Revista sraic nr 3 (iulie septembrie 2016)

www.sraic.eu

Vol. XIII - No. 3 / July - September 2016

JOURNAL OF THE ROMANIAN

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

SUMMARY Psychological stimuli with triggering role in bronchial asthma attacks

13

Iamandescu IB et al

Cognitive coping role in the management of patients with a history of immediate-type hypersensitivity to drugs

19

Colcear D, Onitiu-Gherman N

RSACI Annual Conference May 12-14, 2017

Angioedema due to acquired C1-inhibitor deficiency with late onset and unclear cause. Case report

29

Leru PM, Anton VF

Role of genetics in characterizing endotypes and phenotypes of respiratory allergies

33

Berghi O et al

SRAIC

Societatea Română de

Alergologie și Imunologie Clinică

ISSN 1584-7330

The role of the human microbiota in the development of spondyloarthritis Huhu M R et al

42

JOURNAL OF THE ROMANIAN

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

Vol. XIII, No. 3, July - September 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

JOURNAL OF THE ROMANIAN SOCIETY OF ALLERGOLOGY AND CLINICAL IMMUNOLOGY is covered by the following services: SCIPIO and CMR 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.

3

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 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

Due to a regrettable mistake, in the 1st and 2nd issues of this journal’s printed edition, in the editorial board section, the position of Adjunct Editor-in-Chief held by Professor Diana Deleanu was omitted. We sincerely apologize and rectify the error starting with this issue.

Publishing House:

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

5

Print: MM&LM WORK TECH

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

JOURNAL HOME PAGE

JOURNAL OF THE ROMANIAN

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

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

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

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

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

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

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

6

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. 3, July - September 2016

CONTENTS

Editorial 10

Elena Camelia Berghea

review article Psychological stimuli with triggering role

13

in bronchial asthma attacks Ioan Bradu Iamandescu, Carmen Rapiteanu, Ioana Cioca

Original articles and brief communications Cognitive coping role in the management of patients with

19

a history of immediate-type hypersensitivity to drugs Doina Colcear, Nadia OniČ&#x203A;iu-Gherman

Angioedema due to acquired C1-inhibitor deficiency

29

with late onset and unclear cause. Case report Polliana Mihaela Leru, Vlad Florin Anton

Awareness, Training and Education Role of genetics in characterizing endotypes

33

and phenotypes of respiratory allergies Ovidiu Berghi, Constantin Bara, Roxana Sfrent-Cornateanu

News and Current Perspectives The role of the human microbiota in the

42â&#x20AC;&#x2018;

development of spondyloarthritis Mihaela Roxana Huhu, Octavian Ioghen Costin, Elena Camelia Berghea

Instructions for authors

47 9

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

EDITORIAL

T

deficiency, and published by Polliana Mihaela Leru and Vlad Florin Anton from Colentina Clinical Hospital, Bucharest.

In the section of awareness, training and education, an interesting communication which brings to the attention of young medical doctors the role of genetics in characterizing endotypes and phenotypes of respiratory allergies is provided by Ovidiu Berghi, Professor Constantin Bara and lecturer Roxana Sfrenţ-Cornăţeanu from “Carol Davila” University of Medicine and Pharmacy. Because allergic rhinitis and asthma are heterogeneous diseases, phenotyping and endotyping are modern concepts aiming to characterize and personalize their treatment.

Under the news and current perspectives heading, Mihaela Roxana Huhu from “Carol Davila” University of Medicine and Pharmacy and her co-authors present the new aspects of the complex, and yet not fully understood, interaction between microbiota and the pathogenesis of ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and enteropathic arthritis.

his new number of the Journal of the Romanian Society of Allergology and Clinical Immunology (RSACI) continues its strategy of awareness, communication and discussions on scientific knowledge in the specialty of allergy and clinical immunology in our country.

In the first review article, Professor Ioan Bradu Iamandescu from ”Carol Davila” University of Medicine and Pharmacy and Carmen Rapiteanu from the Faculty of Psychology of ”Titu Maiorescu” University, Bucharest, discuss the psychological factors as risk factors for asthma exacerbations, emphasizing epidemiological and experimental arguments regarding the intervention of psychological triggers in asthma.

Under the heading of original articles and brief communications, Doina Colcear and Nadia Onițiu-Gherman from “Iuliu Hațieganu” University of Medicine and Pharmacy evaluated the cognitive coping role in the management of patients with personal history of immediate drug hypersensitivity, revealing that the differences between the functional and dysfunctional behavior can be partially explained by the cognitive coping.

A case report of angioedema due to C1-inhibitor deficiency with late onset presented to the Allergology Department of Colentina Clinical Hospital for recurrent attacks of facial and peripheral angioedema, considered iniatially to be associated with angiotensin-converting enzyme inhibitors, was assessed as acquired C1-inhibitor

On behalf of the editorial board, I invite the interest/ working groups of our society and all RSACI members to contribute with manuscripts to our RSACI journal.

Elena Camelia Berghea RSACI Vicepresident Executive

10

11

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

review article

Psychological stimuli with triggering role in bronchial asthma attacks Ioan Bradu Iamandescu¹, Carmen Rapiteanu², Ioana Cioca¹

¹”Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania ²”Titu Maiorescu” University, Faculty of Psychology, Bucharest, Romania

ABSTRACT The role of psychological stimuli for triggering asthma attacks was grounded on clinical observations and experimental proves. Etiological involvement of psychological factors may alternate with those of allergens and non allergical triggers (e.g. viruses, drugs, respiratory irritants, etc.). Psychological stimuli are usually represented by psychic stress (acute-triggering and chronic-favourising role), but they may sometimes provoke attacks by conditioned reflexes or suggestion (hypnosis, especially). Experimental stress can induce bronchoconstriction, and music- bronchodilation, both certified by ventilatory tests (apud the works of author and his PhD students). Psychological stimuli often act on the bronchi with a mild or important obstruction, and in asthmatics with great distress vulnerability.

KEYWORDS: bronchial asthma, psychological stress, conditioned reflexes, music-therapy

A. G eneral considerations

One of the most authentic psychosomatic diseases, bronchial asthma (BA), is rightfully considered by Freour (1979) as an entity constituted by the ensemble of attacks on the one hand, and by the ensemble of facts that include the background and the personality of the patients, that is the somatic and psychological disturbances, the history and the nature of the human relationships, and the relation with the general environment in which the patient is living. This concept, attempting to achieve a “sincretic globality” (Freour, ibid.), raises the problems of psychological stress (PS), generating asthma attacks, but also of the PS that occurs as a consequence of the dramatic events lived by the patient during the intense distress provoked by dyspnea.

The role of psychological factors in the etiopathogeny of asthma attacks has become more and more evident, but it is necessary to integrate these factors (triggers and favourising factors) in the multi-factorial complex of allergic and non allergic causes of asthma.

Understanding this role, the allergist must be very empathic and supportive with his asthma patients and “realize psychological help directly, routinely without the need for consultation” (Akdis and Agache, 2013).

The proof of the etiological involvement of psychological triggers is grounded on both neurological mechanisms and clinical observations.

Corresponding Author: Prof. dr. Ioan Bradu Iamandescu 35 Banu Manta street, ap. 25, postal code 011223, Bucharest, Romania; E-mail: iamandb@yahoo.com, Phone: 0040 745 035 942; Submission date: 20/08/2016; Acceptance date: 02/10/2016; Publication date: 24/10/2016

13

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

review article

The bronchial asthma attack (bronchial obstruction that is totally or partially reversible, either spontaneously or following therapy) implies, indifferent of its etiology, three major mechanisms: edema of the mucosa, spasm of the smooth muscle fibers and viscous bronchial hiper-secretion. The psychological factor may intervene at the level of any of these three mechanisms.

The common denominator of the two major etiological forms (allergic and non-allergic) is the nonspecific bronchial hyperresponsiveness, demonstrated by positive tests induced with histamine, acetylcholine, sulfur dioxide, ozone, cold air, etc. In patients with intrinsec bronchial asthma this hyperresponsiveness is “sufficient” for the triggering of asthma attacks following the exposure to the non-specific etiological agents mentioned above.

In allergic asthma patients, this is an “additional” receptivity to the non-specific triggering agents of the attacks, beside the allergic ones. The morpho-pathological substrate of this non-specific bronchial hyperresponsiveness is the inflammation of the bronchial mucosa, the marked infiltration with eosinophillic cells (Reed, 1989; Barnes, 1993) - but also with other types of cells including neutrophils, mononuclear, basophils, etc.

(Nsouli, 1988). This inflammation develops on a “constitutional” respiratory background, insufficiently understood for the time being. The concomitant existence of an atopic background, reflecting at the general level the condition of the immune system, results, in the case of allergic asthma, in the involvement of the bronchial ways - besides other shock organs (see rhinitis, urticaria, etc.) in the framework of allergic manifestations.

Between the non-specific factors of asthma attacks, psychological stimuli hold an important place, either as direct etiological agents, or as “summation” factors, added to the effects of other etiological (allergic and non-allergic) agents (Iamandescu, 1980).

Since 1860 Slaver (cit, by Iamandescu 1980) has mentioned the triggering of asthma attacks in certain patients following emotional changes, and the role of psychological factors in the genesis, triggering and evolution of bronchial asthma is not disputed by any author. The controversies that still exist are mainly related to the mechanism of action, especially the acceptance of psychogenic asthma, as an exclusively psychogenic clinical form (Hansen, 1961). The older statistics of Hansen, Graham, Findeisen, Seropian and Mathov cite figures ranging between 7 and 30%.

A series of clinical observations and experimental studies support the role of psycho-emotional factors in

the triggering of bronchial asthma attacks. Thus, besides the existence of a particular psychological background of the asthma patient (anxiety, phobias, highly emotional reaction), a series of emotional circumstances have been evidenced, capable to determine - in association or not with other factors - the triggering or the modulation of the frequency of bronchial asthma attacks (Graham, 1977). The legitimity of pure psychogenic asthma is no longer admitted, today, but this term was replaced by another term “Bronchial asthma with psychogenic trigger” (Iamandescu 1980, 1985) which appoints only those cases of asthma - either allergic or intrinsic - with a supplementary trigger of psychological nature (ibid.).

B. M odalities of intervention of the psychological stimuli with triggering role in bronchial asthma attacks Psychological stress (PS) The asthma literature is rich in clinical observations that relate the psychological stress to the induced asthma attacks.

In the endeavor to make a brief classification of emotional excitants types, one should mention, in the first place, “acute stress situation” which elicit brutal neuro-vegetative reactions accompanied by massive release of mediator agents which exert their effects on a hyper-active bronchus.

There are also chronic stress situations characterized by slow accumulation of “negative affective effects” associated to family disputes, professional conflicts, fraternal rivalry, inaccessibility of the proposed aims, sentimental disappointment, material shortage, etc., occurring in subjects that cannot adapt to life difficulties (Kourilsky, 1969).

Conditioned reflexes Other examples are provided by the occurrence of attacks in identical clinical circumstances suggesting a psychological conditioning such as, for instance, the patient who has a bronchial asthma attack in front of the same sweets shop, years after having left the town, or an orchestra conductor who has an asthma attack each time he conducts a certain passage from a musical work suggesting that there is a pathologic conditioning of emotional situations associated to the contact with massive amounts of allergens.

This has led to a series of experiments based on conditioned reflexes, according to the Pavlovian school

14

Psychological stimuli with triggering role in bronchial asthma attacks

(Noelpp and Eschenhagen, 1954). These authors, as well as some others, have noticed that in emotional situations respiratory disturbances occur, and can result in asthma attacks; it was also observed that in introverted subjects pathologic conditioning is easier to achieve (Cruchaud, 1966). In fact, the problem of reproducing asthma attacks by reflex conditioning stems from the well-known observation by Mackenzie (1886) of the asthma attack in a female patient who looked at an artificial rose.

However, one cannot exclude too easily a PS determined by the fear of an attack usually induced by natural roses, although the example associated “the seeing of a rose with pollen inhalation and consecutive triggering of the asthma attack”.

After the above-mentioned experiments (NoelppEschenhagen, 1954), another series of studies were carried out in which the conditioned reflexes reproduced these experiments, during which, in a first stage, pollen is introduced in the room where asthma patients allergic to pollen will be exposed. In the second step, asthma attacks could be elicited without pollen, by verbal stimulation.

Other observers have noted too, the occurrence of asthma attacks triggered by reflex conditioning, when patients in front of their TV sets see images from a cat exhibition (report by R. Paun and I.G. Popescu, 1974) or a fight with down-filled pillows (original observation, Iamandescu, 1984). The patients were known to be very allergic to cat hair and respectively, to feathers - which they needed to avoid.

With regard to the conditioned reflex mechanism that is invoked in the triggering of certain asthma attacks of allergic asthma to pollen, this could be supported by the significant improvement of the symptoms of children sensitive to mite house dust when they are removed from their usual environment, although exposure to the same allergens is continued. These experiments by Lamont suggest, as a possible cause, the “asthmogenic parents”, although another possibility would be that, beside the role of the parents (not always a stressing factor for their children), conditioned stimuli could also play a role, just as the furniture and other stimuli from the house, finally achieving a true pattern of conditioned excitants related to the occurrence of the attacks that they can trigger by summation with the effects of the allergen originally involved.

experience with the roses, with chambers filled with pollen, and even the presence on the TV screen of the causative allergen, trigger the asthma attack through suggestion. An example of the implication factors is given by Luparello, who has obtained a bronchial-obstructive response in half of the 40 asthma patients to whom physiologic saline was given under the form of an aerosol supposed to contain the allergen that the patients had to avoid. However, this bronchial-constrictive response could be prevented if atropine was given before the experiment. When the patients were told that the aerosol contains a bronchial-dilating substance, some of them, reacted by bronchial dilatation. Another example is that of Brush and Mathe (1993), with asthma patients that at the Raw and Sgaw testing had obstructive phenomena at bronchial level both when they inhaled a colored solution of methacoline, and when they were given a dye solution alone. This occurred with 6 of the 9 patients tested.

Kotses and co-workers (1987) achieved a similar effect in healthy subjects suggesting suffocation.

Another type of experiment, carried out in children who presented with exercise-induced asthma, showed that it was possible to avert the attacks - induced while the patients exercised on an ergometric bicycle - by using placebos that the 44 patients investigated believed to be salbutamol or chromoglycate. A prophylactic effect was obtained in 45% of the cases and this is above the median figure a 30% (considered to apply to the placebo-effect in general) obtained with suggestion methods.

Data on the subclinical allergic inflammation that Canonica (1994) suggested to be initiated, among other factors, by liberation of adhesion molecules as a result of constant exposure to low concentrations of allergens, supports the triggering of asthma attacks by psychological factors as a consequence of their summation (addition) with allergens’ action.

These observations and experiments illustrate the fact that distress, or simply the conditioned reflexes to asthmogenic stimuli, acts as psychogenic triggering factors on “modified bronchia”.

C. Epidemiological and experimental arguments concerning the intervention of psychological stimuli (triggers) in occurrence and evolution of bronchial asthma

Suggestion factors These examples could be interpreted as conditioned reflexes to previous exposure to allergens, and an objective cause for the triggering of asthma attacks. Both the

The role of the psychological factors in the occurrence and evolution of bronchial asthma can be un-

15

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

review article

derstood by placing psychological triggers between other triggers of clinical manifestations and by involving them in mechanisms of allergic inflammation edification.

Also, the relationship between the psychological factors and the clinical manifestation in bronchial asthma is understood by endorsing some behaviors of prevention of the contact with allergens and by psychological determination of treatment adherence.

Concerning the effects of psychological factors in the occurrence and evolution of bronchial asthma, there are a lot of arguments both epidemiologically (clinical observations, rigorous studies with statistical processing and attempts of isolation of the psychological factors from other triggers) and experimentally (both on human beings and animals), implementing a series of experimental models of causing psychical stress for investigation on the possibility of occurrence, not only of the asthma attacks, but also the modification of some respiratory parameters (PEF, FEV and especially respiratory resistance which is plethysmographic measured) or bronchial inflammation (for example, the dosing of cytokines and eosinophils in BAL).

We shall present a series of evidences starting with some clinical observations to dosing neuromediators of stress or of inflammation.

at home for self-administration. A current method is still the stressing interview with reference to the problems of patient and clinical examination and /or analysis of the possible resistance during interview.

2. Distress experimentally induced A series of experimental methods - some of them have already been mentioned in a study of Serghiescu - tried to determine, at the asthmatic individuals, the modifications of airways resistance at different levels of respiratory tract (PEF, FEV, Tiffeneau Index), the changes of inflammatory parameters in BAL (broncho-alveolar lavage) with an estimation of the number of eosinophils and the concentration of hormones and cytokines. a) Types of stressful tasks In general, the stressful tasks were represented by projection of aversive accident and operation films (Mathe and Knapp, 1971), loud noise (Kuhn and Engel,1980, Ritz et al.,2000) and mental arithmetic (Miller and Kotses, 1995, Kotses et al., 1987).

Often, this stressful tasks were combined at the same patient in order to estimate the two types of fundamental coping responses to distressing tasks: active (at the mental arithmetic test) and passive (at the aversive accident or operation films and at the loud noise), such as Ritz et al. (2000) and Lehrer et al. (1996) were doing. b) Using hypnosis to induce negative mood or some distressing moments bounded with avoidance of some previous stressful situations is relevant for making evident some vagal mechanisms involved in modulation of suggestions and emotions in airways calibre modifications. (Isenberg et al., 1993). c) Animal models Most frequently used were murine models (Joachim et al., 2003, Forsythe et al., 2004). The subjects are mice sensitized by intraperitoneal injection with ovalalbumin and examined in stress conditions (ultrasound and other stressors). Researchers observed a series of modification of airways hyperresponsiveness and of inflammationâ&#x20AC;&#x2122;s markers.

The results were compared with those of the control group consisting of unstressed mice.

1. Clinical Observations In the first period of psychosomaticâ&#x20AC;&#x2122;s development under the influence of psychoanalysis, there were described a series of patients who had asthma attacks under the influence of psychological trauma, which are fanciful interpreted (concerning the psychological reason) but it is important the fact that the asthma attacks are certainly induced by psychological factors.

There is a parallelism between the worsening of asthma and the prolonged conflict realized with the method of chronological concordance between the negative event of life and the increase of the frequency of asthma attacks. (Kourilsky, 1963).

Here is a framing of the reproducing of asthma attacks by conditioned reflexes.

For example, the occurrence of asthma attacks when patients were looking at an artificial rose or at images with cats or with down-filled pillows on the TV. (Mackenzie and Paun, authors mentioned by Iamandescu IB, 1998).

Clinical observations concerning at the effect of psychical factors in occurrence of clinical manifestations of allergic diseases can be substituted with questionnaires applied to the patients in hospital or posted

3. Conclusions of experimental studies a) The effects of the airways resistance In general, this effect is bronchoconstrictive especially in prolonged distress.

An exception could be the acute psychical stress, when the abrupt and the massive unloading of catecholamine determined a bronchodilatator effect, as Laube et al. (2003) demonstrated on a group of asthmatic

16

Psychological stimuli with triggering role in bronchial asthma attacks

women whose early pulmonary response to inhaled allergen is attenuated while verbally re-experiencing an acute emotional stressor.

It has often happened that, after a transient improvement it was possible to appear a late asthma attack after 8 -12 hours.

One of us, Iamandescu (1980), observed that patients had asthma attacks during the night following the day when they had a significant distress, although in previous weeks they haven’ t had any asthma attacks.

Another important conceptual problem is, in the Lehrer’s opinion, that the psychophysiological response of the organism related to type of coping can be bronchodilator in the active coping response to stressful tasks (represented by mental arithmetic test) or bronchoconstrictive in the passive coping response (during looking at aversive accidents or operation films).

This type of division of the physiological response of the organism can correspond to the prevalence of catecholamine reaction of stress, in active coping and to a vagal activation in passive coping.

In fact, the balance between the two types of β-adrenergic and cholinergic activation is actuated of a lot of factors among a great importance has the degree of inflammation and of bronchial obstruction in the moment of the test, like Iamandescu suggested in 1977 and 1980.

His hypothesis was based on the fact that during a personal stressful experimental test, Iamandescu (1977) obtained the diminution of FEV1 only at the asthmatic individuals who, before the test, had low values of FEV1 and FEV1/VC. A possible mechanism incriminated in increasing the airways resistance can be the excitation of neural receptors that liberated neurokinins or send activatory impulses of cholinergic type (Iamandescu, 1998).

All of these interpretations of the psychological stimuli effects on the bronchial calibre, at the asthmatic individuals, proved the complexity of the involved mechanisms and the possibility of intervention of another variables insufficient known and justify the reticences of other author (Ritz et al., 2000) to differentiate the bronchial responsiveness depending on the type of coping reponse (in the active coping - catecholaminic reaction, in the passive coping -vagal excitation).

Regardless of the type of bronchial calibre modifications (dilatation or constriction), psychological stimuli proved their importance in the occurrence of clinical and subclinical manifestation in bronchial asthma.

Some studies in the frame of Ph students doctoral theses under supervision of Iamandescu have evidenti-

ated broncho-obstruction (especially MEF-50 and PEF) (Popilean et al., 2012) during an experimental stress test, and a bronchodilating effect (MEF-50, PEF) in asthmatics - with poor initial ventilatory results - who listened to classical music pieces ( Popilean et al., 2012, Cioca, 2011, Rapiteanu cit by Popilean et al., 2013) b) The effects of the bronchial inflammation The above-mentioned studies, performed on BAL (broncho-alveolar lavage), before and after inducing experimentally distress, revealed an increase of interleukins (IL-6, IL-9, IL-13) and of the number of eosinophils. (Forsythe et al., 2004, Joachim et al., 2003).

Forsythe sustained the hypothesis that different mechanisms of the chronic inflammation depending on the duration of distress: in acute distress (less than three days) cytokines are implicated and in chronic distress (more than seven consecutive days) inflammatory cells, especially eosinophils, are engaged. c) The cortisolic reaction during distress appears to be less evident to asthmatic subjects than healthy individuals.

This fact is demonstrated both at the central levels of nervous system , through detecting a blunted response of hypothalamic-adrenal medullary axis (Mathé et al., 1971), and at the peripheral level, through an absent or minimal salivary cortisol concentration, after the administration of Trier Psychosocial Stress Test at the patient with bronchial asthma with psychological triggers. (Serghiescu et al., 2006).

Epidemiological and experimental arguments, above mentioned, sustain the harmful role of distress on bronchial asthma and suggest that there are a series of mechanisms and modalities of interaction between configuration and features of stimuli, on one hand, the somatic and psychological characteristics of the asthmatic patients, on the other hand.

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

References 1. Akdis CA. Vision, Roadmap and A Land-Marking Event. In: Akdis CA, Agache I. Global Atlas of Asthma. Publ. by European Academy of Allergy and Clinical Immunology. Zurich, 2013. p.175-6.

2. Barnes PJ. Nonadrenergic, noncholinergic nerves and neuropeptides. In: Bronchial Asthma - Mechanisms and Therapeutics. eds.

Weiss E and Stein M., 3rd ed. Little-Brown Boston Toronto, London, 1993. p.232-52.

3. Boushey HA. Asthma and bronchial hyperactivity. In: Herzog H and

17

Psychological stimuli with triggering role in bronchial asthma attacks

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

Perruchoud AP. (Eds.), Asthma and bronchial hyperractivity. Karger, Basel, 1985. p. 124-36 Brush J, Mathe A. Psychiatric aspects. In: Bronchial AsthmaMechanisms and Therapeutics, eds. Weiss E and Stein M. 3rd ed.

Little-Brown, Boston (Toronto) London, 1993. p. 1121-31.

Canonica GW. Role of Adhesion Molecule in the Pathophysioiogy of Allergy. ACI-News, 1994, Suppl. 3:S3-6.

Creer TL, Kotses H. Asthma: psychologic aspects and man¬agement.

In: (Eds) Middleton FJr., Reed CE, Ellis EF. Allergy, Principles and practice. Mosby Co., St. Louis, Toronto, London, 1993. p. 1015-36 Cruchaud S. L’asthme: quelques aspects cliniques et physio-patologiques Bronches, 1966, 2, 73.

Forsythe P, Ebeling C, Gordon JR, Befus AD, Vliagoftis H. Opposing effects of short- and long-term stress on airway inflammation. Am J Respir Crit Care Med. 2004 Jan 15;169(2):220-6. Epub 2003 Nov 6.

French TM and Alexander R. Psychogenic factors in bronchial asth¬ma. Psychosom. Med. Monogr. 4:2, 1941.

Freour P. L’asthme - terrain d’affrontement pour les conceptions medicales. Nouv. Presse Med., 1979, 8, 30, 2449-2650.

Gallefoss F, Bake PS, Kjaersgaard P. Quality of life assessment after patient education in a randomized controlled study of asthma and COPD. Graham P. Childhood asthma: A psychosomatic disorder? Some epidemiological considerations. Br. J. Prev. Soc. Med. 21:78, 1977.

Hansen K. Allergie. Thieme Verlag, Stuttgart, 1961.

Iamandescu IB. Corelatii psiho-somatice in astmul bronsic. Teza de Doctorat. IMF Bucuresti, 1980.

Iamandescu IB. Rolul factorilor psihoemotionali in etiopatogenia stmului bronsic. Viata Medicala 1985, 1, p. 34-9.

Iamandescu IB. Psychoneuroallergology. Ed. Romcartexim , Bucuresti, 1998 Ionescu N, Iamandescu IB, Popovici R. Studiul modificarilor rinoscopice si ventilatoriii pulmonare pentru bolnavii psihosomatici si nevrotici in cursul psihic de stres. Simpozion Actualitati in ORL, Sovata, 1977.

Isenberg et al. The effects of suggestion and emotional arousal on pulmonary function in asthma: a review and a hypothesis regarding vagal mediation. Psychosom. Med, 1992: 54, p. 192-216.

Joachim RA, Quarcoo D, Arck PC, Herz U, Renz H, Klapp BF. Stress enhances airway reactivity and airway inflammation in an animal model of allergic bronchial asthma. Psychosom Med. 2003 SepOct;65(5):811-5.

Kamps AW, Roorda RJ, Kimpen JL, Overgoorvan de Groes AW, van Helsdingen-Peek LC, Brand PL. Impact of nurse-led outpatient management of children with asthma on healthcare resource utilization and costs. Eur Knapp PH. Short term immunological effects of induced emotion.

Psychosom. Med. 1992, 54,133-135.

Kock and Brandt. Cholinergic mechanism. In: Asthma and bronchial hyperreactivity (Eds.) Herzog H, Perruchoud AP. Karger, Basel, 1985. p. 143-52

23. Kotses H, Westlund R, Creer TL. Performing mental arithmetic increases total respiratory resistance in individuals with normal respiration. Psychophysiology 1987;24:67-2.(Medline) 24. Kourilski R. Les mechanisms psychoogiques dans l asthma. Bordeaux medical, 1969,1120-1126 25. Laube BL, Curbow BA, Fitzgerald ST, Spratt K. Early pulmonary response to allergen is attenuated during acute emotional stress in females with asthma. Eur Respir J. 2003 Oct;22(4):613-8.

26. Lehrer PM, Hochron S, Carr R, Edelberg R, Hamer R, Jackson A, Porges S. Behavioral task-induced bronchodilation in asthma during active and passive tasks: a possible cholinergic link to psychologically induced airway changes. Psychosom Med. 1996 Sep-Oct;58(5):413-22.

27. Luparello T et al. Influence of suggestion on airway reactivity in asth¬matic subjects. Psychosom. Med. 30:819, 1968.

28. Luparello T et al. The interaction of psychologic stimuli and pharmacologic agents on airway reactivity in asthmatic subjects. Psychosom.

Med. 5:512, 1970.

29. Mathé AA, Knapp PH. Emotional and adrenal reactions to stress in bronchial asthma. Psychosom Med 1971; 33: 323–40 30. Mathov E. New classification of bronchial asthma. Alergol. et Immunopathol. (Pamplona Spain), 1981, 3, 241-245.

31. Noelpp-Eschenhagen I, Noelpp B. New contributions to experi¬mental asthma. Prog. Allergy 1954, 4:361.

32. Nsouli TM, Nsouli SM Bellanti JA. Neuroimmunologic inflam¬mation: new pathogenic concepts and feature perspectives of immediate and late allergic reactions. Part I and II Annals of Allergy, 1988 60,683-697.

33. Oehling A. Immunological aspects of the pathogenesis of bronchial asthma. Allergol. et Immunopathol., 10, 6: 417-22, (1982).

34. Paun R, Popescu IGr, Jelea A. Astmul bronsic. Ed. Medicala Bucuresti, 1974.

35. Popilean F, Cioca I, Iamandescu IB. Bronchial dilatation due to music in asthmatics depends of the type of music. EAACI Congress Geneve, 16-20 June, 2012; Poster session 36. Reed CE. Editorial. L’asthme, ou bronchite desquamative chronique a eosinophiles. Triangle (Sandoz), XXXIX, 1: 3-9, 1989.

37. Ritz T, Steptoe A, DeWilde S, Costa M. Emotions and stress increase respiratory resistance in asthma. Psychosom Med. 2000 MayJun;62(3):401-12.

38. Ritz T, George C, Dahme B. Respiratory resistance during emotional stimulation: evidence for an nonspecific effect of experienced arousal?

Biol Psychol 2000;52:143-160.

39. Seropian E. Terapia antialergica nespecifica, Ed. Medicala Bucuresti, 1972.

40. Serghiescu I, Gierens A, Hellhammer D, Steffke T, Sgarbura O, Iamandescu IB. Salivary cortisol level dynamics after an experimental psycho-social stress test in asthmatics. XXV EAACI Congress, Vienna, 2006; Poster session 41. Tiffeneau R. Examen pulmonaire de l’asthmatique. Presse Medicale, 1960, 23, 864-875

18

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

original articles and brief communications

Cognitive coping role in the management of patients with a history of immediate-type hypersensitivity to drugs Doina Colcear1, Nadia Onițiu-Gherman1

“Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

1

ABSTRACT A history of immediate-type hypersensitivity reactions to drugs may cause distress and maladaptive coping (mechanisms) interfering with the therapeutic act.

The latest international guidelines acknowledge the role of stress and anxiety in relation to allergic events, but do not define cognitive factors involved in maladaptive coping (mechanisms/types) (“NICE clinical guideline 183”, 2014; “International Consensus on drug allergy”, 2014).

Objective: to identify cognitive coping (types) in patients with a history of drug allergy returning to the allergist on their own initiative (functional behavior) compared to those returning to the allergist forced by circumstances (illness, investigations, etc.) (dysfunctional behavior).

Participants: 25 patients in the functional group and 25 patients in the dysfunctional group.

Results: The functional group showed significant correlations between the perceived severity of previous allergic reactions and the cognition type positive refocusing’ (p = 0.0550). The dysfunctional group presented, compared with the functional group, more frequent beliefs (coping mechanisms) like: self-blame (p = 0.0244), catastrophizing (p = 0.0328), acceptance (p = 0.0336), refocusing on planning (p = 0.0277), positive re-evaluation (p = 0.0004), putting into perspective (p = 0.0298) and a higher correlation between the negative expectations about the risk of a new allergic incident and the total (p = 0.0289) and dysfunctional (p = 0.0291) distress.

Conclusions: the differences between the functional behavior (returning to the allergist of oneself) and the dysfunctional behavior (returning to the allergist forced by circumstances) can be partially explained by the cognitive coping.

KEYWORDS: Immediate-type hypersensitivity; Drugs; Coping; Cognitions

Corresponding Author: Doina Colcear “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania, Surgery I Department; E-mail: colceardoina@gmail.com Submission date: 19/08/2016; Acceptance date: 15/09/2016; Publication date: 24/10/2016

19

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

original articles and brief communications

Introduction

al. (1984, 1987) divided coping types into two major categories: problem focused coping (direct coping) and emotion-centered coping (indirect coping). Even if the division mentioned is generally accepted, it poses a problem of decoding coping strategies, as it doesn’t highlight the role of cognition in generating the two broad categories of coping (“what you think” vs. “what you do”) (Holahan, Moss and Bonin, 1999). Even though in recent years the relationship between coping (strategies/types) and psychopathology was clearly defined (Compas et al., 2001; Endler and Parker, 1990; Thoits, 1995), it is unclear to what extent certain influences could be specifically attributed to cognitive aspects in the sense that nobody knows exactly how beliefs influence coping directly and indirectly. It is assumed that cognitive strategies refer to patients’ styles of coping with negative life events, which are non-superimposable with personality traits because in some cases people use specific cognitive strategies that differ from the strategies they would otherwise use. It is also assumed that the cognitive coping strategies can be affected, changed, learned or forgotten, for example, through psychotherapy, intervention programs or individual experiences. In order to influence the patients’ cognitive coping it was necessary to have the tools to evaluate the cognitive components of emotion regulation in adolescents and/or adults. It was observed that no such instruments were available (Garnefski et al., 2001). Following that observation, the Cognitive Emotion Regulation Questionnaire (CERQ) was developed (Garnefski et al., 2001; Garnefski, Kraaij and Spinhoven, 2002). Further studies carried out by Garnefski et al. (2002, 2003), using CERQ, showed that a large measure of Rumination, Catastrophizing, and Self-blame was associated with the presence of psychopathological symptoms. These seemingly maladaptive coping (strategies/types) can be, therefore, an important factor in the prevention and / or management of the emotional response to the negative life events.

CERQ calibration on the Romanian population was made in 2010 (Garnefski N, Kraaij V, Spinhoven P, Perțe A and Țincaș I, 2010).

The history of immediate-type hypersensitivity reactions to drugs (DHRs) generates, depending on their intensity, different degrees of emotional distress.

Immediate DHRs include urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, gastrointestinal symptoms [nausea, vomiting, diarrhea, and abdominal pain], anaphylactic shock; they typically occur within 1– 6 h after the last drug administration (Demoly P. et al., 2014).

The need to use new drugs reactivates in these patients, irrational beliefs related to previous emotional distress and dysfunctional behaviors (maladaptive coping) that may interfere with their management (e.g. denial, resignation, fatalism) (Iamandescu and Diaconescu, 2010).

Latest guidelines and international consensus acknowledge the role of stress and anxiety related to allergic events and that the hypersensitivity reactions to drugs is more likely related to the patients’ psychological profile; they make recommendations for counseling but do not show exactly which psychological factors are involved in generating these events and do not refer to coping strategies involved in these cases (“NICE clinical guideline 183, Drug allergy Diagnosis and management of drug allergy in adults, children and young people Clinical guideline 183 Methods, evidence and recommendations”, 2014; “International Consensus on drug allergy”, 2014).

Background There have been numerous studies that have shown the involvement of psychological factors in the immediate hypersensitivity reactions to drugs (drug allergies) (Demoly et al., 2005, 2014; Diaconescu, 2006, 2007; Gomes et al., 2004, 2005; Iamandescu, 1993, 1999, 2002, 2003, 2004, 2009, 2010; Johansson et al., 2004; Kamei et al., 1998; Kovacs and Arato, 1997; Ziffra and Gollan, 2009). They have demonstrated that there is an important psychological component associated to both the onset and the maintenance of the hypersensitivity reactions to drugs so that after a severe allergic incident psychic vulnerability is generated that can be further responsible for an inappropriate perception of a new hypersensitivity or intolerance reaction to drugs is generated.

The problem of maladaptive coping (mechanisms/ types) is intensely debated internationally. Lazarus et

Aim of the study/ objectives Assessment of the disparities between the perception of the seriousness of the previous immediate-type hypersensitivity reactions to drugs, perception of the allergy reassessment risk, cognitive coping strategies (cognitive emotion regulation), the distress generated by the re-evaluation of the drug hypersensitivity in patients with a functional coping type (coming for re-

20

Cognitive coping role in the management of patients with a history of immediate-type hypersensitivity to drugs

the Allergy Center for the (re)assessment of immediate-type hypersensitivity to drugs on their „own initiative”; GROUP B - included 25 patients who presented to the Allergy Center for the (re)assessment of immediate-type drug hypersensitivity “forced by circumstances” (illness, investigations, etc.).

Patients were randomly included in the study, in the order of their arrival into the Allergy Center. Pre-study, patients were informed about the study objectives, about the issues related to privacy and protection of personal data and, after that, they signed the Informed Consent Form.

evaluation “on their own initiative”) and the same items for patients who present a dysfunctional coping type (coming for re-evaluation “forced by circumstances” due to surgery, illness, investigations, etc.).

The working assumption Based on the results obtained by Garnefski et al.

(2002, 2003) using the Cognitive Emotion Regulation Questionnaire (CERQ), which showed that a large measure of Rumination, Catastrophizing, and Self-blame is associated with the presence of psychopathological symptoms, we expect significant differences between the cognitive coping (types) in the group returning to the allergist on their own initiative (functional behavior) compared with the group returning to the allergist forced by circumstances (illness, investigations, etc.) (dysfunctional behavior).

To verify the assumption, we proceeded to make the following statistical analysis: 1. correlation analysis between the real severity grade and the perceived seriousness of the previous immediate-type hypersensitivity reactions to drugs in patients who come to the re-evaluation “on their own initiative” compared with patients who come to re-evaluation “forced by circumstances”; 2. correlation analysis between the perception of the severity of the previous immediate-type hypersensitivity reactions to drugs and cognitive coping (cognitive emotion regulation) in patients who come for the re-evaluation „on their own initiative” compared with patients who come for reevaluation „forced by circumstances”; 3. c orrelation analysis between the expectations of the risk for a new immediate-type hypersensitivity reaction to drugs and the emotional distress before re-evaluation in patients who come to re-evaluation “forced by circumstances” compared with patients who come for re-evaluation “on their own initiative”; 4. c omparison between the 2 groups with regard to cognitive coping (types).

a. Inclusion criteria: - Patients with a history suggestive of an immediatetype hypersensitivity reaction (regardless of severity and regardless of the drug); the symptoms assessment utilized the ENDA drug allergy questionnaire (Demoly et al., 1999); - Adults (≥18 years) at the time of enrollment. b. Exclusion criteria: - pregnancy; - treatment with antihistamines or other medications that interfere with the allergologic diagnostic tests accuracy, acute allergic reaction at presentation.

Measurement tools: - 5 standardized tests were used (licensed) (recognized by the Romanian College of Psychologists). They were chosen to operationalize psychological constructs described in the objective and formulated hypothesis.

We used the following tests: TEST 1: - a numerical assessment scale of the perception of the seriousness of the previous immediatetype hypersensitivity reactions to drugs (1 to 10); TEST 2: - a numerical scale for assessing expectations of a risk for new immediate-type hypersensitivity reactions to drugs (during the re-evaluation of the drug allergy)(1 to 10); TEST 3: - Cognitive Emotion Regulation Questionnaire (CERQ) (Cognitrom licence) – a multidimensional questionnaire, designed to identify cognitive coping types, which one uses after experiencing negative life events or situations. In contrast to other questionnaires on coping, which do not make a clear distinction between a person’s thoughts and behavior, CERQ refers exclusively to a person’s thoughts after having lived a negative experience. Psychometric data: CERQ is a self-evaluation questionnaire with 36 items

Method Participants: There were 50 patients with a history of immediatetype hypersensitivity reaction to medication included in the study. They were divided into 2 groups: GROUP A - included 25 patients who presented to

21

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

original articles and brief communications

and 9 rating scales for assessing Cognitive coping strategies (Self-blame, Acceptance, Rumination, Positive refocusing, Refocus on planning, Positive reappraisal, Putting into perspective, Catastrophizing, Other-blame) and is targeting the children and adults of normal and clinical populations. For the different sub-scales in the various populations, Cronbach’s alpha coefficients are good to very good (in most cases more than 0.70 and in many cases even more than 0.80). Regarding the homogeneity of scales, most correlations between items and the rest of the scale are well above 0.40, while the lowest value does not fall below 0.35 which confirms that no item can be classified as inappropriate and/or proposed for exclusion (Garnefski et al., Manual for the use of the Cognitive Emotion Regulation Questionnaire, 2010); TEST 4: - Emotional Distress Profile questionnaire (PDE)(RTS licence) - a questionnaire designed to identify the perceived emotional distress of the patient BEFORE re-evaluating of the hypersensitivity to drugs; PDE is a scale with 26 items that measure functional negative emotions (“concern”, “sadness”) and dysfunctional negative emotions (“anxiety/fear”, “depression”) (David D, 2012). The test can be used both for persons without psychopathology and for those with various forms of psychopathology and has two components: total distress (PDE-TOT) and dysfunctional distress (PDE-disf ). It is recommended for use in people over 14 years, in normal and clinical populations; TEST 5: - same PDE questionnaire in order to identify the perceived emotional distress to the patient AFTER re-evaluating the hypersensitivity to drugs.

- Ethics Committee Approval no. 224/ 01.06.2016 in order to conduct the study within the Clinical Emergency County Hospital, Cluj-Napoca, Allergy Centre; - Ethics Committee Approval no. 64 / 03.14.2016 of the “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca for the design of the study and report.

Preparation of the documentation: Consent Forms, Questionnaires.

Database establishment: The database was established using the MICROSOFT EXCEL program so as to contain the following items (columns): a. personal data: name (initial), gender, age, origin (urban/rural areas) b. reason for the re-evaluation of the immediatetype hypersensitivity to drugs: • version 1 = “own initiative” • version 2 = “forced by circumstances” c. The severity of the allergic drug incident from the patient’s history: urticaria; angioedema; hypotension; bronchospasm/dyspnea; anaphylactic shock; the grade of severity for quantification of immediate hypersensitivity reactions, included: the grade I reactions (cutaneous signs: generalized erythema, urticaria, angioedema), grade II (measurable but not life-threatening symptoms as cutaneous signs, hypotension, tachycardia, respiratory disturbances: cough, difficulty inflating), grade III (life-threatening symptoms: collapse, tachycardia or bradycardia, arrhythmias, bronchospasm) and grade IV (cardiac and/or respiratory arrest) (Mertes et al., and the Working Group of the SFAR and SFA and W Aberer et al. for END and the EAACI Interest Group on Drug Allergy, 2011) Step 2. Patient Selection Patients were randomly selected in order of their presenting to the Allergy centre, based on inclusion criteria. Those included were adults (≥18 years) coming from urban and rural areas.

Step 3. Administration of tests After initial patients’ training on the objectives of the study and after obtaining the patients’ signatures on The Informed Consent forms, patients were handed Test 1, 2, 3, 4 (before re-evaluation of the hypersensitivity reactions to medicines); Test 5 was handed after reassessing the drug hypersensitivity.

Step 4. Collection of tests, scoring and introducing the scores in the database Step 5. Statistical analysis Statistical analysis was performed with software Statistics v. 8 at a significance level of 5%, so p < 0.05

Research design Non-experimental descriptive and correlational clinical trial

Methodology Study duration: 3 months.

Location: A llergy Center of the Clinical Emergency C o u nt y Ho s p i t a l C l u j - Na p o c a , Coordinator of the Allergy Center: Lecturer Nadia Oniţiu- Gherman, Allergist MD Steps: Step 1. Preliminary Obtaining the approvals:

22

Cognitive coping role in the management of patients with a history of immediate-type hypersensitivity to drugs

Group 1 = Own initiative (n=25)

Group 2 = Forced by circumstances (n=25)

Gender– n(%) F (female) M (male) p (difference between F and M)

22 (88.00) 3 (12.00) < 0.0001

20 (80.00) 5 (20.00) < 0.0001

Provenience – n(%) Rural Urban p (difference between rural and urban)

4 (16.00) 21 (84.00) < 0.0001

1 (4.00) 24 (96.00) < 0.0001

Age (years) – average ± standard deviation

47.04±16.55

52.40±15.34

0.2409

Group 1 = Own initiative

Group 2 = Forced by circumstances

p (difference between groups)

Urticaria

12%

20%

0.6366

Angioedema

24%

40%

0.2184

Hypotension

4%

0%

0.3093

Bronchospasm/dyspnea

28%

0%

0.0018

Anaphylactic shock

32%

40%

0.7651

Variables

p (difference between groups) 0.2184

0.1017

Table 1. Demographic characteristics and differences between groups

Table 2. Distribution of the previous immediate-type hypersensitivity reactions to drugs

Results

was considered statistically significant (p = probability of obtaining results, considering that null hypothesis is true; if p < 0.05 the null hypothesis is rejected and research hypothesis is accepted). Parametric tests were used for continuous variables and nonparametric tests for discrete variables (nominal or ordinal).

Demographic characteristics and differences between the 2 groups in terms of gender and origin are summarized in Table 1.

Distribution of the previous immediate-type hyper-

23

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

ORIGINAL ARTICLES AND BRIEF COMMUNICATIONS

Group 1 = Own initiative (n=25)

Group 2 = Forced by circumstances (n=25)

Spearman

p-level

Spearman

p-level

PSA-U & T1

-0.3414

0.0948

-0.4336

0.0304

PSA-A & T1

-0.3213

0.1173

0.0354

0.8666

PSA-hTA & T1

0.2086

0.3170

n.a.

n.a.

PSA-BPD & T1

-0.0585

0.7811

n.a.

n.a.

PSA-AS & T1

0.5007

0.0108

0.3854

0.0571

PSA= previous severity grade of allergic reaction T1(Test 1)= the perception of the seriousness of the previous immediate-type hypersensitivity reaction to drugs U= urticaria; A= angioedema; HTA= hypotension; BPD=bronchospasm/dyspnea; AS= anaphylactic shock n.a.= Not available (it cannot be calculated because there are no PAI-HTA and PAI-BPD subjects in group 2)

Table 3. Correlation between real seriousness and the perception of the seriousness of the previous immediate-type hypersensitivity reaction to drugs

Group 1 = Own initiative (n=25)

Group 2 = Forced by circumstances (n=25)

Spearman

p-level

Spearman

p-level

T3-SB

& T1

-0.2285

0.2720

0.0169

0.9361

T3-AC

& T1

0.2628

0.2044

-0.2340

0.2602

T3-RU

& T1

0.1162

0.5802

-0.0172

0.9351

T3-PR & T1

0.3884

0.0550

0.0905

0.6670

T3-REP & T1

0.2113

0.3105

0.1262

0.5477

T3-PREA & T1

0.0962

0.6473

-0.2563

0.2162

T3-PP & T1

-0.2535

0.2214

-0.2682

0.1950

T3-CA

& T1

-0.0540

0.7975

0.0020

0.9924

T3-OB

& T1

-0.0962

0.6474

-0.2086

0.3170

T3 (Test 3)= Cognitive Emotion Regulation Questionnaire (CERQ) SB=Self-blame, AC=Acceptance, RU=Rumination, PR=Positive refocusing, REP=Refocus on planning, PREA=Positive reappraisal, PP=Putting into perspective, CA=Catastrophizing, OB=Other-blame Table 4. C orrelation analysis between the perception of the severity of the previous immediate-type hypersensitivity reactions to drugs (T1) and cognitive coping (cognitive emotion regulation) (T3-)

24

Cognitive coping role in the management of patients with a history of immediate-type hypersensitivity to drugs

reactions to drugs (T1) and cognitive coping (type)(cognitive emotion regulation) (T3-) in patients who come for the re-evaluation on „own initiative” compared with patients who come to re-evaluation „forced by circumstances” (Table 4).

- in group 1 (own initiative) we didn’t find statistically significant correlations except the correlation between T1 and beliefs of „positive refocusing” (p = 0.0550 ); - in group 2 (forced by circumstances) we didn’t find any statistically significant correlations.

sensitivity reactions to drugs is presented in Table 2. In group 2 the most common incidents were allergic angioedema (40%) and anaphylactic shock (40%) and in group 1 the most frequent was a history of anaphylactic shock (32%). Hypotension (4%) and bronchospasm/ dyspnea (28%) were identified solely in group 1.

Bronchospasm/allergic dyspnea was the only incident in history significantly more frequent in group 1 versus group 2 (p = 0.0018) Statistical analysis performed in order to verify the assumption 1. Correlation analysis between the real severity grade and the perception of the seriousness of the previous immediate-type hypersensitivity reactions to drugs in patients who come for re-evaluation on “own initiative” compared with patients who come for re-evaluation “forced by circumstances” (Table 3).

- in group 1 (own initiative), we found a strong and positive correlation (statistically significant) between the real seriousness and the perception of the seriousness of the previous immediate-type hypersensitivity reactions to drugs in patients who have had anaphylaxis (p = 0.0108); - in group 2 (forced by circumstances), we found a strong and negative correlation (statistically significant) between the real seriousness and the perception of the seriousness of the previous immediate-type hypersensitivity reactions to drugs in patients who have had urticaria (p=-0.4336).

3. Correlation analysis between expectations of a risk for a new immediate-type hypersensitivity reaction to drugs (T2) and the emotional distress before re-evaluation (T4) in patients who come for re-evaluation “forced by circumstances” compared with patients who come for re-evaluation “on their own initiative” (Table 5).

We found a positive correlation (statistically significant) in group 2 between expectations of a risk for a new immediate-type hypersensitivity reaction to drugs and total/dysfunctional distress (T4 PDE-TOT/ T4 PDE-disf ).

4. Comparison between the 2 groups with regard to cognitive coping strategies (T3) (Table 6).

When comparing cognitive coping (T3-) between the 2 groups we found statistically significant differences (more pronounced in group 2) in the following cognitions: SB=Self-blame (p=0.0244), AC=Acceptance (p=0.0336), REP=Refocus on planning (p=0.0277), PREA=Positive reappraisal (p=0.0004), PP=Putting into perspective (p=0.0298) and CA=Catastrophizing (p=0.0328).

2. Correlation analysis between the perception of the severity of the previous immediate-type hypersensitivity

Group 1 = Own initiative (n=25)

Group 2 = Forced by circumstances (n=25)

Spearman

p-level

Spearman

p-level

T4 PDE-TOT & T2

0.1649

0.4308

0.4372

0.0289

T4 PDE-disf & T2

0.1880

0.3681

0.4365

0.0291

T2 (Test 2) = a numerical scale used for assessing expectations of a risk for new immediate-type hypersensitivity reactions to drugs T4 PDE- TOT = total distress evaluated with T4 T4 PDE-disf = dysfunctional distress evaluated with T4 Table 5. C orrelation analysis between expectations of a risk for a new immediate-type hypersensitivity reaction to drugs (T2) and total distress (T4 PDE-TOT), respectively dysfunctional distress (T4 PDE-disf)

25

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

ORIGINAL ARTICLES AND BRIEF COMMUNICATIONS

Group 1

Group 2

T3-SB

T3-AC

T3-RU

T3-PR

T3-REP

T3-PREA

T3-PP

T3-CA

T3-OB

average

3.52

4.84

4.48

4.96

4.72

4.68

5.04

5.32

3.60

stdev

1.81

1.93

2.06

2.19

2.19

1.60

1.59

1.68

1.61

median

3

4

5

6

5

5

5

6

4

Q1

2

4

3

3

4

4

4

5

2

Q3

5

7

6

7

7

6

6

6

5

average

4.96

5.96

5.44

5.88

6.12

6.16

6.00

6.12

4.08

stdev

2.44

1.27

1.64

1.67

1.05

1.57

1.15

1.39

1.89

median

6

7

6

7

7

7

6

7

4

Q1

4

5

4

5

5

6

5

6

2

Q3

7

7

7

7

7

7

7

7

5

0.0244

0.0336

0.1031

0.1253

0.0277

0.0004

0.0298

0.0328

0.3773

p

T3 (Test 3) = Cognitive Emotion Regulation Questionnaire (CERQ) SB=Self-blame, AC=Acceptance, RU=Rumination, PR=Positive refocusing, REP=Refocus on planning, PREA=Positive reappraisal, PP=Putting into perspective, CA=Catastrophizing, OB=Other-blame average = average of the frequencies stdev = standard deviation median =mean part of the series Q1 = quartile 1 (inferior 25% of the series), Q3= quartile 3 (superior 25% of the series) Table 3. Correlation between real seriousness and the perception of the seriousness of the previous immediate-type hypersensitivity reaction to drugs

Discussions

nal factors generated by the need for re-evaluation.

The fact that PR=Positive refocusing was found to be correlated with positive coping in functional group 1, partially validates the hypothesis that these patients frequently encounter positive cognitions which corresponds with the results of Garnefski et al., 2010; Positive refocusing occurs when we think of more pleasant things, instead of thinking about the negative events of life.

The positive correlation (statistically significant) in group 2 between expectations of a risk for a new immediate-type hypersensitivity reaction to drugs and total/ dysfunctional distress can be explained by the fact that they did nothing to clarify their hypersensitivity to drugs and now they are again faced with this problem plus the new issue of a medical nature.

Significant differences in terms of gender (more women than men; p <0.0001) and in terms of place of origin (more patients in urban than rural areas p <0.0001) correspond to the data in the literature (Barranco and Lopez-Serrano, 1998; Bernard and TeckChoon Tan, 2011; Kando and Yonkers, 1995; Haddi et al., 1990). A possible explanation for the increased frequency in women is that they use more antibiotics than men (Macy and Poon, 2009).

Correct assessment of the gravity of anaphylactic shock in both groups can be explained by the fact that this is most easily assessed; â&#x20AC;&#x153;paradoxicalâ&#x20AC;? assessment of Urticaria in group 2 can be explained by lack of knowledge in the field or by other cognitive or emotio-

26

Cognitive coping role in the management of patients with a history of immediate-type hypersensitivity to drugs

2. Bernard Y-H Thong, Teck-Choon Tan. Epidemiology and risk factors for drug allergy. Br J Clin Pharmacol. 2011; 71(5), 684–700. doi: 10.1111/j.1365-2125.2010.03774.x 3. Compas BE, Connor-Smith JK, Saltzman H, Thomsen AH, Wadsworth M. Coping with stress during childhood and adolescence: Progress, problems, and potential. Psych Bull. 2001;127:87–127.

4. David D. Tratat de psihoterapii cognitive si comportamentale, Ed Collegium Polirom, Ed II. 2012; 104.

5. Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity.

Allergy 1999;54:999–1003.

6. Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, Khan DA, Lang DM, Park H-S, Pichler W, SanchezBorges M, Shiohara T, Thong BY-H. International Consensus on drug allergy. Allergy. 2014; 69, 420–437.

7. Diaconescu L. Implicații psihologice ale tratamentului farmacologic, In: Popa-Velea (edited by), Diaconescu L, Necula Cioca I, Psihologie medicală, Editura Universitară “Carol Davila”, București. 2006.

8. Diaconescu L, Iamandescu IB. Allergic-type reactions to drugs, In: IB Iamandescu (edited by), Psychoneuroallergology (2nd ed.), Editura Medicală Amaltea, București. 2007.

9. Endler NS, Parker JDA. Multidimensional Assessment of Coping: A Critical Evaluation. Journal of Personality and Social Psychology.

1990;58(5), 844-854.

10. Garnefski N, Kraaij V, Spinhoven P. Negative life events, cognitive emotion regulation and depression. Personality and Individual Differences. 2001;30, 1311–1327.

11. Garnefski N, Kraaij V, Spinhoven P. Manual for the use of the Cognitive Emotion Regulation Questionaire, Leiderdorp, The Netherlands: DATEC. 2002.

12. Garnefski N, Kraaij V, Spinhoven V, Perțe A, Țincaș I. CERQ Manualul de utilizare a Chestionarului de coping cognitiv-emoționalAdaptarea și standardizarea CERQ pe populația din România, ASCR. 2010;9-14 13. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunology. 2005; 5, 309–316.

14. Gomes ER, Cardoso MF, Praca F, Gomes L, Marino E, Demoly P. Selfreported drug allergy in a general adult Portuguese population. Clin Exp Allergy. 2004; 34, 1597–1601.

15. Haddi E, Charpin D, Tafforeau M, Kulling G, Lanteaume A, Kleisbauer JP, Vervloet D. Atopy and systemic reactions to drugs.

Allergy. 1990; 45, 236–9.

16. Holahan CJ, Moos RH, Bonin L. Social context and depression: An integrative stress and coping framework. In: Joiner T, Coyne J, editors.

The interactional nature of depression: Advances in interpersonal approaches. Washington, DC: American Psychological Association; 1999; p. 39–63.

17. Iamandescu IB. Stresul psihic şi bolile interne. Ed.ALL, Bucureşti.

1993.

18. Iamandescu IB. Psihologie Medicală, ed.a 2-a, Ed.Infomedica, Bucureşti. 1996.

19. Iamandescu IB. Psychoneuroallergology, Romcartexim, Bucureşti.

1998.

20. Iamandescu IB. Elemente de psihosomatica alergologica, In: I.B. Iamandescu (edited by), Elemente de psihosomatica generala si aplicata, Editura Infomedica, Bucuresti. 1999.

The fact that patients in the group 2 had more dysfunctional cognitions like Self-blame and Catastrophizing than patients in group 1 corresponds to the results obtained by Garnefski et al. (2002, 2003). More “functional” cognitions at group 2 like Acceptance, Refocus on planning, Positive reappraisal and Putting into perspective can be interpreted as a cognitive coping strategy that reduces the emotional distress of the moment (feeling better) without generating a functional behaviour leading to the clarification of the medical situation (getting better).

Conclusions The fact that some significant differences were identified between the 2 groups regarding perception of the severity of the previous immediate-type hypersensitivity reactions to drugs, regarding cognitive coping related to the perception of the previous allergic incident (significant for “positive refocusing” in group 1), regarding emotional distress related to expectations of a new allergic incident at re-evaluation (higher in group 2) and regarding the cognition types (higher in group 2) can allow us to say that the assumption of the study is partially validated. Further studies are necessary to a complete validation of the hypothesis that there are significant differences between cognitive coping mechanisms in the group returning to the allergist on their own initiative (functional behavior) compared with the group returning to the allergist forced by circumstances (illness, investigations, etc.) (dysfunctional behavior).

Acknowledgement The questionnaires used were licensed and were donated by dr. Doina Colcear, psychiatrist, practicing psychotherapist without other financial implications for patients, for “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca or Emergency County Hospital, Cluj- Napoca.

Conflicts of interests: The authors declare no conflicts of interests.

References 1. Barranco P, Lopez-Serrano MC. General and epidemiological aspects of allergic drug reactions. Clin Exp Allergy. 1998; 28(Suppl 4), S61–S62.

27

Cognitive coping role in the management of patients with a history of immediate-type hypersensitivity to drugs

21. Iamandescu IB. Stresul psihic din perspectivă psihologică și psihosomatică, Editura Infomedica, București. 2002.

22. Iamandescu IB, Chivu A. Alergia medicamentoasa, In: IB Iamandescu (ed), Psihologie Medicala- Psihosomatică Generală și Aplicată, Editura Infomedica, București. 2009.

23. Iamandescu IB, Diaconescu L. Stress Vulnerability in Patients with Drug Allergy –Psychological Aspects Revealed from some Personal Studies. Romanian Journal of Internal Medicine. 2010;4, 371-377.

24. Iamandescu IB, Luban-Plozza B. Stresul psihic – placă turnantă a Medicinii Psihosociale, In: B Luban-Plozza and IB Iamandescu (edited by), Dimensiunea psihosocială a Practicii Medicale, Editura Infomedica, București. 2003.

25. Johansson SGO, Bieber T, Dahl R. et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004; 113, 832–836.

26. Kamei T, Tsuda T, Kitagawa S, Naitoh K, Nakashima K, Ohhashi T. Physical stimuli and emotional stress-induced sweat secretions in the human palm and forehead; International Cyber Congress on Analytical BioSciences. 1998; no. 1, JAPON (21/08/1997), 365, 1–3 (334 p.) (16 ref.), p. 319–326.

27. Kando JC, Yonkers KA, Cole JO. Gender as a risk factor for adverse events to medications. Drugs. 1995;50, 1– 6.

28. Kovacs M, Arato M. The prevalence of allergic diseases in affective and anxiety disorders, European Neuropsychopharmacology. 1997;7, suppl. 2, S273–S274.

29. Lazarus RS, Folkman S. Stress, Appraisal and Coping. Springer Publishing Company, New York. 1984.

30. Lazarus RS, Folkman S. Transactional Theory and Research on emotions and coping. European Journal of Personality. 1987;1, 141-169.

31. Macy E, Ho NJ. Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management. Ann Allergy Asthma Immunol. 2012;108, 88–93 32. Macy E, Poon K-Y T. Self-reported Antibiotic Allergy Incidence and Prevalence: Age and Sex Effects, The American Journal of Medicine.

2009;122, 8, 778.e1–778.e7.

33. Mertes PM, Malinovsky JM, Jouffroy L, and the Working Group of the SFAR and SFA and Aberer W, Terreehorst I, Brockow K, Demoly P, for ENDA and the EAACI Interest Group on Drug Allergy, Reducing the Risk of Anaphylaxis During Anesthesia: 2011 Updated Guidelines for Clinical Practice. J Investig Allergol Clin Immunol.

2011; 21(6): 442-453) 34. NICE clinical guideline 183 Drug allergy. Diagnosis and management of drug allergy in adults, children and young people. Clinical guideline 183 Methods, evidence and recommendations. 2014.

35. Thoits PA. Stress, coping, and social support processes: Where are we? What next? Journal of Health and Social Behavior. 1995;35, 5379.

36. Ziffra MS, Gollan JK. Management of the psychologically complicated patient, In: LC Grammer & PA Greenberger(eds), Patterson’s Allergic Diseases, 7th edition, Lippincott Williams & Wilkins. 2009; 662–670.

28

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

ORIGINAL ARTICLES AND BRIEF COMMUNICATIONS

Angioedema due to acquired C1-inhibitor deficiency with late onset and unclear cause Polliana Mihaela Leru1,2, Vlad Florin Anton1

“Colentina” Clinical Hospital, Bucharest, Romania “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 1

2

ABSTRACT We report a case of a 73 years old woman addressed to the Allergology Department of our hospital for recurrent attacks of facial and peripheral angioedema since the age of 66, considered first to be induced by treatment with angiotensin-converting – enzyme inhibitors (ACEI). She continued to have angioedema attacks for seven years after discontinuation of ACEI, with progressive aggravation during the last year. The extended medical evaluation for inflammation, allergy, autoimmunity and cancer was negative. The plasma levels of C1 inhibitor esterase (C1-INH) and C4 were significantly decreased at all measurements, but no diagnostic criteria for a disease known to induce C1-INH deficiency could be found. We first initiated daily prophylactic treatment with tranexamic acid, with no amelioration after three months. During the last more severe attack we have switched to attenuated androgen danazol. The clinical evolution was very good, with prompt remission of angioedema and significant increase of C1-INH and C4 plasma levels after two weeks of daily danazol use. No angioedema attack occurred during the next two years since introduction of danazol, with the lowest daily maintenance dose and no side effects of this therapy were noted.

KEYWORDS: acquired angioedema, attenuated androgens, C1 Inhibitor deficiency

Introduction

hereditary angioedema (HAE) were identified as separate forms (Cicardi M et al., 2014). Acquired angioedema mediated by histamine is called histaminergic, being usually related to various allergic stimuli, infectious or autoimmune diseases, but also idiopathic or spontaneous when no cause can be identified (Zingale LC et al., 2006).

Acquired angioedema mediated by bradykinin may be induced by treatment with angiotensin-converting enzyme inhibitors or may be due to acquired deficiency of C1 inhibitor or may have no identified cause. Angioedema due to acquired deficiency of C1-INH (C1-INH-AAE) is a rare disease that may look like hereditary angioedema,

Angioedema is defined as localized and self-limited edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive mediators (Zuberbier T et al., 2009). Angioedema may be accompanied by urticaria, usually due to allergies, or without urticaria. In this last situation angioedema is considered a distinct disease that may have hereditary or acquired forms. According to the recent classification of angioedema without urticaria, four types of acquired angioedema (AAE) and three types of

Corresponding Author: Polliana Mihaela Leru 8 Dr. Nicolae Manolescu street, postal code 050583, Bucharest; E-mail: polianaleru@yahoo.com Submission date: 07/04/2016; Acceptance date: 05/10/2016; Publication date: 24/10/2016

29

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

ORIGINAL ARTICLES AND BRIEF COMMUNICATIONS

Figure 1. We report a case of a 73 years old woman who came to the Allergology Department of our hospital for recurrent episodes of angioedema since the age of 66, considered first to be induced by treatment with angiotensin-converting â&#x20AC;&#x201C; enzyme inhibitors (ACEI) for mild hypertension.

but without family history and with onset after the age of 40 years. Most of the cases are secondary to malignant tumors, usually lymphoma or autoimmune disorders such as systemic lupus erythematosus, but others remain idiopathic and may rise severe clinical problems (Hauptmann G et al., 1976)). The clinical picture consists in recurrent episodes of angioedema of the face, tongue and upper airways, although any part of the body can be involved (Zingale LC et al., 2006). Gastrointestinal swelling attacks are less common in C1-INH-AAE patients compared with HAE cases (Bouillet -Claveyrolas L et al., 2003).

Laboratory tests that confirm diagnosis are reduced activity of C1-INH below 50% and antigen levels similarly reduced. The presence of cleaved C1-INH may give apparently normal C1-INH antigen in about 20% cases (Zuraw BL et al.,1986). Significantly reduction of C4 plasma levels is almost invariably present.

enzyme inhibitors (ACEI) for mild hypertension. She continued to have angioedema attacks at weeks or months intervals for seven years after discontinuation of ACEI, with progressive aggravation during the last year. The previous multiple evaluations in other hospitals did not succeed to give a clear diagnosis and treatment (Figure 1).

Patient history The patient had no relevant medical history and has taken no medication for at least two years, when episodes of angioedema became more frequent and severe.

No relation with possible allergic stimuli could be identified and she had no clinical signs between attacks.

Angioedema was painful, not accompanied by urticaria or abdominal symptoms, located variably to face, neck, arms or buttocks and usually lasted 72 hours, irrespective corticosteroids and antihistamines treatment. The frequency of attacks increased from one at two-three months intervals to almost weekly. The last angioedema attack was more severe and prolonged, accompanied by respiratory symptoms and laryngeal edema. The extended medical evaluation included complete blood tests for inflammation, allergy, autoimmunity and can-

Case presentation We report a case of a 73 years old woman who came to the Allergology Department of our hospital for recurrent episodes of angioedema since the age of 66, considered first to be induced by treatment with angiotensin-converting â&#x20AC;&#x201C;

30

Angioedema due to acquired C1-inhibitor deficiency with late onset and unclear cause

Date June-2009

C1INH antigen

C4

0.22 (N>0.26 g/L)

8 (N>10 mg/dL)

Apr-2010

C1INH activity

8

May-2011

0.19

Jun-2011

0.22

8

Aug-2013

0.19

6

Jan-2014

0.19

2

47 %

01/09/2014

0.15

1

4%

Dec-2014

0.36

15

115 %

*Mar-2015

0.29

9

86 %

**Apr - 2015

0.21

3

Jun - 2015 Sep - 2015

8 0.26

8

Mar – 2016 May - 2016

58 %(N>70%)

9 0.318

13

110%

01/09/2014 – start Danazol treatment After 2 weeks without treatment ( Danazol ) After 1 month without Danazol Table 1. Distribution of the previous immediate-type hypersensitivity reactions to drugs

cer that were all negative. Full body CT scan and bone marrow examination were normal. No criteria for lymphoproliferative, myeloproliferative or autoimmune disease could be found. Genetic tests were not performed, given the patient’s advanced age and lack of familial history of angioedema. The C1 inhibitor (C1INH) plasma level was significantly decreased at all measurements, with low activity ranging from 58% to 4% and constantly low C4.

with tranexamic acid for three months, with no amelioration. During the last severe attack we have switched to attenuated androgen danazol, given 400 mg the initial dose, reduced to 200 mg after one week and then to 100 mg daily. The clinical evolution after nine months was very good, no angioedema attack occurred since the introduction of danazol. C1INH and C4 plasma levels increased after two weeks treatment and became normal after one month (Table 1). The patient decided to try to discontinue danazol for two weeks, which has led to decrease of C1-INH and C4 plasma levels, but with no angioedema attack, therefore she restarted danazol at the lowest dose daily. The clinical outcome after two years treatment with danazol was very good, no angioedema attack or other symptoms have occurred. No side effect of danazol therapy was noted. We recommended close monitoring of liver function and lipid profile, with complete medical evaluation after one year or in case of any clinical or laboratory change.

Treatment and evolution Angioedema attacks before hospitalization were usually treated with antihistamines and systemic corticosteroids which proved ineffective. Since no pathogenic therapy, such as C1INH concentrate, antagonists of bradykinin receptors (icatibant) or selective inhibitor of plasma kallikrein (ecallantide) was available, we first initiated daily prophylactic treatment

31

Angioedema due to acquired C1-inhibitor deficiency with late onset and unclear cause

Discussion

Patient consent for publication

Angioedema due to acquired deficiency of C1-INH is a very rare disease, its prevalence being estimated at 1:10 from that of the hereditary form, meaning around 1:500.000 (Zingale LC et al., 2006). The awareness of this disease within medical community is very low, since most of the cases of angioedema are generally considered allergies. The onset at advanced age and lack of any familial or personal history, as well as negative allergologic investigation should prompt the physician to search underlining causes of C1-INH deficiency. The pathophysiologic mechanisms are consumption of C1-INH and classical pathway complement components and activation of contact system, with bradykinin release during attacks. The lymphoproliferative disease, frequently found in these patients, could directly contribute to consumption of C1-INH (Cugno M et al.,1996). Autoantibodies neutralizing C1-INH function can be found in collagen vascular diseases such as systemic lupus erythematosus (SLE). Data from the literature mention that about 10% of the AAE cases due to acquired C1INH deficiency remain idiopathic, with no underlining disease. Treatment of AAE due to C1-INH deficiency should consider the underlining disease, as well as the frequency and severity of angioedema attacks.

Symptomatic treatment for angioedema recurrences can be provided using C1-INH replacement therapy and bradykinin-targeted drugs, which are generally not available in many countries. Less expensive alternatives for long term prophylaxis are either tranexamic acid, which is considered by some authors as drug of choice for C1-INH-AAE or attenuated androgens, which may appear a still useful treatment option in some cases (Agostoni A et al., 2004).

The patient gave written informed consent for publication of the medical report, including personal photos. A copy of the written consent is available for review by the Chief Editor of the journal.

Conflicts of interests: The authors declare no conflicts of interests.

References 1. Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114 (Suppl3):S51-S131 2. Bouillet-Claveyrolas L, Ponard D, Drouet C, Massot C. Clinical and biological distinctions between type I and type II acquired angioedema. Am J Med 2003;115:420-421.

3. Cicardi M, Aberer W, Banerji A, Bas M, Bernstein JA, Bork K, Caballero T et al. Classification, diagnosis and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Position paper. Allergy 69 (2014), 602-616 4. Cicardi M, Zanichelli A. Acquired angioedema. Allergy Asthma Clin Immunol 2010;6:14.

5. Cugno M, Cicardi M, Coppola R, Agostoni A. Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies.

Immuno-pharmacology 1996;33:361-364.

6. Hauptmann G, Lang JM, Noth ML, Oberling F, Mayer G, Lachmann P. Acquired C1-inhibitor deficiencies in lymphoproliferative diseases with serum immunoglobulin abnormalities. A study of three cases. Blut 1976;32:195-206.

7. Zingale LC, Beltrami L, Zanichelli A, Magionni L, Pappalardo E, Cicardi B et al. Angioedema without urticaria: a large clinical survey. CMAJ 2006;175:1065-1070 8. Zingale LC, Castelli R, Zanichelli A, Cicardi M. Acquired deficiency of the inhibitor of the first complement component: presentation, diagnosis, course and conventional management. Immunol Allergy Clin North Am 2006;26:669-690.

9. Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Gimenez-Arnau A et al. EAACI/GA2LEN/EDF/WAO Guideline: definition, classification and diagnosis of urticaria.

Allergy 2009;64: 1417-1426.

10. Zuraw BL, Curd JG. Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients. J Clin Invest 1986;78:567-575.

Conclusions The reported case is illustrative for various clinical presentations of recurrent angioedema due to acquired C1 INH deficiency, that may have no clear cause for many years in rare cases and for therapeutic options also. We concluded that attenuated androgens represent a possible effective prophylactic choice, with good safety profile and low price, when other modern and more expensive drugs are not available.

The long term follow-up of these patients should be considered, since clinical evidence of an underlining disease may occur at any time.

32

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

awareness, training and education

Role of genetics in characterizing endotypes and phenotypes of respiratory allergies Ovidiu Berghi1, Constantin Bara2, Roxana Sfrent-Cornateanu2

Anima Clinic, Bucharest , Romania “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania 1

2

ABSTRACT Allergic rhinitis and allergic asthma are complex and heterogeneous diseases. Many pathological mechanisms contribute to create a clinical picture. Phenotype and endotype are modern concepts proposed in order to help scientists and clinicians to characterize, diagnose and finally to personalize the treatment for this condition.

Genetics has important roles in this classification. This article takes a short review of this important concept and presents the most recent findings related to genetic aspects of the respiratory allergic diseases.

KEYWORDS: allergy, rhinitis, asthma, endotypes, genetics

Introduction

Respiratory allergies are represented by allergic rhinitis and allergic asthma. Allergic rhinitis (AR) is characterized by 4 important symptoms: sneezing, nasal itching, nasal drainage and congestion and it affects around 15-25% of the general population, depending on the population studied (Varshney J, Varshney H, 2015; Bousquet J et al., 2008). Asthma is a common, chronic respiratory disease characterized by wheezing, shortness of breath, chest tightness and/ or cough and by variable expiratory airflow limitation, affecting 1-18% of the population in different countries (Masoli M et al., 2004; Lai CKW et al., 2009). The symptoms are triggered by different factors such as allergens, irritants, viral respiratory infections, changes in the weather conditions or exercise (GINA, 2016). For the last decade, the concept of allergic respiratory diseases evolved: for example, for asthma, which was used to be considered as a unique disease, nowadays, it is recognized as a complex, disease characterized by large, heterogeneous, special in

Allergy has been defined as the result of an immune reaction to antigens known as allergens. In the last decades it has been accepted that there is a genetic basis for susceptibility to most common diseases, including allergies. Individual susceptibility and environmental factors play the most important roles.

Atopy is defined as “genetically predisposition to produce specific immunoglobulin E (IgE) after exposure to allergens”. Susceptibility to allergic disease is influenced from the inheritance of multiple genetic elements, each of them with small and different roles.

Many of the molecular pathways implicated in the pathogenesis of the allergic diseases have been elucidated in murine and human studies, but there is still a lot of work to do regarding the specific biochemical defects at the cellular level that trigger initiation of allergic reaction and are still, many of them, unknown (Adkinson et al., 2014)

Corresponding Author: Roxana Sfrent-Cornateanu “Carol Davila” University of Medicine and Pharmacy, Dionisie Lupu Street, 37-39, district 1, Bucharest, Romania; E-mail: roxanasfrent@yahoo.com Submission date: 20/08/2016; Acceptance date: 04/10/2016; Publication date: 24/10/2016

33

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

awareness, training and education

terms of clinical presentation and response to therapy (Muraro A et al., 2016; Papadopoulos NG, Guibas GV, 2016; Desai M, Oppenheimer J, 2016; Ciprandi G et al., 2016). This situation led to the conclusion that it is mandatory to characterize asthma and rhinitis more profound and that in the last 15 years, terms like phenotype and endotype regarding the characterization of allergic diseases emerged.

Related to this relatively new concept, recently, (2016), Desai M and Oppenheimer J have defined a disease phenotype as a term which describes “observable characteristic” - in terms of clinical and laboratory aspects and, also, as a response to treatment, “without a relation to the underlying pathophysiological mechanisms” (Desai M, Oppenheimer J, 2016). Also, they defined a person’s disease phenotype as “a result of the interaction between genes and” which “can change over time” (Desai M, Oppenheimer J, 2016).

Specific phenotypes were described in AR as well as in asthma which seems to be considered nowadays as being one disease: allergic respiratory disease (Giavina-Bianchi P et al., 2016). There are few phenotypes described in AR based on symptom duration (intermittent/persistent), the magnitude of quality of life’s affection (mild or moderate/severe), pattern of the sensitization (monosensitized versus polysensitized) and the existence of concurrent asthma (Lötvall J et al., 2011). Recently, there was described a new type - local allergic rhinitis, which includes those patients which present a localized nasal allergic response without any sign of sensitization - negative skin prick test as well as non-detectable serum specific IgE antibodies (Rondón C et al., 2012). The most common phenotypes of asthma include: allergic asthma (most easily recognized, commences in childhood, associated with personal and/or family history of allergic diseases, eosinophilic airway inflammation, good response to inhaled corticosteroid therapy (ICS), nonallergic asthma (adults, neutrophilic inflammation, poor response to corticosteroids), late-onset asthma (adults, particularly women, debut in adult life, require higher doses of ICS or relatively refractory to steroids), asthma with fixed airflow limitation (due to airway wall remodeling) and asthma with obesity (some obese patients with prominent respiratory symptoms and small eosinophilic inflammation) (GINA, 2016).

A disease endotype was defined by Desai M and Oppenheimer J as “a specific biological pathway (defining an etiology and/or a consistent pathophysiologic mechanism) that explains the observable prop-

erties of a phenotype” (Desai M, Oppenheimer J et al., 2016). For rhinitis, the European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy, Asthma & Immunology (AAAAI) have proposed the following endotypes: a type 2 immune response rhinitis (characterized by a high number of eosinophils, mast cells, type 2 innate lymphoid cells -ILC2- and high levels of soluble and local IgE, IL4, IL5, IL13), type 1 immune response rhinitis (neutrophilic, IFNγ, IL17, TNF), neurogenic rhinitis - characterized by over-expression of transient receptor potential channels on trigeminal nerves, substance P, neurokinins (not shown in the figure), (primary or secondary to type 1 or type 2 immune response (Choy DF et al., 2015) (Figure 1).

Legend: AR, allergic rhinitis; IR, immune response; IL, interleukin; ILC2/3, type 2/3 innate lymphoid cells; TSLP, thymic stromal lymphopoietin; GCSF, Granulocyte Colony Stimulating Factor; GM-CSF, Granulocyte Macrophage Colony-Stimulating Factor; LIGHT, homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes; epithelial*=cytokines produced by epithelial cells; ILC3 ⦂= cytokines produced by ILC3; Neutrophiles x =cytokines produced by neutrophils.

The classification of patients with asthma by endotype was first proposed by a board of EAACI and AAAAI experts in 2010 in order to facilitate future research for establishing genetic associations and identifying new biomarkers and novel therapeutic targets (Agache I, Akdis CA, 2016). Asthma has 2 major endotypes: a type 2 immune response driven complex endotype and a non-type 2 immune response driven complex endotype (Giavina-Bianchi P et al., 2016; Papadopoulos NG et al., 2015) (Figure 1). Type 2 immune response has had for a number of years the leading role in comprehending asthma’s pathophysiology (Lötvall J et al., 2011). Type 2 immune response asthma endotype is characterized by a high number of Th2 cells, type 2 B cells, ILC2, eosinophils, basophils, mast cells and a group of NK- cells and NK-T cells secreting IL4. The main cytokines secreted are IL4, IL5, IL9 and IL13 from immune stem cells and IL25, IL31, IL33 and thymic stromal lymphopoietin (TSLP) from epithelial cells (Agache I, Akdis CA, 2012).

Other bio-markers suggested to be implicated in this endotype is periostin (Zedan MM et al., 2016; Agache I et al., 2015) (Figure 1).

34

Role of genetics in characterizing endotypes and phenotypes of respiratory allergies

Figure 1. Characteristics of allergic rhinitis and asthma endotype (Muraro A et al., 2016; Giavina-Bianchi P et al., 2016; Papadopoulos NG et al., 2015; Lötvall J et al., 2011; Agache I, Akdis CA, 2016; Agache I, Akdis CA, 2012; Zedan MM et al., 2016; Agache I et al., 2015; Choy DF et al., 2015).

Several sub-endotypes were described within the type 2 immune response such as IL5- high (also known as IL5/eotaxin), IL13-high (IL4/IL13) and soluble IgE – high endotype (Simpson JL et al., 2007). Recent data supports the relevance of a non-type 2 endotype in asthma. This endotype is related to neutrophilic inflammation, Th17 pathway activation, neurogenic inflammation, tissue remodeling and barrier defects and it was also associated to allergic diseases. In non-type 2 endotype there were postulated 2 leading mechanisms: dysregulated immune response (including neutrophils abnormalities) and the activation of IL17–dependent pathway (Agache I, Akdis CA, 2016). Dysregulation of immune response found to be related to non-type 2 endotype and seems to be due to an altered gene expression of a number of genes such as Toll like receptors

genes and the genes involved in the TNF-α/nuclear factor – kB and IL-1β pathways (Simpson JL et al., 2007).

IL17 is an important player for the recruitment of neutrophils in the lungs. The major source of IL17 are Th17 cells followed by newly identified population of innate lymphoid cells. The link between IL17 and asthma was demonstrated in murine models of asthma (implicated in the development of airway hyperreactivity and remodeling) and human studies (important correlation between IL17 and neutrophils in blood and induced sputum) (Agache I, Akdis CA, 2016). It was also described a mixed type2/Th17 endotype. Th2 cells can differentiate in dual positive Th2/Th17 cells that were identified in BAL fluid and it was related to glucocorticoid resistance in vitro and hyperreactivity and airway obstruction in asthma patients. Gene expression

35

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

awareness, training and education

YEAR

COUNTRY

SUBJECTS

GENE IMPLICATED

RELATION WITH ASTHMA AND /AR

MOFFATT et al.

2007

Great Britain, Germany

994 patients with asthma vs 1243 controls

ORMDL3 GSDMA/GSDMB

Susceptibility loci for asthma

WEIDINGER et al.26

2008

Germany

1530 patients vs 9769 controls

FCER1A RAD50

Susceptibility locus for IgE levels

Iceland, Europe, East Asia

patients with asthma: 9392 (Icelandic), 12118 (European), 5212 (East Asian) vs 44890 controls

IL1RL1 WDR36 TSLP RAD50 MYB IL33

Association with blood eosinophil count and susceptibility to asthma

China

84 patients with TDI-induced asthma vs 263 controls

CTNNA3

Increased airway hyperresponsiviness to environmental toxins

Europe

10365 patients with physiciandiagnosed asthma vs 16110 controls

IL18R1 HLA-DQ IL33 SMAD3 IL2RB ORMDL3/GSDMB

422 patients with AR 118 patients with AR & concomitant asthma) vs 2153 controls (children from longitudinal cohort BAMSE)

TLR6-TLR1

AUTHOR

24

GUDBJARTSON et al.27

KIM et al. 28

MOFFATT et al.25

NILSSON et al. 31

2009

2009

2010

2014

Sweden

Association with total serum IgE concentration Association with childhood-onset disease

Association with AR AR phenotype

Table 3. GENETIC WIDE ASSOCIATION STUDIES (GWAS) RELATED TO RESPIRATORY ALLERGIC DISEASES

analysis revealed 3 major clusters in cross-sectional studies of asthmatics with varying grades of severity: Th2-high, Th17-high and Th2/Th17-low (Agache I, Akdis CA, 2016). Th2-high and Th17-high patterns in

individual patient samples were mutually exclusive and their genes signatures were inversely correlated and deferentially regulated by IL13 and IL-17A (Choy DF et al., 2015).

36

Role of genetics in characterizing endotypes and phenotypes of respiratory allergies

GENETIC APPROACH OF ALLERGIC RESPIRATORY DISEASES

table 1). This was the first GWAS study which identified the asthma susceptibility locus on chromosome 17q12-21.1 (Moffatt MF et al., 2007). Few years later, also on Caucasian population, Moffatt et al. conducted a large GWAS study in GABRIEL consortium where 10.365 persons with physician-diagnosed asthma and 16.110 unaffected persons from Europe were analyzed and the following genes associated to susceptibility for asthma were identified: IL18R1 (involved in Th2 responses), HLA-DQ (involved in T-cell responses) on 6p21, IL33, SMAD3 (transcriptional modulator activated by TGF-β) on 15q22, IL2RB (involved in T-cellmediated immune responses) on 22q12, IL13,RORA, SLC22A5 and IgE levels IL13, HLA, STAT6, IL4R,IL21R (Moffatt MF et al., 2010) (Table 1).

Also, the genome wide scan studies were performed in relation to some biological markers of allergic sensitization. Weidinger et al. performed a genome wide scan related to IgE levels on allergic sensitization in 1530 European individuals and identified FCER1A gene which encodes Fc fragment of IgE high-affinity receptor 1 and RAD50 (product: RAD50 homologimplicated in DNA repair) on 5q31 as a new susceptibility locus for IgE levels (Weidinger S et al., 2008).

Moreover, Gudbjartsson and coworkers performed a very large GWAS study (7,996 cases vs 44,890 controls) related to the blood eosinophil counts in 10 different populations, both of Caucasian and non-Caucasian origin, and identified SNPs from genes involved in regulation of Th2 response eg. IL1RL1 (gene product: IL-1 receptor-like 1) on 2q12, and IL33 on 9p24 as being associated with susceptibility to asthma (Gudbjartsson DF et al., 2009). Also, they found that SNPs located in WDR36 (WD repeat domain 36) gene on 5q22 chromosome, as well as those from MYB (myeloblastosis viral oncogene factor: nuclear transcription factor) gene on 9p24 seems to be associated with blood eosinophils count and atopic asthma (Gudbjartsson DF et al., 2009) (see table 1).

Kim et al. studied TDI (toluene diisocyanate induced) asthma in 84 asthma cases and 263 unexposed, Koreans healthy controls and demonstrated the role of CTNNA3 (catenin alpha-3) in increasing airway hyperresponsiveness to environmental toxins (Kim SH et al., 2009) .

Other susceptibility loci for allergic phenotype including respiratory allergic diseases, identified in the last years are C11-orf-30/LRRC (epithelial barrier function/regulatory T–cell functions and immune tolerance) on chromosome 11q13, DENND1B (expressed in dendritic cells and activates T cells) on 1q31, TLR6-

As we have mentioned before in our short presentation of phenotype and endotype, genetics has an important role in allergic diseases. The benefits of genetic studies of allergic diseases are many: explanation of disease pathogenesis by identifying genes and molecular pathways, generating novel pharmacological targets; identification of environmental-genetic interactions and prevention of disease through environmental modification; detection of susceptible individuals through screening early in life, allowing targeted interventions; sub-classification of disease by genetics enabling therapies to be tailored to at-risk individuals and determination of the likelihood of a therapeutic response as the basis for individual treatment plans.

Several approaches have been used to study the genetics of allergic diseases. Candidate gene association studies evaluate genetic variation in the regions of genes that are physiologically suggested to be involved in the disease pathogenesis, for example for cytokines, chemokines, their receptors, transcription factors and the IgE receptor.

Genome-wide linkage studies use prototypical data from all available members of a family (affected and unaffected) and DNA sequences to examine whether the markers cosegregate with the phenotype of interest. Genome-wide association studies (GWAS) scan the whole genome of cases and controls in a hypothesis-independent manner to identify multiple susceptibility genes, each of which contributes with a small effect(Adkinson et al., 2014).

GWAS offered many useful information in the process of identification of genetic factors underlying allergic disease (Ober C, Yao TC, 2011). GWAS may identify novel genes and pathways, including genes with small effects (Adkinson et al., 2014).

Asthma has been the most extensively studied allergic disease with respect to genetics with more than 1000 publications examining polymorphisms in several hundred genes. Several GWAS were performed with great success. On Caucasian population, Moffat et al. performed first GWAS study regarding childhood-onset asthma in 994 asthmatics vs 1243 controls and replicated their result in two case-control studies in 2320 (German) and 3301 (UK) (Moffatt MF et al., 2007).

They found that genes ORMDL3 (gene product: orosomucoid 1 – like 3 a transmembrane protein) and GSDMA/GSDMB (gasdermin A and B expressed in epithelium) were associated with novel-asthma (see

37

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

awareness, training and education

TLR1 (pathogen recognition and activation of innate immunity) on 4p14, IL6R (regulatory T- cell functions) on 1q21, PDE4D (involved in the airway smooth muscle contraction) on 5q12, CDHR3 (epithelial polarity, cell-cell contact) on 7q22, ZBTB10 (Sp1 transcription factor, regulates multiple immune relatedgenes) on 8q21, CLEC16A (inflammatory cell function) on 16p13, NFIA (control monocyte/macrophage differentiation programme) on 1q31, GATA3 (master regulator of Th2 differentiation), IKZF4 (involved in differentiation of regulatory T cells) on 12q13 (Li J et al., 2015; Portelli MA et al., 2015; Nilsson D et al., 2014).

Although characteristic for atopic dermatitis, filaggrin (FLG) was involved through genetic defects in the development of asthma (FLG null variants 2282del4 and R501X) (Ponińska J et al., 2011). It was suggested that asthma susceptibility in asthma patients with loss-of-function FLG mutations was related to allergic sensitization that occurs after breakdown the epithelial barrier (March ME et al., 2013).

Significant fewer information are known for the genetics of AR. Several studies (genome-wide linkage studies) identified MRPL4 (involved in inflammatory adhesion process) on chromosome 19p13, BCAP (involved in activation, development and maturation of B cells), C11-orf-30/LRRC and TLR6-TLR1 as potential disease susceptibility loci for AR (Li J et al., 2015; Nilsson D et al., 2014). Another approach of investigating the genetic influence on susceptibility to diseases is to study candidate gene related to their pathophysiologic mechanisms. In asthma, the candidate gene studies also revealed useful insights into the pathogenesis of this complex disease. SNPs in genes that encode proteins regulating Th2 cell production, such as IL13, GATA3 (encoding GATA-binding protein 3), TBX21 (encoding T-bet, the transcription factor for Th1 development), STAT6 (encoding the downstream signal transducer), IL4 (encoding the cytokine) and (encoding the receptor for IL4) have been associated with increased susceptibility to various endotypes and phenotypes of asthma (Adkinson et al., 2014).

As we have mentioned before, in the last years, Th17 cells were found to be involved in the pathogenesis of asthma which increased the interest for studying the possible genetic influence of IL-17 gene- the main cytokine secreted from these cells- related to the development of allergic respiratory diseases. Different SNPs were investigated in the last years in different populations and they pointed new roles for IL17, most of them

on Asian population (see table 2). A small study from China that enrolled 125 asthma patients and 132 healthy controls provided evidence that IL-17 SNPs (rs763780, rs2275913, and rs8193036) is associated with susceptibility to asthma (DuJ et al., 2014). Another study, which also investigated Chinese population, indicated that some IL17A and IL17F SNPs have potential association with AR and asthma co-morbidity (particular IL-17A SNP rs3819024) (Wang JY et al., 2009).

This study included 279 patients with allergic rhinitis (AR), 197 patients with allergic rhinitis with asthma (AR-A) and 281 control patients. They found that there are SNPs in IL17A (rs1892280 and rs10807439) specifically associated with AR, and also, there are SNP (rs13192563) in IL-17F gene specifically associated with AR-A. Haplotype analysis showed significant AR risk in haplotype AA (rs1892280G–rs13192563A) and AR protective effect in haplotype GT (rs7758579A– rs11966760T); the haplotype AT (rs7758579– rs11966760) were considered AR-A risk. Based on this study, the authors proposed that allergic rhinitis and allergic rhinitis associated with asthma may represent 2 phenotypes of allergic rhinitis, but these findings should be confirmed in larger patients cohorts in multicenter cohorts (Rondón C et al., 2012). A pediatric study investigated the polymorphisms of interleukin 17A gene in Taiwanese population of pediatric asthma and found that IL17A promoter polymorphism rs8193036 has an independent role in this condition.

The group study included 1939 subjects, consisting of 1027 asthma patients and 931 subjects in control group (Wang JY et al., 2009).

Genetic studies of asthma have also reinforced the observations epidemiological studies from the past about the importance of early-life events in determining asthma susceptibility. For example, polymorphisms in ADAM33 are associated with early-life measurement of lung function at 3 years of age (Simpson A et al., 2005). The values of spirometric measures (FEV1, FVC and FEV1/FVC) in asthma patients were also influenced by gene polymorphisms in pediatric populations (Soler Artigas M et al., 2011; Tang MF et al., 2016).

Obviously, the genetic studies contributed to a better understanding of the pathophysiologic mechanisms in allergic diseases, including asthma and AR. These studies showed that the genetic background contributes to: 1) Atopy (Th2 cells or IgE switch genes – α chain of the high affinity IgE receptor are associated with

38

Role of genetics in characterizing endotypes and phenotypes of respiratory allergies

2. Agache I, Akdis CA. Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine. Allergol Int. 2016 Jul;65(3):243-52. doi: 10.1016/j. alit.2016.04.011. Epub 2016 Jun 6. Review. PubMed PMID: 27282212 3. Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012 Jul;67(7):835-46. doi: 10.1111/j.1398-9995.2012.02832.x. Epub 2012 May 17. Review.

PubMed PMID: 22594878 4. Agache I, Sugita K, Morita H, Akdis M, Akdis CA. The Complex Type 2 Endotype in Allergy and Asthma: From Laboratory to Bedside. Curr Allergy Asthma Rep. 2015 Jun;15(6):29. doi: 10.1007/s11882-015-0529-x. Review. PubMed PMID: 26141574 5. Berry A, Busse WW. Biomarkers in asthmatic patients: Has their time come to direct treatment? J Allergy Clin Immunol.

2016 May;137(5):1317-24. doi: 10.1016/j.jaci.2016.03.009.

PubMed PMID: 27155028 6. Bousquet J et al. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008 Apr;63 Suppl 86:8-160.doi: 10.1111/j.1398-9995.2007.01620.x. Review.

No abstract available. PubMed PMID: 18331513 7. Choy DF, Hart KM, Borthwick LA, Shikotra A, Nagarkar DR, Siddiqui S, Jia G, Ohri CM, Doran E, Vannella KM, Butler CA, Hargadon B, Sciurba JC, Gieseck RL, Thompson RW, White S, Abbas AR, Jackman J, Wu LC, Egen JG, Heaney LG, Ramalingam TR, Arron JR, Wynn TA, Bradding P. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015 Aug 19;7(301):301ra129. doi: 10.1126/scitranslmed. aab3142. PubMed PMID: 26290411 8. Ciprandi G, Tosca MA, Cirillo I, Gallo F, Ricciardolo FL, Sadatsafavi M, Mark FitzGerald J. The asthma control in daily practice. Allergy. 2016 Jun;71(6):907-9. doi: 10.1111/all.12893.

No abstract available. PubMed PMID: 27168014 9. Desai M, Oppenheimer J. Elucidating asthma phenotypes and endotypes: progress towards personalized medicine. Ann Allergy Asthma Immunol. 2016 May;116(5):394-401. doi: 10.1016/j.anai.2015.12.024. Review. No abstract available.

PubMed PMID: 27153739 10. Du J, Han JC, Zhang YJ, Qi GB, Li HB, Zhang YJ, Cai S. SingleNucleotide Polymorphisms of IL-17 Gene Are Associated with Asthma Susceptibility in an Asian Population. Med Sci Monit.

2016 Mar 8;22:780-7. PubMed PMID: 26954344 11. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, FitzGerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002 Jul 25;418(6896):426-30.

Epub 2002 Jul 10. PubMed PMID: 12110844 12. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many.Nat Rev Immunol. 2015 Jan;15(1):57-65. doi: 10.1038/nri3786. Review. PubMed PMID: 25534623

sensitization and serum IgE levels) (Holloway JW et al., 2010); 2) Interaction of environmental factors with disease (genes that determine responses to factors that drive Th1/Th2 skewing of the immune response e.g. CD14 and TLR4 polymorphisms and early childhood infection (Holloway JW et al., 2012); genes that modulate the effect of exposures involving oxidant stress such as air pollution and tobacco smoke on asthma susceptibility – glutathione S-transferase genes (Holloway JW et al., 2012); genes that alter interactions between environmental factors and established disease – genetic polymorphisms regulating responses to respiratory syncytial virus infection and asthma symptoms) (Larkin EK, Hartert TV, 2015); 3) Determination of target-organ disease (asthmasusceptibility related genes-OPN3,CHML (White JH et al., 2008); genes which regulate propensity of lung epithelium and fibroblasts for remodeling in response to allergic inflammation – ADAM33 (Van Eerdewegh P et al., 2002); 4) Modification of disease severity risk of disease severity was found to be related to TNF-α polymorphisms in asthma (Padrón-Morales J et al., 2013); 5) Pharmacogenetics (β2-adrenergic receptor polymorphism and response to β2-agonists) (Adkinson et al., 2014).

Genetic studies led to the identification of many loci related to allergic respirator y diseases.

Establishing the causative effects between genetic modifications and the phenotype contribute to the definition of endotype which represents the next step to improving diagnosis methods as well as choosing the most appropriate treatment for allergic patients.

Future studies should evaluate more deeply the impact of gene modification in defining more specific sub-phenotype and sub-endotype of allergic diseases in order to find genetic tests as biomarkers which will allow to predict the course of the disease and to find specific target-molecule for precision treatment and personalized medicine.

Conflicts of interests: The authors declare no conflicts of interests.

References 1. Adkinson NF, Bochner BS, Burks AW, et al. Middleton’s Allergy.

2014. 8th ed – Volume 1 p. 343-60.

39

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

awareness, training and education

13. Giavina-Bianchi P, Aun MV, Takejima P, Kalil J, Agondi RC. United airway disease: current perspectives. J Asthma Allergy.

2016 May 11;9:93-100. doi: 10.2147/JAA.S81541. eCollection 2016. Review. PubMed PMID: 26792205 14. Global Initiative for Asthma. Global strategy for asthma management and prevention. Update 2016.

15. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, Williams C, Hui J, Beilby J, Warrington NM, James A, Palmer LJ, Koppelman GH, Heinzmann A, Krueger M, Boezen HM, Wheatley A, Altmuller J, Shin HD, Uh ST, Cheong HS, Jonsdottir B, Gislason D, Park CS, Rasmussen LM, Porsbjerg C, Hansen JW, Backer V, Werge T, Janson C, Jönsson UB, Ng MC, Chan J, So WY, Ma R, Shah SH, Granger CB, Quyyumi AA, Levey AI, Vaccarino V, Reilly MP, Rader DJ, Williams MJ, van Rij AM, Jones GT, Trabetti E, Malerba G, Pignatti PF, Boner A, Pescollderungg L, Girelli D, Olivieri O, Martinelli N, Ludviksson BR, Ludviksdottir D, Eyjolfsson GI, Arnar D, Thorgeirsson G, Deichmann K, Thompson PJ, Wjst M, Hall IP, Postma DS, Gislason T, Gulcher J, Kong A, Jonsdottir I, Thorsteinsdottir U, Stefansson K. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009 Mar;41(3):342-7. doi: 10.1038/ng.323. Epub 2009 Feb 8.

PubMed PMID: 19198610 16. Holloway JW, Savarimuthu Francis S, Fong KM, Yang IA. Genomics and the respiratory effects of air pollution exposure.

R e s p i r o l o g y.

2012 May ;17(4):590-600. doi: 10.1111/j.1440-1843.2012.02164.x. Review. PubMed PMID: 22404320 17. Holloway JW, Yang IA, Holgate ST. Genetics of allergic disease.

J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S81-94. doi: 10.1016/j.jaci.2009.10.071. Review. PubMed PMID: 20176270 18. Kim SH, Cho BY, Park CS, Shin ES, Cho EY, Yang EM, Kim CW, Hong CS, Lee JE, Park HS. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp A l l e r g y.

2009 Feb;39(2):203-12. doi: 10.1111/j.1365-2222.2008.03117.x. PubMed PMID: 19187332 19. Lai CK, Beasley R, Crane J, Foliaki S, Shah J, Weiland S; International Study of Asthma and Allergies in Childhood Phase Three Study Group. Global variation in the prevalence and severity of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax. 2009 Jun;64(6):476-83. doi: 10.1136/ thx.2008.106609. Epub 2009 Feb 22. PubMed PMID: 19237391 20. Larkin EK, Hartert TV. Genes associated with RSV lower respiratory tract infection and asthma: the application of genetic epidemiological methods to understand causality.Future Virol.

2015 Jul;10(7):883-897. PubMed PMID: 26478738 21. Li J, Zhang Y, Zhang L. Discovering susceptibility genes for allergic rhinitis and allergy using a genome-wide association study strategy. Curr Opin Allergy Clin Immunol. 2015 Feb;15(1):33-40. doi: 10.1097/ACI.0000000000000124. Review.

PubMed PMID: 25304232 22. Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB,

Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011 Feb;127(2):355-60. doi: 10.1016/j. jaci.2010.11.037. Review. PubMed PMID: 21281866 23. March ME, Sleiman PM, Hakonarson H. Genetic polymorphisms and associated susceptibility to asthma.Int J Gen Med. 2013 Apr 17;6:253-65. doi: 10.2147/IJGM.S28156. Print 2013.

Print 2013. PubMed PMID: 23637549 24. Masoli M, Fabian D, Holt S, et al.. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59:469-78. Review. No abstract available.

PubMed PMID: 15080825 25. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO; GABRIEL Consortium. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010 Sep 23;363(13):1211-21. doi: 10.1056/NEJMoa0906312.

PubMed PMID: 20860503 26. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, Heinzmann A, Simma B, Frischer T, Willis-Owen SA, Wong KC, Illig T, Vogelberg C, Weiland SK, von Mutius E, Abecasis GR, Farrall M, Gut IG, Lathrop GM, Cookson WO. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.Nature.2007.26;448(7152):470-3. Epub 2007 Jul 4.

PubMed PMID: 17611496 27. Muraro A, Lemanske RF Jr, Hellings PW, Akdis CA, Bieber T, Casale TB, Jutel M, Ong PY, Poulsen LK, Schmid-Grendelmeier P, Simon HU, Seys SF, Agache I. Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitisPRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2016 May;137(5):1347-58. doi: 10.1016/j.jaci.2016.03.010. Review.

PubMed PMID: 27155030 28. Nilsson D, Henmyr V, Halldén C, Säll T, Kull I, Wickman M, Melén E, Cardell LO. Replication of genomewide associations with allergic sensitization and allergic rhinitis. Allergy. 2014 Nov;69(11):1506-14. doi: 10.1111/all.12495. Epub 2014 Sep 6.

PubMed PMID: 25066275 29. Ober C, Yao TC.The genetics of asthma and allergic disease: a 21st century perspective.Immunol Rev. 2011;242(1):10-30. doi: 10.1111/j.1600-065X.2011.01029.x. Review. PubMed PMID: 21682736 30. Padrón-Morales J, Sanz C, Dávila I, Muñoz-Bellido F, Lorente F, Isidoro-García M. Polymorphisms of the IL12B, IL1B, and TNFA genes and susceptibility to asthma. J Investig Allergol Clin Immunol. 2013;23(7):487-94. PubMed PMID: 24654313 31. Papadopoulos NG, Bernstein JA, Demoly P, Dykewicz M, Fokkens W, Hellings PW, Peters AT, Rondon C, Togias A, Cox LS. Phenotypes and endotypes of rhinitis and their impact on management: a PR ACTALL rep or t. Al lerg y. 2015 May;70(5):474-94. doi: 10.1111/all.12573. Epub 2015 Feb 19.

PubMed PMID: 25620381 32. Papadopoulos NG, Guibas GV. Rhinitis Subtypes, Endotypes,

40

Role of genetics in characterizing endotypes and phenotypes of respiratory allergies

and Def initions.Immunol Allerg y Clin Nor th Am. 2016;36(2):215-33. doi: 10.1016/j.iac.2015.12.001. Epub 2016 Feb 28. Review. PubMed PMID: 27083098 33. Ponińska J, Samoliński B, Tomaszewska A, Raciborski F, SamelKowalik P, Walkiewicz A, Lipiec A, Piekarska B, Komorowski J, Krzych-Fałta E, Namysłowski A, Borowicz J, Kostrzewa G, Majewski S, Płoski R. Filaggrin gene defects are independent risk factors for atopic asthma in a Polish population: a study in ECAP cohort. PLoS One. 2011 Feb 18;6(2):e16933. doi: 10.1371/journal.pone.0016933. PubMed PMID: 21365004 34. Portelli MA, Hodge E, Sayers I. Genetic risk factors for the development of allergic disease identified by genome-wide association.Clin Exp Allergy. 2015;45(1):21-31. doi: 10.1111/ cea.12327. Review. PubMed PMID: 24766371 35. Rondón C, Campo P, Togias A, Fokkens WJ, Durham SR, Powe DG, Mullol J, Blanca M. Local allergic rhinitis: concept, pathophysiology, and management. J Allergy Clin Immunol. 2012 Jun;129(6):1460-7. doi: 10.1016/j.jaci.2012.02.032. Epub 2012 Apr 18. Review. PubMed PMID: 22516477 36. Simpson A, Maniatis N, Jury F, Cakebread JA, Lowe LA, Holgate ST, Woodcock A, Ollier WE, Collins A, Custovic A, Holloway JW, John SL. Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function. Am J Respir Crit Care Med. 2005 Jul 1;172(1):55-60.

Epub 2005 Apr 1. PubMed PMID: 15805180 37. Simpson JL, Grissell TV, Douwes J, Scott RJ, Boyle MJ, Gibson PG. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax. 2007 Mar;62(3):211-8. Epub 2006 Jul 14. PubMed PMID: 18844729 38. Soler Artigas M, Loth DW, Wain LV, Gharib SA, Obeidat M, Tang W, Zhai G, Zhao JH, Smith AV, Huffman JE, Albrecht E, Jackson CM, Evans DM, Cadby G, Fornage M, Manichaikul A, Lopez LM, Johnson T, Aldrich MC, Aspelund T, Barroso I, Campbell H, Cassano PA, Couper DJ, Eiriksdottir G, Franceschini N, Garcia M, Gieger C, Gislason GK, Grkovic I, Hammond CJ, Hancock DB, Harris TB, Ramasamy A, Heckbert SR, Heliövaara M, Homuth G, Hysi PG, James AL, Jankovic S, Joubert BR, Karrasch S, Klopp N, Koch B, Kritchevsky SB, Launer LJ, Liu Y, Loehr LR, Lohman K, Loos RJ, Lumley T, Al Balushi KA, Ang WQ, Barr RG, Beilby J, Blakey JD, Boban M, Boraska V, Brisman J, Britton JR, Brusselle GG, Cooper C, Curjuric I, Dahgam S, Deary IJ, Ebrahim S, Eijgelsheim M, Francks C, Gaysina D, Granell R, Gu X, Hankinson JL, Hardy R, Harris SE, Henderson J, Henry A, Hingorani AD, Hofman A, Holt PG, Hui J, Hunter ML, Imboden M, Jameson KA, Kerr SM, Kolcic I, Kronenberg F, Liu JZ, Marchini J, McKeever T, Morris AD, Olin AC, Porteous DJ, Postma DS, Rich SS, Ring SM, Rivadeneira F, Rochat T, Sayer AA, Sayers I, Sly PD, Smith GD, Sood A, Starr JM, Uitterlinden AG, Vonk JM, Wannamethee SG, Whincup PH, Wijmenga C, Williams OD, Wong A, Mangino M, Marciante KD, McArdle WL, Meibohm B, Morrison AC, North KE, Omenaas E, Palmer LJ, Pietiläinen KH, Pin I, Pola Sbreve Ek O, Pouta A, Psaty BM, Hartikainen AL, Rantanen T, Ripatti S, Rotter JI, Rudan I, Rudnicka AR, Schulz H, Shin SY, Spector TD, Surakka I, Vitart V, Völzke H, Wareham NJ, Warrington NM, Wichmann HE, Wild SH, Wilk

JB, Wjst M, Wright AF, Zgaga L, Zemunik T, Pennell CE, Nyberg F, Kuh D, Holloway JW, Boezen HM, Lawlor DA, Morris RW, Probst-Hensch N; International Lung Cancer Consortium; GIANT consortium, Kaprio J, Wilson JF, Hayward C, Kähönen M, Heinrich J, Musk AW, Jarvis DL, Gläser S, Järvelin MR, Ch Stricker BH, Elliott P, O’Connor GT, Strachan DP, London SJ, Hall IP, Gudnason V, Tobin MD. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat Genet. 2011 Sep 25;43(11):1082-90. doi: 10.1038/ ng.941. PubMed PMID: 2946350 39. Tang MF, Sy HY, Kong AP, Ko FW, Wang SS, Liu TC, Chan WC, Wong GW, Hon KL, Chan JC, Hui DS, Leung TF. Genetic effects of multiple asthma loci identified by genomewide association studies on asthma and spirometric indices. Pediatr Allergy Immunol. 2016 Mar;27(2):185-94. doi: 10.1111/pai.12505.

Epub 2016 Jan 8. PubMed PMID:26534891 40. Varshney J, Varshney H. Allergic Rhinitis: an Overview.Indian J Otolaryngol Head Neck Surg. 2015 Jun;67(2):143-9. doi: 10.1007/s12070-015-0828-5. Epub 2015 Jan 31. PubMed PMID: 26075169 41. Wang JY, Shyur SD, Wang WH, Liou YH, Lin CG, Wu YJ, Wu LS. The polymorphisms of interleukin 17A (IL17A) gene and its association with pediatric asthma in Taiwanese population.

A l l e r g y.

2009 Jul;64(7):1056-60. doi: 10.1111/j.1398-9995.2009.01950.x. Epub 2009 Feb 5. PubMed PMID: 19210369 42. Wang M, Zhang Y, Han D, Zhang L. Association between polymorphisms in cytokine genes IL-17A and IL-17F and development of allergic rhinitis and comorbid asthma in Chinese subjects. Hum Immunol. 2012;73(6):647-53. doi: 10.1016/j.humimm.2012.03.010. Epub 2012 Apr 13. PubMed PMID: 22507625 43. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, Behrendt H, Heinrich J, Novak N, Bieber T, Krämer U, Berdel D, von Berg A, Bauer CP, Herbarth O, Koletzko S, Prokisch H, Mehta D, Meitinger T, Depner M, von Mutius E, Liang L, Moffatt M, Cookson W, Kabesch M, Wichmann HE, Illig T. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 2008 Aug;4(8):e1000166. doi: 10.1371/journal.pgen.1000166. Epub 2008 Aug 22. PubMed PMID: 18846228 44. White JH, Chiano M, Wigglesworth M, Geske R, Riley J, White N, Hall S, Zhu G, Maurio F, Savage T, Anderson W, Cordy J, Ducceschi M; GAIN investigators, Vestbo J, Pillai SG. Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation. Hum Mol Genet. 2008 Jul 1;17(13):1890-903. doi: 10.1093/hmg/ddn087. Epub 2008 Mar 15. PubMed PMID: 18344558 45. Zedan MM, Osman AM, Laimon WN, Zedan MM, Abo-Elkheir NY, Zaki A. Airway Inflammatory Biomarker: Could It Tailor the Right Medications for the Right Asthmatic Patient? Iran J Immunol. 2016 Jun;13(2):70-88. doi: IJIv13i2A1. PubMed PMID: 27350629

41

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

news and current perspectives

The role of the human microbiota in the development of spondyloarthritis Mihaela Roxana Huhu1, Octavian Ioghen Costin1, Elena Camelia Berghea2

“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania “MS Curie” Clinical Emergency Hospital for Children, Bucharest, Romania

1 2

ABSTRACT The human microbiota represents the community of microorganisms that are colonizing the human body.

Due to the recent developments in biotechnology, its correlation with specific health issues is the subject of an ever-growing number of studies and new insights are coming to light. Spondyloarthritis (SpA) is an umbrella term including a group of diseases that affect both the joints and entheses. The purpose of this review is to summarize the most important recent findings regarding the interaction between microbiota and the pathogenesis of autoimmune diseases, spondyloarthritis in our case, as it is complex and is yet to be fully understood. Even though, the idea of manipulating the microbiota in order to answer the questions regarding the aethiopathogenesis, diagnosis, prognosis and treatement of SpA arises.

KEYWORDS: autoimmune diseases, spondyloarthritis, microbiota, interaction

Introduction

sights are coming to light (Palm NW el al., 2015, Yamanaka T et al., 2013).

The human microbiota represents the community of microscopic organisms that are colonizing the human body. The genome of the microbiota is called microbiome. Our body contains ten times more bacteria than human cells and the microbiome sums up 1000 times more genes than the human genome. Microbiota plays an important role in nutrient metabolism, xenobiotic and drug metabolism, antimicrobial protection and immunomodulation (Ursell LK et al., 2012).

Due to the recent developments in biotechnology, the interactions between resident microorganisms and host are being studied in depth. The link between these microbes and specific health issues is the subject of an ever-growing number of studies and new in-

The relationship between the microbiota and the immune system Antimicrobial protection provided by gut microbiota consists in the education of the immune system. It has a role in the development of Payer patches and other gut-associated-lymphoid tissues. Depletion of B and T cells was observed in germ-free mice (Smith K et al., 2007, Hill DA and Artis D, 2010). The lifespan of two circulating myeloid cells (granulocytes and inflammatory monocytes) is modulated by the peptidoglycan from the gut microbiota (Hergott CB et al., 2016).

Corresponding Author: Mihaela Roxana Huhu 15 Aleea Lipanesti street, Bl J20, postal code 32506; E-mail: huhu_mihaela_roxana@yahoo.ro Submission date: 26/08/2016; Acceptance date: 04/10/2016; Publication date: 24/10/2016

42

The role of the human microbiota in the development of spondyloarthritis

important role in the onset of the disease. The HLAB27 transgenic mice develop a disease that resembles the human spondyloarthritis. The mice that grew up in a germ-free environment did not develop the disease.

The reconstitution of intestinal microbiota triggered the disease. The cecum microbiota of HLA-B27 transgenic mice is different from that of non-transgenic mice. Among the differences, Prevotella spp. was overabundant and Rikenellaceae spp. had a decrease in abundance (Hill DA and Artis D, 2010, Taurog JD et al., 1994, Lin P et al., 2014).

Wu et al. used the K/BxN mouse model for autoimmune arthritis and demonstrated the role of segmented filamentous bacteria in the onset of the disease. The disease was strongly attenuated when the mice were raised in germ-free conditions. A loss of splenic T helper 17 was also observed. Interestingly, neutralization of IL-17 secretion with blocking antibodies prevented the development of the disease (Wu HJ et al., 2010).

The commensals of microbiota induce immunological tolerance. Two ways by which the immune system tolerates the microbiota are stratification and compartmentalization.

Stratification means that the direct contact between gut commensals and epithelial intestinal cells is minimized and compartmentalization means that the expose of the microbiota to the systemic immune compartment is limited. The tolerogenicity of the intestinal dendritic cells compared to systemic dendritic cells and the hyporeactivity of toll like receptors (TLRs) are also worth to be mentioned (Hooper LV et al., 2012, Hill DA and Artis D, 2010).

The immune system has the role to maintain the delicate balance between being sufficiently active to protect the body against non-self antigens such as pathogens but not too active in order to avoid destroying itself (autoimmunity) and, at the same time, to avoid destroying beneficial commensals (Ciccia F et al., 2016).

Due to the mutual interactions between the microbiota and the immune system, the alteration of microbiota, also called dysbiosis results in a systemic inflammatory response and is correlated with higher risk of developing certain autoimmune diseases such as spondyloarthritis, multiple sclerosis, type 1 diabetes etc (B, C, G). An explanation could be the fact that microbes provide proteolytic enzymes that cleave proteins into peptides with the potential of becoming autoantigens under certain conditions; staphylococci and streptococci produce staphylokinases, streptokinases, plasminogen activators, enteric bacteria produce collagenase etc. (Opdenakker G et al., 2016).

An increasing number of studies have focused on the connection between spondyloarthritis (SpA) (also called spondyloarthropathies) and alteration in the composition of microbiota (Bazso A et al., 2015, Scher JU et al., 2015, Bisanz JE et al., 2016).

SpA is an umbrella term including a group of diseases that affect both the joints and entheses. It consists of ankylosing spondylitis (AS), reactive arthritis (RA), psoriatic arthritis (PsA), arthritis associated to inflammatory bowel disease (IBD), also called enteropathic arthritis (EA), juvenile SpA (JSpA) and undifferentiated SpA. One of the common features of many SpA patients is the presence of major histocompatibility complex (MHC) class I allele human leukocyte antigen B27 (HLA-B27) (Manasson J and Scher JU, 2015, Gill T et al., 2016).

Ankylosing spondylitis AS is a chronic, systemic rheumatic disorder that mainly affects the spine and the sacroiliac joints. The aethiopathogenesis of this disease is not fully understood.

The role of the genetic component is well documented; the presence HLA-B27 was demonstrated in >90% of the patients diagnosed with AS. The role of HLA B27 is to present peptidic antigens to T cells. The simple presence of the HLA-B27 gene is not sufficient to trigger disease since it is also found in healthy individuals (Smith JA, 2015, Bowness P, 2002, Acar M et al., 2012).

Stebbings et al. wrote a review that briefly hypothesized the AS aethiopathogenesis. The start point is the intestinal inflammation which increases permeability of the intestinal mucosa. The next step would be the loss of tolerance to certain species of the microbiota resulting in a CD4+ lymphocyte response. Bacterial antigens pass through the permeable mucosa and disseminate into the joints where macrophages and lymphocytes are activated; this leads to chronic synovitis. The loss of tolerance to autologous Bacteroides spp. as well as overabundance of Bacteroides vulgatus and Paraprevotella spp. in HLA-B27 transgenic animals than wild type animals were shown (Stebbings S et al., 2002, Forbes JD et al., 2016).

It is well known that breastfeeding plays an important role in colonization of the gut. It was suggested that breastfeeding has a protective effect on the development of AS (Montoya J et al., 2015).

The microbiota of patients with AS seems to be more

Mouse models for spondyloarthritis A noteworthy study on HLA-B27 transgenic mice provided direct evidence that the microbiota plays an

43

Journal of the Romanian Society of Allergology and Clinical Immunology

Vol. XIII, No. 3, July - September 2016

ORIGINAL ARTICLES AND BRIEF COMMUNICATIONS

Streptococcus spp./Propionibacterium spp. was higher (Castelino M et al., 2014).

abundant in sulfate-reducing bacteria, whose abundance is also correlated with inflammatory bowel disease (Stebbings S et al., 2002).

The mapping of microbiota using culture-independent 16S rRNA gene sequencing showed a significantly increased abundance of Lachnospiraceae spp., Veillonellaceae spp., Prevotellaceae spp., Porphyromonadaceae spp. and Bacteroidaceae spp. in AS patients compared to healthy controls (Costello ME et al., 2014).

The gut microbiota of the AS patients is thought to contribute to the development of AS by inducing the production of proinflammatory cytokines, such as IL23p19, and the differentiation of potentially pathogenic innate lymphoid cells producing IL-22 and IL-17 (Ciccia F et al., 2016).

Enteropathic arthritis Even though only seven percent of the SpA patients are also diagnosed with IBD, intestinal inflammation is present >60% of SpA patients, being subclinical in the majority of them. Some mechanisms involved in the aethiopathogenesis - especially in the processing of intracellular pathogens and cytokine cascades - of psoriasis, PsA, AS and IBD overlap. The alterations in the IL-17- IL 23 axis and NFkB signalling pathways are noteworthy (Stoll M, 2015).

Another link between IBD and SpA may be the Th17 cell-mediated immune response. The Th17 cells express proinflammatory molecules like interleukins (IL17A, IL17F, IL-22, IL-23) and tumor necrosis factors (TNF-alpha and TNF-beta) (Fantini MC et al., 2009).

Reactive arthritis Reactive arthritis is an autoimmune disorder triggered by a gastrointestinal or genitourinary infection, the most incriminated germs being Salmonella spp., Shigella spp., Campylobacter spp. and Chlamydia trachomatis. The mechanism is still unclear, cross-reaction with self-antigens being incriminated (Stavropoulos PG et al., 2015).

Conclusion The interaction between microbiota and the pathogenesis of autoimmune diseases, spondyloarthritis in our case, is complex and is yet to be fully understood.

It is hard to establish a cause and effect relationship between the alterations of the microbiota and the onset or presence of disease since there is a mutual interaction between microbiota and host. However, the animal models have provided important evidence for the hypothesis that modifications in the microbiota can trigger the disease. Thus, new insights that are strongly connected with human health are revealed every day by using the newest available technology.

Since there are still unanswered questions regarding the aethiopathogenesis, diagnosis, prognosis and treatment for SpA, a new answer could be the manipulation of microbiota.

Psoriatic arthritis Psoriatic arthritis is a chronic arthritis developed by patients with psoriasis, a chronic inflammatory skin disease. Expansion of CD8+ and CD4+ cells was observed in the synovia and peripheral blood of patients with psoriatic arthritis (Eppinga H et al., 2014).

Subclinical gut inflammation was observed in psoriatic arthritis patients. A decrease in bacterial diversity of the gut microbiota together with a decrease in Coprococcus spp., Akkermansia spp., Ruminococcus spp., and Pseudobutyrivibrio spp. species was described in patients with psoriatic arthritis. (Scher JU et al., 2015, Scarpa R et al., 2000). Alistipes spp. was also lower in abundance in PsA patients but also in patients with Crohnâ&#x20AC;&#x2122;s disease, an IBD (Scher JU et al., 2015, Willing BP et al., 2010).

It was also hypothesized that the skin microbiota may play an important role in the aethiopathogenesis of psoriatic arthritis. Two studies that compared the microbiome from psoriatic plaques to the microbiome of healthy controls showed similar results: the genera Firmicutes was over-abundant in psoriatic plaques and the ratio

Conflicts of interests: The authors declare no conflicts of interests.

References 1. Acar M, Cora T, Tunc R, et al. HLA-B27 subtypes in Turkish patients with ankylosing spondylitis and healthy controls.

Rheumatol Int. 2012;32(10):3103-5.

2. Bazso A, Szodoray P, Suto G. Importance of intestinal micro-

44

The role of the human microbiota in the development of spondyloarthritis

environment in development of arthritis. A systematic review.

Immunol Res. 2015;61(1-2):172-6.

3. Bisanz JE, Suppiah P, Thomson WM, et al. The oral microbiome of patients with axial spondyloarthritis compared to healthy individuals. PeerJ. 2016;4:e2095.

4. Bowness P. HLA B27 in health and disease: a double-edged sword? Rheumatology (Oxford). 2002;41(8):857-68.

5. Castelino M, Eyre S, Upton M, et al. The bacterial skin microbiome in psoriatic arthritis, an unexplored link in pathogenesis: challenges and opportunities offered by recent technological advances. Rheumatology (Oxford). 2014;53(5):777-84.

6. Ciccia F, Rizzo A, Triolo G. Subclinical gut inflammation in ankylosing spondylitis. Curr Opin Rheumatol. 2016;28(1):89-96.

7. Costello ME, Ciccia F, Willner D, et al. Intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol. 2014.

8. Eppinga H, Konstantinov SR, Peppelenbosch MP, et al. The microbiome and psoriatic arthritis. Curr Rheumatol Rep. 2014;16(3):407.

9. Fantini MC, Pallone F, Monteleone G. Common immunologic mechanisms in inflammatory bowel disease and spondyloarthropathies. World J Gastroenterol. 2009;15(20):2472-8 10. Forbes JD, Van Domselaar G, et al. The Gut Microbiota in Immune-Mediated Inflammatory Diseases. Front Microbiol.

2016;7:1081.

11. Hergott CB, Roche AM, Tamashiro E et al. Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis. Blood. 2016;127(20):2460-71.

12. Gill T, Asquith M, Rosenbaum JT. The intestinal microbiome in sp ondy lo ar t hr it is. Cur r O pin R heumatol. 2015 Jul;27(4):319-25.

13. Hill DA, Artis D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol. 2010;28:623–667.

14. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science.

2012;336(6086):1268-73.

15. Lin P, Bach M, Asquith M, et al. HLA-B27 and human beta2microglobulin affect the gut microbiota of transgenic rats.

PLoS One 2014; 9:1–9; e105684.

16. Manasson J, Scher JU. Spondyloarthritis and the microbiome: new insights from an ancient hypothesis. Curr Rheumatol Rep. 2015;17(2):10.

17. Montoya J, Matta NB, Suchon P, et al. Patients with ankylosing spondylitis have been breast fed less often than healthy controls: a case-control retrospective study. Ann Rheum Dis.

2016;75(5):879-82.

18. Opdenakker G, Proost P, Van Damme J. Microbiomic and Posttranslational Modifications as Preludes to Autoimmune Diseases. Trends Mol Med. 2016. pii: S1471-4914(16)30077-6.

19. Palm NW, de Zoete MR, Flavell RA. Immune-microbiota inte ra c t i ons i n he a lt h and d is e as e. C l i n Immunol.

2015;159(2):122-7.

20. Scarpa R, Manguso F, D’Arienzo A, et al. Microscopic inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without bowel symptoms. J Rheumatol.

2000; 27:1241–1246.

21. Scher JU, Ubeda C, Artacho A, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 2015;67:128–39.

22. Smith JA. Update on ankylosing spondylitis: current concepts in pathogenesis. Curr Allergy Asthma Rep. 2015;15(1):489.

23. Smith K, McCoy KD, Macpherson AJ. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin Immunol. 2007;19(2):59-69 24. Stavropoulos PG, Soura E, Kanelleas A, et al. Reactive arthritis. J Eur Acad Dermatol Venereol. 2015;29(3):415-24.

25. Stebbings S, Munro K, Simon MA, et al. Comparison of the faecal microflora of patients with ankylosing spondylitis and controls using molecular methods of analysis. Rheumatology (Oxford). 2002;41(12):1395-401.

26. Stoll M. Gut microbes, immunity, and spondyloarthritis. Clin Immunol. 2015;159(2):134-42.

27. Taurog JD, Richardson JA, Croft JT, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994;180:2359–2364.

28. Ursell LK, Metcalf JL, Parfrey LW, et al. Defining the Human Microbiome. Nutr Rev. 2012;70 Suppl 1:S38-44.

29. Willing BP, Dicksved J, Halfvarson J, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles var y with inf lammator y b owel dis eas e phenotyp es.

Gastroenterology. 2010;139:1844–1854.

30. Wu HJ, Ivanov II, Darce, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity. 2010;32(6):815-27.

31. Yamanaka T, Helgeland L, Farstad IN et al. Microbial colonization drives lymphocyte accumulation and differentiation in the follicle-associated epithelium of Peyer’s patches. J Immunol. 2003;170(2):816-22.

45

conferenceseries.com 11th International Conference on

Allergy, Asthma & Clinical Immunology August 16-17, 2017 Edinburgh, Scotland

RSACI

RSACI CONFERENCE

Romanian Society of

Allergology and Clinical Immunology

n

12-14 May 2017

”THE NEED OF PRECISION MEDICINE IN ALLERGY, ASTHMA AND CLINICAL IMMUNOLOGY”

Scientific Sessions State-of-the-Art presentations Poster Discussion Sessions Company Sponsored Symposia n

n

n

n

Workshops

46

Journal of the Romanian Society of Allergology and Clinical Immunology

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

INSTRUCTIONS FOR AUTHORS

Author guidelines for manuscript preparation and submission

Welcome to the Journal of the Romanian Society of Allergology and Clinical Immunology

Publishing ethics and conflict of interests Submission is considered on the conditions that the manuscript does not have any instances of plagiarism, of fabricated or falsified information, does not represent a duplicate or multiple submission, does not have inappropriate authorship and all authors have read and approved the content, and all authors have also declared potential conflict of interests, and that the work complies with ethical policies of RSACI, EAACI and WAO, and has been conducted under internationally accepted ethical standards. If the manuscript involves human subjects or experimental animals, the authors must give details of the approvals obtained from the ethics committees. If the manuscript reports medical research involving human subjects, statements confirming that informed consent was obtained and that the research was carried out according to the World Medical Association Declaration of Helsinki, must be included. Any form of registration that may identify a patient must be excluded. When clinical images of patients are submitted it is the responsibility of the authors to obtain, prior to submission, full informed consent by the patient for the use of the photographs, and to ensure that full anonymity is preserved.

All authors are responsible for adhering to guidelines on good publication practice. Authors are responsible to disclose any potential conflict of interest related to the article or to the subject of their manuscript. The authors must acknowledge financial support for the research work and other financial or personal connections to the work.

The RSACI journal is a national premier scientific and academic journal devoted to reporting the latest, research progress and findings of research and clinical practice in the fields of interest of our society members. It was launched in 2004 and is published trimonthly (4 issues annually), and starting with 2016, it is published in English.

We encourage our society members and those interested in the activities of RSACI to submit manuscripts to the Journal of the Romanian Society of Allergology and Clinical Immunology, 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 constantly try to enhance the value of our society journal.

Manuscript submission general information Authors must be sure they are submitting to the most suitable journal, make sure that their manuscript is accurate and readable and understand the copyright policy.

Articles written in accurate scientific English and suitable for publication should be submitted to: secretariat@sraic.eu Please follow the instructions given below. If authors encounter difficulties they may contact the Associate Editor, dr. Adelaida Marinescu, at the following email address: adela@target-consulting.ro

Copyright information The author identified as the corresponding author for the paper will receive an email to be informed about the need to sign a copyright transfer agreement regarding the terms of use, retained rights, permitted use by contributor, copyright notice, contributorâ&#x20AC;&#x2122;s representations, use of information aspects.

English language editing Authors for whom English is a second language may choose to use the services of a professional editing service provider, either a professional company or a qualified colleague, with expertise and experience in English language editing of scientific and medical manuscripts. Such services are paid for and arranged by the author, and does not guarantee acceptance or preference for publication.

Categories of manuscripts 4 Editorials must be up to 1500 words, usually commissioned by the editorial board, after consultation with Editor-in-Chief and Associate Editor.

47

Instructions for authors

4 Review articles may be reviews or minireviews dedicated especially to recent developments in a particular field of allergy and immunology (up to 15 printed pages).

4 Original articles and brief communications include original work, research papers, clinical trials, observational studies, case reports (up to 15 printed pages), and short communications (up to 5 pages).

4 Awareness, training and education section may include position papers, guidelines or practice parameters, evidence-based medicine articles, diagnostic and therapeutic advances, topic highlight articles by or for medical doctors in training and young specialists, awareness and educational materials (up to 20 printed pages).

4 News and current perspectives may be presentations of most recent developments and concepts, new frontier articles or field of vision commentaries, academic points of view and perspectives (up to 12 printed pages).

4 Reader services may include selected commentaries or points of view, letters to the editor, correspondence and information for readers (also in the Romanian language).

starting on a separate page.

Figures must be submitted as digital version separately PowerPoint, TIFF or JPG files format only. The photos submitted should be high-resolution figures (300 dpi) format.

If authors wish to use a figure, illustration or a table that has been previously published, they must acknowledge the original source and submit written permission from the copyright holder to reproduce the material. The responsibility is entirely of the authors, when using figures, illustrations or tables without permission and/or without mentioning in the manuscript details regarding the source. Each figure/table should have a legend containing sufficient information to make it intelligible without reference to the text.

References should be numbered consecutively in aphabetical order. The reference list is a separate section at the end of the manuscript. All references must be upto-date. Avoid footnotes. Authors are recommended to consider the International Committee of Medical Journal Editors (ICMJE) guidance, the recommended style for references is based on the National Information Standards Organization NISO Z39.29-2005 (R2010) Bibliographic References as adapted by the National Library of Medicine for its databases, samples of formatted references being available online: www.nlm.nih.gov/bsd/uniform_requirements.html Example of citing of a published article from a journal with a Digital Object Identifier (DOI) example: Popescu FD. Cross-reactivity between aeroallergens and food allergens. World J Methodol. 2015 Jun 26;5(2):31-50. doi: 10.5662/wjm.v5.i2.31. PubMed PMID: 26140270; PubMed Central PMCID: PMC4482820.

Manuscript format Manuscripts should be typewritten in A4 page format, with 1,5 lines spacing, and page numbering. Times New Roman font, 12-point size, is required. They must be provided as Word files (not PDF).

Title page should carry the following information: the title of the manuscript (concise and informative), authorsâ&#x20AC;&#x2122; names and their institutional affiliations, department(s) and institution(s). Corresponding author and its address must be stated, e-mail address must be indicated.

An abstract must accompany each manuscript and should not exceed 300 words. Following the abstract, a list of 3-10 keywords is important for indexing purposes.

Structure of the manuscript depends on the category submitted. Original articles must include background, including the aims/objectives of the study, methods/ methodology, results, discussions and conclusions.

Acknowledgements placed after the Discussion or before references, should specify any contributions that need acknowledgment but do not justify authorship.

Appropriate units of measurement and nomenclature must be used. Only abbreviations and symbols generally accepted should be used, unfamiliar ones must be defined when first used. In-text citations must name authors in parentheses when you cite their work. For the work of one or two authors use (Author, Year of publication) or (Author 1 and Author 2, Year of publication), and for the work of three or more authors use (Author 1 et al., Year of publication).

Tables must be included in the main manuscript file,

Acceptance for publishing, offprints and author material archive policy Submitted manuscripts are subject to review and editing in order to be accepted for publication. After a manuscript is submitted, authors are permitted to supply names of potential referees. Although manuscripts are subject to review and editing, the Journal of the Romanian Society of Allergology and Clinical Immunology and the Romanian Society of Allergology and Clinical Immunology (RSACI) does not hold itself responsible for statements made by contributor authors.

Access to the PDF offprint of an accepted article may be available for the authors, by request. Please note that unless specifically requested otherwise, our Journal policy is to dispose of electronic material submitted, three months after publication. Therefore, if you require the return of any material submitted, please inform the editorial office as soon as possible.

49

Journal of the Romanian Society of Allergology and Clinical Immunology

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

RSACI HOME PAGE

SRAIC

Societatea Română de

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

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

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

To become a member of the Romanian Society of Allergology and Clinical Immunology please contact the Secretariat of the Society at: Emails: secretariat@sraic.eu Fax: + 40 21 230 52 63 sraic.rsaci@gmail.com RSACI is National Society Member of the European Academy of Allergy and Clinical Immunology

RSACI is Member Society of World Allergy Organization

50