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Vol. XIII - No. 1 / January - March 2016

JOURNAL OF THE ROMANIAN

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

SUMMARY Chronic urticaria mechanisms and treatment: where are we today?

Church D, Church M

New insights into the drug eluting stents with immunopharmacologically active agents used for their antiproliferative properties RSACI Annual Conference

Ghilencea LN, Popescu F

Genetic factors involved in hypersensitivity pneumonitis

Secureanu FA et al May 13-15, 2016 Bucharest

Child with asthma and obesity SRAIC

Societatea Română de

Alergologie și Imunologie Clinică

Goția S

Homo neanderthalensis DNA in modern human genome and immune responses Secureanu FA, Popescu FD

ISSN 1584-7330

JOURNAL OF THE ROMANIAN

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

Vol. XIII, No. 1, January - March 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.

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 1, January - March 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

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. 1, January - March 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.

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

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Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 1, January - March 2016

CONTENTS

Editorial 10

Florin-Dan Popescu

Review Articles Chronic urticaria mechanisms and treatment:

where are we today? Diana S Church, Martin K Church

Original Articles and Brief Communications New insights into the drug eluting stents with

immunopharmacologically active agents used for their antiproliferative properties Liviu Nicolae Ghilencea, Florica Popescu

Awareness, Training and Education Genetic factors involved in hypersensitivity pneumonitis

Florin Adrian Secureanu, Mariana Vieru, Carmen Saviana Ganea

Child with asthma and obesity

Stela GoČ&#x203A;ia

News and Current Perspectives Homo neanderthalensis DNA in modern human genome

and immune responses Florin Adrian Secureanu, Florin-Dan Popescu

Instructions for authors

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 1, January - March 2016

EDITORIAL

elcome to the new format of the Journal of the Romanian Society of Allergology and Clinical Immunology (RSACI), the launch of this modern version, published entirely in English, represents a significant progress after more than a decade of existence. The editorial staff is pleased to serve the members of RSACI, and wants to promote a scientifically rigorous approach. With this new reader-friendly format, we intend to make the contents more accessible to our readers, and with the help of authors, our editorial board and reviewers, the journal of RSACI will continue to be the premier journal for communication of science-based knowledge in our specialty areas of interest, in Romania.

Medicine and Pharmacy of Craiova, present new insights into the coronary drug eluting stents with immunopharmacologically active agents used for their antiproliferative properties, this bringing together immunological agents involved in vascular smooth muscle cell cycle regulation and cardiological perspectives. Under the heading of awareness, training and education, Associate Professor Florin Adrian Secureanu, from the Department of Genetics, ”Titu Maiorescu” University, Bucharest, together with Assistant Professor Mariana Vieru and Carmen Saviana Ganea, present interesting genetic aspects involved in hypersensitivity pneumonitis, an inflammatory syndrome of the lung, caused by repetitive inhalation of antigenic agents in a susceptible host, and bring to our attention a detailed presentation of the genetic studies for the extrinsic allergic alveolitis susceptibility in different ethnic groups, emphasizing their potential to detect genetic biomarkers for this respiratory disease occurrence and outcome. In another article, Professor Stela Goția, from the ”Gr. T. Popa” University of Medicine and Pharmacy, Iași, Romania, approaches the hot topic of the child with asthma and obesity, from the point of view of genetic’s point of view, environmental factors, pathogenesis mechanisms, roles of leptin, adipokines, adiponectin, mast cells, vitamin D, chronic inflammation, pulmonary dysfunction, clinical manifestations and multidimensional therapeutic approach. Under the news and current perspectives heading, Associate Professor Florin Adrian Secureanu and his coworker from the ”Nicolae Malaxa” Clinical Hospital, Bucharest, present recent genetic studies revealing that Neandertal DNA is present in the genome of modern humans, being involved also in innate immune re-

In the first article under the heading of review articles, Diana Church from Southampton, UK, and Professor Martin Church, from the Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Germany, suggested that chronic urticaria has an IgE-dependent, possibly autoallergic, mechanism, that results in the stimulation of histamine release from dermal mast cells, with subsequent wheal and itch symptoms. On this basis, the authors present the most effective drugs for its symptomatic treatment, which are the new generation H1 antihistamines, to reduce the stimulatory effects of histamine, and omalizumab, a recombinant humanized monoclonal antibody that selectively binds to human immunoglobulin E and interrupts the IgE-dependent components of the disease. In the section of original articles and brief communications, Liviu Nicolae Ghilencea from the ”Carol Davila” University of Medicine and Pharmacy, Bucharest, and Professor Florica Popescu from the University of

EDITORIAL

sponses. Neandertals were hominins adapted to pathogens, diets and local climate in Europe, and some of their archaic genes controlling immune responses persisted in modern human DNA. Interestingly, archaic-like alleles are recently suggested to be associated with increased susceptibility to allergic diseases.

diagnosis, management, and prevention of these diseases, which are rising in prevalence around the world. This year’s theme is Pollen Allergies - Adapting to a Changing Climate, because climate change worsens allergies globally. I strongly recommend all of our society members and our journal readers to explore the website: www.worldallergyweek.org

As always, on behalf of the editorial board, I invite all RSACI members to contribute with original articles and brief communications of their clinical or basic research activity, awareness, training and education materials, news and current perspectives, and, not least, opinions and comments for the reader services, as we try to further enhance the value of our society journal. I would like to take this opportunity to reinforce my invitation to the Annual Conference of the Romanian Society of Allergology and Clinical Immunology (RSACI), which will be held in Bucharest, May 13-15, 2016, and it is a great pleasure for me to inform you that our event will be attended by prestigious professional personalities, internationally recognized in their medical fields. Moreover, it is an honour to announce you that the EAACI Executive Committee has decided to accept my request for EAACI speakers support for this RSACI Annual International Conference 2016, and has agreed to support with two speakers to participate in our meeting, Associate Professor Ioana Agache, EAACI Vice-President Communications & Membership, and Professor Ömer Kalayci, EAACI Asthma Section Chairperson.

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

I want to announce all the members of the Romanian Society of Allergology and Clinical Immunology in this new format of our society journal about the World Allergy Week 2016, scheduled for 4-10 April 2016. This annual initiative of the World Allergy Organization (WAO), together with its Member Societies, which also include our national society, is intended to raise awareness of allergic disease and related disorders, and advocate for the provision of training and resources in the

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 1, January - March 2016

Review Articles

Chronic urticaria mechanisms and treatment: where are we today? Diana S Church1, Martin K Church2

Chessel Practice, Sholing, Southampton, UK. 2 Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité - Universitätsmedizin Berlin, Berlin, Germany. 1

ABSTRACT Urticaria is one of the most frequent skin diseases. It is characterized by pruritic wheal and flare-type skin reactions with or without angioedema that usually persist for <24 h. In some patients, only angioedema is present. According to the current EAACI/GA2LEN/EDF/WAO urticaria guideline(1), urticaria can be classified into spontaneous urticaria, physical urticaria and other urticaria types. KEYWORDS: chronic urticaria; H1-antihistamines; anti-IgE (omalizumab)

pontaneous urticaria is further divided into acute and chronic spontaneous urticaria (disease duration for less and more than 6 weeks, respectively). The chronic physical and other urticaria types, which may be grouped under the heading of chronic inducible urticaria (CIndU) share the attribute that symptoms are induced by different triggers, e.g. low temperatures, heat, pressure or exercise. In contrast, in chronic spontaneous urticaria the lesions usually occur without an obvious stimulus. It should be pointed out here for clarity that the term ‘chronic idiopathic urticaria’ (CIU) has been replaced by the term ‘chronic spontaneous urticaria” (CSU) (2), to emphasize that wheals develop spontaneously, i.e. independent of external stimuli.

ported by the findings of increased concentrations of histamine in skin tissue fluid(3) and the clinical responsiveness of urticaria to H 1 -antihistamines. But what stimulates mast cells to degranulate, and why does this happen only in the skin? Classically it was thought that, with rare exceptions, mast cell degranulation in chronic urticaria occurs through IgE independent mechanisms (such as activation by the complement components, neuropeptides etc.). However, recent evidence is changing this paradigm, with current thinking suggesting that chronic urticaria, including CSU, has several mechanisms which seem to be IgE-dependent, possibly with autoimmune and/or autoallergic components (Figure 1). The involvement of IgE is supported by the recent findings that omalizumab is highly effective in treating all forms of urticaria (4-7). Omalizumab, which was originally introduced for the treatment of allergic asthma (8,9),

The activation of dermal mast cells and their release of inflammatory mediators are regarded as the final common pathway all forms of urticaria. This is sup-

Corresponding Author: Professor Martin Church Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany; Phone: +49-30-450-518042; Fax: +49-30-450-518972; E-mail: mkc@soton.ac.uk Submission date: 10/01/2016; Acceptance date: 11/01/2016; Publication date: 31/03/2016

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Figure 1. The possible IgE-dependent mechanisms for urticaria. A. IgG-autoantibodies (yellow) are raised against IgE (red) and/or its receptor, FcεRI. Cross-linking by IgG leads to mast cell degranulation. B. IgG-IgE complexes stimulate the formation of complement C5a which induces mast cell degranulation. C. Binding of IgE, especially high-cytokinergic-IgE (HC-IgE, blue) leads to mast cell priming. D. The generation of allergens in the skin induces a local autoallergic response.

is a humanized, monoclonal, anti-IgE antibody that binds to free IgE in the blood and interstitial space, forming biologically inactive IgE complexes that are unable to bind to FcεRI on the surface of mast cells and basophils(10). In the short term, omalizumab will reduce the levels of soluble IgE in the blood and intravascular spaces. This results, in the longer term, to the loss of mast cell and basophil bound IgE and the subsequent loss of the surface expression of its high affinity receptor, FcεRI .

duce IgG autoantibodies against their own IgE (5–10%) or FcεRI, the high affinity for IgE on mast cells (35– 40%). Binding of these IgG autoantibodies to mast cell bound IgE or unoccupied FcεRI on mast cells and basophils causes their degranulation(13,14). Interestingly, the IgG subclasses that appear to be pathogenic in CSU are IgG1 and IgG3(15) both of which are capable of activating complement C5a, an established stimulator of skin mast cells, but not other mast cells, in human subjects (16). Consequently, there is the possibility that IgG-IgE complexes activate the complement system to generate C5a which in turn activates the skin mast cell to degranulate via its C5a receptor(16) (Figure 1B). These two IgG-dependent mechanisms are not mutually exclusive and could coexist, with a different preponderance between different patients or even in the same patient in different conditions. For example, in the case of an infection complement-dependent mast cell activation might be enhanced, explaining why

The suggestion of the involvement of autoantibodies in chronic urticaria stems from the observation by Clive Grattan in 1986(12) that serum from a patient with CSU when re-injected into the dermis produced a wheal response (Figure 1A). This is the so-called autologous serum skin test (ASST), which is positive in up to 45% of patients with CSU. Subsequent analysis of serum revealed that this is essentially a Coombs and Gell type II hypersensitivity reaction, in which affected patients pro-

Chronic urticaria mechanisms and treatment: where are we today?

Patient name: Date (dd mmm yyyy):

Date of birth (dd mmm yyyy):

Instructions: You have urticaria. The following questions should help us understand your current health situation. Please read through each question carefully and choose an answer from the five options that best fits your situation. Please limit yourself to the last four weeks. Please don’t think about the questions for a long time, and do remember to answer all questions and to provide only one answer to each question. 1. How much have you suffered from the physical symptoms of the urticaria (itch, hives (welts) and/or swelling) in the last four weeks?

❐ very much

❐ much

❐ somewhat

❐ a little

❐ not at all

2. How much was your quality of life affected by the urticaria in the last 4 weeks?

❐ very much

❐ much

❐ somewhat

❐ a little

❐ not at all

3. How often was the treatment for your urticaria in the last 4 weeks not enough to control your urticaria symptoms?

❐ very often

❐ often

❐ sometimes

❐ seldom

❐ not at all

4. Overall, how well have you had your urticaria under control in the last 4 weeks?

❐ not at all

❐ a little

❐ somewhat

❐ well

❐ very well

The response options for the UCT going left to right are 1 – 5, giving a score of 4 for very poorly controlled disease and 20 for free of symptoms Figure 2. Urticaria Control Test (UCT)

many people with chronic urticaria experience disease flares during infection. A further mechanism stems from the observation that patients with CSU frequently exhibit increased total IgE levels (17). The binding of monomeric IgE to mast cells in the absence of cross-linking, although not causing direct degranulation, can have a priming effect thereby augmenting mast cell survival and activity(18) (Figure 1C). Furthermore, it has been suggested that IgE-autoantibodies to thyroperoxidase (TPO) and double-stranded and single-stranded DNA and b-galactosidase, which have been shown in significant amounts CSU, may be different from normal IgE. These antibodies have been described as high-cytokinergic IgE (HCIgE) because they are especially effective at enhancing mast cell survival, degranulation, adhesion, migration and expression of mast cell cytokines (13,19). The consequence of raised IgE levels, and in particular HC-IgE, is that mast cells are likely to live longer and be more ‘twitchy’, with a lower threshold for responding to nonspecific mast cell activators in patients with CSU than in healthy individuals.

CSU patients have IgE against allergens generated locally in the skin (Figure 1D). While this is an attractive proposition there is, as yet, negligible evidence to support it. The mechanisms underlying the different types chronic inducible urticaria have usually been suggested to be non-immunological mast cell activation induced in response to external physical stimuli. However the recent observation that all forms of chronic inducible urticaria are also inhibited by omalizumab (20) in the majority of patients suggests that they also may have an IgE-dependent autoallergic mechanism, possibly stimulated by local dermal allergens.

Assessment of disease activity and impact Disease activity in CSU assessed with the UAS7(1) (Table 1) is a useful clinical marker both in day-to-day practice and in clinical trials. As an objective measure of the severity of disease, it can guide the level of management interventions and also assess objectively the level of response at follow up. To obtain a UAS7, the signs and

The final possible ‘autoallergic’ mechanism is that

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sedation, drowsiness, fatigue and impaired concentration and memory, causing detrimental effects on learning and examination performance in children and on impairment of the ability of adults to work and drive (23,24). Also, the cumulative use of first generation antihistamines with anticholinergic activity in the elderly is associated with an increased risk for dementia (25). Consequently, the use of first generation H 1-antihistamines should be discouraged. Furthermore, physicians should advise their patients not to purchase these drugs from the pharmacy for self-medication.

symptoms are evaluated daily by the patient. Because CSU is inherently variable, daily UAS are summed to give a 7day score, UAS7. A more recent assessment method is the urticaria control test (UCT)(21) (Figure 2). This simple four-question form, which is also completed by the patient, takes into account both quality of life and control of symptoms by therapy.

Management of chronic urticaria The principles of the management of chronic urticaria are eliminating or avoiding the causative trigger or stimulus, inducing tolerance, or providing symptomatic relief with pharmacological treatment. Clearly, the first of these relates almost exclusively to chronic inducible urticaria where the physician and patient should work together to identify the trigger and develop a plan for avoidance or reduction of exposure; it is also relevant for situations where a drug (e.g. ACEI, NSAIDs, OTC, herbal products, etc.) or an infection has been shown to be the triggering factor of symptoms. Inducing tolerance can be useful in some subtypes of urticaria, for example, in cold urticaria, cholinergic urticaria, and solar urticaria. However, tolerance is short lasting and exposure to the stimulus has to be repeated regularly, often daily(1).

The newer second‑generation H1‑antihistamines are safer, cause less sedation and are more efficacious. Of these, azelastine, olopatadine, cetirizine, loratadine, may cause drowsiness in some individuals(26), but this is generally mild. Recent publications have suggested that, at manufacturer’s recommended doses, levocetirizine is less sedating than cetirizine and desloratadine causes negligible somnolence(23). However, it should be pointed out that “mean results” do not reveal everything as some patients may show considerable somnolence whereas others are unaffected. While discussing somnolence, special mention should be made of fexofenadine and bilastine. Positron emission tomography (PET) scanning has shown that the occupancy of histamine H1-receptors in the brain of these two drugs is negligible(26,27) and in psychomotor tests, they are not significantly different from placebo(28,29). This because both drugs are substrates for P-glycoprotein, a membrane pump that limits their passage across the blood--brain barrier.

The main option for the management of chronic urticaria of all types is pharmacological therapy aimed at symptomatic relief. The EAACI/GA2LEN/EDF/WAO urticaria guideline(1) recommendations for drug treatment are as follows. Modern second generation H1-antihistamines are the first line of treatment. If symptoms persist after 2 weeks, then the second line is to increase the dosage of second generation H1-antihistamines up to fourfold. If symptoms persist after 1–4 further weeks, the third line treatment is to add omalizumab, cyclosporine or montelukast on to second line.

What patients require from an H1-antihistamine is a rapid onset of action, good efficacy and a long duration of action. In general all second generation H1-antihistamines have an onset of action of about 1 to 4 hours. Also, they are clinically effective for at least 24 hours making once daily dosing a practicality. With regard to efficacy, very few back-to-back studies have been performed with H1-antihistamines in CSU so comparisons are largely anecdotal. However, studies have compared levocetirizine and desloratadine and have shown levocetirizine to be the more effective in both mild and moderate severe chronic urticaria(30,31).

H1-antihistamines H1-antihistamines were developed originally from anticholinergic drugs more than 70 years ago. They act as inverse agonists rather than antagonists of histamine H 1receptors(22), i.e. histamine binds to the H1-receptor and activates it, while an H1-antihistamine binds to a different part of the receptor to stabilize it in the inactive form and so prevent histamine activating it. The older first generation H1-antihistamines, including chlorpheniramine, diphenhydramine, hydroxyzine and ketotifen, penetrate readily into the brain to cause

Histamine released from mast cells reaches high local concentrations in the skin because of poor diffusion from the site of degranulation. This is different from histamine release at mucosal sites (for example in the nose)

Chronic urticaria mechanisms and treatment: where are we today?

Score

Wheals

Pruritus

None

Mild (< 20 wheals/24h)

Mild (present but not annoying or troublesome)

Moderate (20-50 wheals/24h)

Moderate (troublesome but does not interfere with normal daily activity or sleep)

Intense (> 50 wheals/24h or large confluent areas of wheals)

Intense (severe pruritus which is sufficiently troublesome to interfere with normal daily activity or sleep)

Sum of score: 0â&#x20AC;&#x201C;6 for each day is summarized over one week (maximum 42). Table 1. The UAS7 for assessing disease activity in CSU

where the looser structure of the nasal lining facilitates histamine diffusion and consequently histamine does not build up to similarly high levels. Because of the high local levels of histamine in the skin, standard doses of H 1-antihistamines are often not able to control the symptoms. In this case the EAACI/GA2LEN/EDF/WAO urticaria guideline(1) recommends if symptoms persist after 2 weeks, then the second line is to increase the dosage of second generation H1-antihistamines up to fourfold. This is usually done in two steps. First is to increase the dose to two tablets given approximately 12 hours apart and then, if the symptom control is still not achieved, increase to four tablets, again given in two divided administrations. A further point that should be made here is that all H1-antihistamines act in the same way with no other additional mechanisms of action demonstrated clinically. Therefore, mixing different antihistamines will not have additional benefits in term of adding other potential actions. Also, choosing a single antihistamine for updosing will reduce patient confusion regarding the treatment administration and help patient compliance, and, consequently, increase effectiveness(32). It is also important to advise your patients to take their medicines regularly rather than just when their symptoms are getting worse (on demand)(33).

bances. However, daytime somnolence was significantly higher in patients taking an evening dose of hydroxyzine. It is clear, therefore, that it is better to aim at the effective control of urticaria symptoms with a non-sedating antihistamine than to offer a sedating antihistamine at night. In conclusion, the current standard therapy with regularly dosed H 1-antihistamines leads to an absence of symptoms in <50% of patients with chronic spontaneous urticaria. Increasing the dose up to fourfold improves treatment responses but still every third to fourth patient will remain symptomatic(35). In these patients a trial of montelukast is a possible option, especially in non-specialist settings. However, if no benefit is noticed in 4-6 weeks this treatment is unlikely to show further benefits. In this situation or if patients experience severe symptoms despite stepping up the H1-antihistamine dose, it is recommended to refer the patient to an allergy specialist centre where one of the other 3rd line therapies can be offered, i.e. omalizumab or cyclosporine. Omalizumab Omalizumab (Anti-IgE) is recommended by the EAACI/GA2LEN/EDF/WAO urticaria guideline(1) as a third line treatment for the treatment of H1-antihistamine resistant chronic urticaria. Following many successful clinical trials(4-7) omalizumab, was approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) as add-on therapy for CSU.

Finally, many clinicians believe that to treat urticaria effectively, a non-sedating H 1-antihistamine should be given in the morning and a sedating drug, such as hydroxyzine, should be given at night to aid sleep. However, a recent study has compared treatment with levocetirizine alone with treatment where the evening dose of levocetirizine was replaced with hydroxyzine(34). The results showed that the regimens were similarly effective in reducing symptoms night-time sleep distur-

Clinical experience from more than 1250 injections of omalizumab in 51 patients over four years indicates that omalizumab is a rapidly acting, highly effective and safe

Journal of the Romanian Society of Allergology and Clinical Immunology

drug in not only CSU but also in all forms of chronic inducible urticaria(20). As with its effect in other allergic conditions, for example asthma, omalizumab does not ‘cure’ chronic urticaria but only suppresses symptoms for around four weeks after which a further dose is required(36). Interestingly, there appears to be two speeds of response to omalizumab. In around 60% of patients there is a rapid response, omalizumab completely suppressing symptoms within one week, and sometimes within one day of the first injection. In the remainder of patients there is a slower response, taking up to two to three months in some patients(20). Therefore, in practice, initial injections of 300 mg are usually given monthly for three months to establish whether a patient is likely to respond or not. There is no need to adjust the dose for body weight or serum IgE levels, as is the case in asthma. Following that, omalizumab doses and the time interval between doses may be increased or decreased to suit the patients’ needs(20).

The results with omalizumab have shown that it induces complete remission of urticaria symptoms in around 80% of the patients. If it is not effective then cyclosporine may be a therapeutic alternative(1). However in the first instance in these patients is important to reevaluate the diagnosis and consider other potential causes or co-morbidities that could explain the poor response to treatment.

10.

11.

Conclusions In this short review we have suggested that chronic urticaria has an IgE-dependent, possibly autoallergic, mechanism that results in the stimulation of histamine release from dermal mast cells and subsequent wheal and itch symptoms. Based on this, the most effective drugs for symptomatic relief are H 1-antihistamines, to reduce the stimulatory effects of histamine, and omalizumab, which will interrupt the IgE-dependent components of the disease.

12.

13.

14. 15.

References

16.

1. Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW, et al. The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014;69(7):868-887. 2. Maurer M, Bindslev-Jensen C, Gimenez-Arnau A, Godse K, Grattan

17.

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CE, Hide M, et al. Chronic idiopathic urticaria (CIU) is no longer idiopathic: time for an update. Br J Dermatol 2013;168(2):455-456. Kaplan AP, Horakova Z, Katz SI. Assessment of tissue fluid histamine levels in patients with urticaria. J Allergy Clin Immunol 1978;61(6):350-354. Saini S, Rosen KE, Hsieh HJ, Wong DA, Conner E, Kaplan A, et al. A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol 2011;128(3):567-573 e561. Maurer M, Altrichter S, Bieber T, Biedermann T, Brautigam M, Seyfried S, et al. Efficacy and safety of omalizumab in patients with chronic urticaria who exhibit IgE against thyroperoxidase. J Allergy Clin Immunol 2011;128(1):202-209 e205. Maurer M, Rosen K, Hsieh HJ, Saini S, Grattan C, Gimenez-Arnau A, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med 2013;368(10):924-935. Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, et al. Omalizumab in chronic idiopathic/spontaneous urticaria patients symptomatic despite standard combination therapy. J Allergy Clin Immunol 2013;In Press. Holgate S, Buhl R, Bousquet J, Smith N, Panahloo Z, Jimenez P. The use of omalizumab in the treatment of severe allergic asthma: A clinical experience update. Respir Med 2009;103(8):1098-1113. Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract 2014;2(5):525-536 e521. Hochhaus G, Brookman L, Fox H, Johnson C, Matthews J, Ren S, et al. Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma. Curr Med Res Opin 2003;19(6):491-498. Metz M, Staubach P, Bauer A, Brehler R, Gericke J, Kangas M, et al. Omalizumab normalises levels of high affinity IgE receptor-positive skin cells in patients with chronic spontaneous urticaria: a randomized, double-blind, placebo-controlled study. Allergy 2014;69:8788. Grattan CE, Wallington TB, Warin RP, Kennedy CT, Bradfield JW. A serological mediator in chronic idiopathic urticaria--a clinical, immunological and histological evaluation. Br J Dermatol 1986;114(5):583-590. Chang TW, Chen C, Lin CJ, Metz M, Church MK, Maurer M. The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria. J Allergy Clin Immunol 2015;135(2):337-342. Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy 2009;39(6):777-787. Fiebiger E, Hammerschmid F, Stingl G, Maurer D. AntiFcepsilonRIalpha autoantibodies in autoimmune-mediated disorders. Identification of a structure-function relationship. J Clin Invest 1998;101(1):243-251. Benyon RC. The human skin mast cell. Clin Exp Allergy 1989;19(4):375-387. Staubach P, Vonend A, Burow G, Metz M, Magerl M, Maurer M. Patients with chronic urticaria exhibit increased rates of sensitisation to Candida albicans, but not to common moulds. Mycoses 2009;52(4):334-338.

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18. Asai K, Kitaura J, Kawakami Y, Yamagata N, Tsai M, Carbone DP, et al. Regulation of mast cell survival by IgE. Immunity 2001;14(6):791-800. 19. Kawakami T, Kitaura J. Mast cell survival and activation by IgE in the absence of antigen: a consideration of the biologic mechanisms and relevance. J Immunol 2005;175(7):4167-4173. 20. Metz M, Ohanyan T, Church MK, Maurer M. Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: a retrospective clinical analysis. J Dermatol Sci 2014;73(1):57-62. 21. Weller K, Groffik A, Church MK, Hawro T, Krause K, Metz M, et al. Development and validation of the Urticaria Control Test: a patientreported outcome instrument for assessing urticaria control. J Allergy Clin Immunol 2014;133(5):1365-1372, 1372 e1361-1366. 22. Leurs R, Church MK, Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 2002;32(4):489-498. 23. Church DS, Church MK. Pharmacology of antihistamines. World Allergy Organ J 2011;4(3 Suppl):S22-27. 24. Church MK, Maurer M, Simons FE, Bindslev-Jensen C, van Cauwenberge P, Bousquet J, et al. Risk of first-generation H(1)antihistamines: a GA(2)LEN position paper. Allergy 2010;65(4):459-466. 25. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med 2015;175(3):401-407. 26. Yanai K, Zhang D, Tashiro M, Yoshikawa T, Naganuma F, Harada R, et al. Positron emission tomography evaluation of sedative properties of antihistamines. Expert Opin Drug Saf 2011;10(4):613-622. 27. Farre M, Perez-Mana C, Papaseit E, Menoyo E, Perez M, Martin S, et al. Bilastine vs. hydroxyzine: occupation of brain histamine H1 -receptors evaluated by positron emission tomography in healthy volunteers. Br J Clin Pharmacol 2014;78(5):970-980.

28. Hindmarch I, Shamsi Z, Kimber S. An evaluation of the effects of high-dose fexofenadine on the central nervous system: a doubleblind, placebo-controlled study in healthy volunteers. Clin Exp Allergy 2002;32(1):133-139. 29. Church MK. Safety and efficacy of bilastine: a new H(1)-antihistamine for the treatment of allergic rhinoconjunctivitis and urticaria. Expert Opin Drug Saf 2011;10(5):779-793. 30. Staevska M, Popov TA, Kralimarkova T, Lazarova C, Kraeva S, Popova D, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol 2010;125(3):676-682. 31. Church MK, Maurer M. H(1)-antihistamines and urticaria: how can we predict the best drug for our patient? Clin Exp Allergy 2012;42(10):1423-1429. 32. Schulz S, Metz M, Siepmann D, Luger TA, Maurer M, Stander S. [Antipruritic efficacy of a high-dosage antihistamine therapy. Results of a retrospectively analysed case series]. Hautarzt 2009;60(7):564-568. 33. Weller K, Ardelean E, Scholz E, Martus P, Zuberbier T, Maurer M. Can on-demand non-sedating antihistamines improve urticaria symptoms? A double-blind, randomized, single-dose study. Acta Derm Venereol 2013;93(2):168-174. 34. Staevska M, Gugutkova M, Lazarova C, Kralimarkova T, Dimitrov V, Zuberbier T, et al. Night-time sedating H1 -antihistamine increases daytime somnolence but not treatment efficacy in chronic spontaneous urticaria: a randomized controlled trial. Br J Dermatol 2014;171(1):148-154. 35. Maurer M, Weller K, Bindslev-Jensen C, Gimenez-Arnau A, Bousquet PJ, Bousquet J, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA(2)LEN task force report. Allergy 2011;66(3):317-330. 36. Metz M, Ohanyan T, Church MK, Maurer M. Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. JAMA Dermatol 2014;150(3):288-290.

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 1, January - March 2016

Original Articles and Brief Communications

New insights into the drug eluting stents with immunopharmacologically active agents used for their antiproliferative properties Liviu Nicolae Ghilencea1, Florica Popescu2

Elias Emergency University Hospital, „Carol Davila” University of Medicine and Pharmacy, Bucharest 2 Department of Pharmacology, University of Medicine and Pharmacy of Craiova, Romania

ABSTRACT The development of stent thrombosis after placement of bare-metal stent or drug-eluting stents and the residual rate of restenosis are two reasons for the development of newer coronary artery stents. Nonantibiotic macrolide rapamycin or sirolimus and rapamycin derivatives, such as everolimus and zotarolimus, are immunopharmacologically active agents used to lower the risk of in stent restenosis, due to their antiproliferative properties. Complex molecular mechanisms of actions of these agents involve the inhibition of the mTOR pivotal protein kinase that mediates mitogen-induced cell proliferation, and also several cyclins and cyclindependent kinase inhibitors which play important roles in vascular smooth muscle cell cycle regulation. Optical coherence tomography is able to provide information to enhance the understanding of the mechanism and patterns of in-stent restenosis. KEYWORDS: drug eluting stents, sirolimus, zotarolimus, everolimus

rug-eluting stents (DES) were developed as a natural evolution of the bare-metal stent (BMS) to overcome the restenosis due to the inflammation produced by the stent during angioplasty. Most of the DES are based on the platform of the BMS, coated typically by a polymer, which is absorbing a drug designed to prevent restenosis, by inhibiting the neointimal growth. These immunopharmacologically active agents have antiproliferative properties,

and also decrease the local inflammatory process. The polymer is forming a mixture with the drug which is eluting slowly into the arterial wall at the implanted place by contact transfer, and into the surrounding tissues of the atheroma of the coronary artery. The polymer coating consists in one to three layers, sometimes even more. The first layer of polymer is for adhesion to the scaffold, while the main layer is due to hold and release the drug into the arterial wall by con-

Corresponding Author: Liviu Nicolae Ghilencea Elias Emergency University Hospital, 17 Mărăşti Blvd., Bucharest, postal code 011 461 E-mail: ghilencea@yahoo.com Submission date: 20/03/2016; Acceptance date: 22/03/2016; Publication date: 31/03/2016

New insights into the drug eluting stents with immunopharmacologically active agents used for their ...

Figure 1. Schematic representation for the actionâ&#x20AC;&#x2122;s mechanism of immunopharmacologically active agents used for their antiproliferative properties in drug-eluting stents.

(the so called III-rd generation of DES), provide a promise for reduction in rates of these adverse outcomes. New biopolymers are discovered and new antifibrotic substances have been tested (Cutlip and Abbott, 2016). Immunopharmacologically active drugs used for their antiproliferative actions are nonantibiotic macrolide sirolimus (rapamycin), and rapamycin derivatives, such as everolimus and zotarolimus (Yates et al, 2016). The schematic mechanism of action of immunopharmacologically active agents used for their antiproliferative properties in DES is presented in Figure 1. Sirolimus binds to its major intracellular receptor FKBP12 (FK506 binding protein) and inhibits the mammalian target of rapamycin (mTOR). mTOR is a pivotal protein kinase that mediates mitogen-induced cell proliferation. mTOR (mechanistic target of rapamycin / mammalian target of rapamycin) is also known as FK506-binding protein 12-rapamycin-associated protein 1. The inhibition of mTOR by sirolimus attenuates the degradation of p27Kip1, a cyclin-dependent kinase inhibitor (CKI) which plays a crucial role for vascular smooth muscle cell cycle regulation. Mitogen-mediated proliferation of vascular smooth muscle cells represents a critical event for the formation of neointimal hyperpla-

tact transfer. Sometimes a third top coat is covering the first two layers with the aim to slow down the release of the drug and extend its effect. The first few drug-eluting stents to be licensed used durable coatings. Studies have shown that first generation coating polymers have caused immunological reactions, and some possibly led to late stent thrombosis, neointimal hyperplasia, hypersensitivity, and restenosis (Nikam et al, 2014). In the past, synthetic polymers, such as poly(ethylene) (PE), polyurethanes (PUR), poly(glycolide) (PGA), and poly-L-lactic-acid (PLA), as well as naturally occurring substances like phosphorylcholine, have been the material of choice for implants and other medical devices. As the first generation of DES used durable coatings, this has driven experimentation and development of new coating approaches, including bioresorbable polymers, after or as the drug is eluted. Typical representatives of biodegradable polymers are polyhydroxycarboxylic acids, such as PGA, PLA, poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)), and PCL (Strohbach and Busch, 2015). The new types of stents, including DES with bioresorbable polymers (the so called II-nd generation of DES) and completely bioresorbable vascular scaffolds

Journal of the Romanian Society of Allergology and Clinical Immunology

muscle cells (König et al, 2013). Everolimus is a hydroxyethyl derivative of sirolimus and acts similarly as an inhibitor of mTOR. It is a proliferation signal inhibitor that acts on several cell types including vascular smooth muscle cells. It inhibits the proliferation of these cells by inhibiting the activation of ribosomal protein S6 kinase and phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, and downregulating proliferating cellular nuclear antigen. Everolimus induces cell cycle arrest at the G1 phase, by downregulating cyclin D1 and upregulating p27, and increased apoptosis by downregulating Bcl-2, upregulating Bad and activating capsase-3 and polyADP ribose polymerase. Moreover, everolimus enhances autophagy by increasing the conversion of microtubuleassociated protein 1 light chain 3 (LC3)-I to LC3-II, and upregulating Beclin 1 (Tang et al, 2014). In addition, everolimus eluted from the stents can decrease the percutaneous coronary intervention-induced increase of the Toll-like receptor 4 (TLR4) expression on the surface of monocytes (Shokri et al, 2015). TLR3 and TLR4 are potential clinical biomarkers for in-stent restenosis in drug-eluting stents patients (Liang et al, 2016). Zotarolimus is a potent mTOR inhibitor, with antiproliferative and anti-inflammatory properties. It is an antiproliferative agent used exclusively in the design of

sia. Moreover, sirolimus inhibits migration of vascular smooth muscle cells, this effect being predominantly mediated by p27Kip1, because this CKI inhibits migratory cell capacity. Umirolimus/biolimus, a macrocyclic lactone, is a highly lipophilic derivative of sirolimus, also used in DES. Other different antiproliferative agent used in DES is paclitaxel. It is a microtubule-stabilizing taxane compound with potent antiproliferative properties and antimigration effects. It impacts predominantly during the mitosis phase of the cell cycle through centrosomal impairment, induction of abnormal spindles, and suppression of spindle microtubule dynamics, and as a downstream event, consecutive up-regulation of p53 may occur that may lead to further cell cycle arrest in G1, possibly through the induction of p21Cip1. Because paclitaxel arrests cells at a stage at which they are supposed to divide, pro-apoptotic mechanisms, in part mediated by p53, are likely to occur, thus eventually leading to apoptotic cell death. Paclitaxel may inhibit vascular smooth muscle cell migration, most likely triggered by interactions with the cytoskeleton (Wessely et al, 2006; Steinfeld et al, 2012; Hiltrop et al, 2016). Moreover, inhibition of store-operated Ca2+ entry based on Orai channels and the resulting suppression of Ca2+ transcription coupling is a key mechanism of the antiproliferative activity of sirolimus in human coronary artery smooth

DES

Vol. XIII, No. 1, January - March 2016

Eluted drug

Trials and references

Clinical primary endpoint reached BioMatrix Flex

Biolimus A9

LEADERS

Cypher

Sirolimus

SIRIUS

Endeavor

Zotarolimus

ENDEAVOR-II, -III and -IV

Resolute

Zotarolimus

RESOLUTE-AC

Taxus Liberté/ Element

Paclitaxel

TAXUS-IV and -V (221, 222) / PERSEUS-WH

Xience V

Everolimus

SPIRIT-III and –IV

Angiographic primary endpoint reached Nevo

Sirolimus

NEVO RES I

Nobori

Biolimus A9

NOBORI-I Phase-1 and -2

Yukon

Sirolimus

ISAR-Test

Selection is based on adequately powered RCT with a primary clinical or angiographic endpoint. With the exception of LEADERS and RESOLUTE (all-comers trials), efficacy was investigated in selected de novo lesions of native coronary arteries. a Promus Element device elutes everolimus from a different stent platform. DES ¼ drug-eluting stent. Table 1. Recommended drug-eluting stents (in alphabetical order) that have achieved a primary clinical or surrogate angiographic endpoint. From eurheartj.oxfordjournals.org

New insights into the drug eluting stents with immunopharmacologically active agents used for their ...

coronary drug eluting stents. Its potent antiproliferative activity on coronary smooth muscle cells is associated with a reduced potential for systemic immunosuppression. Zotarolimus, like everolimus, is a semisynthetic analogue of sirolimus, designed with increased lipophilicity, but preserving its specificity for mTOR inhibition. mTOR, a phosphatidylinositol kinase-related family of serine/threonine kinase, exists in two distinct protein complexes with specific binding partners, including raptor in mTOR complex 1 (mTORC1) and rictor in mTOR complex 2. The best known mTORC1 substrates are S6 kinase (S6K) and eIF4E-binding proteins (4E-BP), whereas mTOR complex 2 phosphorylates the hydrophobic motif of Akt. There is a key role for mTOR and its downstream effectors in processes critical for endothelial recovery after arterial injury, and of these pro-

cesses, cell proliferation may be the most essential and likely the exclusive domain of S6K (Chen et al, 2007; Steinfeld et al, 2012; Habib et al, 2013). The first two major DES, Taxus and Cypher have used different durable polymers. The Cypher DES (trade mark of J&J, Cordis) based on a 316L stainless steel BxVelocity stent (140 µm struts) contains sirolimus, which elutes from a 3 coating layers of 12.6 µm polymer (polyethylene-co-vinyl acetate/poly Nbutyl methacrylate polymer), over a period of about 30 days. The Taxus DES (Boston Scientific) uses a 316L stainless steel Express2 stent (132 µm struts) and adds a 16 µm single layer styrene-isobutylene-styrene (SIBS) polymer coating containing paclitaxel. Paclitaxel elutes over a period of about 90 days (Shand and Menown, 2010). There have been proposed and tested many drugs to

Figure 2. Angiography and Optical Coherence Tomography (OCT) of the left anterior descending artery (LAD) of a 74 years old man, known with multi-vessel coronary artery disease, with history of Class 3 CCS angina-pain, and with risk factors: hypertension, hypercholesterolemia. Previous angiogram (02/2010) – sub-occlusive ostial atheroma with diffuse distal disease of the mid-distal left anterior descending artery (LAD) and MCSA less than 4 mm2. OCT aspect of mid LAD serial stenosis, with subintimal calcifications, before rotablation, correlating with the angiography. Two of the serial stenosis, have MCSA of 1.54 and 1.44sq.mm, compared with the proximal and distal reference area of 6.77sq.mm and 4.07sq.mm. EES (Everolimus Eluting Stent) have been implanted distaly, improving considerably the patency of the distal LAD. The struts of the stent will be covered by intima within up to 12 months.

Journal of the Romanian Society of Allergology and Clinical Immunology

Figure 3. Cross-sectional and longitudinal view of the EES 2,75x28mm close to the moment of deployment (implantation), after rewiring the OM (obtuse marginal artery) â&#x20AC;&#x201C; branch of the circumflex artery. The well apposed struts of the stent are shown in contact with the intima of the artery, with posterior shadow. They will release the everolimus agent in order to prevent restenosis. Within several months the struts will be covered by a thin intima.

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Figure 4. Optical coherence tomography of a BES (biolimus eluting stent), implanted one year before, which confirmed well covered struts of the stent deployed on the circumflex artery.

and in-stent restenosis. Optical coherence tomography is able to provide information to enhance the understanding of the mechanism and patterns of in-stent restenosis among bare metal stents and drug eluting stents (Akhtar and Liu, 2016).

reduce neointimal hyperplasia and/or inflammation, as not all agents are equally safe and effective for use on a DES. The olimus-eluting family seems to be the class of choice for DES. Sirolimus Eluting Stent (SES) which uses sirolimus, the prototype drug, provides excellent durable antiproliferative and anti-inflammatory properties, and also safe results, as proved by the clinical trials (Table I). The most of DES are using everolimus (EES, like Xience, Promus [Boston Scientific Corporation], and BVS), zotarolimus (ZES, like Endeavor, Resolute), biolimus A9 (BES, like Axxess [Devax, Inc., Irvine, CA] and others), myolimus (Elixir Medical Corporation, Sunnyvale, CA) (Shand and Menown, 2010). Optical coherence tomography (OCT) is a modern tool for the assessment of the mechanism of resorption, neointimal coverage, shrinkage and late lumen enlargement (Di Mario et al, 2010; Mattesini et al, 2014). The assessment of bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease was recently published (Di Mario and Caiazzo, 2015). Figures 2-4 (personal photo archive) reflect the importance of such OCT imaging in the process of endothelization of the struts of the DES

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

References 1. Akhtar M, Liu W. Use of intravascular ultrasound vs. optical coherence tomography for mechanism and patterns of in-stent restenosis among bare metal stents and drug eluting stents. J Thorac Dis. 2016 Jan;8(1):E104-8. doi: 10.3978/j.issn.2072-1439.2016.01.48. PubMed PMID: 26904234; PubMed Central PMCID: PMC4740139. 2. Chen YW, Smith ML, Sheets M, Ballaron S, Trevillyan JM, Burke SE, Rosenberg T, Henry C, Wagner R, Bauch J, Marsh K, Fey TA, Hsieh G, Gauvin D, Mollison KW, Carter GW, Djuric SW. Zotarolimus, a novel sirolimus analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression. J Cardiovasc Pharmacol.

New insights into the drug eluting stents with immunopharmacologically active agents used for their ...

2007 Apr; 49(4): 228-35. PubMed PMID: 17438408. 3. Cutlip D, Abbott JD. http://www.uptodate.com/contents/coronaryartery-stent-types-in-development. Mar 2, 2016. 4. Di Mario C, Caiazzo G. Biodegradable stents: the golden future of angioplasty? Lancet. 2015 Jan 3; 385(9962): 10-2. doi: 10.1016/S01406736(14)61636-6. Epub 2014 Sep 14. PubMed PMID: 25230592. 5. Di Mario C, Iakovou I, van der Giessen WJ, Foin N, Adrianssens T, Tyczynski P, Ghilencea L, Viceconte N, Lindsay AC. Optical coherence tomography for guidance in bifurcation lesion treatment. EuroIntervention. 2010 Dec; 6 Suppl J: J99-J106. doi: 10.4244/ EIJV6SUPJA16. Review. PubMed PMID: 21930500. 6. Habib A, Karmali V, Polavarapu R, Akahori H, Nakano M, Yazdani S, Otsuka F, Pachura K, Davis T, Narula J, Kolodgie FD, Virmani R, Finn AV. Metformin impairs vascular endothelial recovery after stent placement in the setting of locally eluted mammalian target of rapamycin inhibitors via S6 kinase-dependent inhibition of cell proliferation. J Am Coll Cardiol. 2013 Mar 5; 61(9):971-80. doi: 10.1016/j. jacc.2012.12.018. PubMed PMID: 23449430; PubMed Central PMCID: PMC3942872. 7. Hiltrop N, Ughi GJ, Dubois C, Adriaenssens T. Optical coherence tomography-based assessment of bifurcation stenting using the Axxessª Biolimus A9ª-eluting stent system. EuroIntervention. 2016 Jan 22;11(9):1027. doi: 10.4244/EIJV11I9A208. PubMed PMID: 26788704. 8. Kandzari DE, Tcheng JE, Zidar JP. Coronary artery stents: evaluating new designs for contemporary percutaneous intervention. Catheter Cardiovasc Interv. 2002 Aug;56(4):562-76. Review. PubMed PMID: 12124974. 9. König S, Browne S, Doleschal B, Schernthaner M, Poteser M, Mächler H, Wittchow E, Braune M, Muik M, Romanin C, Groschner K. Inhibition of Orai1-mediated Ca(2+) entry is a key mechanism of the antiproliferative action of sirolimus in human arterial smooth muscle. Am J Physiol Heart Circ Physiol. 2013 Dec 1;305(11):H1646-57. doi: 10.1152/ajpheart.00365.2013. Epub 2013 Sep 20. PubMed PMID: 24056904. 10. Liang S, Aiqun M, Jiwu L, Ping Z. TLR3 and TLR4 as potential clinical biomarkers for in-stent restenosis in drug-eluting stents patients. Immunol Res. 2016 Apr; 64(2): 424-30. doi: 10.1007/s12026-0158685-6. PubMed PMID: 26318748. 11. Mattesini A, Pighi M, Konstantinidis N, Ghione M, Kilic D, Foin N, Dall’ara G, Secco GG, Valente S, Di Mario C. Optical coherence tomography in bioabsorbable stents: mechanism of vascular response and guidance of stent implantation. Minerva Cardioangiol. 2014 Feb;

62(1): 71-82. PubMed PMID: 24500218. 12. Nikam N, Steinberg TB, Steinberg DH. Advances in stent technologies and their effect on clinical efficacy and safety. Med Devices (Auckl). 2014 Jun 3;7:165-78. doi: 10.2147/MDER.S31869. eCollection 2014. Review. PubMed PMID: 24940085; PubMed Central PMCID: PMC4051714. 13. Shand JA, Menown IBA. Drug-eluting Stents: The Next Generation; Interv Cardiol. 2010; 2(3):341-350. Future Medicine Ltd. 14. Shokri M, Bagheri B, Garjani A, Sohrabi B, Habibzadeh A, Kazemi B, Movassaghpour AA. Everolimus-Eluting Stents Reduce Monocyte Expression of Toll-Like Receptor 4. Adv Pharm Bull. 2015 Dec; 5(Suppl 1): 643-7. doi: 10.15171/apb.2015.087. Epub 2015 Dec 31. PubMed PMID: 26793610; PubMed Central PMCID: PMC4708035. 15. Steinfeld DS, Liu AP, Hsu SH, Chan YF, Stankus JJ, Pacetti SD, Tai JT. Comparative assessment of transient exposure of paclitaxel or zotarolimus on in vitro vascular cell death, proliferation, migration, and proinflammatory biomarker expression. J Cardiovasc Pharmacol. 2012 Aug; 60(2): 179-86. doi:10.1097/FJC.0b013e31825aa742. PubMed PMID: 22561362. 16. Strohbach A, Busch R. Polymers for Cardiovascular Stent Coatings. International Journal of Polymer Science. Volume 2015 (2015), Article ID 782653, http://dx.doi.org/10.1155/2015/782653 17. Tang B, Dong X, Wei Z, Qiao H, Jiang H, Liu B, Sun X. Enhanced autophagy by everolimus contributes to the antirestenotic mechanisms in vascular smooth muscle cells. J Vasc Res. 2014; 51(4): 25968. doi: 10.1159/000365927. Epub 2014 Sep 3. PubMed PMID: 25196016. 18. Wessely R, Schömig A, Kastrati A. Sirolimus and Paclitaxel on polymer-based drug-eluting stents: similar but different. J Am Coll Cardiol. 2006 Feb 21; 47(4): 708-14. Epub 2006 Jan 26. Review. PubMed PMID: 16487832. 19. Yates DJ, Savage ML, Walters DL, Raffel OC. Retrospective Study of First-Generation Drug-Eluting Stents, Second-Generation DrugEluting Stents and Non-Drug Eluting Stent Methods in the Treatment of Native Vessel In-Stent Restenosis in Real-World Clinical Practice. Heart Lung Circ. 2016 Apr; 25(4): 342-51. doi: 10.1016/j. hlc.2015.09.002. Epub 2015 Oct 9. PubMed PMID: 26530435. 20. ***The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on myocardial revascularization. European Heart Journal. doi:10.1093/eurheartj/ehq277. Downloaded from eurheartj.oxfordjournals.org

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 1, January - March 2016

Awareness, Training and Education

Genetic factors involved in hypersensitivity pneumonitis Florin Adrian Secureanu1,2, Mariana Vieru1,3, Carmen Saviana Ganea1

Clinical Hospital „Nicolae Malaxa”, Bucharest, Romania Department of Genetics, „Titu Maiorescu” University, Bucharest, Romania 3 Department of Allergology, „Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 1

ABSTRACT Hypersensitivity pneumonitis (HP), or extrinsic allergic alveolitis, is an inflammatory syndrome of the lung caused by repetitive inhalation of antigenic agents in a susceptible host. Individual risk factors are not yet characterized in detail. Since only a small proportion of individuals exposed to HP-related antigens develop respiratory disease, a genetic predisposition is largely suspected. A review of the genetic studies for HP susceptibility in different ethnic groups, even if insufficient in numbers till nowadays, is presented. Such genetic studies in HP have the potential to detect genetic biomarkers for this respiratory disease occurrence and outcome. KEYWORDS: hypersensitivity pneumonitis, genetic predisposition, human leukocyte antigen (HLA)

tioned. Serum IgG which can be determined by immunoassay is specific to antigens from microorganisms: Alternaria alternata, Aspergillus fumigatus, Candida albicans, Cladosporium herbarum, Micropolyspora faeni, Penicillium chrysogenum, Thermoactinomyces vulgaris, and serum proteins, feathers and droppings from pigeons, budgerigars and parrots. Skin prick testing are not helpful in the diagnosis. HP is more commonly manifested as farmer’s lung, bird fancier’s lung, and chemical worker’s lung. HP is an interstitial lung disease due to a combined type III and IV immune reactions with a granulomatous type of inflammation. Patients with HP should be referred also to pulmonology centers with expertise, as the overlap with other forms of interstitial lung disease may be substantial. The disease varies in

ypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a complex pulmonary syndrome mediated by immunological mechanisms, and caused by inhalation of a wide variety of antigens to which the individual has been previously sensitized. These protein or glycoprotein antigens are inhaled, and represented by organic antigens from microorganisms, plant or animal protein, low molecular weight organic substances or drugs. A large number of occupational agents/antigens have been described as potential cause of HP in a wide variety of occupations classifiable into six broad categories that include bacteria, fungi, animal (glyco)proteins, plant (glyco)proteins, low molecular weight chemicals, and metals. Immunoallergological workup must be men-

Corresponding Author: Associate Professor Florin Adrian Secureanu Clinical Hospital „Nicolae Malaxa”, 12 Soseaua Vergului, postal code 022441, Bucharest E-mail: a_secureanu@yahoo.com Submission date: 30/12/2015; Acceptance date: 01/03/2016; Publication date: 31/03/2016

Genetic factors involved in hypersensitivity pneumonitis

intensity, clinical presentation, and natural history, depending on the inciting agent. In most cases, disease can be reversed with prompt diagnosis followed by identification and removal of exposure risks (Girard şi Cormier, 2010; Popescu, 2012; Agache and Rogozea, 2013). HP is considered a rare disease with an estimated incidence of about 0.9 cases per 100 000 person-years for the period 1991-2003 (Quirce et al, 2016). The proportion of patients who develop HP for most antigens is unknown. It is estimated that 0.5% to 3% of farmers will develop HP, and the general prevalence of this respiratory disease seems to be lower than what had been reported 20 years ago (Lacasse et al, 2003). The clinical presentation of HP has classically been categorized as acute, sub-acute, and chronic depending on the condition of exposure and other clinical features. HP is characterized by strong cellular and humoral responses to inhaled antigens. Lung cellular influx and inflammatory responses characteristic of HP are initiated by causative agents via immune cell receptors called Toll-Like Receptors (TLRs). In HP, when specific TLRs are activated, they react through an intracellular pathway, known as the MyD88 pathway, to release many proinflammatory cytokines and mediators. There is proliferation of cytotoxic lymphocytes (CD8+) and a striking production of IgG antibodies, presumably from proliferation of plasma cells stimulated by CD4+ Th1 lymphocytes. Th1 and Th17 cells are responsible for the production and release of tumor necrosis factor (TNF), interferon-α, IL-12, IL-17, IL-18, and IL-22-secreting Th17 cells in HP (Joshi et al, 2009; Simonian et al, 2009). Moreover, increased T regulatory cells may help to down regulate the disease and prevent the development of the disease (Park et al, 2009). The transcription factor GATA binding protein-3 (GATA-3) that is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of HP. Overexpression of GATA-3 attenuated HP by shifting the lung Th1/Th2 balance toward Th2, and especially by suppressing interferon (IFN)-gamma production (Matsuno et al, 2007). HP is considered to occur through immunological mechanisms in which genetic predisposition and environmental exposure contribute to its progression following antigen exposure. Since only a small proportion of individuals exposed to HP-related antigens develop the respiratory disease, a genetic predisposition is largely suspected (Falfán-Valencia et al, 2013). However, genetic studies for HP susceptibility are insufficient. HLA molecules present intracellular or extracellular antigens to T-cell receptors, resulting in T-cell activation. HLA alleles are associated with many types of immunological

disorders. Some genetic factors are known to be involved in HP (Furukawa et al, 2015). Several studies revealed links between HLA types and HP, with an increased occurrence of HLA-DR7 in pigeon fancier’s lung (Selman et al, 1987; Quirce et al, 2013), HLA-DR3 in pigeon breeder’s lung (Rittner et al, 1983), HLA-B8 in pigeon fancier’s lung and farmer’s lung (Flatherty et al, 1975; Quirce et al. 2013), and HLADQw3 in Japanese summer-type HP (Ando et al, 1989; Quirce et al. 2013). It was found that susceptibility to sporadic HP is associated to genes located within the major histocompatibility complex (MHC) (Flaherty et al, 1980; Rittner et al, 1983; Ando et al, 1989; Camarena et al, 2001; AquinoGalvez et al, 2008). The frequencies of PH-associated MHC alleles can vary in different ethnic groups. The presence of several cases in the same family seems to be uncommon and, interestingly, was particularly found in pediatric patients (Ceviz et al, 2006). No genetic studies on the familial form of HP have been reported. MHC encodes a variety of molecules, which are involved in the antigen processing and presentation as part of the adaptive immune response, and the interactions with NK cells. Polymorphisms in the promoter region of the TNF gene have also been associated with increased risk to a number of inflammatory diseases. Regarding this genetic aspect, only two single nucleotide polymorphisms (SNPs) at -308 and -238 in the promoter region gene have been commonly studied (Kroeger et al, 1997; Kroeger et al, 2000; Abraham et al, 2001). In a study performed by researchers from Germany and United Kingdom, genotyping for the -308 TNF-alpha promoter polymorphism and the TNF-beta intron 1 gene polymorphism was assessed in patients with farmer’s lung, breeder’s lung and controls. Increased production of TNF after hay dust challenge in farmer’s lung patients, but not in sensitized asymptomatic controls was found. The frequency for the TNFA2 allele, a genotype associated with high TNF-alpha production in vitro, was significantly higher in farmer’s lung patients versus controls or patients with pigeon breeder’s lung. Genotyping for TNF-beta revealed no relevant abnormalities. These genetic findings suggested a genetic predisposition for increased TNF-alpha production in the pathogenesis of alveolitis in farmer’s lung. Since farmer’s lung patients usually do not develop pulmonary fibrosis, such genetic findings might be useful for evaluation of the predisposition to a better outcome in allergic alveolitis (Schaaf et al, 2001). An important study conducted a family-based research, that includes nine multicase Mexican families

Journal of the Romanian Society of Allergology and Clinical Immunology

with at least two related HP patients (RHP). It evaluated RHP individuals, additional healthy first-degree relatives (REA) and healthy unrelated individuals (HUI). HLA class II typing (HLA-DRB1/3/4/5, -DQA1, -DQB1, -DPA1, -DPB1, -DMA and -DMB), and -863, -308 and -238 polymorphisms in the promoter region of TNF-alpha were performed by PCR based methods. The authors identified an increased frequency of HLADRB1*04:07, DRB1*04:05, DRB1*11:01 and DRB1*13:01 alleles in RHP individuals compared to healthy controls. A significant higher frequency of DRB1*04:07D QB1*03:02, DRB1*04:05-D QB1*03:02, and DRB1*04:03-DQB1*03:02 haplotypes was also detected in the group of patients. Similarly, TNF-238 GG genotype was more frequent in the RHP group as compared to REA. The combination of HLA-DRB1*04 alleles and TNF-238 GG was significantly increased in the RHP group. These genetic findings revealed that genes located within the MHC region confer susceptibility to familial HP in Mexicans (Falfán-Valencia et al, 2013). The results of a previous study suggested that there is an association between some genotype of the PSMB (low molecular weight proteosome LMP, currently named PSMB) genes and hypersensitivity pneumonitis in Mexican population. Particularly PSMB8 KQ genotype may play a role in the development of HP, while PSMB8 QQ might play a protective role. Additional larger complex studies could help to establish the real significance and deleterious effects of these variations located in the coding region of LMP gene in the susceptibility to HP (Camarena et al, 2010). The summer-type HP (SHP) is the most common form of HP in Japan (Ando et al, 1991). Occurrence of HP in Japanese patients may not only be related to the environmental factors, such as the duration of inhalational exposure and climate, but also to the host’s hereditary susceptibility to antigens. In a recent study, Japanese HP patients had HLA-DR9 (Asai et al, 2016). A previous study performed in patients with Japanese SHP induced by Trichosporon spp revealed an increased frequency of HLA-DQw3, and the association between HLA-DQw3 as an immune suppression gene and the respiratory disease was discussed (Ando et al, 1989). The occurrence of SHP has also been reported to be related to HLA-A2 and DR9 (Makimoto et al, 1991). In conclusion, making the correct diagnosis of HP has critical therapeutic and prognostic implications. Genetic studies in HP have important utility in research programs, in order to understand why only a small proportion of individuals exposed to HP-related antigens develop the respiratory disease, and to try to detect genetic

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biomarkers for this respiratory disease occurrence and outcome. Conflict of interests: The authors declare no conflict of interests.

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lung disease. Am Rev Respir Dis. 1980 Sep; 122(3): 437-43. PubMed PMID: 7416619. Flatherty DK, Iha T, Chmelik R, Dickie H, Reed CE. HL-A-8 in farmer’s lung. Lancet. 1975 Sep 13; 2(7933): 507. PubMed PMID: 51323. Furukawa H, Oka S, Shimada K, Tsuchiya N, Tohma S. Genetics of Interstitial Lung Disease: Vol de Nuit (Night Flight). Clin Med Insights Circ Respir Pulm Med. 2015 Apr 29; 9(Suppl 1): 1-7. doi: 10.4137/CCRPM.S23283. eCollection 2015. Review. PubMed PMID: 26056507; PubMed Central PMCID: PMC4444491. Girard M, Cormier Y. Hypersensitivity pneumonitis. Curr Opin Allergy Clin Immunol. 2010 Apr;10(2):99-103. doi: 10.1097/ ACI.0b013e3283373bb8. Review. PubMed PMID: 20093932. Joshi AD, Fong DJ, Oak SR, Trujillo G, Flaherty KR, Martinez FJ, Hogaboam CM.Interleukin-17-mediated immunopathogenesis in experimental hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2009 Apr 15; 179(8): 705-16. doi: 10.1164/rccm.2008111700OC. Epub 2009 Jan 16. PubMed PMID: 19151189. Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol. 1997 Apr; 34(5): 391-9. PubMed PMID: 9293772. Kroeger KM, Steer JH, Joyce DA, Abraham LJ. Effects of stimulus and cell type on the expression of the -308 tumour necrosis factor promoter polymorphism. Cytokine. 2000 Feb; 12(2): 110-9. PubMed PMID: 10671295. Lacasse Y, Selman M, Costabel U, Dalphin JC, Morell F, ErkinjunttiPekkanen R,Mueller NL, Colby TV, Schuyler M, Jomphe V, Cormier Y; HP Study Group.Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol. 2009; 149(2): 161-6. doi: 10.1159/000189200. Epub 2009 Jan 6. PubMed PMID: 19127074. Makimoto N, Kajimoto K, Inoki A, Irie S, Naniwa J, Fujita T, Ueno K, Shiraishi T, Tada S, Kimura I. Familial outbreak with hypersensitivity pneumonitis. Nihon Naika Gakkai Zasshi. 1991 Jul 10; 80(7): 1132-3. PubMed PMID: 1919226. Matsuno Y, Ishii Y, Yoh K, Morishima Y, Haraguchi N, Kikuchi N, Iizuka T, Kiwamoto T, Homma S, Nomura A, Sakamoto T, Ohtsuka

M, Hizawa N, Takahashi S.Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2007 Nov 15; 176(10): 1015-25. Epub 2007 Aug 23. PubMed PMID: 17717199. 20. Park Y, Oh SJ, Chung DH. CD4(+)CD25(+) regulatory T cells attenuate Hypersensitivity Pneumonitis by suppressing IFN-gamma production by CD4(+) and CD8(+) T cells. J Leukoc Biol. 2009 Dec; 86(6): 1427-37. doi: 10.1189/jlb.0908542. Epub 2009 Sep 9. PubMed PMID: 19741155. 21. Popescu FD. Evaluarea alergologică în pneumonitele de hipersensibilitate, In: Imunologie şi imunopatologie, sub redacţia Alexandru G. Ierima, Editura Zigotto, Galaţi, 2012, pp. 429-446. 22. Quirce S, Vandenplas O, Campo P, Cruz MJ, de Blay F, Koschel D, Moscato G,Pala G, M R, Sastre J, Siracusa A, Tarlo SM, WalusiakSkorupa J, Cormier Y. Occupational hypersensitivity pneumonitis: An EAACI Position paper. Allergy. 2016 Feb 23. doi: 10.1111/all.12866. [Epub ahead of print] PubMed PMID: 26913451. 23. Rittner C, Sennekamp J, Mollenhauer E, Rösinger N, Niese D, Lüttkenhorst M, Baur MP, Stroehmann I. Pigeon breeder’s lung: association with HLA-DR 3. Tissue Antigens. 1983 May; 21(5): 374-9. PubMed PMID: 6408759. 24. Schaaf BM, Seitzer U, Pravica V, Aries SP, Zabel P. Tumor necrosis factor-alpha -308 promoter gene polymorphism and increased tumor necrosis factor serum bioactivity in farmer’s lung patients. Am J Respir Crit Care Med. 2001 Feb; 163(2): 379-82. PubMed PMID: 11179110. 25. Selman M, Terán L, Mendoza A, Camarena A, Martínez-Cordero E, Lezama M, Rubio HM. Increase of HLA-DR7 in pigeon breeder’s lung in a Mexican population. Clin Immunol Immunopathol. 1987 Jul; 44(1): 63-70. PubMed PMID: 3496181. 26. Simonian PL, Roark CL, Wehrmann F, Lanham AK, Diaz del Valle F, Born WK, O’Brien RL, Fontenot AP. Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis. J Immunol. 2009 Jan 1; 182(1): 657-65. PubMed PMID: 19109199; PubMed Central PMCID: PMC2766086.

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Vol. XIII, No. 1, January - March 2016

Child with asthma and obesity Stela Goția

“Grigore. T. Popa” University of Medicine and Pharmacy, Iași, Romania

ABSTRACT Bronchial asthma and obesity can evolve simultaneously in child due to the interaction of some hereditary inheritance, with polymorphisms and genes fragilizations under the influence of environmental factors (in utero and after birth). Common pathogenetic relays associated to those specific for every disease are the bases for some peculiar clinico-biologic manifestations and for the aggravation and chronicization. In these conditions, the bronchial asthma can be included in the category „problematical”. It is required a multidimensional therapeutic approach that combines specific measures from the international guidelines, but very individualized. The monitorization is difficult, the remission of the asthma will be successfully obtained when the body mass index will gradually decrease. KEYWORDS: bronchial asthma, obesity, multidimensional treatment.

ronchial asthma (BA) and obesity (Ob) are some of the fetal programmed illnesses of the complex transmission category in which the genetic inheritance interacts with polymorphisms and genes fragilizations gained through the gene-environment- life style relation. Recently, the genome’s modern scannings (‘systematic genome wide association study’) proposed the existence of a common gene (DENNDIB) for both BA and Ob(1). The frequency of these two illnesses increased by approximately 40%, in almost parallel curves, for the last two decades. Their simultaneous evolution has a less known frequency taking into account the difficulties created by the asthmatic type symptomatology in obese, both adults and children (especially in teenagers). The population studies reported a frequency of approximately 17% for bronchial asthma in children, 21% of whom connected with obesity(2).

The debut moment of the BA – Ob association and pathogenetic binding stays an open research problem. Under the age of 6, both illnesses can start simultaneously with a progressive potential during childhood until adult life. Over this age the overweight and obesity, especially in the female teenagers, precede the apparition of asthmatic symptoms and of the frequent non-atopic asthma (IgE negative)(3).

Etiopathogeny elements Decoding the dominant pathogenetic mechanism in BA – Ob association encounters difficulties especially in children. The epigenetic risks for BA pre, post natal and subsequent (better decoded) intertwine with epigenetic risks of obesity. In fetus, the pulmonary development of the

Corresponding Author: Professor Stela Goția 16, Vasile Stroescu street, Iasi, postal code 700079; E-mail: dgotia@yahoo.com Submission date: 02/02/2016; Acceptance date: 01/03/2016; Publication date: 31/03/2016

Child with asthma and obesity

quency of BA – Ob association. However, a meta- analysis of 6 studies regarding the apparition of BA in obese children, signaled a higher frequency of affecting the boys (Castro-Rodriquez J.A. 2001 quote 8). Obesity induced insulinoresistance aggravates the risk for allergic BA in a big child. At this category of subjects/ patients a polysensitization to the aeroallergens was reported both in adults and children(9). The pathogenetic impact of physical activity lack in the BA—Ob association (common behavioural trait in both illnesses) stays a controversy. Recent data suggests either independent associations of sedentarism in both illnesses, or sedentarism’s aggravation and closing of a vicious circle by wheezing’s apparition. There is a persistent positioning dilemma of sedentarism in child ‘did asthma precede obesity or was it favoured by obesity’s evolution?’. Obesity’s presence was frequently correlated with the development and severity of BA both in adults and children. Weight loss and physical activity rise ameliorated bronchial asthma symptoms, the pulmonary function and that of the pulmonary status indicators(10). In BA – Ob immunopathogenesis association obesity’s mechanical effects bind with complex inflammatory and immunological processes. Obesity as well as the BA is an inflammatory state in which the adipocytes have an important role. The leptin, an adipocyte hormone which at the hypothalamus level has the role to signal the satiety and to activate the metabolism (neuropeptide Y activator), has proportional increased levels with the body mass index. In fetal lung, leptin interferes with the development, in bronchi sympathetic vegetative commands’ development and maturation, in surfactant synthesis and tracheal epithelium proliferation. Leptin increased levels in umbilical cord’s blood are significantly correlated with obesity’s early debut and that of recurrent wheezing. In children with BA – Ob, leptin’s values were two times higher than in obese children without BA(11). Leptin is a Th1 differentiation promoter and an inductor generator for IFNᵧ, Il-6 and TNFᾳ. It also determines the increase in production of TNFᾳ, Il-6 and Il-12 in masts activated by lipopolysaccharides. On the other hand, neuropeptide Y, whose plasma value increases in asthmatic exacerbations (more obvious in obese), mediates leptin’ s effect in Th2 activating and Il-4 release, simultaneously with Th1 depression and IFNᵧ production (12). Adipokines (cytokines produced by the adipocyte): Il-6, TNFᾳ, Il-1β, Il-17, RANTES and other factors, have direct pro-inflammatory effects. In the case of the allergic Ob – BA association, adipokines bind their effects

innate and adaptive immune system, the structural and functional integrity of the allergens’ pathways (cutaneous, respiratory and gastrointestinal) are influenced by the pregnant’ s diet, her well being, infections, pollution exposure, stress, life style and C section. The association of genetic inherited or maternal acquired obesity and its hormonal pathology, the newborn abnormal weight, the prematurity, increase the risks for a BA precocious/early debut associated with Ob(4). Postnatal, along the other risk factors we can find the artificial diet, excess foods intake, non-individualized diversification (unbalanced), aggressions against the microbiome, stress, etc. Individual adiposity is developed through a complex mechanism in which it interferes with the genetic determinism, appetite, the quantity and quality of ingested food, physical activities, energy consumption. The environment, stress and life style influence the development of food preferences and activity types. Different DNA methylation levels in children with BA and Ob, highlighted in the peripheral mononuclear cells, associated with post natal immune activations and with Th2 domination, argue the genic vulnerability of these subjects in in utero and post natal environment(5). In preschool and primary students with allergic BA associated with Ob, polysensitization is frequent, situation which imprints the illness with a severe evolution with resistance to the standard therapy. During childhood and teenage years, the clinical status worsens through the intervention of hormonal changes, life style and psycho-social factors’ accumulation(2). Fast-food increased consumption is suspected to be the disturbing factor of the intestinal microbiome, aggravating the risk for BA, so much the more in the child with early installed Ob(6). At the ages of 1 – 5 years old, the overweight and obesity influence concerning the risk for allergic or nonallergic BA was evaluated discrepant, but the relation over weight and obesity with the recurrent wheezing is already known. Some of these subjects/patients are sensitized and can be delimited as allergic BA - Ob. This delimitation has a special importance for the therapeutic approach and for the prognostic assessments(7). The relation BA – Ob is better outlined in girls than in boys. Obesity presence at 6-11 years old increased by 7 times the risk for asthmatic symptoms at 11- 13 years. The over weight/obese girls who had no wheezing at 6-8 years old, acquired it between 11 – 15 years, which suggests the estrogens intervention in leaning the frequency ratio girls/boys to favour girls. At young ages, there is no reported difference between sexes regarding the fre-

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50% cases in teenagers). In many countries the frequency of these situations is alarming(17). Pulmonary dysfunction in chidren with BA-Ob. Age related anatomo-functional particularities favour a vulnerability of pulmonary function at the presence of overweight, aggravated by the allergic inflammation association and bronchial hyperreactivity (BHR). In morbid obesity in infant and small child a respiratory resistance appears (pulmonary residual capacity decrease) accompanied by an increase of the pleural and esophagus pressure, atelectasis, that reduces the gas exchange surface. Wheezing through brochiolitis or asthmatic exacerbation puts life in danger(18). Cohort studies in children with BA- Ob signaled a decrease of FEV1/FVC ratio altogether with the body mass index increase (restrictive respiratory dysfunction), bronchial hyperreactivity and obstruction to effort, uncorrelated with BA severity (Zerah C.1993 quote by 2). Obesity worsens BA inherent pulmonary dysfunction through direct effect onto the respiratory mechanics, pulmonary volumes change, bronchial muscle tone change, BHR and chronic inflammation aggravation (affecting small respiratory airways), acceleration and aggravation of bronchial remodeling. Respiratory dysfunction becomes frequent at teenage years. The particularities lie in mixed or restrictive type ventilatory dysfunction, intolerance to effort(19).

with those of the mediator cytokines in the allergic inflammation(2). Il-6 stimulates the CRP production in the liver. Increased values of CRP in these subjects’ serum signal a sub-clinical inflammation in the respiratory airways and a coronary suffering. Adiponectin is an anti-inflammatory adipose cytokine with low values in obese, correlated with the hyperinsulinism degree and insulino-resistance. Body mass index decrease favours adiponectin’ s increase and pro-inflammatory adipokines’ values decrease. (TNFᾳ, Il-6). It also inhibits the kB nuclear factor (it reduces the nuclear command for the pro-inflammatory cytokines), induces the anti-inflammatory cytokines production (Il10, Il-1RA), decreases the adhesion molecules activation and in culture it decreases the proliferation/migration of smooth muscle cells(13). Mast cells have a key position in inflammation and fibrosis pathogeny in airways with BA-Ob association. Adipokines and adipocyte hormones, psychological stress and environment factors activate masts which release pro-inflammatory mediators (Il-6, Il-8, Il-13, TNFᾳ) and factors involved in airways fibrosis (histamine, TGFβ, tryptase). This way the masts mediate BA↔obesity reciprocal aggravation. The pathogenetic importance is amplified by the resistance to the inhaled corticosteroids of subepithelial mast cells. Clinical studies, still in experimental stage, follow the effects of some natural flavonoids, mast inhibitors, associated with inhaled corticosteroids as a therapeutic possibility in BA-Ob association(14). Obesity – atopic association is not epidemiological well documented yet. In small obese child there was a significant correlation noticed between the cutaneous test’ s positivity and the atopic dermatitis’ incidence with severe evolution(15). Vitamin D deficit which accompanies both obesity and BA aggravates Th1 polarization, induces aberrant immune responses, favours hyper-IgE and decreases the response to corticotherapy(16). Chronic inflammation in respiratory airways has mixed traits (Th1, PMN, eosinophils, Th2, masts) resulted from the action binding of both illnesses characteristic pro-inflammatory factors, severely affecting small respiratory airways. Thus, BA associated with Ob outlines as a distinct phenotype with a persistent evolution, severe, with frequent exacerbations and reduced/ limited response to standard treatment(2). Overweight/ obesity enrolls next to the moderate/severe allergic rhinitis and to the social-economical poor status as a decisive factor of BA persistently uncontrolled (approximate

Clinical manifestations Obesity (body mass index calculated after the age of 2 ≥ 95) presents a chronic respiratory symptomathology lying in shortage of breath, wheezing, cough, intolerance to effort, more or less obvious according to severity. These symptoms are episodically exacerbated to those who associate with bronchial asthma in the presence of trigger factors, fact which prolongs physical inactivity. The aggravations are more frequent and more severe than in normal weight asthmatics. The evolution of common obesity and asthma comorbidities lying in gastroesophageal reflux and sleep disturbances (apnea and snoring), aggravates the respiratory dysfunction and adds to the clinical board digestive and behavioural manifestations. The diathesis to sensitizations and allergy of these subjects (more frequent in obese child than in obese adult) determines the association of perennial allergic rhynitis, atopic dermatitis etc. Severe obesity in teenager may accompany with the glucose tolerance decrease, hyperglycemia type 2/type 2 diabetes, fatty liver, polycystic ovary, hypercorticism

Child with asthma and obesity

8 detecting the obesity specific comorbidities and those of BA as well as those common in both. • Detecting all mental, behavioural issues, information gathering regarding physical activity and the number of hours spent on the computer, in front of television, tablet, school, home environment etc. • Evaluation of BA severity level depending on the frequency of the specific symptoms, value of pulmonary function parameters, the number of short acting bronchodilator treated exacerbations and systemic corticosteroids, severity fluctuations correlated with previous treatment (or with its neglecting). Getting information regarding the response to the short acting bronchodilator before the test of effort(21). • Evaluation of family information level (parents and child) regarding causes, chronic evolution and potential complications of BA-Ob, chronic treatment difficulties and necessity (long standing) for these diseases. The conclusions of the specialists team participating to these evaluations (pediatrician, allergist, nutritionist, psychologist) will stay at the base for an individualized therapeutic plan elaboration, oriented/directed by international treatment guidelines for each of the two illnesses. There are still no treatment guidelines for the BA - Ob association.

(aggravated by asthma necessary corticotherapy), arterial hypertension, pulmonary hypertension, migraines. Depending on duration and severity of the two illnesses (BA-Ob) behavioural and mental disturbances associate, aggravated by social stigma and family overprotection. Self -image deterioration manifests through depression, social isolation, physical inactivity, rejection or reduced adherence to treatment (2, 8,22, 23). Psychological stress itself induces an inflammatory process by amplifying production of Il-5, Il-13 and eosinophilia(20).

Multidimensional therapeutic approach of a child with bronchial asthma and obesity Asthma associated with obesity belongs to the ‘difficult to treat’ or ‘problematic’ phenotype. Obesity’s important pathogenetic contribution reduces the BA response to standardized treatment in international guidelines. BA persistence closes an obesity aggravating vicious circle. Necessary guidelines to start therapeutic approach. • Positive diagnostic evaluation and differential diagnostic elaboration for each of the two illnesses (BA-Ob), detecting common comorbidities and complications specific to each one of them 4 recording of signs/clinical symptoms and anamnesis for the debut age of each of the two illnesses, pre and post natal risk factors, apparition’s age for some of the comorbidities, the response to previous treatments, the evolution of the weight curve correlated with the evolution of feeding/diet and life style, events that could have interfered with the health state etc. 4 allergological, biochemical, genetic investigations, psychological evaluations which will contribute to: 8 delimitation of IgE dependent allergic BA from non-IgE BA. Allergological cutaneous tests, IgE specific serum positive and association with other allergic manifestations are more frequent in children with BA-Ob compared to adults with the same pathology. The existence and severity of inflammation in respiratory airways can be explored through serum specific markers from sputum or breath(8). 8 obesity delimitation through excess food intake (obese child with tall stature) from the symptomatic obesity of a genetic syndrome or of a endocrinopathy (obese child with short stature, dysmorphias and other specific clinical manifestations).

Multidimensional treatment. Frey U. and his collaborators (2015) have proposed a multidimensional approach for these patients having as objectives setting the BA treatment in order to gain control, gradually increase of physical effort capacity, adaptation to dietary adjustments with the conditions of life style change until body mass index correction, obtaining an age normal psycho-social insertion(2). • BA and Ob treatment optimization. Quinto K. and his collaborators (2011) have signaled the low response to inhaled corticosteroids in overweight asthmatic children, increased frequency of exacerbation and the necessity of a short acting bronchodilator(22). This resistance to the inhaled corticosteroids has been explained through the association of obesity’s mechanical effects to the proinflammatory ones. For example, under the TNFᾳ effect inactive forms of glucocorticosteroids receptors accumulate or they can associate with genetic variations of these receptors. However, the introduction of ‘controller’ medication will correspond with the severity level, choosing the highest recommended dose in international guidelines(2,22). Depending on the asthma phenotype, biological and/or allergen specific immunotherapy treatments can be recommended (after the age of 5). Simultaneously comorbidi-

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adherence in treatment, BA control and body mass index correction. Therapeutic education and psychological assistance are recommended with every check up. A great number of individual factors, from environment, economical and educational, work together creating numerous obstacles in ameliorating this pathology and in life quality growth. Many reports underline that only with body mass index decrease a good control over BA is obtained.

ties management, therapeutic education and environment control are performed. The majority of common or specific BA comorbidities will ameliorate together with the weight loss(23). • Gradually dietary adaptations correlated with physical activity level (23). At the ages of 2 - 3 years old for a relative sedentary activity is to be ensured 1000 kilocalories/day, and for a moderate/increased activity 1400 kcal. For girls between 4-8 years old relatively sedentary 1200 kcal./day, and according to activity increase 14001800; between 9-13 years old for a relatively sedentary activity 1600 kcal./day parallel increasing with the activity to 2000-2200; at 14-18 years old 1800 kcal./day for an increased level of sedentarism and 2000-2400 according to physical activity increase. For boys at 4-8 years old relatively sedentary 1400 kcal./day growing to 1600-2000 according to physical activity increase; at the age of 9-13 1800 for relatively sedentary, growing to 2200-2600 once with the activity level increase; at 14-18 years old 2200 for those with sedentarism growing to 2400-2800-3200 in accordance with physical performances increase. Daily diet will incorporate foods that can be consumed unlimited, with low nutritional value, low calorie, with low content in fats and high in fibers (fruits and vegetables). It is associated with foods of whose consumption is limited, with low nutritional value, but with high content in calories and fats (lean meat, dairy products, farinaceous products, cereals and refreshing drinks). High calorie foods, sugar and fats will be eliminated (fatty meat, sweets, sweetened refreshing drinks, fried foods). Foods distribution per dinners will be however flexible, the child’s wish being taken into account. In order to obtain a weight loss, parents’ collaboration is necessary, family food habits changed, industrial processed foods consumed outside family environment excluded. • Lifestyle’s change with the exclusion of sedentarism and with the gradually increase of physical activity level in a context of attractive social and emotional pursuits with parents participation in which they are the role model. Before administration of a short acting beta agonist tones down the effort induced asthma. Fresh air exercises are recommended avoiding temperatures lower than 15ºC or higher than 30ºC, effort duration being of 5 minutes in the beginning, weekly growing in duration, and intensity too, until 60-120 minutes of moderate/intensive effort(2). • In BA-Ob more frequent evaluations are necessary than in BA in child with normal weight regarding the

Conclusions Pathogenetic bases of BA-Ob association treatment being incomplete decoded, less clinical studies in child and the lack of a specific rough guidance make this complex pathology to represent a continuous challenge for researchers and practitioners. Conflict of interests: The authors declare no conflict of interests.

References 1. Melen E., Granell R., Kogevinas M. Et al. Genome-wide association study of body mass index in 23.000 individuals with and without asthma. Clin Exp Allergy. 2013;43:463-474. 2. Frey D., Latzin P., Usermann J. et al. Asthma and obesity in children: current evidence and potential systems biology approaches. Allergy. 2015;70:26-40. 3. Tantisira K.G., Weiss S.T. Complex interactions in complex traits: obesity and asthma. Thorax. 2001;56(suppl.2):ii64-ii73. 4. Lockett G.A., Huoman J., Holloway J.W. Does allergy begin in utero? Ped Allergy and Immunol. 2015;26:394-402. 5. Rastogi D., Suzuki M., Greally J.M. Differential epigenom-wide DNA methylation patterns in childhood obesity associated asthma. Sci Rep. 2013;3:2164-2170. 6. Trompette A., Gollwitzer E.S., Yadava K. Gut microbiota metabolism of dietary fiber influences airway disease and hematopoesis. Nat Med. 2014;20:159-166. 7. Rzehak P., Wijga A.H., Keil T. Et al. Body mass index trajectory classes and incident asthma in childhood: results from 8 European birth cohorts. J Allergy Clin Immuno.l 2013;131:1528-1536. 8. Bacharier L.B., Robert C.S. Asthma in Older Children in Leung D.Y.M., Sampson H.A., Geha R., Szefler S.J. Pediatric Allergy. Principles and Practice. Sec. Ed., Ed.Saunders Elsevier, 2010:404-422. 9. Husemoen L.L.N., Glṻmer C., Lau C. et al. Association of obesity and insulinoresistence with asthma and aeroallergen sensibilization. Allergy. 2008; 63:575-582. 10. Hakala K., Stenius-Aarniala B., Sovijarvi A. Effects of weight loss on peak flow variability, airway obstruction and lung volumes in obese patients. Chest. 2000;118:1315-1321.

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11. Mai X.M., Bȍttcher M.F., Leijon I. Leptin and asthma in overweight children at 12 years of age. Pediatr Allergy Immunol. 2004;15(6):523-530. 12. Groneberg D.A., Foljerts G., Peiser G. Et al. Neuropeptide Y Pulm Pharmacol Therapy. 2005;115:173-180. 13. Wolf A.M., Wolf D., Rumpold H. et al. Adiponectin induces the antiinflammatory cytokines Il-10, Il-1RA in human leukocytes. Biochim Biophys Res Commun. 2004;323:630-635. 14. Sismanopoulos N. Do mast cells link obesity and asthma?. Allergy. 2013;68:8-15. 15. Silverberg J.I., Kleiman E., Lev-Tor H. Et al. Association between obesity and atopic dermatitis inchildhood; a case-control study. J allergy Clin Immunol. 2011;127:1180-1186. 16. Hawrylowicz C., Ryanna K. Asthma and allergy: the early and beginnings. Nat Med. 2010;16:274-275. 17. Ferreira-Magalhaes M., Pereira A.M., Sa-Sousa M. Et al. Asthma control in children is associated with nasal symptoms, obesity and health in surance: a nationwide survey. Pediatr Allergy Immunol. 2015;26:466-473.

18. Behazin N., Jones S.B., Kohen R.I. et al. Respiratory restriction and elevated pleural and esophageal pressures in morbid obesity. J Appl Physiol. 2010;108:212-218. 19. Goția Stela, Russu Georgiana. Manifestările pulmonare în obezitatea copilului. Rev Med Chir. 2008;112(3):590-597. 20. Chen Y.C., Hanson M.D., Paterson L.Q. et al. Socioeconomic status and inflammatory processes in childhood asthma: the role of psychological stres. J Allergy Clin Immunol. 2006;117:1014-1020. 21. National Asthma Education and Prevention Program: Expert Panel Report 3 (EPR 3) Guidelines for Diagnosis and Management of Asthma-summary report 2007. J Allergy Clin Immunol. 2007;120 (suppl.):594. 22. Quinto K.B., Zuraw B.L., Poon K.Y. et al. The association of obesity and asthma severity and control in children. J Allergy Clin Immunol. 2011;128:964-968. 23. Gahagan S. Overweight and obesity in Kliegman R.M., Stanton B.F., St Geme III J.W., Schor N.F. Nelson Textbook of Pediatrics. Ed.20, Ed.Elsevier, 2016:307-315.

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News and Current Perspectives

Homo neanderthalensis DNA in modern human genome and immune responses Florin Adrian Secureanu1,2, Florin-Dan Popescu1,3

ABSTRACT Recent genetic studies revealed that Homo neanderthalensis DNA is present in the genome of modern humans, being involved in innate immune responses. Neandertals are extinct hominins and had been living in Europe for a considerably longer period of time before modern humans, so they were better adapted to pathogens, diets and local climate. Archaic genes controlling immune responses and their persistence in modern human DNA were beneficial in prehistoric times, but nowadays some of them may cause diseases, because modern lifestyles and environments are very different. Interestingly, archaic-like alleles are recently suggested to be associated with increased susceptibility to allergic diseases. KEYWORDS: Homo neanderthalensis, genes, immune responses, allergy

closest relatives of modern humans, their genomes being at least 99.5% identical (Noonan et al, 2006). The 1856 discovery of the Neandertal type specimen (Neandertal 1) in a valley east of Düsseldorf in Germany marked the beginning of human paleontology. The valley became known by about 1850 as the Neander Valley (Neanderthal) in honor of Joachim Neander, a church teacher who often visited the area. In 1901 an orthographic reform in Germany changed the spelling of Thal (valley) to Tal, therefore the German name of the valley was officially changed to Neandertal. Some scientists have extended the change to the name of the species, some have not. Scientific name, Homo neanderthalensis remained unchanged. The Neanderthal Museum in Mettmann, located at the

key event in human evolution is the expansion of modern humans of African origin across Eurasia between 60 and 40 thousand years ago, replacing all other archaic hominins (Hershkovitz et al, 2015, Árnason, 2016). Genome sequencing of our closest extinct relatives, the Neandertals and the more recently discovered Denisovans (related group of Neandertals from Siberia), has greatly increased the understanding of how modern humans leaving Africa interacted with hominin groups already present in Eurasia (Stoneking and Krause, 2011). Neandertals or Neanderthals represent an extinct subspecies of ancient hominins in the genus Homo (Homo sapiens neanderthalensis). Neandertals are the

Corresponding Author: Florin-Dan Popescu Clinical Hospital „Nicolae Malaxa”, 12 Soseaua Vergului, postal code 022441, Bucharest; E-mail: florindanpopescu@allergist.com Submission date: 18/03/2016; Acceptance date: 21/03/2016; Publication date: 31/03/2016

Homo neanderthalensis DNA in modern human genome and immune responses

site of the first discovery retains also the original spelling (Schmitz et al, 2002). In 2016, prestigious journals such as Science, American journal of human genetics, Journal of human evolution, American journal of physical anthropology or Molecular biology and evolution, use the form Neandertal (Bailey et al, 2016; Dannemann et al, 2016; Gibbons, 2016; Pääbo, 2016; Quam et al, 2016; Weyer and Deschamps et al, 2016), while others, such as Nature, Gene or Genome research, still use the form Neanderthal (Árnason, 2016; Callaway, 2016; Hsieh et al, 2016). The presence of Neandertal DNA in the whole-genome sequences of actual non-African individuals is accepted to be a consequence of admixture, likely due to limited interbreeding between modern and archaic humans. Genetic admixture occurs when two or more previously isolated populations begin interbreeding. Some scientists discuss Neandertal genetic affinities with contemporary humans from the point of view of introgression versus common ancestral polymorphisms. Introgression describes the incorporation of alleles from one species into the gene pool of a second, divergent species. If a haplotype was introduced by introgression from archaic humans, the reason for continued survival in present-day humans may be that it was affected by positive selection or balancing selection, or that it was not removed from the population by negative selection or genetic drift (Lowery et al, 2013; Lohse et al, 2014; Racimo et al, 2015). Modern humans in their great journey out of Africa were confronted with environmental challenges including different climate, novel foods and pathogens. The discovery of introgression from now-extinct Neandertals into modern humans entering Eurasia raises the possibility the latter ones might have benefitted from the introduction of alleles that existed in archaic humans, well adapted to the environment (Dannemann et al, 2016). There is evidence that during the Middle to Upper Palaeolithic interface, Neandertals and modern humans contemporaneously inhabited southern Levant, close in time to the likely interbreeding event with Neandertals (Hershkovitz et al, 2015). Neandertals contributed genetically to modern humans outside Africa 47,000 - 65,000 years ago. In addition to later interbreeding events, Neandertals ancestors from the Altai Mountains and early modern humans interbred, possibly in the Near East, many thousands of years earlier than previously thought (Kuhlwilm et al, 2016). From an evolutionary genetics approach, modern humans seem to be haunted by the past, due to mod-

ern consequences of Neandertal DNA. The abundant collected DNA sequencing data from modern and ancient humans recently revealed multiple historic phases of interbreeding that have left an important fraction, about 1.5% to 4%, of Neandertal DNA in modern human genomes (Burgess et al, 2016). Interestingly, 6-9% of the genome of an early modern human from Romania is derived from Neandertals, more than any other modern human sequenced to date, this 37,000 - 42,000-year-old individual from Peştera cu Oase being one of the earliest modern humans in Europe (Fu et al, 2015). Candidate genes for archaic Neandertal adaptive introgression in humans are involved in innate immunity and defence against pathogens (several TLR and HLA genes, STAT2, OAS1), skin pigmentation (MC1R) and lipid catabolism (SLC16A11 and SLC16A13) (Racimo et al, 2015). Moreover, a functional single nucleotide polymorphism upstream of the beta-2 adrenergic receptor gene (ADRB2) is associated with obesity in some populations. An evolutionary analysis implies that a mutation at rs34623097 occurred in the Neandertal genome and then the rs34623097-A allele flowed into the ancestors of present-day humans, and the possibility that rs34623097-A was beneficial for Neandertals cannot be excluded (Naka et al, 2013). A breakthrough study on the phenotypic legacy of archaic admixture between modern humans and Neandertals was very recently published. Scientists, including population geneticists and evolutionary genomicists, joined forces and searched for more than 6000 Neandertal haplotypes in genetic data from more than 28,000 adults of European ancestry, and they discovered and replicated associations of Neandertal alleles with specific phenotypes, such as neurological (depression, which can be triggered by disturbed circadian rhythms), dermatological (actinic keratoses, linked to sun exposure and light conditions of prehistoric Europe) and hematological (hypercoagulation, favorable for prehistoric conditions with traumatic bleedings or births of children with larger skulls) phenotypes (Simonti et al, 2016). The innate immune system provides a first line of defense against pathogens. The mammalian Toll-like receptor (TLR) family consists of 13 members, and recognizes specific patterns of microbial components, called pathogen-associated molecular patterns (PAMPs). In humans, TLR1, TLR6 and TLR10 occur on the cell surface and are known to detect bacterial, fungal, and parasitic components, including glycolipids and flagellin. They are essential for eliciting the inflam-

Journal of the Romanian Society of Allergology and Clinical Immunology

matory and anti-microbial responses, as well as for activating an adaptive immune response (Takeda and Akira, 2015; Dannemann et al, 2016). Human genes regulating innate immunity provide a valuable tool to assess the pressure imposed by microorganisms on host genomes. Regarding innate immunity genes, among those presenting the highest Neandertal ancestry, the TLR6-TLR1-TLR10 cluster was very recently decribed, cluster which also contains functional adaptive variation in Europeans. The three genes function together to regulate the expression of toll-like receptors on the surface of white blood cells, probably boosting the innate immune response. Neandertals lived in Europe and Middle East for more than 200,000 years before modern humans got there, and were probably well adapted to the environment and local pathogens. Modern humans took an evolutionary shortcut, when entered new environment with new pathogens, by picking up beneficial genes from archaic hominins that had lived there longer, emphasizing the genetic control importance of innate immunity pathways in natural conditions (Deschamps et al, 2016). The abovementioned three of the human toll-like receptors (TLR10, TLR1, TLR6) encoded in a cluster on chromosome 4 are among the top 1% of genes with the highest Neandertal introgression. This TLR cluster is specially interesting because of its critical role in innate immunity (Dannemann et al, 2016). A genome-wide association meta-analysis identified an association between TLR1 and Helicobacter pylori seroprevalence, the genetic variations in TLR1 may help explain some of the variation in individual risk for Helicobacter pylori infection (Mayerle et al, 2013). A similar genetic analysis identified shared and allergy-specific susceptibility loci, including 4p14 near TLR1, TLR6 and TLR10 (Hinds et l, 2013). Archaic-like alleles underlie differences in the expression of the TLR genes and are associated with increased microbial resistance and increased allergic disease in large cohorts. There are significantly associated single nucleotide polymorphisms (SNPs) with H. pylori seroprevalence or allergic disease overlapping archaiclike SNPs. For the two phenotypes (H. pylori seroprevalence and susceptiblity to allergic disease) the associated SNPs revealed overlap with multiple archaic-like SNPs (Dannemann et al, 2016). The highly polymorphic human leukocyte antigen (HLA) region in chromosome 6 seems to show signatures of adaptive introgression, though in this case by balancing selection (Racimo et al, 2015). The Neandertals better adaptation to local pathogens al-

Vol. XIII, No. 1, January - March 2016

most certainly involved changes in HLA class I, as exemplified by the modern human populations who first colonized the Americas. Neandertal admixture contributed to B*07, B*51, C*07:02, and C*16:02-bearing haplotypes in modern humans, and was likely the sole source of these allele groups. C*07:02 is a strong C1 ligand for KIR2DL2/3 and B*51 is strong Bw4 ligand for KIR3DL1, such properties suggesting that adaptive introgression of these HLA alleles was driven by their role in controlling NK cells, cells essential for immune defense and reproduction (Abi-Rached et al, 2011). Other immunity related loci, such as the innate immunity STAT2 (an innate immune gene that is involved in interferon response after viral infection) and OAS1 genes (OAS gene cluster helps to inhibit viral replication as part of the innate immune response), carry distinct haplotypes in modern humans that appear to have introgressed from Neandertals, most likely conferring, in some cases, a selective advantage to modern humans. Several genomic regions of very high Neandertal ancestry may be involved in phenotypes involving the immune system, such as IL-18 levels, lupus erythematosus or Crohnâ&#x20AC;&#x2122;s disease (Mendez et al, 2012; SĂŠgurel et al, 2014; Racimo et al, 2015). In conclusion, modern human genome retain DNA inherited from interbreeding with Neandertals, but the influence of this genetic admixture on human traits is just recently started to be researched. Such studies are just at the beginning, and scientists search for more Neandertal variants passed on in ancient encounters. Archaic genes controlling immune responses and their persistence in modern human DNA were beneficial in prehistoric times, but nowadays some of them may cause diseases, because modern lifestyles and environments are very different from the distant past. Interestingly, archaic-like alleles are reecently suggested to be associated with increased susceptibility to allergic diseases (Dannemann et al, 2016). Conflict of interests: The authors declare no conflict of interests.

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Homo neanderthalensis DNA in modern human genome and immune responses

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