur in approximately 0.5% of breastfed infants. In about 90% of the cases, the clinical picture is present in the first 3 months of life, the onset of its manifestations being linked to the moment of the infant’ s first exposure to cow’ s milk proteins. The allergy to cow’ s milk proteins is rarely developed after 12 months of age.

The clinical picture in CMPA presents various aspects. There is no pathognomonic symptom. Depending on the immune type of mediation (IgE or non IgE), the onset of symptoms occurs immediately (several minutes after a small intake of cow’ s milk, even a few drops) or late (after a few days or weeks from the ingestion), with a slow evolution and consequences over child’ s growth and development.

The strategies to prevent allergic manifestations focus on environment factors, which include exposure to food proteins/food allergens to avoid allergic sensitization and promoting oral tolerance induction through the modulation of the immune system.

Dietary recommendations in primary prevention of food allergies (APLV) approach alike pregnancy, breastfeeding, milk formula introduction and diversification.

During pregnancy, the woman should benefit of a balanced diet, rich in fibers, vegetables and fruits.

Exclusion of potentially allergenic foods from the pregnant’ s diet is not recommended. There is no evidence of a reduced risk for food allergy in children by excluding these foods. It has been recommended fatty fish consumption (up to 3 times a week) as this can reduce the risk of developing dermatitis in the first years of life. Up to date, there is not enough data to support that the use of probiotics during pregnancy plays a significant role.

Post natal, exclusive breastfeeding in the first 4 – 6 months of life is recommended, mother’ s milk having a protective role. In the absence of breastfeeding, the introduction of a partial hydrolyzed milk formula in high risk infants is recommended.

Diversification begins after the 4th month of life and before the 7th. There are no benefits related to delaying the introduction of solid foods or in avoiding allergenic foods during the first year of life. Late diversification in the first year increases the risk for allergies and asthma in childhood.

Research results outline the idea that early exposure to different food allergens increases the development of immune tolerance.

World Allergy Organization (WAO) guidelines published in 2016 recommend the use of prebiotics only in high/low risk infants that are mixed fed. Exclusively breastfed infants require no use of prebiotics.

Keywords: atopy, food allergies, child

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Allergic fungal rhinosinusitis – Diagnosis and treatment Claudiu Manea, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Fungal rhinosinusitis is a clinical entity frequently underestimated in what it concerns its incidence and disease severity. This paper presents the current diagnostic and therapeutic guidelines needed in this still very controversial issue.

Allergic rhinitis in children: current guidelines and recommendation versus real world (a pediatrics perspective for the practitioners) Cristian Gheonea University of Medicine Craiova, Romania Allergic rhinitis in children is currently a hot topic both in allergology and paediatrics, and this is emphasised by the latest accumulation of reviews, position papers, recommendations and guidelines authored by prestigious specialists and boards. Nevertheless, the recent body of evidence emerging from more and more clinical trials with dedicated design for paediatric patients has to be implemented in the real world. Efficacy is different from efficiency, and issues like compliance and adherence are cornerstones of any therapeutic approach.

Allergic rhinitis often presents its debut in early childhood (allergic rhinitis-like symptoms may be present in children as young as 2 years of age or younger!). The diagnosis and the treatment of paediatric patients raise specific challenges and uniquely involve an ongoing relationship with both the child and the families/caregivers. This is why the awareness of practitioners is of utmost importance and the case management team should include specialists with competences in paediatric patients.

SCIENTIFIC SESSION

- 15 -

Short session on Atopic dermatitis Atopic dermatitis - a dermatologist’s perspective Daciana Branisteanu ”Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania Atopic dermatitis (AD), or atopic eczema is a skin manifestation of atopy, defined as a chronic, pruritic inflammatory disorder, with undulating course in flares interspersed with periods of remission. Its prevalence continues to increase, being considered a “stigma” of developed countries due to Western lifestyle.

The onset of AD is in the first year of life in about 48-75% of the cases. Its incidence in the general population ranges from 5 to 25%, children being affected in a higher percentage (15-20% children compared to 1-3% adults). The disease can persist into adulthood or relapse, with a particular clinical picture compared to the infantile form.

Although the disease etiopathogenesis is not fully elucidated, today it is widely accepted that AD occurs in individuals genetically predisposed to atopy, syndrome with genetic determinism also characterized by increased specific IgE synthesis against common environmental allergens. On this background the environmental factors act and trigger skin flare-ups (foods, elements in the household and urban habitat, high level of pollution, excessive skin hygiene etc). Of the factors most commonly involved in triggering the flares of AD we mention the infectious factors (Staphylococcus aureus, Pityrosporum ovale etc), stress, neuroendocrine factors (neuropeptides), professional factors, factors related to socioeconomic status etc.

One of the main features of AD is dry skin (one of the atopic “stigmata”, together with double lower eyelid crease, palmar hyperliniarity, follicular keratosis etc). Skin barrier function is altered, the changes with the appearance of a “wall with missing bricks” being mostly caused/induced by filaggrin gene perturbations/mutations.

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In the broader frame of atopy, AD may be associated with asthma, allergic rhinitis, food allergy, urticaria and/or atopic angioedema, allergic conjunctivitis, atopic migraine, etc. The “atopic march” theory is increasingly popular in the literature, given the new evidence supporting it.

Viewed in terms of its immunological features, AD can be extrinsic (IgE-mediated immune response) in 70-85% of cases and intrinsic (IgE-mediated immune response is induced by self-antigens, especially intracytoplasmic).

Sometimes, the clinical picture of AD can be deceiving, with age-related clinical particularities: newborn and infantile AD, childhood AD, adult AD. Most commonly, to skin dryness are added skin changes typical to endogenous eczema, with symmetrical distribution of lesions in various stages of progression (acute, subacute, or chronic eczema) and lesions caused by scratching , secondary to intense itching. The complications of AD skin lesions are common: pyodermization, lichenification, erythrodermization.

Lately, the treatment of AD underwent significant changes, having as main objectives: to suppress skin inflammation, relieve itching and restore the skin barrier. Treatment is primarily aimed not only at healing the skin lesions of acute AD flares, but also at preventing relapses, achieving complete remission of the lesions (in order to prevent the “atopic march”), avoidance of complications, and, last but not least, increasing the quality of life of patients.

SCIENTIFIC SESSION

- 16 -

From history to interdisciplinarity Chairpersons: Ioan-Bradu Iamandescu, Georgeta Sinitchi

History of hereditary angioedema Georgeta Sinitchi “Apollonia” University, Iasi, Romania Abstract: Hereditary angioedema is a genetic disease characterized by transitory and transient subcutaneous and submucosal edemas with laryngeal frequent localization, that can lead to deaths (25%) and abdominal localization leading to abdominal pain, pseudo-occlusive syndromes and hypovolemic shock. The first clinical descriptions were made by the German doctor Von Quincke in 1882, and in 1888 the Canadian Sir William Osler described the first cases of death. In 1886, the gene that codes for C1 esterase inhibitor on chromosome 11 was described. This can be through anomaly or through lack, describing the two types of angioneurotic edema. In 1998, Nussberger shows that the key mediator is bradykinin. Kinin-genesis is described for the first time in the year 2000 and so it was cataloged as the third type of angioedema and the identification of the gene that codes for the Hageman factor was in the year 2006. Molecular cytogenetics in heredopathology has led to an important diagnostic and therapeutic contribution in the last 50 years. So, the study of linkage described by T. H. Morgan, next to the study of numeric chromosomal anomalies or structures done by M. Berthone and C. Junien, next to the cellular hybridization described by D. Pantecervo and molecular hybridization in situm with marked probes done by Disselroth, studies that lead to many clarifications in genetic and molecular medicine. A. T. Harvig has brought a contribution in chromosomal pathology through a great statistic next to the Mendel-Morgan concept in genetic pathology. Hereditary angioedema is associated with two genes in cause: the SERPING gene and the F12 gene. Current treatment acts on different levels of the Kinin – Kallikrein activation ways, the veritable cascade activated through factor XII (the Hageman factor), engaging production and accumulation of bradykinin.

Conclusions: recent enzymatic and genetic diagnostic determinations, current proper therapeutics, but in which we can make a history of hereditary angioedema.

Key words: hereditary angioedema, history, genetic and enzymatic determinations.

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The evolution of the concept of psychogenic trigger of asthma.

Retrospective evaluation of personal research (1977 – 2015) Ioan Bradu Iamandescu “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Background Background. A new etiological form of asthma, “psychogenic asthma”, was introduced during the third decade of the 20th century, having its origin from initial name “asthma nervosa”, used by Weiss (1922) and French and Alexander. After 1950, other authors as Hansen, Findeisen, Oehling, Seropian have also used this term of “psychogenic asthma”.

Method. Between 1980 and 2006, we have undertaken some epidemiological studies - coupled with psychological tests- in more than 500 asthmatics, and have sometimes registered - during their clinical evolution - asthma attacks induced by stress among patients with both allergic and intrinsic asthma. From this reason we considered these asthmatics as belonging to a special clinical etiological form, named Bronchial Asthma with Psychogenic Trigger (BAPT).

Results. At an early stage of asthma evolution, the psychological trigger attacks were encountered only in 25% patients, but its etiological involvement increased depending on the age of the disease and having the top (84%) in corticodependent asthmatics.

Psychological background of patients with BAPT suggested a high distress vulnerability expressed in high values of some MMPI scales as Hypochondria, Hysteria, Paranoia, Psychasthenia and anxiety. Clinical peculiarities in these asthmatics were: female sex predominance, thyreo-ovarian commorbidities, high frequency of attacks, AINS intolerance and a low cortisol response to Trier psycho-social stress. Psychotherapeutic effects in such patients were pointed out by some studies of our PhD students: cognitive behavioral therapy and music therapy, applied in weekly sessions for 3 months improved clinical scores and ventilatory recordings (Nicoara 2015), and the same ventilatory parameters were improved by music (symphonic and chamber pieces), used during “acute experiments” (Rapiteanu-2010, Cioca 2012, Popilean (2014) proved the most favourable effects of music on VEMS, PEF and especially MEF 50 but only in asthmatics who had appreciated the musical pieces and had high education.

Conclusions. BAPT includes those patients with either allergic or intrinsic asthma, having a supplementary, facultative trigger of attacks by the stress - due to a stress vulnerability (anxiety, depression, emotional reactivity etc.) - but able to benefit from the effects of psychotherapy and anti-distress strategies.

Experimental study regarding the effects of music upon respiratory parameters of asthmatic patients Ioana Cioca, Florin Popilean, Ioan Bradu Iamandescu “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Background: Relaxation effects of music have been demonstrated in a series of medical fields, including bronchial asthma.

Method: In 40 asthmatics with mild or moderate bronchial obstruction were recorded values of FEV1 and MEF 50 before and after listening to symphonic music pieces: four of them with joyful/exuberant and other four with meditative/relaxing character.

Results: Both FEV1 and MEF50 have increased significantly after listening to both kind of music but in a different manner: meditative music increased more FEV1 (mean FEV1 before audition = 71,73, mean FEV 1 after audition = 75,35), than MEF 50 (t=7,491, DF=9, p<0,001) and conversely, joyful music increased more MEF50 (mean MEF 50 before audition = 16,83 and mean MEF50 after audition =21,10), than FEV1 (t=6,32, DF=9, p<0,001).

Conclusion: General bronchial dilatation effects of music in asthmatics suggest intervention of catecholamines released by listening to music although other more mediators may be involved. Receptive music therapy may become a useful additional therapy in asthmatics.

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Interdisciplinarity in latex produced allergies Georgeta Sinitchi “Apollonia” University, Iasi, Romania Abstract: Interdisciplinarity is a new concept, according to UNESCO initiated projects, at the beginning of the 7th decade in different countries; it was established according to the „integrated sciences”. Transdisciplinarity is a superior form of interdisciplinarity, assuming universal concepts and language. Latex sensitivity is produced by the antigenic determinant “hevein” and can produce oral clinical manifestations, contact dermatitis, respiratory manifestations, cardio-vascular manifestations (the great anaphylaxis). Latex allergy through the multiple possibilities of sensitization, the numerous clinical manifestations, medical and professional components, together with the possibility of cross-sensitization, imposes the collaboration of a large number of specialists from different fields for diagnosis, preventive and causal immunologic treatment, as of research, creating transdisciplinary orientation workshops in the problems of study of latex allergy.

Key words: latex allergy, transdisciplinarity, interdisciplinarity.

SCIENTIFIC SESSION

- 17 Varia session

Chairpersons: Corina Ureche, Mariana Vieru

Is there an association between allergy and cardiovascular disease?

Corina Ureche, Ligia Bancu, Katalin Mako Targu-Mures, Romania Cardiovascular diseases are the most important cause of death in developed countries. Equally important health and social problem in these countries is the occurrence of allergic diseases. It is estimated that allergies occur in up to 40% of the human population and in more than 80 million Europeans. Both groups of diseases, due to the very high prevalence and the possibility of serious complications, contribute to a significant deterioration in patients’ quality of life and their daily and professional activity. The pathogenesis of both diseases is complex, both discussing specific types of inflammatory, cardiovascular diseases are certainly mostly related to lifestyle and the allergic ones are clearly linked to atopy, the innate tendency to produce excessive IgE. Among the factors associated with allergic diseases which could influence the development / worsening cardiovascular disease are high levels of IgE, mast cells and basophils stimulating release of mediators (histamine, pro -inflammatory cytokines) -they can lead to endothelial damage, release of free radicals, the oxidation of lipoproteins; allergic manifestations occur in high levels of acute phase protein synthesis leading to metalloproteinase synthesis, discontinuities of atheromatous plaque and thrombus formation. Drugs used in allergic diseases: corticosteroids, beta-mimetics, antihistamines lead to cardiovascular complications related to dyslipidemia, diabetes, hypertension, arrhythmias, conduction abnormalities (QT prolongation). One of the novelties in elucidating the pathogenesis of allergy / allergic asthma is the low vitamin D, it also increases the risk of insulin resistance, hypertension, hypertriglyceridemia, which are major risk factors in cardiovascular diseases. Most characteristic and most feared manifestation of an allergic disease is anaphylaxis characterized by severe manifestations of heart and circulation. Mast cells of the myocardium, activated in these clinical situations of emergency issued unusually large quantity of mediators: chymase (acting on the angiotensin convertase), leukotrienes, PGD2, PAF can induce arrhythmias, decrease coronary flow, can lead to heart attack, sudden cardiac death. Although these assumptions study arousing interest and seem to open a possible link between allergic diseases, chronic inflammation induced by these reflected in high levels of pro-inflammatory cytokines and their contribution to pathological changes in the cardiovascular pathology, literature data are still inconclusive, trials associating these particular pathologies are not yet sufficient.

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Textile dye mix and its components, concomitant reactivities and cross reactivities: two case reports Sonia Badulici, Mirela Radu Bucharest, Romania Introduction: The selection of textile dyes, to be introduced in patch test hapten series, was justified by the diversity of exposure sources.

Patients, methods A retrospective study of 49 patients files (two of them being presented below), tested by European Baseline Series supplemented by textile dye mix and its eight components (Disperse Blue 35, Disperse Orange 1, Disperse Orange 3, Disperse Red 1, Disperse Red 17, Disperse Yellow 3, Disperse Blue 106, Disperse Blue 124) was made. Case I Man, 30 years old, with a chronic eczema of the hands evolving for approximately 7 years, was tested by patch and prick methods (to aeroallergens). Case II Man, 67 years old, with a supposed allergic contact dermatitis with tendency to generalization, was tested by patch method only.

Results: These two patients (4% among those tested) presented positive reactions (++) to textile dye mix and/or to their components. In the first case, patch-tests were also positive, at three successive lectures, to N-Isopropyl-N-phenyl-4-phenylenediamine (IPPD) (++), Methylisothiazolinone+ Methylchloroisothiazolinone (MI+MCI) (++), p-Phenylene-Diamine (PPD) (+), and the prick-tests to Dermatophagoides farinae, two mixture of pollens and an individual pollen. The tests proved their pertinence: the patient was occupationally exposed to both, flour dust and a black rubber mixture, and the positive result to Disperse Orange 1 was explained by the cross reaction between this one and PPD, described in the literature. The second patient presented a positive test (++) to blue pigment Disperse Blue 35, beside the following positive tests, also (++): neomycin sulfate, Balsam Peru (Myroxylon pereirae resin), fragrance mix I, formaldehyde.

Once again the pertinence of the tests was demonstrated: the blue pigment, as formaldehyde, too, are present in jeans - patient’ s favourite garment clothing; «baneocin» (association between neomycin and bacitracin) was frequently used; in the composition of domestic products for the household maintenance were found components of both, fragrance mix I and Balsam Peru.

Conclusions: The results of the tests were pertinent in both cases; the condition to include a hapten in baseline series being that positive reactions at this one to be present at more than 1% of tested population, our study confirms once again the opportunity of the introduction of textile dyes in European baseline of epicutaneous tests.

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Posters Posters Abstracts

Precision outcomes for higher quality of individual life exemplifying in child with atopic eczema Magdalena-Mihaela Andrei M.C.D.T. Roma, Bucharest, Romania Background: The epidemiological and genetic evidences reposition atopic eczema (AE) as first manifestation of atopic phenotype. The increasing prevalence of food allergy in developed countries links to lifestyle and has a profound impact on quality of life (QoL) for patients and their families.

Patient and Methods: We report a case of an 8-year girl with atopic phenotype from an early age, sensitized to food allergens.

I have selected key clinical criteria for diagnostic of AE, and I have applied the scoring atopic dermatitis (SCORAD) severity index, the Children Dermatology Life Quality Index, and the Dermatitis Family Impact questionnaires.

We have used laboratory tests to investigate atopy, and multiplex tests based on allergen and molecules extracts for measurement of specific IgE (sIgE) reactivity.

Results: SCORAD severity grade places the case in moderate to mild AE endotype, correlated with grade of QoL impairment and family impact.

Molecular tests emphasize IgE-mediated food allergy to alpha-lactalbumin milk protein and a high sensitization to crustaceans.

First, despite of low sIgE to milk, the microarray components add important diagnostic information. The immune response to alpha-lactalbumin without detectable levels of sIgE antibodies to beta-lactoglobulin, bovine serum albumin and casein is marker of transient milk allergy, and predicts baked milk non-reactivity. Prescribing baked milk products represents an important shift in the paradigm of milk allergy treatment.

Second, because of high sIgE level to crustaceans, it is likely that tropomyosin (the major protein high involved in cross-reactivity among arthropod species), would be markedly elevated, although the mite sensitization not occurred.

Nevertheless, the major culprit in paediatric population allergic to shrimp, lobster, and crab species seems to be sensitization to sarcoplasmic calcium-binding protein, involved in cross-reactivity among crustaceans only. History shows that the little girl habitually eats foods from Japanese cuisine; it is why we advise complete avoidance of the offending foods.

Food allergy and its management have a large impact on child development and on QoL in psychological, emotional and social domains.

Conclusions: Food allergy can be a triggering factor of AE. A careful balance is required between misinterpreting of allergy testing and the risk of unnecessary nutritional compromise. Molecular diagnosis allows an increased accuracy in diagnosis of food allergy, prognosis and suitable management. Nevertheless, dietary control is only one aspect of AE management, which must include therapeutic strategies and communication skills to improve the patientâ&#x20AC;&#x2122; s life quality.

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Food allergy in small children - clinical evolutive complexity and interdisciplinary management Monica Alexoae, Stela Gotia, Evelina Moraru, Aurica Rugina, Alina Murgu, Irina Criscov, Paula Popovici, Bogdan Stana, Ileana Ioniuc Second Pediatric Clinic, UMF ‘’Grigore T. Popa” Iasi, Romania Food allergy is the most common cause of skin, respiratory or digestive allergy in young children. The objective of this study is the clinical-progressive evaluation of IgE mediated food allergies in infants and young children in relation with risk factors and the impact of dietary and drug measures, individually applied for a follow-up period of 22 months.

Methods: We conducted a 48 months retrospective study in 116 children diagnosed with food allergies in The Second Pediatric Clinic, “Sf Maria” Hospital, Iasi. Admission criteria: proven food sensibilization demostrated by elevated specific IgE (QuantiScan) for food allergens +/- skin testing (prick test), suggestive clinical manifestations, family compliance for the exclusion diet, drug therapy, periodic evaluation. The therapeutic protocol was personalized considering the age, clinical manifestations and the indictable food.

Resulta: The real onset of food allergy was at an early age (5 to 11 months) with gastrointestinal (5/116 cases), respiratory (55/116 cases) and/or skin (66/116 cases) manifestations. Risk factors for food sensitization: formula fed in the first days of life (74%), urban areas (67%), family atopy (57%), mother atopy (25%), caesarean delivery (47%), breast-feeding less than 3 months (45%), prolonged and/or repeated antibiotherapy (29%). Children with skin manifestations associated allergic respiratory symptoms in about 50% during the follow-up period. Oral tolerance was installed in 43/116 children, most frequent for cow milk and egg white.

Conclusions. Food allergy has an early onset because of complex interaction between genetic predisposition, environmental factors, immunological age-dependent immaturity. Therapeutic measures, both dietary and drugs, did not stop the evolution towards complex clinical manifestations through multiple food sensitivities.

Asthma and sensitization to fish Marina Andriuta, Irena Manea, Diana Deleanu “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Asthma is defined by chronic inflammation of the respiratory tract, frequently associated with atopic diathesis, and it can coexist with other atopic diseases. Exacerbations of asthma may occur in the context of food allergy. Hypersensitivity to fish is the main cause of food allergy in adults and carries a high risk of anaphylaxis.

This paper discusses the interrelationship between asthma and food allergies and also displays the multiple aspects of fish allergy.

We report the case of a 47-year-old male patient, who lives in urban area working as a chef assistant, with a personal history of atopy and known to suffer from asthma since 2011. The patient is referred to the Ambulatory of Allergology of the Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, for respiratory symptoms: shortness of breath, wheezing, and nonproductive cough, which typically onset at the workplace, and are related to the direct exposure to fish vapors. According to his medical history, the patient presents contact urticaria to uncooked fish and had experienced two episodes of facial angioedema from ingestion of salmon and lobster. Laboratory investigations confirm the presence of atopic diathesis and sensitization to fish.

Sensitization to food allergens can have resounding effects on the respiratory tract. Respiratory manifestations may be a part of clinical picture of anaphylaxis or, in rare cases it is the only form of expression of immediate hypersensitivity to food allergens.

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Churg-Strauss syndrome with a neurological debut Madalina Blaga, Cristina Petrar, Diana Deleanu “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Eosinophilic granulomatosis with polyangiitis (EGPA), known as Churg-Strauss syndrome, is a syndrome that affects small and medium sized blood vessels(arteries), associated with antineutrophil cytoplasmic autoantibodies (ANCAs). This condition is of unknown etiology and has an autoimmune pathogenesis. EGPA is a multisystemic disorder that can associate allergic rhinitis, asthma (in over 90% of patients), persistent eosinophilia, peripheral neuropathy, especially mononeuritis multiplex which is present in over 75% of patients. Two thirds of patients have cutaneous manifestations with palpable purpura and cutaneous or subcutaneous nodes. Skin or nerve biopsies confirm the diagnosis. Cardiac involvement is a factor for negative prognosis.

IL-10 gene polymorphism in respiratory allergic diseases Corina Bocsan, Raluca Pop, Sergiu Pasca, Adriana Bujor, Stefan Vesa, Diana Deleanu, Anca Buzoianu “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj Napoca, Romania Introduction: IL-10 is an important cytokine that mainly suppresses the immune response. 50-70% of IL-10 synthesis’ variation is due to genetic factors. The promoter region polymorphisms IL-10 -1082 G/A has an important role in modulation of IL-10 production. A allele in position -1082 of IL-10 gene determines an impaired secretion of IL-10 in asthmatic patients. A allele is also correlated with high total IgE and a reduced pulmonary function in asthmatic patients compared to control group in Caucasian population.

The aim of the study was to investigate the relationship between -1082 G/A polymorphisms, IL-10 level and severity of the respiratory allergic diseases (asthma and allergic rhinitis).

Material and methods: 30 patients with allergic rhinitis and 30 patients with asthma were included in the study. 37 volunteers without atopy were also included to determine genotype distribution. The patients were clinically evaluated regarding disease severity. In patients with asthma spirometry was also performed. IL-10 -1082 G/A polymorphism was determined using PCR-RFLP technique. The plasmatic level of IL-10 was determined using ELISA method. The results were statistically analyzed, with significance at p<0.05.

Results: A allele is significantly dominant in patients with respiratory allergic diseases compared to control group (p=0.0014).

There is no difference between asthma and rhinitis subgroups regarding IL-10 genotypes distribution. Plasmatic level of IL-10 is significantly reduced in patients with asthma compared to control group (p=0.041). Number of exacerbation is increased in patients with AA and AG genotypes, compared to GG genotype, but the difference is not statistically significant.

Conclusion: IL-10 gene 1082 G/A polymorphism is not correlated with asthma or allergic rhinitis severities.

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Delayed reaction to betalactams or skin manifestations induced by infection?

1

Victoria Brocovschii1, Irena Manea2, Diana Deleanu2 “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Republic of Moldova 2 ” Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

Skin manifestations of the drug hypersensitivity reactions may vary as time of the onset and clinical presentation from erythema and urticaria to Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

We present a case of a 38 y.o. female known with Lyme disease from 2015, admitted to the infectious diseases department for antibacterial therapy. She was treated with Cefotaxim (3 weeks), and 3 days after antibiotic cessation she presented generalized maculopapular erythema, mostly on the cephalic part, accompanied by burning sensation. The same symptoms appeared in the context of a viral infection. The patient is referred to the Ambulatory of Allergology of the Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca.

For the possible allergic reaction to betalactams she underwent in vitro tests with penicillin determinants, which were negative, and in vivo tests (skin prick and intradermal testing) – negative in 30 minutes and 1 hour after testing, but late positive sensitization (in 24 hours after testing) was documented for Cefotaxim. Clinical manifestations together with positive allergy workup permit us to diagnose this case as a delayed hypersensitivity reaction to Cefotaxim. Considering Lyme disease and further antibiotic therapy we tested the patient’s tolerance to other cephalosporins.

Conclusions: A complete in vitro and in vivo allergy workup is required for a differential diagnosis between hypersensitivity reactions to betalactams and skin manifestations caused by infection.

Oral tolerance induction in a child suffering from severe allergy to cow’ s and goat’ s milk Carmen-Teodora Dobrican, Irena Manea, Diana Deleanu “Iuliu-Hatieganu”University of Medicine and Pharmacy, Cluj-Napoca, Romania Background: Cow’ s milk allergy (CMA) is one of the most common causes of severe food-induced hypersensitivity reactions in early childhood. Avoiding the incriminated food and carrying an epinephrine autoinjector are the current conventional management strategies. Cross-reactivity is an important issue in food allergic patients. CMA children can also be allergic to goat and soy milk or beef. In this context, oral tolerance induction represents a great tool in reducing the burden of disease caused by food allergy.

Case report: We report a case of oral tolerance induction to cow’ s milk in a 5 years old male patient, diagnosed with atopic dermatitis and severe IgE-mediated allergy to cow’ s milk, breast fed, mother followed elimination diet. Diagnostic work-up revealed intense in vitro, as well as in vivo sensitization to cow’ s and goat’ s milk, to hen’ s egg and beef. Patient followed the restriction diet until age 5, when CMA diagnosis was reassessed. Skin prick testing was positive to goat’ s and cow’ s milk. In vivo tests showed a persistent high level of specific IgE to cow’ s and goat’ s milk, as well as to beef and hen’ s egg. A positive oral food challenge with cow’ s milk confirmed the diagnosis. The treatment consisted of an induction phase, performed with increasing doses, and the tolerated dose was continued at home daily. We achieved a safe milk intake of 200 ml a day.

Conclusions: Oral tolerance induction is an effective treatment for milk-allergic children, which brings a significant favorable impact on family and social life, reduces the risk of major reactions and avoids nutritional deficiency.

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Gastrointestinal manifestations of hereditary angioedema.

Data from the Romanian Registry for hereditary angioedema Gabriella Gabos1, Eniko Mihaly2, Noemi-Anna Bara3, Valentin Nădășan3,4,Dumitru Moldovan2,3,4 1 Gastroenterology Clinic, Mures County Hospital, Tîrgu Mureș 2 Allergology-Immunology Dept., Mures County Hospital, Tîrgu Mureș 3 Romanian Network for Hereditary Angioedema 4 University of Medicine and Pharmacy, Tîrgu Mureș Background. Hereditary angioedema (HAE) is a rare disease with an autosomal dominant inheritance. Abdominal manifestations of the angioedema attacks are usually misdiagnosed until the correct diagnosis is established based on low levels of C1 inhibitor activity. Recurrent sudden onset abdominal pain is its most common presenting symptom, associated frequently with nausea, vomiting, and diarrhea, with a duration of 2-4 days. Misdiagnosis may lead to unnecessary surgical intervention. Gastroenterologists are usually consulted, but the diagnosis remains obscure in most cases over the years. The aim of this presentation is to raise awareness about HAE as a potential cause of recurrent, unexplained abdominal pain, to aid in the early recognition of this rare condition and to avoid surgery. In some cases, prompt recognition of HAE could be lifesaving.

Materials and methods. All 91 patients from the Romanian Registry of HAE were contacted by phone and asked for the numbers of peripheral, abdominal, facial and upper respiratory attacks in the past twelve months, i.e. 2015. Questions about misdiagnosis, abdominal surgery and proposals for abdominal surgery were added.

Results. Of the 91 HAE patients, 87 could be contacted and have responded to our questionnaire. We have recorded 951 peripheral, 799 abdominal, 175 facial and 90 upper respiratory attacks in the last 12 months.

During their lifetime, these 87 patients reported 25 likely unnecessary surgeries, as appendectomy, laparotomy, and laparoscopy. The abdominal involvement of HAE was often confused with gastroenteritis, appendicitis, cholecystitis, pancreatitis and ischemic bowel.

Conclusion. Symptomatic involvement of the gastrointestinal tract is an important clinical feature of HAE, occurring in more than 90% of HAE patients at adult age. An accurate diagnosis is paramount in order to provide appropriate treatment to patients with HAE. A multi-disciplinary approach to management of HAE is necessary.

Otitis media with effusion in allergic children Ileana Ioniuc, Evelina Moraru, Aurica Rugina, Alina Murgu, Irina Criscov, Alice Azoicai, Paula Popovici,Bogdan Stana, Monica Alexoae ”Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania Otitis media with effusion is frequently associated with allergic diseases. The high incidence of atopy in childhood involves a multidisciplinary approach of children with adenoid inflammation, Eustachian tube dysfunction and otitis, for an adequate pathogenic treatment. The purpose of the study is the underlying of the association of otitis media with allergic diseases, and the implications of this association in the treatment and the evolution of the patients. Methods: 92 children, aged between 6 month and 6 years, admitted in II Pediatric Clinic, Clinical Hospital of Children “Sf Maria” Iasi with diagnosis of acute otitis media, for a period of 1 year (January 2015- January 2016), was retrospective analysed. Results: the majority of cases (61) have been suppurate otitis with S pneumoniae, Staphilococcus aureus, Moraxella catarhallis and more rarely Haemophilus influenzae and 31 cases of otitis media with sterile effusion. Association with allergic diseases has been more frequent in children with serous otitis media (26/31 cases – most rhinitis or allergic adenoid hypertrophy in association or not with other atopic diseases) and more rarely in those with suppurate otitis media (15/61 cases). It has been necessary to associate antihistamins and topic intranasal corticoids in the treatment of serous otitis, with favourable evolution for long term. Of the patients with suppurate disease, 4 have developed allergic reaction to the prescribed antibiotics with implication in the management of the cases. In conclusion, the children with otitis media, especially those with serous form should be investigated for atopy, treatment of these cases being multidisciplinary – allergologist, pediatrician and otorhinolaryngologist.

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Lethal outcome in unknown hereditary angioedema patient.

A case report Eniko Mihály1,2, Noemi Bara2, Valentin Nădășan2,3, Gabriella Gabos2,4, Dumitru Moldovan1,2,3 1 Mures County Hospital Tîrgu Mures, Romania 2 Romanian Network for Hereditary Angioedema 3 University of Medicine and Pharmacy Tîrgu Mures, Romania 4 Gastroenterology Clinic, Mures County Hospital, Tîrgu Mureș, Romania Background: Fatal outcome caused by laryngeal edema remains the most unexpected and dramatic feature of hereditary angioedema (HAE) attacks. Asphyxiation is reported in 30% of the families affected by HAE. Case report: Our staff was contacted to give assistance to a patient recently diagnosed with C1INH deficiency. From the case history, we have learned that her father died of asphyxiation at the age of 42. He woke up with a sensation of a lump in his throat. Gradually he developed dysphagia and after about 8 hours later or so, he became dysphoniac, but refused to attend the ED, arguing that is better treated at home by his wife, a nurse, with corticosteroids. After another hour, he could not swallow anymore, and suddenly breathlessness became extreme. In desperation, he took a knife, and tried, to make a self-tracheotomy. His wife tried to finish the tracheotomy, but was unsuccessful. An ambulance was called and after two minutes he lost his consciousness. The ambulance didn’t come with a physician, hence, no intubation was done. Cardiac massage was performed, 5 mg of epinephrine was administered until the attended patient arrived at the county hospital. The ECG showed electric activity, but the patient remained in respiratory arrest. This fatal laryngeal attack was the first one in his life. Before, he had repeatedly experienced both peripheral and abdominal attacks, but he wasn’t checked for C1INH deficiency. The HAE diagnosis of this patient was confirmed retrospectively, one month later, when his daughter was found with low C1INH protein for peripheral and abdominal symptoms.

Conclusions: Patients with HAE have a permanent risk to die of asphyxiation. Current evidence shows that the risk is higher in undiagnosed HAE patients and the first laryngeal attack may be lethal, as in our case. Improving the rate of HAE diagnosed patients, followed by providing education to patients and their relatives, and by extending the availability of recently registered drugs are of paramount importance in reducing mortality of HAE patients.

Ibuprofen induced Stevens-Johnson syndrome Sandra Munthiu, Irena Manea, Diana Deleanu ‘’Iuliu Hatieganu’’ University of Medicine and Pharmacy, Cluj-Napoca, Romania Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions, most commonly triggered by medications, characterized by extensive necrosis and detachment of the epidermis. Viral infections can also trigger SJS. We present the case of a 68 years old female patient with a family history of SJS to NSAIDs, known with drug allergy (history of erythema multiforme to Ciprofloxacin, Cotrimoxazole, Penicillin, Streptomycin, and a history of anaphylaxis to Iodipamide), who presented in the Emergency Service, Cluj-Napoca, for malaise, painful mucosal lesions, ulcerative genital and oral manifestations which onset after ingestion of Fluconazole and Ibuprofen. The approach focused on the determination of the etiologic diagnosis.

Patients with Stevens-Johnson are, not infrequently, exposed simultaneously to several drugs, which hampers the identification of the agent issue. History of severe drug side effects contraindicates oral challenge tests, and lymphocytic transformation tests are frequently negative. In this context, identification of the causative drug might prove a difficult task for the clinician.

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The child allergies - recent years challenge Ramona Nedelcuta, Gigi Calin, Ligia Stănescu, Cristian Gheonea University of Medicine and Pharmacy, Craiova, Romania Introduction: Due to the intense pace of industrialization, pollution, use of surfactants, synthetic soaps, perfumes, ultra processed food, allergies have experienced a boom in the last decade. Highlighting the etiologic allergenic agent is a perpetual challenge due to limitations of the applicability of pediatric allergy panel at an early age and the interaction of the genetic inheritance with a cumulation of confounding factors. The allergological “waterfall”, because of the antigenic memory of the body, will take place very rapidly on contact with the allergen trigger.

Methods: We conducted a retrospective study for 1 year, 1 278 cases, of which about 25% had some form of allergic reaction (skin or respiratory). Approximately 30 cases (10% of children with allergic manifestations) completed pediatric allergy panel and have confirmed the existence of multiallergens. 50 cases with atopic inherited genetic asthma experienced recurrent phenomena unnoticed until hospitalization with 6 cases of severe allergic phenomena, Quincke edema, at the moment of hospitalization.

Results: All the cases responded to topical local therapy or systemic corticosteroid inhaler therapy, respectively.

Conclusions: Allergies in children show an incomplete explored territory, growing in recent years, that would require complex protocols and diagnostic screening tests capable of detecting early, complete and correct allergens and interactions with an immature body.

Anaphylaxis to esomeprazole Anamaria Nicoara, Claudia Mihaila, Irena Manea, Diana Deleanu “Iuliu Hatieganu “ University of Medicine and Pharmacy, Cluj-Napoca, Romania Adverse reactions to drugs are defined as the unintended and harmful responses that appear in the context of the administration of an appropriate dose of a drug utilised with prophylactic, diagnostic or therapeutic purposes. Severe immediate hypersensitivity reactions induced by proton pump inhibitors are rare.

We report the case of a 27 years old patient living in an urban area, working as a nurse, with a medical history of atopy and known with Hashimoto thyroiditis, persistent moderate-severe allergic rhinitis, who is brought to ER with 3rd degree anaphylaxis, affirmatively occurring 30 minutes after the administration of a dose of Movalis. Extended anamnesis revealed the concomitant administration of esomeprazole.

The diagnosis protocol identified the etiological factor and confirmed the tolerance for Movalis, with a proven in vitro and in vivo sensitisation to esomeprazole.

Drug hypersensitivity can take severe forms, even fatal, and an incomplete anamnesis can overlook essential details necessary for an accurate diagnosis. Identifying the etiological factor is essential in the case of the patient with drug allergies.

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Controversial diagnoses in atopic patients Olesea Nicu, Ecaterina Stasii, Olga Cirstea, Tatiana Gorelco, Tatiana Culesin “Nicolae Testemitanu” State University of Medicine and Pharmacy, Chisinau, Republic of Moldova Background. The incidence of allergies is increasing worldwide, and one in four school-age children is allergic. Food allergies occur mainly in subjects with atopy. At the same time the number of children with viral infections accompanied by skin manifestations is increased thus, a differentiated approach for atopic patients is essential for a correct diagnosis and therapeutic management of individual development.

Clinical case. 7-year-old patient presents facial erythema, fine maculopapular rash on the upper limb with a duration of two days. It is known that the child is sick for a week with fever, swelling and pain in the knee joints and discrete cataral signs.

Allergological anamnesis is positive: food allergy to fish, which had manifested by Quinqke’s edema (at the age of 5). The father was diagnosed with bronchial asthma and persistent allergic rhinitis. At the time of admission the patient ‘s father also started to manifest similar symptoms, with itching skin, erythematous rash on the lower limbs and myalgia. Both patients consumed the same food including potentially allergic products like fish, chocolate and oranges.

After analyzing the clinical signs and also the anamnesis data, it was considered necessary to differentiate between an allergic eruption and a viral exanthem. The results of the investigations: total IgE and specific IgE resulted within the normal limit values, Parvovirus B19 Ig M positive - 14 (cut off 0.9), Parvovirus B19 Ig G positive- 36 (cut off 0.9). The patient’s father was also investigated and the results were positive for Ig M, Ig G Parvovirus B19.

Clinical diagnosis: Erythema infectiosum (family case). The patient was subject to a symptomatic treatment to reduce itching. Clinical signs regressed within 5-6 days.

Discussion: Parvovirus B19 infections are common in children, and are one of the most common eruptive diseases of childhood. There may be asymptomatic forms, so that 50% of children get this infection until the age of 15 and almost 80% of adults have antibodies to Parvovirus B19. Rash, especially in atopic patients can lead to a false allergic positive diagnosis that requires unnecessary treatment and unjustified hypoallergenic diet.

Exercise-induced anaphylaxis Iuliana Petrea, Irena Manea, Diana Deleanu “Iuliu Hatieganu”, University of Medicine and Pharmacy Cluj-Napoca, Romania Anaphylaxis is a reaction that occurs suddenly and is potentially life threatening, with IgE mediated and non- IgE mediated underlying mechanisms. Exercise-induced anaphylaxis, dependent or non-dependent of food intake is a special category of immediate hypersensitivity reactions clinically presenting as systemic reactions.

We report the case of a female patient, aged 24 years, with no personal or family history of atopy, who is referred to the Ambulatory of Gastroenterology and Hepatology, Cluj- Napoca, for a history of anaphylaxis induced by exercise, which onset when she was a teenager. The frequency was for 4-5 episodes/year. Clinical episodes of exercise-induced escalated in severity over the past year. Subsequent work-up aimed to identify triggers, as well as to rule out other clinical disorders with similar aspect. Sensitization to wheat was documented.

Anaphylaxis which occurs in direct temporal relation with physical exercise and is preceded by food ingestion is a pathological entity with significant impact on patient quality of life. Wheat is reported to be the commonest food allergen involved in exercise induced anaphylaxis. Correct diagnosis, identifying co-factors and patient education are key aspects for an effective approach.

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Causes of persistent hypereosinophilia Carina Petricau, Mihăila Claudia, Irena Manea, Diana Deleanu “Iuliu Hatieganu” University of Medicine and Parmacy, Cluj-Napoca, Romania Introduction: Hypereosinophilia occurs in a wide variety of diseases. An interesting association is that of hypereosinophilia and mast cells disorders, representing a finding in 25% of the cases of systemic mastocytosis. Eosinophils and mast cells often follow the same biological pathways and share a complex network of paracrine interactions. Symptoms are related to mast cell and eosinophil mediator release.

Case report: We report the case of a 58-year-old Caucasian man with a history of partial nephrectomy for clear-cell renal carcinoma who was referred to the allergist for a 1-year generalized severely pruritic erythematous maculopapular rash.

Laboratory work-up revealed persistent peripheral eosinophilia, elevated serum IgE and baseline tryptase, and sensitization to house dust mites. Skin biopsy was compatible with mastocytosis, while the bone marrow biopsy showed hypercellularity in the eosinophil lineage. Testing for c-kit mutation in peripheral blood was negative. However, screening for FIP1L1PDGRFA showed a positive result, which led to a diagnostic dilemma of whether the patient has cutaneous mastocytosis and eosinophilic leukemia, or systemic mastocytosis and co-existing hematologic clonal non-mast cell disease.

Conclusions: Despite advances in the diagnosis of myeloproliferative disorders in patients with overlapping features of myeloproliferative disease and persistent eosinophilia, areas of controversy remain. In such cases, the differential diagnosis might prove a difficult task for the clinician.

Rare cause of angioedema Corina Porr Sibiu County Hospital, Romania We present a patient of 84 years, who came to the emergency room for facial swelling, breathlessness, chest tightness onset three days ago, but accentuated in the last day, after eating mushrooms picked by him in the forest, including the day of admission. On admission, the patient had pale skin with tachycardia, TA = 170 / 90mmHg with painful abdomen on palpation, deep in the upper abdomen. Highlights include an inflammatory syndrome, hypochromic microcytic anemia.

We conducted Rx thoracic, upper gastrointestinal endoscopy and colonoscopy. It described sessile polyps recitals and the transverse colon passage was interrupted by a stenosis. The abdominal computed tomography showed a transverse colon tumor formation without metastases. The patient was referred to surgery where he spoke with favorable evolution.

Heat contact urticaria. Case presentation Delia Rotaru “Sf. Spiridon” Emergency Hospital, Iasi, Romania Introduction: Heat contact urticaria is a rare physical urticaria defined by the appearance of localized wealing responses after contact heating of the skin, manifestations that appear within minutes after exposure. Recent studies have demonstrated histamine and a neutrophil chemotactic factor release on warming of the skin.

Material and methods: A 38-year-old female patient with personal history of moderate/severe persistent allergic rhinitis sensitized to mites in 2009 and chronic hypertrophic rhinitis in 2014, is hospitalized for the appearance of an itchy erithemato- edematous papular eruption on the wrist and foot after contact heating of the skin.

Results: Challenge testing performed by applying a hot glass cylinder filled with hot water to the skin at a temperature of approximate 45ºC for 5 min has been positive, at the test site appearing a weal and flare type skin reaction associated with a burning and itching sensation.

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Conclusions: In patients that show a positive test reaction, stimulation time and temperature thresholds should be determined.

The patient is following antihistaminic treatment with favorable evolution under treatment. Desensitization by repeated daily immersion in hot baths may be tried, but this approach should be used with caution because systemic reactions are possible.

Interrelation pediatrician-allergologist in the management of bronchial asthma in school children Aurica Rugina, Ileana Ioniuc, Monica Alexoae, Alice Azoicai, Evelina Moraru ”Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania Immunoglobulin E is homocytotropic, with strong affinity for the cells of the host species in which it has been produced, the affinity is high for tissular mastocytes and circulants basofils. The attachment on the mastocytes surface is done via high affinity receptors (Fc-RI) responsible for the allergic symptoms (early and late phases) and via low affinity receptors (Fc- RII) which regulates the production of IgE from B lymphocytes. The aim of the study is to analyze the relationship between the aeroallergen sensitivity and the severity asthmatic step in school children. Methods: the study lot included 74 children (6-18 years) diagnosed with asthma, admitted in II Pediatric Clinic, Clinical Emergency Hospital “Sf. Maria” Iasi, between July 1st, 2014 to December 31st, 2014. The criteria for inclusion in the study have been represented by ages over 6, the diagnosis of asthma and the determination of the specific IgE levels- Pediatric Panel. Results: the average age of diagnosis has been 6-9 years in males (21/44 cases) and 12-13 years in girls (9/30 cases). The majority of the patients were in step II in conformity with GINA program (42/74 cases). It has been observed a directly proportional increase of the average value of IgE measurements and specific IgE to dust mites with the step of severity of bronchial asthma. In conclusion, the direct relationship between the severity of the disease and the level of allergic sensitization, recommends the use of specific immunotherapy in pediatric patients by the interrelation pediatrician – allergologist.

Multidisciplinary valences in the assessment of the evolution of the bronchial asthma in infants and small children Aurica Rugina, Monica Alexoae, Ileana Ioniuc, Alice Azoicai, Evelina Moraru ”Grigore T. Popa” University of Medicine and Pharmacy, Iasi, Romania The interaction between atopy and infections is complex by the fact that atopy can influence the response of respiratory tract disease in viral infections, especially with sincitial respiratory virus or rhinovirus. The aim of the study is the clinical and evolutive analysis of bronchial asthma, diagnosed in infants and small children (1-3 years).

Methods: It has been carried out a retro prospective survey on 43 children diagnosed with viral induced bronchial asthma, admitted in II Pediatric Clinic, Children Emergency Hospital „Sf. Maria” Iasi, during January to December 2011, after 3 years from diagnosis. The criteria for study inclusion were the age of the diagnosis under 3 years old, with at least 3 years prior to assessment in the study, by completing the childhood asthma control test. Results: the frequency of the disease has been increased to the 1-2 year group (48,2%). 60,5% was controlled bronchial asthma and 39,5% non controlled bronchial asthma.

In conclusion, the application of the quality of life questionnaires after 3 years from diagnosis has demonstrated the existence of non controlled cases and the need for the resumption of chronic therapy.

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Hyper IgM syndrome. Case report Simona Maria Tirca, Nicolae Viorel Dumitrescu, Adriana Mihaela Tudose Allergology and Clinical Immunology Dpt, “Nicolae Malaxa” Clinical Hospital, Bucharest Primary immunodeficiency disorders are immune system disorders that predispose patients to multiple pathogenesis: infectious, autoimmune diseases and neoplasia. Hyper IgM syndrome belongs to a family of genetic diseases characterized by the elevated immunoglobulin IgM levels.

Objectives. Case report of immunodeficiency disorder diagnosed only at 17 years old in the department of Allergology and Clinical Immunology.

Method. Out of the patients under 18, we selected a case of immunodeficiency disorder and have presented the pacient’s history, clinical changes at admission, diagnosis methods and its evolution since beginning specific treatment.

Results. Although the patient presented with an early onset (at the age of 1) with many respiratory infections resulting with hospitalization, the diagnosis was determined only at 17 years old, after presenting to our clinic.

Prognosis has improved without any infectious episode being present after introducing the immunoglobulin substitutive treatment (in “Alfred Rusescu” IOMC Clinic) Conclusions. However rare, congenital immunodeficiency disorders should be considered in children who present frequent and persistent infections associated with complications that require hospitalization. Unfortunately, in the absence of a molecular diagnosis, a clear differentiation between the subtypes of hyper IgM syndrome cannot be done.

Bibliography:

1. Aloj G, Giardino G, Valentino L, Maio F, Gallo V, Espisito T, Naddei R, Cirillo E, Pignata C. Severe combined immunodeficiencies: new and old scenarios. Int Rev Immunol. 2012;31:43–65.

2. Davies EG, Thrasher AJ. Update on the hyper immunoglobulin M syndromes. Br J Haematol. 2010; 149:167–80 3. Sponzilli I, Notarangelo LD. Severe combined immunodeficiency (SCID): from molecular basis to clinical management. Acta Biomed. 2011;82:5–13.

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