DRUG ALLERGY Neuromuscular blockers (NMBs) account for 63% of reactions. latex 14%. hypnotics 7%.

antibiotics
6%. plasma substitutes 3%. and morphine-like substances 2%. Delayed hypersensitivity reactions
caused by anesthetic agents are less frequent. They are reported mostly association with local
DRUG-I~DUCED ALLERGIC REACTIONS IN PERIOPERATIVE PERIOD
anesthetics. heparin. antibiotics. antiseptics. and substances such as iodine contrast media.
AND DURING DIAGNOSTIC PROCEDURES Classification of agents used during anesthesia is present on Table I.
GENERAL ANESTHETICS, MUSCLE RELAXANTS AND LATEX Before the anesthesia (preoperative). depending on the type of surgery. are used anticholinergics
such as atropine sulfate or scopolamine, for decreasing the production of saliva and secretions of the
Aleksandra Peric-Popadic 1• 2 airway. Atropine can also be used, and upon completion of the operation. in combination with neostigmine,
1
Medical Faculty Unirersity olBelgrade for the elimination of the paralysis induced by neuromuscular blockers are administered after the induction
-' C/inicfor Allergology and Immunology, Clinical Centre ol Serbia of anesthesia. Since the prevalence of severe allergy to atropine is probably very low, screening of large
populations in order to trace patients with this allergy is not warranted. Allergy testing for atropine can be
Authors· address:
done by subcutaneous injection of atropine solution. patch tests. or other testing methods [3].
Associate Professor Aleksandra Peric-Popadic
Clinic/or Allergology and Immunology, Table I. Classification of agents used during anesthesia
Koste Todorovica 2. II 000 Belgrade, Serbia
E-mail: popealeksandra~Lyahoo.com
General anesthesia
ABSTRACT
Anesthesia represents a pharmacologically unique situation, during which patients are exposed to ~-~- ~------~--~-,

multiple foreign substances including anesthetics, which can produce immediate hypersensitivity reactions
or anaphylaxis. Anaphylaxis reaction to anesthetic agents is fortunately rare, ranging from I in 5, 000 to lnhalational Intravenous
25, 000 cases. The severity of the reaction may vary but features may include rash, urticaria, bronchospasm, _I __
hypotension, angioedema, and vomiting. Anaphylaxis is the most severe immune-mediated reaction; it
generally occurs on reexposure to a specific antigen. Anaphylactoid reactions occur through a direct non-
immunoglobulin E-mediated release of mediators from mast cells or from complement activation. Allergenic raoidlv acting
agents are not limited to intravenous drugs or fluids, but include other substances used in the operating
room such as skin disinfectants, latex gloves and catheters. Muscle relaxants and latex account for most Nitrous Ether Dissociative
cases of anaphylaxis during the perioperative period. Mild reactions may be difficult to distinguish from Thiopentone sod.
oxide
Halothane anesthesia
well-described side-effects of drugs, or anaesthesia per se; for example, the transient skin flushing or Methohexital sod
Zenon
hypotension seen with mivacurium. However, where doubt exists, it would seem prudent to refer these
patients for investigation as subsequent re-exposure may be disastrous. Patients who are suspected of an
Enflurane

lsoflurane
Ketamine I ._I_F_en_t_an_v_l_,
Diazepam Propofol

allergic reaction should be referred for further investigation to try to determine the exact cause. If necessary, Lorazepam Etomidate
this may involve provocation testing or skin prick testing and patients should be referred to local Desflurane
Midazolam Droperidol
immunologists. Anaphylaxis needs to be promptly recognised and managed and patients should be advised
Sevoflurane
to wear a medical emergency identification bracelet or similar once they recover.
MPtoxvflur~n
Key words: anesthetics, muscle relaxants, opioids, latex, hypnotics

INTRODUCTION Intravenous (inducing) rapidly acting anaesthetics

Immediate hypersensitivity reactions have been recognized as one of the most common causes
of morbidity and death in anesthesiology practice [I]. They can be either immune mediated
(allergic) or non-immune mediated (pseudoallergic or anaphylactoid reactions) [2]. About 60%-
70% of the immediate hypersensitivity reactions that occur during anesthesia are mediated by
immunoglobulin IgE. The mortality associated with this type of reactions varies from 3% to 9%.
Propofol (alkyl phenol) is responsible for I. 2% to 2% of all peri-operative anaphylactic reactions.
Current formulation in an emulsion of soy oil, egg albumin and glycerol may suggest cautious use in
patients with egg or soy allergy, but there is no evidence to show increased risk of anaphylaxis in this
population. Isopropyl groups present in skin care products may induce lgE sensitisation with
subsequent cross reaction with the isopropyl groups of the propofol molecule [4].

70 ACTA CLINIC A \"ol. IS .'ie3 < 2015 Klinicki ccntar Srbijc. Beograd <· 2015 Khnicki centar Srhije. Beograd ACTA CI.INICA \"ol. 15 N~3 . 71
 ACTA CLINICA

Alergijske reakcije izazvane lekovima

Drug allergy

Dr sci med MIRJANA BOGIC, GOST UREDNIK

MD PhD MIRJANA BOGIC, GUEST EDITOR

VOLUMEN 15 • BROJ 3 • DECEMBAR 2015.

VOLUME 15 • NUMBER 3 • DECEMBAR 2015.

Klinicki centar Srbije, BEOGRAD

Clinical Center of Serbia, BELGRADE
 EDITOR IN CHIEF
UREDNIK
Akademik Dragan Micic Academician Dragan Micic

SEKRETAR SECRETARY
Profesor dr sc. med. Aleksandra Kendereski Professor PhD Aleksandra Kendereski

REDAKCIJA EDITORIAL BOARD

Profesor dr sc. med. Miljko Ristic Professor PhD Miljko Ristic
Profesor dr sc. med. Dorde Bajec Professor PhD Dorde Bajec
Profesor dr sc. med. Mirko Kerkez Professor PhD Mirko Kerkez
Profesor dr sc. med. Zorana Vasiljevic Professor PhD Zorana Vasiljevic
Profesor dr sc. med. Dragoslava Deric Professor PhD Dragoslava Deric
Profesor dr sc. med. Vojko Dukic Professor PhD Vojko Dukic
Profesor dr sc. med. Miroslav Milicevic Professor PhD Miroslav Milicevic
Akademik Vladimir Kostic Academician Vladimir Kostic
Profesor dr sc. med. Zoran Krivokapic, FRCS, dopisni clan SANU Professor PhD Zoran Krivokapic, Fellowship of the Royal College of Surgeons (FRCS ),
Profesor dr sc. med. Zoran Dzamic corresponding member of Serbian Academy of Science and Arts
Profesor dr sc. med. Tomica Milosavljevic Professor PhD Zoran Dzamic
Akademik Dragan Micic Professor PhD Tomica Milosavljevic
Profesor dr sc. med. Milorad Pavlovic Academician Dragan Micic
Akademik Predrag Pesko Professor PhD Milorad Pavlovic
Profesor dr sc. med. Nebojsa Radunovic, dopisni clan SANU Academician Predrag Pesko
Professor PhD Nebojsa Radunovic, corresponding member of Serbian Academy of Science and Arts
IZDAVA CKI SA VET
Akademik Ljubisa Rakic, predsednik EDITORIAL COUNCIL
Akademik Vladimir Bumbasirevic Academician Ljubisa Rakic, president
Profesor dr sc. med. Felipe F. Casanueva, Spanija Academician Vladimir Bumbasirevic
Akademik Vladimir Kanjuh Professor PhD Felipe F. Casanueva, Spain
Profesor dr sc. med. Vesna Garovic, SAD Academician Vladimir Kanjuh
Profesor dr sc. med. Joseph Nadol, SAD Professor PhD Vesna Garovic, USA
Profesor dr sc. med. Robert Dion, Belgija Professor PhD Joseph Nadol, USA
Akademik Miodrag Ostojic Professor PhD Robert Dion, Belgium
Profesor dr sc. med. Michel Paparella, SAD Professor PhD Miodrag Ostojic
Akademik Veselinka Susie Professor PhD Michel Paparella, USA
Academician Veselinka Susie
RECENZENTI
Fahrettin Kele~timur, doktor medicine, Medicinski fakultet Erciyes, Kayseri, Turska REVIEWERS
Profesor dr sc. med. Wilmar Wiersinga, Akademski medicinski centar, Univerzitet u Amsterdamu, Fahrettin Kele~timur MD, Erciyes Medical Faculty, Kayseri, Turkey
Holandija Professor PhD Wilmar Wiersinga, Academician Medical Center, University of Amsterdam,
Profesor dr sc. med. Petar Dukic, Institut za kardiovaskularne bolesti, Klinicki centar Srbije Netherlands
Profesor dr sc. med. Milorad Pavlovic, Institut za infektivne i tropske bolesti, Klinicki centar Professor PhD Petar Dukic, Institute of cardiovascular diseases, Clinical Center of Serbia
Srbije Professor PhD Mil orad Pavlovic, Institute of infectious and tropical diseases, Clinical Center of Serbia
Profesor dr sc. med. Nebojsa Radunovic, Institut za ginekologiju i akuserstvo, Klinicki centar Professor PhD Nebojsa Radunovic, Institut of ginecology and obstetrics, Clinical Center of Serbia.
Srbije, dopisni clan SANU corresponding member of Serbian Academy of Science and Arts

LEKTOR LECTOR
Vesna Kostic Vesna Kostic

< 201' Klinii'ki n·ntar '>rhije. lkol!rad ~ 2015 Clinical Center of Serhia. Ael!lrade \CT\ CLI'\IC.\ Yol. 15 S·'
2 AlTALLli'<ILA Vol. 15J'id
SPISAK DO SADA IZDATIH BROJEVA CASOPISA ACTA CLINICA:
2001. godina (Volumen 1):
Broj 1. (decem bar) HIV infekcija- Gost urednik Dorde Jevtovic
2002.godina (Volumen 2):
Broj 1. (april) Helycobacter pylori- Gost urednik Tomica Milosavljevic
Broj 2. (avgust) Opstipacija- Gost urednik loran Krivokapic . ~ .
Broj 3. (novembar) Interventna radiologija u klinickoj medicini- Gost uredmk Zeljko Markov1c
2003. godina (Volumen 3):
Broj 1. (mart} Bolnicke infekcije- Gost urednik Milorad Pavlovic
Broj 2. Uun) Nagluvost i gluvoca- Gost urednik Dragoslava Deric
Broj 3. (novembar) Prelomi kuka- Gost urednik Borislav Dulic
2004. godina (Volumen 4):
Broj 1. (februar) Hronicna opstruktivna bolest pluca- Gost urednik Vesna Bosnjak-Petrovic
Broj 2. Uun) Funkcionalna ispitivanja u endokrinologiji- Gost urednik Svetozar Damjanovic
Suplement 1. Uun) Trakcione povrede brahijalnog pleksusa- Gost urednik Miroslav Samardzic
Broj 3. (oktobar) Glavobolje- Gost urednik Jasna Zidverc-Trajkovic
2005. godina (Volumen 5):
Broj 1. (februar) Bioloski efekti jonizujuceg zracenja- Gost urednik Ruben Han
Broj 2. (maj) Preventabilno slepilo- Gost urednik loran Latkovic
Broj 3. (oktobar) 0 depresijama- Gost urednik Vladimir Paunovic
2006. godina (Volumen 6):
Broj 1. (mart) Akutni koronami sindrom- Gost urednik Zorana Vasiljevic
Broj 2. Uul) Bolesti neuromisicne spojnice- Gost urednik Slobodan Apostolski
Broj 3. (decembar) Vestacke valvule srca- Gost urednik Petar Dukic
2007. godina (Volumen 7):
Broj 1. (februar) Bronhijalna astma- Gost urednik Vesna Bosnjak-Petrovic
Broj 2. Uul) Gojaznost- Gost urednik Dragan Micic
Broj 3. (decembar) Savremeni principi pacemaker terapije- Gost urednik Goran Milasinovic
2008. godina (Volumen 8):
Broj 1. Uanuar) Hipotireoza- Gost urednik Vera Popovic-Brkic
Broj 2. Uun) Suvo oko- Gost urednik Milenko Stojkovic
Broj 3. (decembar) Promuklost- Gost urednik Vojko Dukic
2009. godina (Volumen 9): ~
Broj 1. (februar) Sindrom hronicnog zamora- Gost urednik Milos Zarkovic
Broj 2. Uun) Diabetes mellitus tip 2- Gost urednik Nebojsa Lalic
Broj 3. (decem bar) Postupci asistirane reprodukcije u lecenju infertiliteta- Gost ur. Nebojsa
Radunovic
f" ~0 I~ Klinicki centar Srhije, Reognd
4 ACTA CLINICA Vol. 15 N23
2010. godina (Volumen 10):
Broj 1. (februar) Trauma jetre- Gost urednik Vladimir Dukic
Broj 2. Uul) Primena biomarkera u laboratorijskoj medicini- Gost urednik Nada Majkic-Singh
Broj 3. (decem bar) Limfoproliferativne bolesti- Gost urednik Biljana Mihaljevic
2011. godina (Volumen 11):
Broj 1. (februar) Multipla skleroza -- Gost urednik Jelena Drulovic
Broj 2. Uun) Odabrana poglavlja iz ehokardiografije- Gost urednik Bosiljka Vujisic-Tesic
., Broj 3. (decembar) Poremecaji hemostaze i tromboze- Gost urednik lvo Elezovic
2012. godina (Volumen 12):
Broj 1. (februar) Aneurizmatska bolest- Gosti urednici Lazar Davidovic i Zivan Maksimovic
Broj 2. Uun) Savremeno lecenje povreda kostano-zglobnog sistema- Gost urednik Marko Bumba-
sirevic
Broj 3. (decem bar) Fakoemulsifikacija kao metoda izbora u operaciji katarakte- Gost urednik Milos
Jovanovic
2013. godina (Volumen 13):
Broj 1. (februar) Akutni koronami sindrom: posebna poglavlja- Gost urednik Zorana Vasiljevic
Broj 2. Uun) Menopauza- Gost urednik Svetlana Vujovic
Broj 3. (decembar) Nova era u kardiohirurgiji- Gost urednik Miljko Ristic
2014. godina (Volumen 14):
Broj 1. (februar) Savremeni pristup dijagnostici i terapiji neuropatija- Gost urednik Zorica Stevie
Broj 2. Uun) Uro-onkologija danas- Gost urednik loran Dzamic
Broj 3. (decembar) Gojaznost: savremena dostignuca- Gost urednik Dragan Micic
2015. godina (Volumen 15):
Broj 1. (februar) Novine u rehabilitaciji kardioloskih i neuroloskih bolesnika- Gost urednik Dragana
Matanovic
Broj 2. Uun) Gastrointestinalna flora u zdravlju i bolesti- Gost urednik Tomica Milosavljevic
Broj 3. Alergijske reakcije izazvane lekovima- Gost urednik Mirjana Bogie
Sledeci broj:
2016. godina (Volumen 16):
Broj 1. (februar) Izazovi u lecenju hematoloskih maligniteta kod bolesnika starije zivotne dobi -- Gost
urednik Biljana Mihaljevic
~ 2015 Klinicki centar Srbiie. Beo!!rad ACTA CI.INICA Vol. 15 .Vo1
LIST OF PUBLISHED NUMBERS OF ACTA CLINICA: 2010. year (Volume 10):
Number I. (february) Li\er injury~ Guest editor Vladimir Dukic
Number 2. Uuly) Application of biomarkers in laboratory medicine~ Guest ed. Nada Majkic-Singh
2001. year (Volume 1): Number 3. (december) Lymphoprolipherative diseases~ Guest editor Biljana Mihaljevic
Number 1. (december) HIV infection~ Guest editor Dorde Jevtovic
2011. year (Volume 11):
2002. year (Volume 2): Number 1. (february) Multiple sclerosis~ Guest editor Jelena Drulovic
Number I. (april) Helycobacter pylori~ Guest editor Tomica Milosavljevic Number 2. Uune) Selected topics in echocardiography ~Guest editor Bosiljka Vujisic-Tesic
Number 2. (august) Obstipation~ Guest editor loran Krivokapic . Number 3. (december) Hemorrhagic syndrome and thrombosis~ Guest editor Ivo Elezovic
Number 3. (november) Intervention radiology in clinical medicine~ Guest editor Zeljko Markovic
2012. year (Volume 12):
2003. year (Volume 3): Number 1. (february) Aneurysmal disease~ Guest editors Lazar Davidovic i Zivan Maksimovic
Number 1. (march) Hospital infections~ Guest editor Milorad Pavlovic Number 2. Uune) Contemporary treatment of osteoarticular injuries~ Guest editor Marko Bumbasirevic
Number 2. Uune) Deafness~ Guest editor Dragoslava Deric Number 3. (december) Phacoemulsification as a method of choise for cataract surgery~ Guest editor
Number 3. (november) Hip fractures~ Guest editor Borislav Dulic Milos Jovanovic
2004. year (Volume 4): 2013. year (Volume 13):
Number 1. (february) Chronic obstructive lung disease~ Guest editor Vesna Bosnjak-Petrovic Number 1. (february) Acute coronary syndrome: special chapters~ Guest editor Zorana Vasiljevic
Number 2. (june) Functional investigations in endocrinology~ Guest editor Svetozar Damjanovic Number 2. (june) Menopause- Guest editor Svetlana Vujovic
Suplement 1. Uune) Tractional injuries of brachial plexus~ Guest editor Miroslav Samardzic Number 3. (december) A new era in cardiac surgery~ Guest editor Miljko Ristic
Number 3. (october) Headaches~ Guest editor Jasna Zidverc-Trajkovic
2014. year (Volume 14):
2005. year (Volume 5): Number 1. (february) Current principles of neuropathies diagnostics and therapy~ Guest editor Zo-
Number 1. (february) Bilogical effects of ionizing radiation~ Guest editor Ruben Han rica Stevie
Number 2. (may) Preventable blindness~ Guest editor Zoran Latkovic Number 2. (june) Uro-oncology today~ Guest editor Zoran Dzamic
Number 3. (october) About depressions~ Guest editor Vladimir Paunovic Number 3. (december) Obesity: recent advances~ Guest editor Dragan Micic
2006. year (Volume 6): 2015. year (Volume 15):
Number 1. (march) Acute coronary syndrome~ Guest editor Zorana Vasiljevic Number 1. (february) Rehabilitation of the cardiac and neurological patients: an update- Guest edi-
Number 2. (july) Diseases of the neuromuscular junction~ Guest editor Slobodan Apostolski tor Dragana Matanovic
Number 3. (december) Artificial heart valves~ Guest editor Petar Dukic Number 2. (june) Gastrointestinal microbiota in health and disease~ Guest editorTomica Milosa\ ljevic
2007. year (Volume 7): Number 3. Drug allergy~ Guest editor Mirjana Bogie
Number 1. (february) Bronchial asthma~ Guest editor Vesna Bosnjak-Petrovic
Number 2. Uuly) Obesity~ Guest editor Dragan Micic Future number:
Number 3. (december) Present principles of peacemaker therapy~ Guest editor Goran Milasinovic
2016. year (Volume 16):
2008. year (Volume 8): Number 1. (february) Challenges in treatment of older patients \Vith hematological malignancy
Number 1. (january) Hypothyroidism- Guest editor Vera Popovic-Brkic Guest editor Biljana Mihaljevic
Number 2. (june) Dry eye- Guest editor Milenko Stojkovic
Number 3. (december) Hoarseness~ Guest editor Vojko Dukic
2009. year (Volume 9):
Number 1. (february) Chronic fatigue syndrome- Guest editor Milos Zarkovic
Number 2. (june) Diabetes mellitus type 2- Guest editor Nebojsa Lalic
Number 3. (december) Assisted reproduction technology in infertility therapy~ Guest ed. Nebojsa
Radunovic

6 ACTA CLIC.:IC\ Yo!. 15 Xc3 c 2015 Clinical Center of Serbia. Belgrade !&:; 2015 Clinical Center of Serbia, Belgrade
ACTA CLI'-JICA \ol. 15 .'1"' 7
--··-----------------------
ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA
GOST UREDNIK
MIRJANA BOGIC, dr sci med, specijalista interne medicine-alergolog i klinicki imunolog,
redovni profesor na katedri za internu medicinu Medicinskog fakulteta Univerziteta
u Beogradu, Klinika za alergologiju i imunologiju, Klinicki Centar Srbije, Beograd.
SARADNICI
BRANKA BONACI NIKOLIC, dr sci med, specijalista interne medicine-alergolog i
klinicki imunolog, vanredni profesor na katedri za internu medicinu Medicinskog
fakulteta Univerziteta u Beogradu, Klinika za alergologiju i imunologiju, Klinicki
Centar Srbije, Beograd.
VOJISLAV DJURIC, dr sci med, specijalista interne medicine-alergolog i klinicki
imunolog, vanredni profesor na katedri za internu medicinu Medicinskog fakulteta
Univerziteta u Beogradu, Klinika za alergologiju i imunologiju, Klinicki Centar
Srbije, Beograd.
SANVILA RASKOVIC, dr sci med, specijalista interne medicine-alergolog i klinicki
imunolog, redovni profesor na katedri za internu medicinu Medicinskog fakulteta
Univerziteta u Beogradu, Klinika za alergologiju i imunologiju, Klinicki Centar
Srbije, Beograd.
ALEKSANDRA PERIC-POPADIC, dr sci med, specijalista interne medicine-alergolog
i klinicki imunolog, vanredni profesor na katedri za internu medicinu Medicinskog
fakulteta Univerziteta u Beogradu, Klinika za alergologiju i imunologiju, Klinicki
Centar Srbije, Beograd.
VESNA TOMIC-SPIRIC, dr sci med, specijalista interne medicine-alergolog i klinicki
imunolog, vanredni profesor na katedri za internu medicinu Medicinskog fakulteta
Univerziteta u Beogradu, Klinika za alergologiju i imunologiju, Klinicki Centar
Srbije, Beograd.
8 ACTA CLINlCA Vol. 15 N2J e 201 <; Klinicki centar Srhiie. Reograd
DRUG ALLERGY
GUEST EDITOR
MIRJANA BOGIC, MD, PhD, specialist in internal medicine-allergology and clinical
im.m~nology, Professo.r of internal medicine, Medical Faculty, University of Belgrade,
Chmc for allergy and Immunology, Clinical Center of Serbia, Belgrade.
ASSOCIATES
BRANKA BONAC:I NIKOLIC, MD, PhD, specialist in internal medicine-allergology
an~ clin~cal immunology, Associate Professor of internal medicine, Medical Faculty,
Umverstty of Belgrade, Clinic for allergy and immunology, Clinical Center of Serbia,
Belgrade.
VOJISLAV DJURIC, MD, PhD, specialist in internal medicine-allergology and clinical
immunology, Associate Professor of internal medicine, Medical Faculty, University
of Belgrade, Clinic for allergy and immunology, Clinical Center of Serbia, Belgrade.
ALEKSANDRAPERIC-POPADIC, MD, PhD, specialist in internal medicine-allergology
and clinical immunology, Associate Professor of internal medicine, Medical Faculty,
University of Belgrade, Clinic for allergy and immunology, Clinical Center of Serbia,
Belgrade.
SANVILA RASKOVIC, MD, PhD, specialist in internal medicine-allergology and clinical
immunology, Professor of internal medicine, Medical Faculty, University of Belgrade,
Clinic for allergy and immunology, Clinical Center of Serbia, Belgrade.
VESNA TOMIC-SPIRIC, MD, PhD, specialist in internal medicine-allergology and
clinical immunology, Associate Professor of internal medicine, Medical Faculty,
University of Belgrade, Clinic for allergy and immunology, Clinical Center of Serbia,
Belgrade.
0 2015 Clinical Center of Serbia, Rei grade ACTA CLINIC A Vol. IS N2J 9
 -
ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA DRUG ALLERGY

SADRZAJ SUMMARY

UVOD 13 PREFACE 14
Prof dr Mirjana Bogie Mirjana Bogie

PATOGENEZAALERGIJSKIH REAKCIJA IZAZVANIH LEKOVIMA 15 PATHOGENESIS OF DRUG HYPERSENSITIVITY 24

Branka Banaei-Nikolic Branka Banaei-Nikolic

ALERGIJA NA BETA-LAKTAMSKE ANTIBIOTIKE 33 BETA-LACTAM ANTIBIOTIC ALLERGY 42

Vesna Tomic-Spiric Vesna Tomic-Spiric

NEIMUNOLOSKI POSREDOVANA PREOSETLJIVOST NAASPIRIN 51 NONIMMUNOLOGICALLY MEDIATED HYPERSENSITIVITY TO ASPIRIN 57

Mirjana Bogie Mirjana Bogie

ALERGIJSKE REAKCIJE IZAZVANE MEDIKAMENTIMA U PERIOPERATIVNOM DRUG-INDUCED ALLERGIC REACTIONS IN PERI OPERATIVE PERIOD
PERIODU I U TOKU DIJAGNOSTICKIH PROCEDURA 63 AND DURING DIAGNOSTIC PROCEDURES 70

OPSTI ANESTETICI, MIORELAKSANSI I LATEX 63 GENERAL ANESTHETICS, MUSCLE RELAXANTS AND LATEX 70
Aleksandra Peric-Popadic Aleksandra Peric-Popadic
JODNA KONTRASTNA SREDSTVA 78 IODINATED CONTRAST MEDIA 84
Mirjana Bogie Mirjana Bogie

ALERGIJSKE REAKCIJE IZAZVANE LOKALNIM ANESTETICIMA 91 ALLERGIC REACTIONS TO LOCAL ANESTHETICS 94

Voj islav Durie Vojislav Djuric

REAKCIJA NA LEKOVE SA EOZINOFILIJOM I SISTEMSKIM SIMPTOMIMA 97 DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS 101
Sanvila Raskovic Sanvila Raskovic

LEKOVIMA IZAZVAN LUPUS 105 DRUG- INDUCED LUPUS 109

Sanvila Raskovic Sanvila Raskovic

Uputstvo autorima 113 Instructions to authors 116

10 ACTA CLINICA Vol. 15 .N"2J L 2015 Klinicki centar Srhiie. Beograd <: 2015 Clinical Center of Serbia, Belgrade ACTA CLINICA Vol. 15 .N"2J II
 ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA

PREDGOVOR

PROFESOR DR
MIRJANA BOGIC
Gost urednik

U 21-om veku~ paralelno sa pojavom novih i boljih lekova za tretman infekcija, hronicnih za-
paljenskih i drugih bolesti, primecen je i porast alergijskih reakcija na iste. Termin "preosetljivost na
lekove" podrazumeva svaku nezeljenu reakciju na lek ispoljavanjem imunoloskog mehanizma.
U nekim slucajevima, ove reakcije mogu biti opasne po zivot. Identifikovanje tih pacijenata, stiti ih
od ponovnog izlaganja stetnom leku. Ovo izdanje ACTA CLINICA-e, posveceno je napretku i daljem
razumevanju epidemiologije preosetljivosti na lekove, njenom dijagnostikovanju, kao i tretmanu
kljucnih, centralnih mehanizama preosetljivosti na lekove~ a to su: imunoglobulin E (lgE), specificnost
humanih leukocitnih antigena i virusna reaktivacija. Alergijske reakcije i preosetljivost izazvana le-
kovima ostace prisutne, alice zahvaljujuci ponavljanom izlaganju dejstvu leka, duzina i kvalitet zivota
pacijenata biti poboljsani. Dublje sagledavanje ove problematike svakako ce doprineti povecanju
bezbednosti pacijenata.

'
J © 2015 Klinicki centar Srbije, Beograd .\CT.\ CLI~IC.\ Yo!. 15 S_' 1~

i.
DRUG ALLERGY ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA

PREFACE PATOGENEZAALERGIJSKIH REAKCIJA IZAZVANIH LEKOVIMA

Branka BonaCi-Nikolic
A1edicinskifakultet, Unit·er::itet u Beogradu
Klinika ::a alergologiju i imunologiju, Klinicki centar Srbija

Adresa aurora:
Profesor Branka BonaCi-Nikolic
Klinika ::a alergologiju i imunologiju,
Koste Todorovica 2, 11 000 Beograd
E-ma i1: branka_bonaci@_1·ahoo. com

MD, PHD
MIRJANA BOGIC
Guest editor
With the increase in new better medications to treat infections and chronic inflammatory and
other diseases in the 21 st century, a parallel increase in drug allergy has been seen. The term ''drug
hypersensitivity" refers to any adverse reactions to drug with a demonstrated immunologic mechanism.
Some of them can be life threatening. Identifying patients with a drug allergy protects them from
reexsposure to culprit medications. This issue of ACTA CLINICA is devoted to advances and further
understanding of the epidemiology of drug hypersensitivity and its diagnosis and treatment for the key
central mehanisms of drug hypersensitivitiy: lgE or non lgE, HLA specificity and viral reactivation.
Drug allergy and hypersensitivity are here to stay, because patients live lon~er and a~e provided wi~h
better quality of life by repeated exposures to drug. Further understandmg of thts problem wtll
contribute to enhanced patient safety.
SAZETAK
Hipersenzitivne reakcije na lekove mogu biti izazvane imunoloskim (T i 8 limfociti) i neimunoloskim
mehanizmima (nespecificna degranulacija mastocita, oslobadanje bradikinina, leukotrijena itd). Lekovi u
formi solubilnih makromolekula su kompletni antigeni i indukuju produkciju lgE iii IgG antitela. Vecina
lekova su hapteni i prvo se kovalentno vezuju za sopstvene proteine (albumine) kako bi doslo do
senzibilizacije. Ako je kompleks lek-nosac solubilni protein, 8 limfocit ima funkciju antigen-prezentujuce
celije (APC) i indukuje dominantno I tip iii III tip preosetljivosti. Ukoliko je nosac nesolubilni (membranski)
protein, druge APC (makrofagi, dendriticne, Langerhansove celije) nakon abrade i prezentacije imunogenog
peptida, indukuju dominantno II iii IV tip preosetljivosti koji je zavisno od citokina posredo\an
T pomocnickim (helper) celijama tip 1 (Th 1), Th2 iii T citotoksicnim limfocitima. Lekovi-prohapteni, u
nativnoj formi ne mogu da reaguju kova1entno sa sopstvenim proteinima, vee prethodno moraju da se
hemijski trasformisu. Poslednjih godina opisan je mehanizam farmakoloske interakcije leka sa imunskim
receptorom (p-i koncept). Hemijski inertan 1ek, bez metabo1izma i interakcije sa proteinima \ ezuje se
nekova1entno za pojedine T celijske receptore (p-i/TCR) iii antigene glavnog histokompatibilnig kompleksa
(p-i/GHK). Ovaj patogenetski mehanizam je vazan u nastanku 1ekom-indukovanih makulopapuloznih i
bu1oznih egzantema. Pose ban tip p-i interakcije nastaje nekovalentnim vezivanjem leka za antigen \ ezujuce
mesto GHK, cime se menja repertoar sobstvenih pepida koji se prezentuju uz raz\·oj autoimunosti. sto je
karakteristicno za lekom-indukovani egzantem pracen eozinofilijom i sistemskim simptomima. Kasne
reakcije preosetljivosti posredovane T limfocitima cesto se kombinuju. lmunogenetska predispozicija
omogucuje individualni pristup u terapiji, sto znacajno smanjenje incidencu teskih sistemskih reakcija
preosjetljivosti na 1ijekove.
Kljucne reci: 1ekovi, patogeneza, a1ergijske reakcije, nealergijske reakcije

KLASIFIKACIJA NEZELJENIH REAKCIJA NA LEKOVE

Nezeljene reakcije na lekove predstavljaju znacajan zdravstveni problem zbog porasta hronicnih
oboljenja i sve cesce primene antimikrobnih lekova, hemioterapije i bioloske terapije. Meta analiza
33 prospektivne studije od 1966. do 1996.god. je pokazala da je 15.6% odraslih hospitalizovanih
pacijenata imalo nezeljenu reakciju na lek [ 1].

•· ~0!' Klinicki ce!'t3r "rbije. Hengrad :c. 2015 Klinicki ccntar Srbije. Heograd ].:;
14 AliAlLII'o.ilA \ol. 15;''"3
 Nezeljene reakcije na lekove dele se na tip A i tip 8 (Tabela 1) [2] . Reakcije u grupi A su
predvidljive i vezane su za farmakoloske efekte leka, primenjenu dozu, nuspojave iii poznatu
interakciju lekova. Reakcije u grupi 8 su znatno rede (manje od 1 na 1000 pacijenata), nisu vezane za
farmakoloske efekte lekova i najcesce ne zavise od doze leka. Smatra se da 20% nezeljenih reakcija
na lekove pripada grupi 8 koja obuhvata 2 osnovne grupe: nealergijske i alergijske reakcije
preosetljivosti (Tabela 1).
Najcesce hipersenzitivne reakcija izazivaju antibiotici, nesteroidni antiinflamatorni Iekovi
(NSAIL.~, antiepil~~tici i lek~~i u t.e:api~i i~fekcije virusom humane imunodeficijencije (HIV) [3].
NealergiJSke reakCIJe preosetljiVOSti IZ3ZIV3JU celije i inflamatomi mehanizmi nespecificne imunost.
Alergijske reakcije pre~setlji.~o~ti izazivaju ~pecificni 8 i T limfociti koje karakterise memorijski
odgovor, klonalna prohferaCIJa 1 somatske h1permutacije [2]. U odnosu na osnovne patogenetske
mehanizme alergijske reakcije se dele u osnovna cetiri tipa (Tabela 1) [2].

Tabela ]· Klasifikacija neieljenih reakcija na lekove

FAKTORI RIZIKA ZA RAZVOJ HIPERZENZITIVNIH
A) Predvidive Mehanizam Lek Klinicka slika
REAKCIJA NA LEKOVE
Predoziranje Hepatotoksicnost Acetaminofen Insuf. jetre
8rojni faktori (hemijske osobine, sastav, nacin primene i doza leka, tip osnovnog oboljenja i
Sporedni efekti Farmakoloski efekat Metilksantini Povracanje genetske karakteristike pacijenta) povecavaju rizik i tezinu klinicke slike hipersenzitivne reakcije na
Sekundami efekat Izmena bakterijske crevne flore Antibiotik Kolitis lek [3].
Interakcija lekova Povecan nivo teofilina u krvi Eritromicin Tahikardija Proteinski makromolekuli, multivalentni lekovi, kao i visoka reaktivnost niskomolekularnih
lekova (hapteni) prema proteinima povecava potencijalnu imunogenost leka [4]. Prisustvo polimera
B) Nepredvidive
leka (aminopenicilini) olaksava senzibilizaciju. Duzina i nacin primene leka odredjuju da lice se razviti
Nealergijske rana iii kasna alergijska reakcije na lek.
Idiosinkrazija Deficit glukozo-6 fosfat Dapson Hemoliticka anemija Neke bolesti udruzene su sa visokim rizikom alergijskih reakcije na lek [5]. Tako, trecina
dehidrogenaze pacijenata sa cisticnom fibrozom ima hipersenzitivnu reakciju na antibiotike, posebno cesto na
,Pseudoalergija'" Degranulacija mastocita piperacilin. Takode, reakcija na sulfametoksazol je deset puta veca kod pacijenata sa sindrom
G protein/vezani receptor Atrakurijum Urtikarija stecene imunodeficijencije u fazama replikacije HIV virusa [1]. Pacijenti sa infektivnom
mononukleozom imaju veliku incidencu makulopapuloznih egzantema na amoksicilin. Atopija u
Altemativna aktivacija Emulzifikatori Urtikarija licnoj iii porodicnoj anamnezi povecava rizik za IgE senzibilizaciju na lek. Deficijencija inhibitora
komplementa- C3a, C5a C 1 esteraze je faktor rizika za nastanak nealergijskog angioedema tokom primene inhibitora
Intolerancija Inhibicija ciklooksigenaze 1 Aspirin Astma angiotenzin konvertujuceg enzima (ACE-I) [6]. Odlozene reakcije na lek posredovane T limfocitima
Porast bradikinina ACE-I Angioedem udruzene su sa genima glavnog histokompatibilnog kompleksa (GHK}, posebno antigenima B klase
Alergijske Tip I: IgE, degranulacija mastocita Monoklon. At Anafilaksa [7]. Pokazanaje i znacajna udruzenost alela van GHK koji ucestvuju u metabolizmu leka (redukcija
1. Kompletni antigeni aktivnosti citohroma CZP2C9) i teskih kutanih reakcija na lek ( fenitoin) [7]. Ne\ irapinom
Tip III: IgG, imunski kompleksi, Antiserum Serumska bolest indukovano ostecenje jetre povezano je za ale lima II klase GHK, dok je ostecenje koze pm ezano
komplement sa alelima I klase GHK [7]. Sa otkricem udruzenosti odredenih alela GHK sa visokim rizikom T
Anafilaksa
2. Hapteni Tip I: IgE, degranulacija mastocita Beta laktami celijske reakcije na neke lekove (Tabela 2) incidenca teskih sistemiskih reakcija se znacajno
Anemija smanjila [2].
Tip II: lgG-posredovana Meti1-dopa
citotoksicnost Lupus Tabela 2: Udruienost HLA ale/a sa teskim hipersenzitivnim reakcijama na lekove
Izoniazid Lek HLAalel Klinicka manifestacija
Tip III: IgG imunski kompleksi, Egzantem,
komplement Karbamazepin eozinofilij a, Abakavir HLA-B 57:01 Sistemski hipersenzitivni sindrom (bela rasa)
sistemski simptomi Stevens-Johnson sindrome (Kina, Indija)
Tip IV podtip a,b,c d: posredovan T Karbamazepin HLA-B 15:02
HLA-A 31:01 DRESS, Stevens-Johnson sindrome (bela rasa)
limfocitima Egzantem, Toksicna epidermalna nekroliza (bela rasa)
Prezentacija u sklopu GHK i1i/i p-i Alopurinol HLA-B 58:01
interakcija Stevens-Johnson sindrome (Kina, bela rasa)
Flukloksacilin HLA-B 57:01 Hepatotoksicnost
ACE-I- inhibitori angiotenzin konvertujuceg enzima,GHK-glavni histokompatibilni kompleks
p-i -farmakoloska interakcija sa imunskim receptorom DRESS-egzantem izazvan lekom pracen eozinofilijom i sistemskim simptomima

16 ACTA cu;-.;ICA \'ol. 15 X~3 :t- 2015 K1inicki centar Srbije, Beograd © 2015 Klinicki centar Srbije. Beograd
17
PATOGENEZA NEALERGIJSKIH REAKCIJA NA LEKOVE
Nealergijske reakcije na lek (Tabela 1) klinicki su identicne alergijskim reakcijama i mogu se
prezentO\ ati angioedemom. urtikarijom. bronhijalnom astmom. gastrointestinalnim simtomima i
anafilaksom. S obzirom da izostaje indukcija speciticnog imunskog odgovora. prik test, kao i speciticna
lgE antitela su negativna. Nealergijske reakcije se odigravaju bez prethodnog kontakta sa lekom [8].
Najcesce nealergijske reakcije izazivaju NSAIL ACE-I. jodna kontrasna sredstva, opijati [3].
Tri osnmna tipa nealergijskih reakcija lekme su: idiosinkrazija . .,pseudoalergija" i intolerancija.
Idiosinkrazije nastaje usled defekta iii potpune deticijencije enzima koji ucestvuje u metabolozmu leka. Tacni
patogenetski mehanizmi svih nealergijskih reakcija nisu definisani. Porast serumske triptaze unutar 2 sata od
reakcije potvrduje primami imunopatogenetski znacaj mast celija. Oslobodena triptaza moze da aktivira
komplement sto dodatno doprinosi razvoju intlamacije [6]. Heparin koji se oslobada iz mastocita dovodi do
aktivacije kontakt-aktivacionog sistema uz oslobadanje bradikinina. Nedavno je pokazano da tluorohinoloni
i neuromisicni blokatori mogu da aktiviraju mast celije preko G-vezanog proteinskog receptora [9].
Direktna degranulacija mastocita ima primarni znacaj u nastanku ranih reakcija (urtikarija.
angioedem, anafilaksa) na visokoosmolama nejonska jodna kontrasna sredstva. Slicnim mehanizmom
agregati prisutni u koloidnim ekspanderima volumena (zelatin, albumin) mogu izazvati !aksu iii tezu
hipersenzitivnu reakciju [6]. Primena nanopartikula i lipozoma u leku koja obezbeduju sporo
oslobadanje leka povecava rizik nealergijskih reakcija. Pojedini rastvaraci parenteralnih lekova
( Politaksel) sadrze micele koje mogu aktivirati alternativno komplement uz porast C3a i C5a
(anafilatoksina) koji degranuliraju mastocite uz razvoj sistemskih i/ili kutanih reakcija (complement
activation-related pseudoallergy-C ARPA) [6].
Posebna grupa nealergijskih reakcija su intolerancije. Klasican primer intolerancije na lek je
aspirinska astma i hronicna urtikarija izazvana aspirinom i drugim neselektivnim NSAIL [3]. Kod
aspirinska astme udruzene sa nazalnom polipozom i eozinofilijom primarni znacaj ima inhibicija
ciklooksigenaze 1 koja kod predisponiranih pacijenata dovodi do porasta bronhokonstriktornih
medijatora, prostanglandin ( PG )02 i leukotrijena C4, uz pad koncentracije bronhodilatatornog
medijatora PGE2. ACE-I smanjuju degradaciju bradikinina i substance P, sto dovodi do povecanja
vaskulame permeabilnosti uz razvoj angioedema [6]. Kod pacijenata koji razvijaju angioedem tokom
primene ACE-I pokazana je smanjena aktivnost aminopeptidaze-P i dipeptidil peptidaze IV koji takode
pm ecavaju degradaciju bradikinina [6].
Treba imati u vidu da nlo retko jodna kontrasna sredstva. lokalni anestetici i NSAIL mogu
izazvati IgE posredovanu alergijsku reakciju.
PATOGENEZA ALERGIJSKIH REAKCIJE NA LEKOVE
Kako /ekovi postaju a/ergeni i indukuju specifican imunski odgovor?
Alergijske reakcije na lekove imaju kompleksnu patogenezu, klinici se heterogeno prezentuju i
mogu predstavljati diferencijalno dijagnostici problem, posebno kasne reakcije koje mogu liciti na
sistemsko oboljenje iii reaktivaciju virusne infekcije [ 10]. General no. imunski sis tern prepoznaje
alergene u multivalentnoj formi u induktorskoj i efektorskoj fazi imunskog odgovora [2]. Do sada je
imunopatogenetski definisano pet nacina na koji imunski sistem prepoznaje lek kao alergen.
Visokomolekularni proteinski lekovi (hormoni. protamin, monoklonska antiteia, enzimi,
rekombinantni citokini, vakcine) i multivalentni lekovi sa vecim brojem epitopa (sukcinilholin i druge
IS \CT\ CLI\'IC \Yo!. 15 -"'"' c 2015 Klinicki ccntar Srhijc. Heograd
. aternerne
k\ . amoniJ.
. _~ urn baze_ ) su komp Ietm_· ~nt1gem,
· · tako da bez vezivanja za sopstvene proteine
md~kUJU speciflc~n !h~ z~_nstan ~umoralm nnunski odgovor [3]. Folikulami B limfocit je cetralna
antigen-prezentuJ_~ca ceiiJa. ~A PC) ko~ lgE (I tip prosetlj ivosti) iii lgG (Ill tip preosetlj i\ osti)
posredm a~e ~lergiJ~~e reakciJe na solubilne visokomolekulc.me proteinske Jekove [2].
. ~ed~ut1m, ~·ecma lekova _su mal_e molekulske tezine < I kDa) i ne mogu u formi haptena da
I_nd_~kuJ~ Imu~.s~I odgov~r. 0~1 m_ora~u da _se kovalentno ve:Zu za makromolekule u plazmi iii na
cehJs_koJ ponsm1. kako b1~ se :orm_Irah m_ulti\·alentn_i hapten-nosac kompleksi (kompletan alergen).
Ak~ J_e ~omple~s lek-no~ac u tonm solubilnog protema, 8 celija moze preuzeti funkciju APC i u tom
s_lucaJu md~_kuJe _se domma~tno_rrodukcija speciticnih lgE (I tip preosetljivosti ) iii lgG anti tela (Ill
tip preosetlJivosti) [2]. Ukohko Je nosac nesolubilni protein (membranski protein), nakon endocitoze
~re_~entuju se neoepitopi u formi imunogenih peptida od strane drugih APC (makrofagi, dendriticne
cei!Je. Largenhansove celije) Ll kontekstLI molekLIIa I iii II klase GHK i zavisno od citokina dolazi do
akti_vaci~~ B lin;tocita (domin_antno II tip) iii T limtocita (IV tip preosetljivosti) [2]. Infek~ija. preko
akti:aciJe AP~ Llbrzava anti_genskLI obradLI kompleksa hapten-protein i omogLica\·a ekspresijLI
kostimLilatormh molekLIIa (signal opasnosti) [4]. Zastitni mehanizam. dehaptenizacija se desava
pararel_~o sa haptenizacijom, tako je samo 0.01% penicilina Ll km alentnoj vezi sa proteinima [2].
lndukciJa T regulatomih limfocita Ll jetri ima va:ZnLI Lllogu Ll inhibiciji alergijske reakcije na kompleks
hapten-nosac [4]. Beta laktamski antibiotici. kinidin. cisplatina. penicilamin. antitiroidni Jekovi
indLikuju imLinski odgovor mehanizmom formiranja kompleksa hapten-nosac[3].
S druge strane brojni lekovi. poznati kao prohapteni. Ll nativnoj tormi ne mogLI da reagLijLI
kovalentno sa sopstvenim proteinima, vee prethodno moraju da se hemijski transtormisLI LIZ nastanak
reaktivnih metabolita (suifonamidi, acetaminofen. fenitoin. halotan. prokainamid) [2]. Transtormacija
prohaptena u hapten odigrava se najcesce Ll jetri i bubregLI. sto moze objasniti lekom indLikO\ an
izoiovani hepatitis iii intersticijski nefritis. Brojni metaboloicki faktori (aktivnost citohroma. nizak
glutationa iii spora acetiiacija) preusmeravaju metaboiizam ka nastankLI reaktivnih intermedijernih
jedinjenja LIZ indukcij Ll imLinskog odgovora ( lgG posredovan hepatitis indLikm an halotan~ml il i
izoniazidom) [I]. Brojni metabolicki produkti leka mogLI izazvati apoptozLI i nekrozu celija sto indLikuje
matur~ciju dendriticnih celija, koje se neophodne za aferentnLI fazu imLinskog odgovora na Iek [4]. .
Cetvrti \azan mehanizam koji obezbedjuje imLinogenost Ieka oznacen je kao farmakoloska
interakcija leka sa imunskim receptorom (p-i, koncept) koji je udruzen sa genima GHK i varijabilnim beta
(V beta) regionom T celijskog receptora (TCR) [7]. Hemijski inertan monovaientan lek (karbamazepin.
lamotrigin, suifametoksazoi) bez metabolizma i interakcije sa proteinima iii peptidima. direktno se \ ezuje
nekovaientno za odreden broj T ceiijskih receptora (p-i/TCR) iii anti gene GHK (p-i~G HK) pq.
SLilfametoksazoi i karbamazemin se vezuje direktno za odredene V beta regione CD8r- T limfocita.
Reaktivacija virusne herpes infekcije iii aktivacija sistemske bolesti (ekspresija molekula GHK i
kostimulatomih molekula) smanjuju prag za aktivaciju T celije, sto snazno amplifikuje odgovor i dm odi
do teskih multiorganskih ostecenja [1]. Ovaj mehanizam prekomeme aktivacije T limfocita karakteristican
je za efekte super-antigena. Nakon aktivacije, proliferacije i produkcije citokina, T limfocit citotoksicnim
mehanizmima (perforin, granzim) dovodi do apoptoze ceiija. Ovaj imunoloski mehanizam je \azan u
patogenezi karbamazeminom i alopurinoiol indukovanog Stevens-Johnson sindroma i toksicne epidem1alne
~ekrolize, kao i tlukloksacilinom indukovanog hepatitis kod nosioca odredenih alela GHK (Tabela 2) [7].
Cesta zahvacenost koze tumaci se prisustvom brojnih efektorskih T celija memorije u kozi. kao i dedriticnih
ceiije koje efikasno prezentuju antigene [ 11 ]. Pojedini lekovi (sultonamidi, tlukloksacilin) mouLI da
istovremeno aktiviraju imunski sistem direktno (p-i mehanizam) i putem klasicne prezen(acije
' 2015 Klinick1 ccntar Srhiic. lko~rad
\( 1.\l: 1\:C.\ \ol. 1:;:; ·
imunodominantnog peptida u kontekstu molekula GHK na membrani APC. Na taj nacin razvija se usled neadekvatne funkcije komplementa iii Fe receptora [3]. Treci tip preosetljivosti prezentuje se kao
poliklonski T celijski odgovora koji je kontrolisan brojnim kostimulatomim i inhibitomim signalima [ 1]. vaskulitis malih krvnih sudova (serumska bolest). Pojedini lekovi (propiltiouracil, izoniazid, doksiciklin)
Peti mehanizam je poseban tip p-i interakcije koji nastaje nekovalentnim vezivanjem leka za indukuju kod genetski predisponiranih pacijenata lekom indukovani lupus, odnosno nekrotizujuci
antigen vezujuce mesto GHK cime se menja repertoar sopstvenih pepida koji se prezentuju, uz vaskulitis [ 15]. Sve cesca primena bioloske terapije (multipla skleroza, reumatoidni artritis, ulcerozni
aktivaciju memorijskih T limfocita i razvoj aloimunskog i autoimunskog odgovora [2]. Abakavir i kolitis, Kronova bolest) povecava broj lekom indukovanih vaskulitisa [16].
karbamazepin kod pacijenata koji su nosioca odredenih alela GHK (Tabela 2) ovim mehanizmom
izaziva najtezu reakciju na lek koja je pracena egzantemom, eozinofilijom i sistemskim simptmima
(eng DRESS-drug rash, eosinophilia, systemic symptoms) [1]. IV tip preosetljivosti
Najnovije studije ukazuju da se hapten-nosac, p-i mehanizam i promena u prezentaciji sopstvenih Nezavisno da li se lek prepoznaje u formi hapten-nosac iii po mehanizmu p-i interakcije. T
peptida odigravaju paraleno kod teskih sistemskih reakcija na lek [2]. celijska aktivacija se odigrava po 4 osnovna tipa, zavisno od citokina i subpopulacija T limfocita koji
ucestvuju u razvoju inflamacije (Tabela 3) [2].
U IVa tip preosetljivosti dominira specifican Th 1-imunski odgovor. Th 1-limfociti luce interferon-
I tip preosetljivosti
gama (IFN-gama) sto dovodi do aktivacije makrofaga, koji je vazan u nastanku lekom-indukovanog
IgE-posredovane reakcije na lek najce§ce nastaju kao rezultat imunskog odgovora na dermatitisa (Tabela 3).
makromolekularne proteinske lekove i na solubilan kompleks kompleks hapten-nosac. Za ovu U IV b tipu preosetljivosti centralnu ulogu imaju Th2 celije koje produkuju IL-4, IL -13 i IL-5,
diferencijaciju neophodna je Th2 celija koja preko membranske CD40-CD40L interakcije i produkcije koji je najvazniji za nastanak eozinofilne intlamacije koja se srece u odlozenim hipersenzitivnim
interleukina (IL )-4/IL-13, preusmerava 8 celiju ka sintezi IgE anti tela [2]. Faza senzibilizacije moze reakcijama na lekove (Tabela 3) [ 17]. Th2 celije u ovom tipu intlamacije ispoljavaju citotoksicnu
biti latentna (cetuximab ), preko ukrstene senzibilizacija na karbohidratne determinante (galktoza a 1-3 funkciju, jer luce perforin i granzim 8 [4] .
galaktoza) venoma nekih insekata [ 12]. IgE antitelo na mast celijama ima kljucnu ulogu u razvoju I tipu
U lYe tipu preosetljivosti centralnu ulogu ima CD8+ T citotoksicni limfocit koji preko perforin/
preosetljivosti. Nakon povezivanja visokoafinitetnih receptora za lgE (FceRI) multivalentnim
granzima 8, Fas-a i granulizina dovodi do lize keratinocita iii hepatocita [5].
alergenom, brojni proinflamatomi medijatori se oslobadaju iz mast celije (histamin, triptaza, leukotrijeni,
U IV d tipu T celije aktivno ucestvuje u nastanku lekom-indukovane inflamacije u kojoj centralni
prostaglandini, faktor nekroze tumora-alfa) koji dovode do razvoja vazodilatacije, povecane vaskularne
znacaj imaju neutrofilni leukociti. Pored hemokina (CXCL8) pokazano je da Th 17 celije ucestn1ju u
permeabilnosti, produkcije mukusa [8, 13]. Lekovi koji najcesce dovode do senzibilizacije I tipa su:
nastanku neutrofilne intlamacije u kozi koju pokrecu neki lekovi (Tabela 3).
beta laktamska grupa antibiotika, misisni relaksansi, platina, bioloska terapija (himerna monoklonska
anti tela), intravenski imunoglobulini (kod deficita lgA), plazma (kod deficita IgA i haptoglobina) [4,5]. Tabela 3: Podtipovi IV tipa preosetljivosti na lekove
Tip IVa IVb IVc 1\'d
II tip preosetljivosti T limfocit Thl Th2 CTL T. Thl7
U II tipi reakcija preosetljivosti, antitelo IgG i/ili IgM klase je specificno za membranski protein Antigen Prezentacija u sklopu Prezentacija u sklopu Prezentacija u sklopu Prezentacija u sklopu
(GPIIb/IIla, fibrinogen receptor ili von Willebrand factor receptor kod kinin-indukovane trombocitopenije) GHK iii direktna T GHK iii direktna T GHK iii direktna T GHK iii dircktna T
iii se pasivno imunski kompleksi vezuje za celijsku povrsinu najcesce hematopoeznih celija (hemoliticka stimulacija stimulacija stimulacija stimulacija
anemija posle dugotrajne primene vecih doza penicilina ili cefalosporina, levodope, metilldope) [3, 4]. Citokin IFN-y IL-4, IL-5 Perforin/granzim B CXCL8 I

Nakon aktivacije komplementa ili putem fagocitoze preko Fc-receptora dolazi do destrukcije eritrocita, TNF-a IL-13 Granzulin GM-CSF
--
Aktivacija Makrofag Eozinofil CTL Neutrofil
leukocita, trombocita kao i maticnih celija hematopeze. Statini mogu indukovati pojavu antitela na ------

3-hidroxyi 3-methiglutaril-coenzyme A reduktazu uz pojavu autoimunske miopatije [14]. Klinicka Kontaktni dermatits Makulopapulozni Sy Stivens-Johnson AGEP
prezentacija egzanten,DRESS TEN, hepatitis
Lek Lokalna primena ~ Karbamazepin Alopurinol Aminopenicilini
III tip preosetljivosti laktamskih antibiotika, Fenitoin Fenitoin Cefalosporini
Imunski kompleksi na lek nastaju kod lekova koji formiraju hapten/nosac kompleks ili kod primene neomicina, lanolina, Abakavir Lamotrigin Celekoksib
prometazina
I

solubilnih visokomolekularnih proteinskih lekova [2]. Serumska bolest prvi put je opisana posle primene Lamotrigin Karbamazepin Hinoloni I

Minociklin Nevirapin Diltiazem

heterologog seruma u cilju pasivne imunizacije. Anti tela se fom1iraju posle 4-10 dana od pocetka terapije.
Alopurinol Kotrimoksazol Terbinafin
Nakon formiranja kompleksa, vezuje se Clq komponenta komplementa, koji na mestu deponovanja
kompleksa u postkapilarnim venulama, dovodi do intlamacije i aktivacije endotela [4]. Leukociti CTL-citotoksicni T limfocit, CXCL8-hemokin, GM-CSF-faktor stimulacije rasta granulocita
IFN-interferon,TNF-faktor nekroze tumora. IL-interleukin, DRESS-egzantem pracen eozinofilijom i
oslobadaju brojne proteoliticke enzime koji dovode do fibrinoidne nekroze u zidu krvnog suda. sistemskim simptomima, TEN-toksicna epidermalna nekroliza, AGEP-akutna generalizovana egzantematozna
Neadekvatan klirens imunskih kompleksa nastaje u slucaju formiranja kompleksa u visku antigena, ili pustuloza, GHK-glavni histokompatibilni kompleks

20 ACT'\ CliNIC'\ Vol. l<;ll{o< <~ 2015 Klinicki centar Srbiie. Beo!!rad i' 201' Klinicki cent~r Srrije. HeC1gnd
Al lA Ll.li'<ll A \ol. 15 _v.,_; 2!
 -
ZAKLJUCAK 16. Banaei-Nikolic B. Jeremic I, Andrejevic S, Sefik-Bukilica M. Stojsavlje\ ic N, DruiO\ ic J. Anti-
Dalji razvoj farmakogenetike, imunohemije i bazicne imunologije omogucice bolje razume\ anje double stranded DNA and lupus syndrome induced by interferon-beta therapy in a patient \\ ith
multiple sclerosis. Lupus. 2009:18:78-80.
kompleksne imunopatogeneze hipersenziti\11ih reakcija na lek. uz mogucnost pre\encije i rane
dijagnoze hipersenzitivnih reakcija na lek. 17. Jeremic I. Vujasinovic-Stupar N, Terzic T, Damjanov N, Nikolic M, Bonaci-Nikolic B. Fatal sul-
fasalazine-induced eosinophilic myocarditis in a patient with periodic fever syndrome. Med Prine
Pract 2015:24:195-7.
LITERATURA:
I. Wheatley LM, Plaut M, Schwaninger JM, Banerji A, Castel IsM. Finkelman FD. et al. Report from
the National Institute of Allergy and Infectious Diseases workshop on drug allergy. J Allergy Clin
lmmunol 20 15; 136:262-71.
2. Schnyder B. Brockow K. Pathogenesis of drug allergy- current concepts and recent insights. Clin
ExpAIIergy 2015:45:1376-83.
3 Celik G, Pichler WJ, Adkinson F. Drug allergy in Allergy. In: Adkinson. ed. Allergy. Philadelphia:
Elsevier, 2009: 1205 -23.
4. Pichler WJ, Naisbitt OJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions.
J Allergy Clin Immunol 20 II ;127:S74-81.
5. Pichler WJ. Drug hypersensitivity In: Rich RR, ed. Clin Immunology Principles and Practice. Phil-
adelphia: Elsevier, 2013: 564-78.
6. Jurakic Toncic R, Marinovic B, Lipozencic J Nonallergic Hypersensitivity to Nonsteroidal Antiin-
flammatory Drugs, Angiotensin-Converting Enzyme Inhibitors, Radiocontrast Media. Local Anes-
thetics, Volume Substitutes and Medications used in General Anesthesia Acta Dermatovenerol
Croat 2009; 17:54-69
7. Pirmohamed M, Ostrov DA, Park BK. New genetic findings lead the way to a better understanding
of fundamental mechanisms of drug hypersensitivity. J Allergy Clin Immunol. 20 15; 136:236-44.
8. Park BK, Naisbitt OJ, Demoly P. Drug hypersensitivity. U: Holgate ST, Church MK, Broide DH,
Martinez FD, eds. Allergy. Edinburg: Elsevier, 2012: 321-30.
9. McNeil 80, Pundir P, Meeker S, Han L, Undem BJ, Kulka Metal. Identification of a mast-cell-
specific receptor crucial for pseudo-allergic drug reactions. Nature 20 15;519:237-41.
I0. Bonaci-Nikolic B. Jeremic I, Nikolic M, Andrejevic S, Lavadinovic L. High procalcitonin in a patient
with drug hypersensitivity syndrome. Intern Med 2009;48: 1471-4.
II. Paulmann M, Mockenhaupt M. Severe drug-induced skin reactions: clinical features, diagnosis,
etiology, and therapy. J Dtsch Derma to! Ges 20 15;13:625-45.
12. Chung CH, Mirakhur B, ChanE, Le QT, Berlin J, Morse Metal. Cetuximab-induced anaphylaxis
and IgE specific for galactose-alpha-! ,3-galactose. N Eng! J Med 2008;358: II 09-17.
13. Bonaci-Nikolic B. Citokini u alergijskoj intlamaciji. In: Bogie M. ed. Atopijske bolesti,
Beograd:Zavod za udzbenike i nastavna sredstva, 1999: 125-37.
14. Limaye V, Bunde II C, Hollingsworth P, Rojana-Udomsart A, Mastaglia F, Blum bergs Pet al.
Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a
reductase in patients with immune-mediated myositis and necrotizing myopathy. Muscle Nerve
2015; 52:196-203.
15. Gajic-Veljic M, Banaei-Nikolic B, Lekic B, Skiljevic D. Ciric J, Zoric Setal. Importance of low
serum DNase I activity and polyspecific antineutrophil cytoplasmic antibodies (ANCA) in propyl-
thiouracil-induced lupus-like syndrome. Rheumatology 20 15;54:2061-70.

')'")
\CT\ CLI"'IC.\ Vol. 15 .'{c< ,. J()j.; KliniL'ki centar '>rbije. He<>gc:.d .\CT\ ll I":C.\ \of. 15 -""-~ 23
DRUG ALLERGY on the dose of the drug. It is believed that 20% of adverse reactions to drugs belonging to the group
8, which includes two main groups: non-allergic and allergic hypersensitivity reactions (Table 1).
Antibiotics, non-steroid anti-inflammatory drugs (NSAIDs), anti-epileptics, and drugs in the
PATHOGENESIS OF DRUG HYPERSENSITIVITY treatment of human immunodeficiency virus (HIV) are the most frequent triggers of hypersensitivity
reactions [3]. Non-allergic hypersensitivity reactions are caused by inflammatory cells and mechanisms
Branka Bonaci-Nikolic of non-specific immunity. Allergic hypersensitivity reactions are triggered by specific 8 and T cells,
Faculty a_{ Medicine. Uni\'ersi(r a./Belgrade characterized by a memory response, clonal proliferation and somatic hypermutation [2]. In relation
Clinic o.l Allergology and Immunology, Clinical Center o_{Serbia to the basic pathogenetic mechanisms, allergic reactions are divided into four types (Table 1) [2].
Table 1: Classification of adverse drug reactions
Author :S· address:
Pro_{essor Branka Banaei-Nikolic A) Predictable Mechanism Drug Presentation
Clinic o.l Allergology and Immunology,
Overdose Hepatotoxicity Acetaminophen Hepatic
Koste Todorovica 2, 11000 Belgrade, Serbia insufficiency
E-mail: branka_bonaci@yahoo.com Side effects Pharmacological effects Mety lxantins Vomiting
Secondary effect Changes of bacterial intestinal flora Antibiotic Colitis
ABSTRACT
Drug interactions Increased theophylline levels Erythromycin Tachycardia
Hypersensitivity drug reactions may be caused by immunological (T and 8 lymphocytes) and non-
immunological mechanisms (non-specific mast cells degranulation, the release of bradykinin, leukotriens etc). B) Unpredictable
Drugs in the form of soluble macromolecules are complete antigens and induce the production of lgE or IgG Non-allergic
antibodies. Most drugs are haptens and must first be covalently linked to self-proteins. If the drug-carrier complex Idiosyncrasy Deficiency of glucose-6 phosphate dehydrogenase Dapsone 1 Hemolytic
is a soluble protein, 8 lymphocyte has function of antigen-presenting cell (APC) and induces dominantly type I 1 anemia I
or type III hypersensitivity. If the carrier is insoluble (membrane) protein, other APCs (macrophages, dendritic, ,.Pseudo allergy'' Mast cell degranulation 1
Largerhans cells), after processing and presentation of the immunogenic peptide, induce dominantly type II or I

type IV hypersensitivity (mediated by helper T cell type 1 (Th) I, Th2 or T cytotoxic lymphocytes, depending G protein-coupled receptor Atracurium i Urticaria
i
of the cytokine environment). The drugs-prohaptens, must be chemically pre-modified, before binding covalently I

to self-proteins. Recently, it was described the pharmacological mechanism of drug interaction with the immune Alternative complement activation - C3a, C5a Emulsifiers : Urticaria --

receptor (p-i concept). Chemically inert drug, without metabolism binds non-covalently to some T cell receptors Intolerance Inhibition of cyclooxygenase 1 Aspirin Asthma
(p-i!TCR) or molecules of mayor histocompatibility complex (p-i/MHC). This is a mechanism of drug-induced
Increase of bradykinins ACE-I Angioedema i
maculopapular and bullous exanthema. The special type of p-i interaction, produced by non-covalent binding of
I
I

Allergic
the drug to the MHC, leads to altered self-peptide presentation and autoimmunity, characteristic for drug-induced I •

1. Complete Type I: IgE, mast cell degranulation Monoclonal. at I Anaphylaxis

exanthema associated with eosinophilia and systemic symptoms. These different mechanisms are often antigens
complementary in late T cell-mediated systemic drug reactions. Immunogenetic predisposition allows personal Type III: IgG-immune complexes, complement Antiserum Serum
approach to the treatment with significantly reduction of severe hypersensitivity drug reactions.
Key words: drugs, pathogenesis, allergic reactions, non- their allergic reactions
2. Haptens Type I: IgE, mast cell degranulation P-lactams Anaphylaxis
CLASSIFICATION OF ADVERSE REACTIONS TO DRUGS Type II: IgG-mediated cytotoxicity Metyl-dopa Anemia
Adverse reactions to drugs represent a major health problem due to the increase in chronic
Type III: IgG immune complexes, complement Isoniasid Lupus
diseases and the growing use of antimicrobial drugs, chemotherapy and biological therapy. Meta-
analysis of 33 prospective studies from 1966. to 1996. showed that 15.6% of the adult hospitalized Type IV subtype a, b, c, d Carbamazepin Egzanthem.
patients developed an adverse reaction to some drug [ 1]. mediated by T lymphocytes eozinophilia.
Adverse drug reactions are divided into type A and type 8 (Table 1) [2]. Reactions in Group A MHC presentation and /or p-i interaction systemic
are predictable and are related to the pharmacologic effects of the drug, applied dose, side effects or symptoms
well-known drug interactions. Reactions in group 8 are significantly less frequently (less than 1 in ACE-I- angiotenzin converting enzyme inhibitors, p-i- pharmacological interaction of drug with the immune
1000 patients), they are not related to the pharmacological effects of drugs and usually does not depend receptor, MHC-major histocompatibility complex

24 c 20 I' K linicki centar Srhije. Rengrad ~ 2015 Klinicki centar Srhiie. Ben~rad 2'i
RISK FACTORS FOR THE DEVELOPMENT OF HYPERSENSITIVITY The three main types of non-allergic reactions are: idiosyncrasy, "pseudoalergy" and intolerance.
DRUG REACTION Idiosyncrasy is caused by a defect or deficiency of the enzyme participating in metabolism of drug.
Numerous factors (chemical properties, composition, \\·ay of administration, dose. type of The exact pathogenetic mechanisms of non-allergic reactions have not been fully defined. The increase
underlying disease and genetic characteristics of patients) increase the risk and the severity of in serum tryptase \\ ithin 2 hours of the reaction confirms the primary imunopatogenetic importance
hypersensitivity drug reactions [3]. of mast cells. The released tryptase can activate complement which further contributes to the
Protein macromolecules, multi\ alent drugs, as \\ell as the high reactivity of low molecular weight development of inflammation [6]. Heparin from mast cells leads to the activation of the contact
drugs (haptens) with proteins increase the potential immunogenicity of the drug [4]. The presence of acti\·ation system (kinogen/ quinine) \\·ith the release of bradykinin. Recently it was shm\·n that
the polymer drug (aminopenicillins) facilitates sensitization. Length and method of administration tluoroquinolones, neuromuscular blockers can activate mast cells via G-protein linked receptor [9].
determines whether early or late allergic reactions to the drug will develop. Direct degranulation of mast cells has a primary importance in the development of earlv reactions
Some diseases are associated with high risk of allergic reactions to the drugs [5]. Thus, a third (urticaria, angioedema, anaphylaxis) to high osmolary non-ionic iodine contrast media."' Colloidal
of patients with cystic fibrosis have a hypersensitivity reaction to antibiotics, especially often to aggregates present in volume expanders (gelatin, albumin) by similar mechanism can cause slight or
piperacillin. Also, the reaction to sulfamethoxazole is I0 times higher in patients with acquired severe hypersensitivity reaction [6]. The use of nanoparticles and liposomes, important for slow release
immunodeficiency syndrome in the stages of HI V replication [ 1]. Patients with infectious of the drug, can increase the risk of non-allergic reactions. Some soh ents of parenteral drugs
mononucleosis have a high incidence of maculopapular exanthema during therapy with amoxicillin. (Politaksel) contain micelles that can activate the alternati\ e system of complement with release of
Atopy in a personal or family history increases the risk of IgE sensitization to the drug. Deficiency of C3a and C5a (anaphylatoxins) which degranulation of mast cells \\·ith the development of systemic
C !-esterase inhibitor is a risk factor for non-allergic angioedema during the therapy with angiotensin and lor cutaneous reactions (complement activation-related pseudoallergy-CARP) [6].
converting enzyme inhibitors (ACE-I) [6]. Delayed drug reactions mediated by T lymphocytes are A special group of non-allergic reactions are intolerances. A classic example of intolerance to
associated with genes of major histocompatibility complex (MHC), especially with class 8 antigens the drug is aspirin asthma and chronic urticaria caused by aspirin and other non-selecti\e ~SA IDs [3].
of MHC [7]. It has been shown a significant association between MHC alleles involved in drug In the pathogenesis of asthma triggered by aspirin which is associated \vith nasal polyposis and
metabolism (reduced activity of cytochrome CZP2C9) and severe cutaneous drug reactions (phenytoin) eosinophilia primary importance has inhibition of cyclooxygenase 1, which, in susceptible patients,
[7]. Nevirapine-induced liver damage is related with the MHC class II alleles, while the skin damage leads to increased production of bronchoconstrictor mediators, prostaglandin (PG) D2 and leukotriene
is associated with MHC class I alleles [7]. The discovery of the association of certain MHC alleles C4, with a drop ofbronhodilatatory mediator PGE2. ACE-I reduce the degradation of bradykinin and
with the high risk of delay T cell hypersensitivity (Table 2), decreases the incidence of severe systemic substance P, which leads to increased vascular permeability with the development of angioedema [6].
reaction to certain drugs [2]. Patients who develop angioedema during the use ofACE-L ha\ e reduced activity of aminopeptidase-P.
and dipeptidyl peptidase IV, which also increases the degradation of bradykinin [6].
Tahle ]: The association ofJ1HC alleles ~rith serere lnpersensitiritr reactions to drugs It should be noted that very infrequently iodine contrast media. local anesthetics and ~SA!Ds
Drug MHC alleles Clinical presentation can cause IgE-mediated allergic reaction.
I Abacavir HLA-B 57:01 . Systemic hypersensitivity syndrome (Caucasians)
Stevens-Johnson syndrome (China, India) THE PATHOGENESIS OF ALLERGIC REACTIONS TO DRUGS
HLA-B 15:02
Carbamazepin
DRESS, Stevens-Johnson sindrome (Caucasians)
HLA-A 31:01
Egzanthem, Toxic epidermal necrolisis (Caucasians) How drugs become allergens and induce a specific immune response?
Alopurinol HLA-B 58:01 Stevens-Johnson syndrome (China, Caucasians ) Allergic reactions to drugs have heterogeneous clinical presentations that may cause a di tfcrential
Flucloxacilin HLA-B 57:01 Hepatotoxicity diagnostic problem, especially late reactions that can mimic the systemic diseases or reacti\ at ion of
viral infection [1OJ. Generally, the immune system recognizes the allergens in multi\ alent form in
DRESS-drug rash. eosinophilia, systemic symptoms
afferent and efferent phase of the specific immune response [2]. Up to nO\\ there are fi\ e
immunopathogeneticaly different ways in which the immune system recognizes drug as an allergen.
THE PATHOGENESIS OF NON-ALLERGIC REACTIONS TO MEDICINES The high protein drugs (hormones, protamine, monoclonal antibodies, enzymes, cytokines,
Non-allergic drug reactions (Table I) are identical clinically to allergic reactions and can present recombinant, vaccines), and drugs with a numerous multivalent epitopes (succinylcholine and other
with angioedema, urticaria, bronchial asthma, gastrointestinal symptoms and anaphylaxis. Since there quaternary ammonium bases), are the complete antigens, so there is no need to attach \\·ith self-proteins
is no the induction of specific immune response, the prick skin test and the specific IgE antibodies are to induce specific humoral Th2-dependent immune response [3]. Follicular 8 lymphocyte is central
negative. Non-allergic reactions occur without prior contact with the allergen [8]. The most common antigen-presenting cells (APCs) in lgE (type I hypersensitivity) or IgG (type III hypersensiti\ ity)
non-allergic reactions are caused by NSAIL drugs, ACE-I, iodine contrast media and opiates [3]. mediated allergic reactions on soluble high molecular protein drugs [2].

\CT.\ Cli:\IC.\ \'ul. 15 .'i·~ L 201 'i Klinit'ki centar <;rhiie. lkn~rad \("1 \ ( ., ,,,(. \ ,.,l, J.::; ,-,;
 However, most drugs are low molecular weight- haptens (<1 kDa) and they can not induce an
immune response. They have first to be covalently bound to macromolecules in the plasma or the cell
surface. in order to fonn a multivalent hapten-carrier complex (complete allergen). If the complex drug-
carrier is in the fonn of soluble proteins, B cells can take over the function ofAPCs with the dominant
production of specific IgE (type I hypersensitivity) or IgG antibodies (type III hypersensitivity) [2]. If
the carrier is insoluble membrane protein, after endocytosis neo-epitopes are presented in the fonn of
immunogenic peptides by other APCs (macrophages, dendritic cells, Largenhansove cells) in the context
of MHC class I or class II molecule and depending on the cytokines, this leads to the activation of B
lymphocytes (predominantly type II hypersensitivity) or T cells (type IV hypersensitivity) [2]. Infection
through APC-activation accelerates processing of hapten-protein complexes and the expression of
costimulatory molecules (danger signals). The protective mechanism, dehaptenisation is going in parallel
with haptenisation, so only 0.01% of penicillin in covalently bound with proteins [2]. Induction ofT
regulatory cells in the liver plays an important role in the inhibition of an allergic reaction to the hapten-
carrier complex [4]. Beta-lactam antibiotics, quinidine, cisplatin, penicillamine, antithyroid drugs induce
an immune response by fonnation of a hapten-carrier complex [3].
On the other hand a number of medications, known as prohaptens, in its native fonn can not react
covalently with its self proteins, but previously they have to be chemically transformed with the
fonnation of reactive metabolites (sulfonamides. acetaminophen, phenytoin, halothane, procainamide)
[2]. Transformation of prohapten to the hapten takes place mostly in the liver and the kidney, which
may explain the isolated drug-induced hepatitis and/or drug-induced interstitial nephritis. A number
of metabolic factors (cytochrome, low glutathione or slmv acetylation) redirect metabolism to making
a reactive intermediate compounds with the induction of immune response (IgG-mediated hepatitis
induced by halothane or isoniazid) [ 1]. A number of metabolic products of the drug can induce
apoptosis and necrosis of cells which induce the maturation of dendritic cells, which are necessary for
the afferent phase of the immune response to the drug [4].
The fourth important mechanism that provides immunogenicity of the drug is designated as
pharmacological interaction of drug with the immune receptor (p-i concept) which is associated with
genes ofMHC and variabile beta (V beta) regions of the T cell receptors (TCR) [7]. Chemically inert
monovalent drug (carbamazepin, lamotrigine, sulfamethoxazole) without metabolism and interactions
with proteins or peptides, directly binds non-covalently to a number ofT cell receptor (p-i /TCR) or
MHC antigens (p-i /MHC) [8]. Sulfamethoxazole and carbamazepine are linked directly to specific V
beta region of CD8 + T lymphocytes. Reactivation of herpes virus infection or activation of systemic
diseases (expression of MHC molecules and costimulatory molecules) reduce the threshold for the
activation ofT cells, which strongly amplify response and lead to severe multi-organ damage [1]. This
mechanism ofT cells overactivation is characteristic for effects of the super-antigens. After activation,
proliferation and cytokine production, T lymphocyte by cytotoxic mechanisms (perforon, granzym B)
cause damage of many organs. This immune mechanism is important in the pathogenesis of
carbamazeminom and alopurinolol induced Stevens-Johnson syndrome and toxic epidermal necrolysis,
as tlucloxacillin-induced hepatitis (Table 2) [7]. Frequent skin involvement can be explain by the
presence of a number of effector memory T cells in the skin, as well as dendritic cells which present
antigens efficiently [ 11 ]. Certain drugs (sulfonamides, tlucloxacillin) can trigger the immune system
through p-i mechanism and through classical presentation of immunodominant peptides in the context
of MHC molecules on the membrane of APCs. In this way, polyclonal T cell response develops which
is controlled by a number of stimulatory and inhibitory signals [1].
c 201 'i K linit'ki cent~r
2R ACTA Cl INICA \'ol. I~ No\
The fifth mechanism is a special type of p-i interactions generated by covalent binding of the
drug to the antigen binding site of the MHC molecule which changes self repertoire of presented
peptides. associated with the activation of memory T cells and the development alloimmune and
autoimmune responses [2]. Abacavir and carbamazepine in patients who are carriers of certain MHC
alleles (Table 2) through this mechanism causes the most serious reaction to a drug which is
characterized by exanthema, eosinophilia and systemic symptoms (DRESS-drug rash, eosinophilia,
systemic symptoms) [ 1].
Recent studies indicate that the hapten-carrier, p-i interactions and the mechanism that leads to change
in the presentation of self peptides may occur simultaneously during some severe drug reactions [2].
Type I hypersensitivity
IgE-mediated drug reactions usually occur as a result of the immune response to the protein
macromolecular drugs and soluble hapten-carrier complex. For this ditTerentiation Th2 cells are
essential via CD40-CD40L membrane interaction and production of (IL-4 )/IL-13, which direct the
synthesis of B cells toward IgE antibodies [2]. The sensitization phase can be latent (cetuximab)
through cross-sensitization to carbohydrate detenninants (galactose 1-3 galactose) of certain insects
venoms [12]. IgE antibody on mast cells play a key role in the development of type I hypersensitivity.
After connecting of the high affinity FceR I by multivalent allergen, numerous prointlammatory
mediators are released from mast cells (histamine, tryptase, leukotriens, prostaglandins, tumor necrosis
factor-a), which lead to the development of vasodilation, increased vascular permeability, mucus
production [8, 13]. Drugs that usually leads to sensitization of type I hypersensitivity are: ~-lactam
antibiotics, muscle relaxants, cisplatin, biological therapy (chimeric monoclonal antibodies),
intravenous immunoglobulin (lgA deficiency), plasma (deficit of IgA and haptoglobin) [4.5].
Type II hypersensitivity
Type II hypersensitivity IgG and/or IgM class antibodies are specific for membrane protein
(G PIIb /Ilia, fibrinogen receptor or von- Wi llebrand factor receptor in a quinine-induced
thrombocytopenia) or are passively bind in the form of immune complexes to the cell surface of
hematopoietic cells (hemolytic anemia after long-tenn use of high doses of penicillin or cephalosporins.
levodopa, methyldopa) [3, 4]. Activation of the complement or phagocytosis via Fc-receptors leads to
the destruction of red blood cells, white blood cells, platelets and stem cell. By this mechanism statins
can induce the appearance of antibodies to 3-hidroxyi 3-methiglutaril-coenzyme A reductase\\ ith the
occurrence of autoimmune myopathies [ 14].
Type III hypersensitivity
Immune complexes are formed with drugs that form a hapten/carrier complex or after therapy
with soluble high molecular weight protein drugs [2]. Serum sickness was first described after
administration of a heterologous serum in order of passive immunization. Antibodies are formed after
4-10 days of the start of therapy. The formation of the complex, and the binding of C 1q complement
component, in the postcapillary venules, leads to inflammation, and activation of endothelial cells [4].
Leukocytes release many proteolytic enzymes that produce fibrinoid necrosis in the wall of the blood
vessel. Inadequate clearance of immune complexes formed in the case of excess antigen, or due to
<;;rt-ije. Heograd r&: 2015 Klinicki centar Srbiie. Beograd ACTA ( l.l'>il.-\ \ul. 15 ,-,";
inadequate function of the complement or Fc receptors [3]. The third type of hypersensitivity is
presented as a small vessel vasculitis (serum sickness). Certain drugs (propylthiouraciL isoniazid,
doxycycline) induce in genetically predisposed patients drug-induced lupus. or necrotizing vasculitis
[ 15]. The increasingly frequent use of biological therapies (multiple sclerosis. rheumatoid arthritis.
ulcerative colitis. Crohn 's disease) increases the number of drug-induced vasculitis [ 16].
CONCLUSION
Further de\·eiopment of pharmacogenetic. immunochemistry and basic immunology \\·iii
allo\,. better understanding of the complex immunopathogenesis of hypersensiti\ ity reactions to
the drug, with the possibility of prevention and early diagnosis of hypersensiti\ ity reactions to
the drug.

Type IV hypersensitivity REFERENCES:

Regardless of whether the drug is recognized in the form of a hapten-carrier complex or by p-i
I. Wheatley LM, Plaut M. Schwaninger JM. Banerji A. Castells M. Finkelman FD. et al. Report from
interaction, T cell activation occurs by 4 types, depending on the cytokine and a subpopulation ofT the National Institute of Allergy and Infectious Diseases workshop on drug allergy. J Allergy Clin
lymphocytes involved in the development of inflammation (Table 3) [2]. Immunol 20 15; 136:262-71.
The type IVa hypersensitivity dominated Th !-specific immune response. Th I cells secrete
2. Schnyder B, Brockow K. Pathogenesis of drug allergy - current concepts and recent insights. Clin
interferon-gamma (IFN-y), which leads to activation of macrophages (Table 3) . Exp Allergy 20 15; 45:1376-83.
In IVb type hypersensitivity, Th2 cells have central role. Thay produce IL-4, IL -13 and IL -5,
3 Celik G. Pichler WJ, Adkinson F. Drug allergy in Allergy. In: Adkinson, ed. Allergy, Philadelphia:
important for the formation of eosinophilic inflammation, often seen in the delayed hypersensitivity
Elsevier, 2009: 1205 -23.
reaction to the drug (Table 3) [ 17]. Th2 cells in this type of inflammation exhibit cytotoxic function
by secretion of perforin /granzyme 8 [4]. 4. Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions.
J Allergy Clin lmmunol 20 I I: 127:S74-81.
In IV c type hypersensitivity central role have CD8 + T cytotoxic cells. Thay induce lysis of
hepatocytes and keratinocytes by mechanism which involve perforin /granzyme 8, Fas and granulyzin [5]. 5. Pichler WJ. Drug hypersensitivity In: Rich RR. ed. Clin Immunology Principles and Practice. Phil-
adelphia: Elsevier, 2013: 564-78.
In type IV d hypersensitivity T cells actively participate in the development of drug-induced
inflammation characterized by accumulation of neutrophil leukocytes (Table 3 ). In addition to CXCL8, 6. Jurakic Toncic R, Marinovic B, Lipozencic J Nonallergic Hypersensitivity to Nonsteroidal Antiin-
Th 17 cells are involved in the development of drug-induced neutrophilic inflammation in the skin flammatory Drugs, Angiotensin-Converting Enzyme Inhibitors. Radiocontrast Media, Local Anes-
(Table 3). thetics, Volume Substitutes and Medications used in General Anesthesia Acta Dermatovenerol
Croat 2009; 17:54-69
Tahle -).· The suhtrpes o{t\pe IV lnpersensitiritr
7. Pirmohamed M, Ostrov DA. Park BK. New genetic findings lead the way to a better understand-
Tip IVa IVb IVc IVd ing of fundamental mechanisms of drug hypersensitivity . .I Allergy Clin lmmunol. 2015;
T ~rmplw(rte Thl Th2 CTL T, Thl7 136:236-44.
Antigen The MHC The MHC The MHC presentation The MHC 8. Park BK. Naisbitt DJ, Demoly P. Drug hypersensiti\ity. U: Holgate ST. Church MK. Broide DH,
presentation or direct presentation or direct or direct T cell presentation or Martinez FD. eds. Allergy. Edinburg: Elsevier. 2012: 321-30.
T cell stimulation T cell stimulation stimulation direct T cell 9. McNeil BD, Pundir P, Meeker S. Han L Undem BJ. Kulka Metal. Identification of a mast-cell-
stimulation
specific receptor crucial for pseudo-allergic drug reactions. Nature 2015:519:237-41.
Citokin IFN-y IL-4. IL-5 Perforin/granzym 8 CXCL8
TN F-a IL-13 granulyzin GM-CSF I0. Banaei-Nikolic B, Jeremic I, Nikolic M. Andrejevic S. La\adinm ic L. High procalcitonin in a patient
Actiration Makrophage Eozinophil CTL Neutrophil with drug hypersensitivity syndrome. Intern Med 2009;-+g: 14 71-4.

Clinical Contact dermatatis Maculopapulous rash. Sy Stivens-Johnson AGEP II. Paulmann M, Mockenhaupt M. Severe drug-induced skin reactions: clinical features. diagnosis.
presentation DRESS TEN, hepatitis etiology, and therapy. J Dtsch Derma to! Ges 2015:13:625-45.
Drug Topical therapy: Carbamazepin Alopurinol Amynopenicilins 12. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M et al. Cetuximab-induced anaphylaxis
~-lactam antibiotics, Fenitoin Fenitoin Cephalosporins and IgE specific for galactose-alpha-! ,3-galactose. N Eng! J Med 2008;358: II 09-17.
neomycin, lanolin, Abacavir Lamotrigin Celexoxib
prometazin Lamotrigin Karbamazepin Hynolons 13. Banaei-Nikolic B. Citokini u alergijskoj inflamaciji. In: Bogie M. ed. Atopijske bolesti. Beograd:
Minociklin Nevirapin Diltiazem Zavod za udzbenike i nastavna sredstva, 1999: 125-37.
Alopurinol Kotrimoksazol Terbinaphin 14. Limaye V, Bunde!! C, Hollingsworth P, Rojana-Udomsart A. Mastaglia F. Blumbergs Petal.
CTL-cytotoxic T lymphocyte. CXCL8-hemokyn. GM-CSF- granulocyte/macrophage colony stimulation factor, Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl-glutaryl-coenzyme a
IFN-interpheron. TNF- tumor necrosis factor. IL-interleukin. DRESS-drug rash. eosinophilia, systemic symptoms, reductase in patients with immune-mediated myositis and necrotizing myopathy. Muscle Nerve
TEN-toxic epidermal necrolisis, AGEP-acute general generalized egzanthematous pustulosis 20 15;52: 196-203.

-\CT-\ CliNIC-\ \"ol. I~ Xo> ' 2015 Klinicki ccntar Srbiic. lko)!rad t 2015 Klinicki ccntar Srbije. Beograd
~I
15. Gajic-Veljic M, Bonaci-Nikolic 8, Lekic 8, Skiljevic D, Ciric J, Zoric Set a!. Importance of low ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA
serum DNase I activity and polyspecific antineutrophil cytoplasmic antibodies (ANCA) in propyl-
thiouracil-induced lupus-like syndrome. Rheumatology 20 15;54:2061-70.
16. Bonaci-Nikolic 8, Jeremic I, Andrejevic S, Sefik-Bukilica M, Stojsavljevic N, Drulovic J. Anti- ALERGIJA NA BETA-LAKTAMSKE ANTIBIOTIKE
double stranded DNA and lupus syndrome induced by interferon-beta therapy in a patient with
multiple sclerosis. Lupus. 2009; 18:78-80. Vesna Tomic-Spiric
17. Jeremic I, Vujasinovic-Stupar N, Terzic T, Damjanov N, Nikolic M, Bonaci-Nikolic B. Fatal sul- lvfedicinski Fakultet, Univer:itet u Beogradu
fasalazine-induced eosinophilic myocarditis in a patient with periodic fever syndrome. Med Prine Klinika za a/ergologij'u i imunologij'u, Klinicki centar Srbij'e
Pract 2015;24:195-7.
Adresa autora:
Profesor Vesna Tomii·-Spiric
Klinika za a/ergologij'u i imunologij'u
Koste Todorovica 2, II 000 Beograd
E-mail: vesnatomicspiric63@gmail.com

SAZETAK
Najvazniji uzroci neposrednih (tip I) reakcija preosetljivosti su antibiotici, posebno 13-laktamski
antibiotici. Oko I0% pacijenata navodi anamnesticki podatak o alergiji na peniciline. Medutim, cak do 90%
ovih pojedinaca zapravo podnosi penicilin i ima neopravdano prijavljenu "alergiju na penicilin". Upotreba
antibiotika sirokog spektra kod pacijenata oznacenih alergicnim na penicilin povezana je sa vecim
troskovima lecenja, povecanom rezistencijom na druge antibiotike i moze imati uticaj na ishod lecenja.
Kljucne reci: beta-laktamski antibiotici, penicilin, hipersenzitivnost, anafilaksa. unakrsna reaktimost

UVOD
Ne:Zeijene reakcije na Iekove su znacajan uzrok morbiditeta i mortaiiteta boinickih i ambulantnih
pacij enata [ 1].
Beta (f3)-Iaktamski antibiotici su medu najcesce propisivanim Iekova u lekarskoj praksi sirom
sveta. Peniciiin pripada vaznoj grupi antibiotika nazvanim f3-Iaktamski antibiotici koji su ugla\ nom
efikasni u suzbijanju uobicajenih bakterijskih infekcija, reiativno su jeftini i zbog toga su u sirokoj
upotrebi. Ova kiasa antibiotika ukijucuje peniciiine i penicilinske derivate kao sto su ampicilin i
amoksiciiin, kao i cefaiosporine, monobaktame, karbapeneme i inhibitore f3-faktamaze. Kao i ,·ecina
Iekova, peniciiin izaziva brojna nezeijena dejstva i reakcije. Pacijenti sa registrovanom aiergijom na
f3-Iaktamske antibiotike Ieee se Iekovima drugog izbora, koji su ugiavnom toksicniji i skuplji [2].

Alergija na penicilin
Peniciiini pripadaju jednoj od najvazniih i najsire primenjenih grupa antibiotika u primarnoj
zdravstvenoj zastiti u Iecenju najcesCih infekcija i jos uvek su Iekovi izbora za mnoge od njih [3, 4].
Razvoj sintetickih penicilinaje prosirio spektar aktivnosti i poboijsao efikasnost ovih Iekova. Medutim,
pojava rezistentnih bakterijskih sojeva je ograniCiia efikasnost penicilina u posiednjih nekoliko god ina
[4]. Ipak, penicilini ostaju Iek izbora za mnoge infekcije i posebno su vazni u odredenim kiinickim
stanjima i tokom trudnoce. Penicilin G je najcesce odgovoran za nastanak aiergijskih reakcija u ovoj
grupi Iekova. Progresija i tok hipersenzitivnosti na penicilin je nepredvidiva, npr. osoba koja je
tolerantna na peniciln na pocetku, moze ispoljiti alergijsku reakciju kasnije, iii obrnuto [I] .

A.CTA. CIII-JICA. Vol. I~ .lfo1

.<: 2015 Klinicki centar Srbije, Beograd 1 r{d 2015 Klinicki centar Srbiie. Beograd .\CTA CLI:\IC.\ \ ul. 15 s.;

J.
Epidemio/ogija minuta nakon primene leka. ali takode mogu biti i odlozene do 72 casa. Ove reakcije se javljaju kod
Tacna prevalencija alergije na penicilin u opstoj populaciji nije poznata. Incidencija samostalno 0.004-0.015% slucajeva primene penicilina i mnogo cesce kod odraslih osoba uzrasta od 20 do 49
prija\ aljenih slucaje\ a alergije na penicilin se krece od 1 do I0°1<> [3J sa pre\ alencijom anafilakticke godina. Ovaj tip preosetlji\·osti se mnogo cesce javlja kod parenteralnog nacina primene leka. Fatalni
reakcije od 0.01 do 0.05% [5]. ishod se javlja u I na 50.000-100.000 slucajeva primene penicilina. Nezeljene reakcije sa zivotno
ugrozavajucim posledicama koje se ja\ ljaju nakon \ ise od 1 sata od primene Penicilina su retke.
Faktori rizika Stanja koja se razvijaju usled raz\ oja hipersenzitivnosti koja nije posredm·ana IgE At su
hemoliticka anemija. intersticijalni nefritis. trombocitopenija, serumska bolest, groznica. morbiliformni
Anamnesticki podatak o nezeljenim reakcijama na peniciline iii cefalosporine je najvazniji faktor
osip, eritema multiforme minor (EM). Stevens-.Johnson sindrom (SJS}, toksicna epidermalna nekroliza
rizika. Pokazano je da atopija kao faktor rizika nema uticaja za razvoj alergije na f3-laktamske
(TEN) i druge. Ove nezeljene reakcije se najcesce razvijaju nakon 72 casa. Obzirom da ovo nisu
antibiotike [6].
IgE-zavisne reakcije, kozni test nema znacaja u proceni preosetljivosti ovih pacijenata [1OJ.
Tahela 1: Klasi{ikactj"a reakctj"a na penicilin
lmunohemija molekula penici/ina
Vreme I I 1Pozitivne
Penicilinski antibiotik se sastoji od f3-laktamskog prstena i brojnih varijabilnih bocnih lanaca. Klasifikacij a I Medijatori Klinicki znaci kozne Komentari
pocetka ! 1

f3-laktamski prsten zajedno sa svojim bocnim lancima ucestvuje u razvoju hipersenzitivnih reakcija probe
[7J. Poput mnogih farmakoloskih agenasa i penicilin je jednostavne strukture i male molekulske mase. Tip I (umerena) <I sat lgE antitelima Anfilaksa ilili Da Mnogo cesce
Supstance male molekulske mase koje su u stanju da izazovu alergijsku reakciju su poznati kao hapteni posredovano hipotenzija. edem kod parenteralne
oslobadanje larynx-a. administracije.
[8J. Sami po sebi nisu u stanju da izazovu stvaranje antitela (At) pa moraju biti vezani za nosece vazoaktivnih angioedem. Letalno u I od
molekule sa kojima formiraju jaku kovalentnu vezu kako bi indukovali imunski odgovor. Pacijenti ne 1medijatora urtikarja

i
50.000- I00.000
ispoljavaju imunski odgovor na sam penicillin vee na raspadne produkte penicilina (izomere) posto i I mastocita i bazotila slucajeva
~-------------
Kasna reakcija 1
se vezu za tkiva i protein plazme u formi kompleksa hapten-nosac. f3-laktamski prsten u sastavu 1

Promenljivo _
degradiranog penicilina je nestabilan i vezuje se za lizinske ostatke u proteinima tkiva i plazme, sto Tip II lgG. komplement ! Postransfuzione lgE nije ukljucen
rezultira pojavom penicilloil epitopa poznatog kao benzilpenicilloil iii ,major determinanta". Ova 1
reakcije. autoimuna
determinanta se proizvodi u najvecoj kolicini pa je dominantna u imunomodulaciji specificnog I hemoliticka anemija ,
odgovora imunskog sistema na penicillin. Iako rede, f3-laktamski prsten, takode, moze da prode kroz I Tip III lgG. lgM imuno Serumska bokst. :\c lmuni kompleksi
kompleksi glomerulonefritis. u tkivu, groznica
molekularne modifikacije, preraspodelom karboksilne i tiolske grupe i da tako formira ,minor I

iRA. SLE
determinantu". Termini ,major" i ,minor" determinante odnose se samo na kolicinu raspolozivu za Tip IV Citokini aktiviraju 1

Kontaktni Ne 1

!
vezivanje sa haptenom, a ne na njihov znacaj u imunskom odgovoru. IIT celije i uzrokuju I dermatitis. TB I

Ovi kompleksi degradacionih produkata i prirodnih proteina bivaju prepoznati kao strani antigeni i direktna celijska i lezije. odbaci\ anje
I • • I
I

ostecenja
~~~~(;p~pularni i~4'Yo S\ih-~
od strane mastocita i bazofila kod pojedinih osoba. Nakon toga, kada se formira dovoljna gustina 1

epitopa Penicilina. nastaje specifican imunski odgovor. "Minor" determinanta izaziva 90-95% ranih ldiopatski Obicno>T2 h --: ili-Nfl
I

IgE-posredovanih reakcija imunskog sistema. "Major" determinanta moze da dovede do ranih IgE- 1
mobiliformni osip pacijenata
1

' . lecenih
posredovnih reakcija, ali cesce dovodi do ubrzanih iii odlozenih reakcija uzrokovanih IgG i IgM [9J.
I _ __ j __ _ ~~__ penicilinom I
Ovo je veoma vazna klinicka razlika. jer ce pacijenti ispoljiti IgE-posredovanu reakciju na ,minor"
I

determinante samo ukoliko kozni testovi sadrze ovu determinantu, dok kod ovih pacijenata alergija
na Penicilin nece biti detektovana ukoliko kozni testovi sadrze samo ,major" determinantu, a to su
ujedno i pacijenti kod kojih je veca verovatnoca da se razvije anafilakticka reakcija.
Klinicke manifestacije
Sa klinickog gledista, najprakticniji metod klasifikacije alergijskih reakcija na penicillinje podela
na nezeljene reakcije posredovane IgE At (I tip preosetljivosti) i hipersenzitivne reakcije koje nisu
posredovane IgE At [ 1OJ (Tabela 1). Na primer, IgE-posredovani tip I preosetljivosti ukljucuje
anafilaksu, angioedem, urtikariju i bronhospazam. Ove IgE-posredovane reakcije se jav1ja nekoliko
Rizik za razvoj anafilakticke reakcije
Dokumentacija ili prijavljivanje alergijskih reakcija su cesto neprecizni, obzirom na cinjenicu
da mnogi pacijenti navode alergiju na neki antibiotik, dok zapravo imaju simptome vezane za prisustvo
infekcije kao sto su groznica ili dijareja. Ukoiliko pacijent pokazuje znake prave alergijske reakcije,
nakon ponovnog izlaganja penicilinu iii slicnim antibioticima. moze doci do razvoja anafilakticke
reakcije opasne po zivot. Ranije se smatralo dace preko 60% pacijenata alergicnih na penicilin razviti
ponovnu alergijsku reakciju, ukoliko se lek ponovo primeni. Medutim. novi podaci govore da je ovaj
procenat zapravo manji od 2%. Nakon analiziranja podataka vise od 3 miliona pacijenata u studiji
sprovedenoj u Velikoj Britaniji, koji su bar jednom bili na terapiji penicilinom. 6212 (0.18%) pacijenata

34 ,. 201 S Klinicki ccntar Srhiie. Bcnl!rad I 35

I
je razvilo alergijsku reakciju tokom prve administracije leka. Iako su ovi pacijenti imali 19 puta manje
sanse od ostalih da ponovo dobiju penicilnsku terapiju, cak 48.5% je bilo na ponovljenoj terapiji ovim
antibiotikom. Sa ponovljenom primenom penicilina, pacijenti koji su tokom prve primene imali
reakciju na penicillin, 11.2 puta cesce su razvili ponovljenu alergijsku reakciju. Uprkos ovako visokoj
relativnoj razlici, apsolutni rizik od ovakvih reakcija kod pacijenata alergicnih na penicilin je iznosio
1.89% nakon ponovljene administracije leka.
Da bi se ovakve reakcije sprecile neophodno je usmeriti paznju na podizanje svesti o znacaju
reekspozicije kao i upoznavanje pacijenata kako da prepoznaju rane znakove i simptome alergije na
Penicilin [ 11, 12]. Pored toga, lekari moraju biti na oprezu u vezi sa mogucim ozbiljnim greskama pri
propisivanju i koriscenju kombinacija razlicitih proizvoda (obicno sa fabric kim imenima) koji sadrze
penicilin.
Znaci i simptomi ana.filakse
Anafilaksa se karakterise simptomima hipotenzije sa dispnejom, urtikarijom i gastrointestinalnim
simptomima, i predstavlja najtezu manifestaciju IgE-posredovane alergije na lekove. Znacajno cesce
se javlja nakon parenteralne primene lekova a retko nakon oralne iii lokalne primene na kozi.
Anafilakticka reakcija se razvija u slucaju prisustva specificnih IgE At na mastocitima, nakon
sistemskog izlaganja antigenu, kada dolazi do simultane degranulacije velikog broja ovih celija i
oslobadanja hi stamina i drugih vazoaktivnih medijatora [ 13] (Tabela 2).
Tabela 2. Simptomi anafilakse
lgE-posredovana reakcija Klinicka manifestacija
Hipotenzija Generalizovane promene po kozi
Yazodilatacija Urtikarija
Bronhospazam Otok grla i usta
Angioedem Promene srcane frekvence
Kardiovaskularni kolaps Teska astma
Abdominalni bol, mucnina i povracanje Iznenadni osecaj
slabosti
Kolaps i nesvestica
Terapija lekovima i hitna medicinska nega
Umerena alergijska rekacija moze biti lecena antihistaminicima kao sto je difenhidramin, koji
dovodi do povlacenja osipa po kozi i svraba. Sa druge strane, ozbiljne anafilakticke reakcije
zahtevaju hitnu primenu adrenalina zbog kardiovaskulamog kolapsa, kao i sistemskih kortikosteroida
kako bi se sanirale posledice oslobodenih medijatora iz mastocita. U slucaju prave anafilakticke
hipersenzitivne reakcije, progresija pogorsanja klinickog stanja pacijenta je fulminantna i ishod
moze biti letalan ukoliko se u kratkom vremenskom roku ne primeni adrenalin i ne omoguci
prohodnost disajnih puteva [14].
Dijagnoza
Dijagnoza alergije na Penicilin zasniva se na anamnestickim podacima o alergijskoj reakciji
nakon terapijske primene Penicilina, pozitivnom fizikalnom nalazu i simptomima koji ukazuju na
prisustvo alergijske reakcije izazvane lekom. U zavisnosti od anamnestickih podataka i rezultata
klinickog pregleda. dijagnozu alergije na penicilin je potrebno potnditi dijagnostickim testovima. kao
sto su kozne probe. dozno prO\ okacioni test i postupak indLikcije tolerancije na penicilin. Ukoliko
postoji sLimnja na prisListvo alergije na penicilin. sve potrebne fizicke i klinicke preglede pacijenta i
dijagnosticke procedure trebalo bi da uradi iskLisni alergolog. Detaljan opis znakova i simptoma
alergijske reakcije od strane pacijenta je vazan deo potvrde i dijagnoze alergije na penicilin. Kao
dodatak detaljnoj anamnezi. potrebno je uraditi i detaljan fizicki pregled pacijenta, koji moze biti od
velikog znacaja Ll definisanjLI potencijalnih mehanizama nastanka alergijske reakcije i koji je znacajna
smemica za dalje dijagnosticke procedure [ 15].
Uloga i znacaj koznog testiranja
Kozno testiranje na penicilin sa obe antigenske determinantnom ,major" i ,minor", je
najpouzdaniji dijagnosticki test za potvrdLI IgE posredovane alergije na penicilin. Kozne probe se
izvode "prick" i intradermalnim testovima. Ovim testiranjem treba da SLI obLihvacene i ,major" i
,minor" determinante. Benzyl peniciloil je ,major" determinanta. Postoji nekoliko razlicitih minor
determinanti (MOM) ukljucujLici benzyl penicilloate, benzyl penilloate, benzyl penicilin ilili benzyl-
n-propylamin. Kozni prick test se izvodi LIZ kontrolLI pozitivnosti na histamin. Ukoliko je prick test
negativn, izvodi se intradermalni test. Pojava kozne reakcije sa eritemom vecim za 3mm od negativne
kontrole, nakon prik iii intradermalnog testa, smatra se pozitivnim nalazom [ 16].
Uopsteno je prihvaceno da je neophodno kozno testiranje sa obe determinane, ,major" i ,minor"
istovremeno, kao najsenzitivniji i najspeciticniji test, obzirom da mali broj pacijenata ima alergijsku
reakciju samo na ,minor" determinantLI (uz najcesci razvoj anafilakticke reakcije ). TrenLitno ne postoji
komercijalni test reagens za kozni test sa izolovanim .,minor" determinantama. Za tu svrhu se
upotrebljava penicilin G i njegovi prodLikti kao mesa\ ina minornih determinanti [ 17].
Pacijent sa anamnestickim podacima o ispoljenom I tipLI preosetljivosti na penicilin i negativnim
koznim testom na obe, ,major" i ,minor" determinantLI. je pod niskim rizikom za razvoj ponovljene
alergijske reakcije na Penicilin [ 18]. Studija Song i saradnika je pokazala da procenat ponovljene
alergijske reakcije na penicilin kod pacijenata sa pozitivnom anamneom o prethodnoj reakciji na
penicilin i negativnim koznim testom na obe determinante. iznosi 2.9-1.2% [ 19].
Pozitivni kozni test na penicilin LlkazLije na prisLISt\ o speciticnih IgE At na penicilin. Pacijenti
sa pozitivnim koznim testovima imajLI veci rizik za raz\ oj reakcija I tipa preosetljivosti na penicilin.
Mali je broj podataka o stvarnoj pozitivnoj prediktivnoj nednosti koznih testova na penicilin.
Ukoliko izvodenje koznih testova na penicilin nije dostLipno iii je rezLiltat pozitivan. preporucLije
se primena antibiotika koji ne pripadaju grupi /3-laktamskih antibiotika, iii se preporucuje primena
postupka desenzibilizacije na penicilin. Ako pacijent ima u istoriji bolesti podatak o hipersenzitivnosti
na penicilin koja nije posredovana IgE At. onda je desenzitizacija na penicilin kontraindikovana.
In vitro testiranje alergije na Penicilin
In vitro testovi (Radioallergosorbent test (RAST) iii en::yme-linked immunosorbent assay
(ELISA)) na prisustvo specificnih IgE At za .. major" determinantLI penicilina G, penicilina V.
amoksicilina i ampicilina, su druga vrsta pristLipa Ll dijagnostici IgE-posredovane alergije na penicilin
[20, 21]. Anamneza koja govori o prisListvLI I tipa preosetljivosti na penicilin, LIZ pozitivan in vitro test,

<' 201' Klini<'ki centar '>rhije. Rengrad r 20 I 5 Klinicki centar Srbiie. Beograd ~7
36 .\CL\ CLI:\ll'.\ \'ol. 15 Xd

i
l-
ukazuje na prisustvo IgE-posredovane alergijske reakcije na penicilin. Sa druge strane, negativan nalaz
in vitro testa ne iskljucuje prisustvo alergije na penicilin, obzirom na njihovu nisku senzitivnost i
nemogucnost testiranja na "minor" determinantu [ 16].
Alergija na cefalosporine
Ukupna incidenca alergijskih reakcija na cefalosporine se krece oko 0.1-2% [22,23]. Nezeljene
reakcije na cefalosporine se cesce javljaju kod pacijenata sa udruzenom alergijom na peniciline, a stopa
prevalencije kod ovih pacijenata se krece od 0.17-15% [24]. Cefalosporinski antibiotici sadrze
f3-laktamski prsten i varijabilne bocne lance. f3-1aktamski prsten i bocni lanci mogu da ucestvuju u
hipersenzitivnim reakcijama na ove lekove. Speficicni hapteni i njihov znacaj kod alergije na
cefalosporine nije utvrden [6].
Klinicke manifestacije
Nezeljene reakcije na cefalosporine podrazumevaju i IgE-posredovanu hipersenzitivnost i
imunski odgovor nezavisan od IgE At. lgE-posredovana hipersenzitivnost se manifestuje urtikarijom,
angioedemom, bronhospazmom i/ili anafilaksom. Anafilakticka reakcija na cefalosporine je retka
(0.00 1-0.1 %), ali ipak postoje dokumentovani slucajevi smrtnog ishoda us led anafilakse [25]. Svi
tipovi nezeljenih koznih reakcija na sefalosporine se javljaju kod 1-3% pacijenata. Ozbiljna stanja
vezana za kozne reakcije usled alergije na cefalosporine su recta nego kod primene penicilina, medutim
postoje dokumentovani slucajevi SJS i ED. Drugi tipovi ne-IgE posredovanih reakcija na cefalosporine
podrazumevaju simptome slicne serumskoj bolesti, groznicu, pozitivan Coombs-ov test.
Dijagnoza
Za razliku od alergije na peniciline, validan kozni test za ispitivanje osetljivosti na cefalosporine
ne postoji. S toga je anamnesticki podatak u istoriji bolesti kljucan za dijagnozu alergije na
cefalosporine. Kompletna istorija bolesti bi trebalo da sadrzi detaljan opis i podatke o ispoljenoj
reakciji, vreme ispoljavanja i podatke o istovremeno uzetim lekovima.
Unakrsna reaktivnost
Postoji delimicna unakrsna reaktivnost izmedu razlicitih tipova penicilina. Pacijent koji je imao
jednu epizodu alergijske reakcije ranog tipa preosetljivosti na penicilin ne bi trebalo da primi u
terapijske svrhe ni jednu drugu vrstu penicilina. Dugo godina je smatrano da unakrsna reaktivnost
izmedu penicilinskih derivata, cefalosporina i karbapenema iznosi oko 10%, zbog zajednickog
~-laktamskog prstena. Noviji podaci pokazuju da je kljucna determinanta imunske reakcije izazvana
hipersenzitivnoscu na bocne grupe prve generacije cefalosporina i penicilina, pre nego na ~-laktamski
prsten [ 12, 26, 27]. To znaci da postoji nizak rizik za razvoj alergijskih reakcija na cefalosporine kod
pacijenata sa IgE-posredovanom hipersenzitivnoscu na penicilin, obzirom da postoji znacajna razlika
u gradi njihovih bocnih lanaca. Cefalosporini kod kojih je pokazano da postoji unakrsna reaktivnost
sa penicilinom su: Cefaleksin, Cefadroksil, Cetlahlor, Cefradine, Cefprozil, Ceftriaksone, Cefpodoksim.
Cefalosporini kojima nedostaju bocni lanci f3-laktamskog prstena su sigumiji i ovoj grupi pripadaju:
Cefazolin, Cefuroksim, Cefdinir, Cefiksim, Ceftibuten.
38 AC lA CLI:\!Ct\ \"ol. IS Nd < 2015 Klinicki centar '>rhije, Beograd
Trebalo bi da budemo S\ esni da unakrsna reakti\ nost na cefalosporine kod pacijenata sa alergijom
na penicilin nije oba\ ezno efekat klase. Da\ anje antibiotske terapije pacijentima sa alergijom na
peniciline mora biti bazirano na tipu alergijske reakcije i hemijskoj gradi leka [26].
Sa druge strane. postoji i dilema da li je bezbedno pacijentima sa alergijom na cefalosporine davati
penicilin. Anafilakticke reakcije na cef~llosporine su znacajno rede nego na peniciline. Pokazano je da
pacijenti koji produkuju lgE odgm or na primenu cefalosporina. proiz\ ode O\ akav odgm or samo za
odredeni cefalosporin. dok pacijenti sa klinicki znacajnim IgE odgmorom na peniciline razvijaju
hipersenzitivnost na raspadne produkte penicilinskog prstena tj. na bilo koji oblik i Hstu penicilina. Kod
pacijenata sa anamnestickim podatkom o potencijalno ozbiljnoj IgE-posredovanoj reakciji na cefalosporin,
veoma je vazno izbegavati izlaganje istom cetalosporinu, cetalosporinu koji ima isti bocni lanac i drugim
~-laktamima koji imaju isti lanac (kao ceftazimid i aztreonam). Dodatno, potrebno je uzeti u obzir podatak
da kod pacijenata sa alergijom na penicilin postoji 3 puta veca sansa za razvojem nezeljenih reakcija na bilo
koji drugi lek, te je potrebno dodatno obratiti paznju na ove pacijente pri davanju bilo koje terapije [28, 29].
Koriscenje cefalosporina - re/ativna kontraindikacija kod a/ergije na penicilin
Uobicajena praksa nekih lekara jeste da se izbegava koriscenje cefalosporina ukoliko pacijent
tvrdi da postoji alergija na penicilin. U \·ecini situacija O\ o je nepotrebno i dovodi do povecane
upotrebe antibiotika sirokog spektra kao i pmecanih troskova. Ceste reakcije na cefalosporine su
navedene ispod (Tabela 3). Najcesca reakcija na cefalosporine predstavlja makulopapuloznu iii
morbiliformnu ospu [6]. Procenjuje se da je danas incidenca unakrsne reaktivnosti za pacijente koji
su alergicni na penicilin izmedu 6-8% [30]. Pristupi lecenju pacijenata sa alergijom na peniciline koji
mogu biti leceni cetalosporinima: a) lzbegavati sve P-laktamske antibiotike- najcesci pristup, koji
vodi povisenim troskovima i povecanoj upotrebi \ ankomicina: 6) Testirati pacijente koznim
testovima- testirati pacijenta na penicilin. zatim dati cefalosporine ukoliko je rezultat negativan. Ovaj
pristup moze biti koriscen u pojedinim situacijama kod pacijenata koji imaju vitalnu indikaciju za
koriscenjem cefalosporina ali u istoriji bolesti zabelezenu ozbiljnu alergijsku reakciju na penicilin.
Tahe/a 3. Ceste reakcije JW cef(r/osporine
I Tip reakcije i uccstalost
i Dermatoloske reakcije I.0-2.X 11 o
f---------------------T-~ - - - . ---·-----
Pozitivan direktni antiglobulinski test 1.0-2.0°/o
Anafilaksa i 0.0001-0.1 'X,
Groznica
f - - - - - - - - - - - - - - - - - - - - - -- ·----------·------
Eozinofilija 2. 7-X.2%
L__----------------"~----------
Upotreba cefa/osporina kod pacijenata sa podatkom o a/ergiji na cefa/osporine
Pacijent koji je prethodno imao alergijsku reakciju na neki od cefalosporina trebalo bi da izbegm a
taj cefalosporin. Ako je neophodna terapijska alternativa iz grupe cefalosporina. radna grupa "Joint
Task Force on Practice Parameters" [ 16] preporucuje jedan od sledecih pristupa: I) iz\ odenje dozno
provokacionog testa sa alternativnim cefalosporinom koji u hemijskom sastm·u ima razlicit bocni lanac
iii 2) razmotriti kozno testiranje sa zeljenim cefalosporin
< 2015 Klinicki centar '>rhiie. lkol!rad 1r I I 1 I "II· I \ nl. I~ \C·'
Zakljucak
Lekari cesto u praksi nailaze na pacijente sa podatkom o alergiji na penicilin i druge ~-laktamske
antibiotike. Medutim. poznato je da oko 90% ovih pacijenata zapravo nisu alergicni i mogu bezbedno
primati ovu grupu antibiotika u terapijske svrhe. Velika ozbiljnost problema koji predstavljaju alergijske
reakcije na lekove je mazda del om i zbog ceste upotrebe reci "alergija", tumacenjem da se ovaj pojam
odnosi na sve imunoloski posredovani reakcije. Prilikom procene alergije na penicilin prvo pitanje je
utvrditi da li zaista postoji alergijska reakcija posredovana IgE At. Umesto toga, ovi pacijenti su cesto
nepotrebno leceni alternativnim antibioticima sirokog spektra, koji povecavaju troskove lecenja i
doprinose razvoju i sirenju rezistencije bakterija na antibiotike.
Cesto navodeni podaci od oko 10% postojece unakrsne reaktivnosti izmedu penicilina i
cefalosporina su najverovatnije precenjeni. Stepen unakrsne reaktivnosti izmedu cefalosporina i penicilina
zavisi od generacije cefalosporina, koja je visa kod cefalosporinima ranijih generacija. Unakrsna
reaktivnost izmedu penicilina i druge i trece generacije cefalosporina je niska i maze biti niza od unakrsne
reaktivnosti izmedu penicilina i drugih antibiotika. Pored toga, ucestalost ranih alergijskih reakcija na
cefalosporine je znatno niza u odnosu na peniciline, i unakrsna reaktivnost izmedu cefalosporina je znatno
niza u odnosu na unakrsnu reaktivnost izmedu penicilina i cefalosporina [12, 27, 31].
LITERATURA:
I. Weiss M.E, Adkinson N.F., Jr. f3-Lactum Allergy. In: Mandell G.L, Bennett J.E, Dolin R, editors.
Douglas and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill
Livingstone; 2000.
2. Wright AJ. The penicillins. Mayo Clin Proc 1999; 74:290-307.
3. Kerr JR. Penicillin allergy: a study of incidence as reported by patients. Br J Clin Pract 1994; 48:5-7.
4. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin
"allergy" in hospitalized patients: A cohort study. J Allergy Clin Immunol 20 14; 133(3):790-6.
5. Anderson J. Penicillin allergy. Current therapy in allergy, immunology and rheumatology-3, ed.
F.A. Lichtenstein LM. 1988, Toronto: BC Delker, Inc. 68-76.
6. Kelkar PS. Li JT. Cephalosporin allergy.[see comment]. New England Journal of Medicine,
200 I:345( II): 804-9.
7. Lin R Y. A perspective on penicillin allergy. Archives of Internal Medicine 1992: 152(5):930-7.
8. Levine BB. Immunologic mechanisms of penicillin allergy: a haptenic model system for the study
of allergic diseases in man. N Eng! J Med 1966;275: 1115-1125.
9. Arroliga E.M, Pien LPenicillin allergy: Consider trying penicillin again.Clevelend Clinic Journal of
medicine 2003;70( 4):331-326.
I0. Greenberger P. Drug Allergy. Part B: Allergic Reactions to Individual Drugs: Low Molecular Weight.
Patterson's Allergic Diseases, ed. G.L.a.G. PA. 2002, Philadelphia: Lippincott Williams and Wilkins.
335-385.
II. Romano A, Mondino C. Viola M, Montuschi P. Immediate allergic reactions to LI-lactums: Diag-
nosis and therapy. Int J Immunopathol Pharmacal 2003; 16:19-23.
12. Atanaskovic-Markovic M, Medjo B. Gavrovic-Jankulovic M, et al. Immediate allergic reactions to
cephalosporins and penicillins and their cross-reactivity in children. Pediatr Allergy Immunol 2005;
16(4):341-347.
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J
13. Petz LD. Immunologic reactions of humans to cephalosporins. Postgrad Med J 1971: 47:64-69.
14. Lockey RF. Bukantz SC. Bousquet J. Allergens and allergen immunotherapy. Informal Health Care.
2004.
15. Warrington R. and Silviu-Dan F. Drug allergy. Allergy Asthma& Clinical Immunology 20 II: 7
(Suppl I ):S I0.
16. Anonymous, Executive summary of disease management of drug hypersensitivity: a practice pa-
rameter. Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma and
Immunology, the American Academy of Allergy, Asthma and Immunology, and the Joint Council
of Allergy, Asthma and Immunology. Annals of Allergy, Asthma, & Immunology, 1999;83(6 Pt
3):665-700.
17. Salden AEO, Rockmann H, Verheij JMT, and Broekhuizen LOB. Diagnosis of allergy against
beta-lactams in primary care: prevalence and diagnostic criteria. Family Practice 20 15; 1-6.
18. Gadde J, eta!. Clinical experience with penicillin skin testing in a large inner-city STD clinic. JAMA
1993;270(20):2456-63.
19. Sogn DD, et al. Results ofthe National Institute of Allergy and Infectious Diseases Collaborative
Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives
in hospitalized adults. Archives of Internal Medicine 1992; 152(5 ): I025-32.
20. Thethi AK, Van Dellen RG. Dilemmas and controversies in penicillin allergy. Immunology & Al-
lergy Clinics of North America 2004;24(3 ):445-61.
21. Wide L, Juhlin L. Detection of penicillin allergy of the immediate type by radioimmunoassay of
reagins (lgE) to penicilloyl conjugates. Clinical Allergy 1971; I(2): 171-7.
22. Norrby SR. Side effects of cephalosporins. Drugs 1987:34 Suppl 2: I05-20.
23. Novalbos A, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to
penicillins. Clinical & Experimental Allergy 200 I :31 (3):43R-43.
24. Daulat S, eta!., Safety of cephalosporin administration to patients with histories of penicillin al-
lergy.[see comment]. Journal ofAllergy & Clinical Immunology 2004;113(6):1220-2.
25. Pumphrey RS, Davis S. Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet
1999; 353(9159): 1157-8
26. Macy, E. Drug allergies: What to expect, what to do. Modern medicine, 2006.
27. Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: a
meta-analysis. Otolaryngol Head Neck Surg 2007: 136:340-347.
28. Madaan A, Li JT. Cephalosporin allergy. lmmunol Allergy Clin.North Am 2004: 24(3):463-476.
29. Ulman K. AANP: Certain Cephalosporins may be safe for patients with penicillin allergies. Modem
medicine, 2007.
30. Apter AJ, et al. Is there cross-reactivity between penicillins and cephalosporins? American Journal
of Medicine 2006;119(4):354 ell-9.
31. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin
"allergy" in hospitalized patients: A cohort study. J Allergy Clin Immunol 20 14; 133(3 ):790-6.
© 2015 Klinicki centar Srbije. Beograd 41
 r
DRUG ALLERGY
BETA-LACTAM ANTIBIOTIC ALLERGY
Vesna Tomic-Spiric
.Hedical Facul(r, Unirersi(r q/Belgrade
Clinic ofAI/ergology and Immunology, Clinical Center qfSrbia
Author :s· address:
Prc~fessor Vesna Tomic-Spirii·
Clinic qf Allergology and Immunology
Koste Todorovica 2, 11000 Belgrade, Serbia
E-mail: resnatomicspiric63@gmail.com
ABSTRACT
The most important causes of immediate (type I) hypersensitivity reactions are antibiotics, particularly
B-lactam antibiotics. Approximately I0% of patients report a history of penicillin allergy. However, up to
90% of these individuals are able to tolerate penicillin and are designated as having "penicillin allergy"
unnecessarily. Use of broad-spectrum antibiotics in patients designated as being "penicillin allergic" is
associated with higher costs, increased antibiotic resistance, and may compromise optimal medical care.
Key words: beta-lactams, penicillin, hypersensitivity, anaphylaxis, cross-sensitivity
INTRODUCTION
Adverse drug reactions are a significant cause of morbidity and mortality in the inpatient and
outpatient setting [I].
Beta-lactam antibiotics are among the most frequently prescribed drugs in general practice
\vorldwide. Penicillin belongs to an important group of antibiotics called beta (B)-lactam antibiotics
which are generally effective in eradication of common bacterial infections and are relatively
inexpensive and therefore widely used. This class of antibiotics includes penicillin and penicillin
derivatives such as ampicillin and amoxicillin as well as cephalosporins, monobactams, carbapenems
and B-lactamase inhibitors. As with most drugs, penicillin exhibits common side effects and adverse
reactions. Patients with recorded B-lactam allergies are likely to be treated with secondary choice, more
toxic and more expensive antibiotics [2].
PENICILLIN ALLERGY
The penicillin family is one of the most valuable groups of antibiotics in primary care and the
most widely used antibiotics for common infections and still the treatment of choice for many
infections [3,4]. Development of synthetic penicillins has both broadened the spectrum of activity and
enhanced the efficacy of these medications. However, emergence of resistant bacterial strains has
limited the usefulness of penicillins in recent years [4]. Nonetheless, penicillins remain the drugs of
choice for many infections and are particularly important in specific situations and during pregnancy.
Penicillin G is the most common drug implicated in drug allergy. The course of penicillin
42 ACTA CLINICA \'ol. 15 Nd < 2015 Klinicki ccntar Srbiic. Beograd
hypersensitivity is unpredictable i.e. an individual \\·ho tolerated penicillin earlier may show allergy
on subsequent administration and \ice versa [I].
EPIDEMIOLOGY
The prevalence of penicillin allergy in the general population is not known. The incidence of
self-reported penicillin allergy range from I to I0% [3.Kerr !994] \\ ith the frequency of life-threatening
anaphylaxis estimated at 0.01% to 0.05% [5].
RISK FACTORS
A history of an adverse drug reaction to penicillin or cephalosporin is the most important risk
factor. A history of atopy does not appear to be a risk factor for allergy to B-lactam antibiotics [6].
IMMUNOCHEMISTRY OF PENICILLIN MOLECULES
The penicillin antibiotics consist of a B -lactam ring and a variety of side chains. The B -lactam
ring or the side chains may participate in hypersensitivity reactions [7]. Like many pharmacologic
agents, penicillin is simple in structure and of low molecular weight. Low molecular weight substances
that are able to produce an allergic response are known as haptens [8]. By themselves they are unable
to induce antibody formation. In order to induce an immune response they must be attached to carrier
molecules that form a strong covalent bond. Patients do not exhibit an immune response to penicillin
itself but rather to the breakdown products of penicillin (isomers) after they bind with tissue and plasma
proteins to form hapten-carrier complexes. The B -lactam ring in the degraded penicillin is unstable
and binds with lysine residues in the tissue and plasma proteins resulting in a penicilloyl epitope known
as benzylpenicilloyl or the "major determinant". This major determinant is produced in the largest
amount and therefore is immunodominant in penicillin specific immune responses. Although less
common, the B-lactam rings can also make molecular rearrangements with carboxyl and thiol groups
and form less dominant or "minor determinants" (Figure I). The terms major and minor refer only to
the am·ount of hapten available for binding and not to the importance of each hapten in an immunologic
response. These complexes of penicillin break down products and native proteins are recognized as
foreign antigens by mast cells and basophils in some indi\ iduals. Subsequently, when a sufficient
density of drug epitopes is formed, a drug-specific immune response ensues. Minor determinants
appear to cause 90-95% of immediate IgE-mediated reactions. Major determinants can cause an
immediate IgE-mediated reaction but more often cause accelerated or delayed reactions caused by IgG
and IgM (9]. This is a very important clinical distinction because patients can have IgE-mediated
reactions to the minor determinant alone and if skin tests only include the major determinant those
patients (who are more likely to have an anaphylactic reaction) will not be identified.
CLINICAL MANIFESTATIONS
From a clinical standpoint, the most practical method of classifying penicillin allergy is to divide
the adverse drug reactions into IgE mediated (immediate-type hypersensitivity reaction) versus non-
IgE mediated hypersensitivity reactions [I 0] (Table I). For example, IgE mediated or immediate-type
reactions include anaphylaxis, angioedema, urticaria, and bronchospasm. These IgE mediated reactions
~: 2015 Klinicki ccntar Srbijc. Beograd \ ( I \ Cl 1'\IC-\ \ol. 15 _..,-,_, 43
occur within minutes after drug administration but can also be delayed up to 72 hours. These reactions who received such prescriptions was high (48.5% ). With repeat penicillin use, those with an allergy
occur in 0.004% - 0.015% of penicillin courses - most often in adults between 20 and 49 years. were 11.2 times more likely than others to experience an allergic event. Despite this relative ditTerence.
Immediate reactions are more common in parenteral administration. Fatal outcomes occur in 1 per the absolute risk of such events in the penicillin-allergic group was reported to be just 1.89%. The
every 50,000 to I00,000 treatment courses. Life threatening reactions occurring beyond I hour of management of such an event therefore needs to focus on awareness to prevent re-exposure. knowledge
penicillin administration are rare. of initial signs and symptoms such as wheezing. light-headedness. slurred speech, rapid or weaker
The non-IgE mediated hypersensitivity reactions include hemolytic anemia, interstitial nephritis, pulse rate. blueness of skin. lips and nail beds. diarrhea, nausea and vomiting along with emergency
thrombocytopenia, serum sickness, drug fever, morbilliform eruptions, erythema multiforme minor medical assistance and drug therapy to cope with the situation, particularly corticosteroids [ 11, 12]. In
(EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and others. These adverse addition, we must be alert with respect to the use of various combination products which all contain
reactions occur most commonly after 72 hours. Because none of these reactions is IgE dependent, skin penicillin. Serious medication errors can occur where doctors prescribe these medicines (often by brand
testing has no role in the evaluation of these patients[l 0]. name) and do not recognize that they contain penicillin.
Table 1: Classification ofpenicillin reactions
Skin SIGNS AND SYMPTOMS OF ANAPHYLAXIS
Time of
I Classification Mediators Clinical Signs Testing Comments
Onset Anaphylaxis, characterized by symptomatic hypotension with associated dyspnoea, urticaria,
I
Useful?
I Type I <I hour IgE mediated cross- Anaphylaxis and/or Yes More likely if and possibly gastrointestinal symptoms, is the most severe manifestation of IgE-mediated drug
I (immediate) linking with mast cells hypotension, laryngeal parenteral allergy. It is most common after parenteral drug administration and is rare with oral or cutaneous
and basophils with edema, wheezing, admin. Fatal in exposure. Anaphylaxis results when antigen-specific IgE is present on mast cells and a systemic
release of vasoactive angioedema, urticaria 1 per 50k-l OOk exposure to antigen occurs, cross-linked with IgE resulting in the simultaneous degranulation of
mediators treatment
large numbers of mast cells with sudden release of histamine and other vasoactive mediators [ 13]
Late reactions Variable (Table 2).
Type II IgG, complement Blood transfusion rxn., No IgE not involved
autoimmune hemolytic Table 2. Svmptoms of anaphvlaxis
anemia IgE-mediated reaction Clinical manifestations
Type III IgG, IgM immune Serum sickness, Tissue No Tissue lodging Hypotension Generalized flushing of the skin
complexes InJUry of immune Vasodilatation Urticaria rash
(glomerulonephritis, RA, complexes; drug Bronchospasm Sense of impending doom
SLE) fever Angioedema Swelling of throat and mouth
Type IV Cytokines activate Tc Contact dermatitis, TB No Cardiovascular collapse Alterations in heart rate
cells causing direct lesions, Graft rejection. Severe asthma
cellular damage Abdominal pain, nausea and vomiting
Idiopathic Usually> Maculopapular or No 1-4% of all Sudden feeling of weakness
72h morbilliform rash patients Collapse und unconsciousness
I receiving pen
DRUG THERAPY AND EMERGENCY MEDICAL CARE
ANAPHYLAXIS RISK MANAGEMENT
A mild allergic reaction can be treated with an antihistaminics like diphenhydramine, which helps
Documentation or reporting of allergies often becomes inaccurate and many patients may report relieve itching and skin rash. However, serious anaphylactic reactions require the urgent administration
that they have an allergy to an antibiotic whereas they may have in fact experienced effects of the of adrenal in to counter the cardiac collapse as well as corticosteroids to counteract the effect of the
infection such as fever and diarrhea. If a patient has exhibited signs of a true allergic reaction, re- mediators released from the mast cell. In the case of a true anaphylactic hypersensitivity reaction, a
exposure to penicillin or related antibiotics can trigger life-threatening anaphylaxis. It has been patient may die unless controlled with adrenaline and their airway is maintained [ 14].
estimated that up to 60% of penicillin-allergic patients will experience another allergic event if given
the drug again. However, new data suggest that this rate is less than 2%. Researchers analyzed data
from more than 3 million patients on the UK General Practice Research Database, who had received DIAGNOSIS
at least one prescription for penicillin. Of this group, 6212 (0.18%) patients had experienced an The diagnosis of penicillin allergy requires a through history and the identification of physical
allergic-like reaction after their initial penicillin prescription. Although these patients were 19 times findings and symptoms that are compatible with drug-induced allergic reaction. Depending on the
t
less likely than others to receive a repeat prescription for penicillin, the percentage of allergic patients history and physical examination results, diagnostic tests such as skin testing, graded chalenge and

44 ACTA CLINICA \'ol. 15 Ne3 t 2015 Klinicki centar Srbije. Beograd I &: 2015 Klinicki centar Srbiie. Beograd 4'i

I
induction of tolerance procedures may be required. Therefore, if penicillin allergy is suspected.
evaluation by an allergist experienced in these diagnostic procedures is recommended
Describing the signs and symptoms experienced by the patient is an important part of
documenting adverse drug reactions. In addition to the detailed history, a careful physical examination
can help to define possible mechanisms underlying the reaction and guide subsequent investigation
and diagnostic testing [ 15].
THE ROLE AND UTILITY OF SKIN TESTING
Penicillin skin testing with both major and minor determinants is the most reliable tool in the
diagnosis of a penicillin allergy mediated by IgE. Penicillin skin testing is performed with prick and
intradermal tests. This includes both the major and minor determinants Benzyl penicilloyl is the major
determinant. Several different MOM include benzyl penicilloate, benzyl penilloate, benzyl penicillin,
and/or benzyl-n-propylamine. After a positive histamine control, the prick test is performed. This is
followed by the intradermal test if the prick test is negative. A wheal of 3 mm or greater with erythema
greater than the control on either the prick or intradermal tests is considered a positive test [ 16].
It is generally accepted that skin testing with both major and minor determinants is necessary in
order to have the most sensitive and specific test probably because a minority of patients have an
adverse reaction to the minor determinant alone (often anaphylaxis). Currently, there is no commercial
source for the minor penicillin skin test reagent. Some use fresh penicillin G and its subsequent break
down products as a minor determinant mixture [ 17].
A patient with a history of an immediate-type hypersensitivity reaction to penicillin and negative
skin test to both, the major and minor determinants, is at a low risk of an immediate-type
hypersensitivity reaction to penicillin. [18]. Study of Song eta!. [19] reported a reaction rate of2.9%
and 1.2%. respectively, in patients who received penicillin with a positive history penicillin allergy
and a negative penicillin skin test to both the major determinant and MOM. Thus, patients with a
history of penicillin allergy and negative skin test to the major determinant and MOM will have a low
occurrence of immediate-type adverse reaction on administration of penicillin.
A positive penicillin skin test reflects the presence of specific IgE antibodies to penicillin.
Patients with a positive skin test to penicillin are at an increased risk of an immediate-type
hypersensitivity reaction to penicillin. Limited data is available on the true positive predictive value
of a positive penicillin skin test.
If penicillin skin testing is not available or penicillin skin test is positive, then a non- /3 -lactam
antibiotic is recommended or penicillin desensitization. If the patient has a history consistent with a non-
lgE mediated adverse drug reaction, then re-challenge or desensitization with penicillin is contraindicated.
IN-VITRO PENICILLIN TESTING IN THE EVALUATION OF PENICILLIN ALLERGY
In vitro assays (Radioallergosorbent test (RAST) or enzyme-linked immunosorbent assay
(ELISA) for IgE antibodies to the major determinants of penicillin G, penicillin V, amoxicillin, and
ampicillin is another approach in the diagnosis of IgE mediated penicillin allergy [20,21]. A history
of an immediate-type hypersensitivity reaction to penicillin with a positive in vitro test would suggest
an IgE mediated penicillin allergy. However, a negative test would not exclude a penicillin allergy
because these tests are relatively insensitive and do not test for minor determinants [ 16].
4A ".Cf'\('f 11\i!(''\ Vo!.l"i."in<
I
CEPHALOSPORIN ALLERGY
Them era II incidence of reaction to cephalosporins appears to be approximately 0.1-2% [22. 23].
The ad\ erse drug reaction rate may be higher in patients allergic to penicillins. Ad\ erse drug reaction
rates in patients with penicillin allergy range from 0.17% -15% [24].
The cephalosporin antibiotics consist of a /3 -lactam ring and a variety of side chains. The /3
-lactam ring or the side chains may participate in hypersensitivity reactions. The specific haptens have
not been clearly identified [6].
CLINICAL MANIFESTATIONS
Adverse drug reactions to cephalosporins include both IgE mediated and non-IgE mediated
adverse reactions. IgE mediated include urticaria, angioedema, bronchospasm, and/or anaphylaxis.
Anaphylactic reactions to cephalosporins seems to be relatively rare (0.00 1-0.1 %), however, deaths
have been reported [25]. All types of adverse drug skin reactions have been reported to occur in
1-3% of patients receiving cephalosporins. Severe skin reactions seem to be less common compared
to penicillins but cases of SJS and ED have been reported . Other types of non-IgE mediated adverse
reactions include serum sickness like reaction. fever and positive Coomb 's test.
DIAGNOSIS
Unlike penicillin allergy. a validated skin testing for cephalosporin antibiotics is not currently
available. Thus, the medical history is essential to the diagnosis of cephalosporin allergy. A complete
history should include description of the reaction, time course of the reaction. and complete
medication history.
CROSS SENSITIVITY
There is partial cross-sensitivity between different types of penicillins. An individual who has
exhibited immediate type of hypersensitivity with one penicillin should not be gi\ en any other type
of penicillin. Until recently it has been accepted that there was up to a I0% cross sensitivity between
penicillin-derivatives, cephalosporins, and carbapenems. due to the sharing of the ~-lactam ring. Recent
papers have shown that the major determinant in the immunological reaction is the similarity bet\\·een
the side chain of first generation cephalosporins and penicillins. rather than the ~-lactam structure that
they share [ 12, 26, 27]. This means that the risk of an allergic reaction to cephalosporins in those with
an established IgE-mediated allergy to penicillin may be low or non-existent. as long as the side chains
are not similar. The cephalosporin medications that are likely to cross-react after penicillin allergies
have been established and include: Cephalexin, Cefadroxil, Ceflaclor, Cephradine, Cefprozil,
Ceftriaxone, Cefpodoxime.
Among those that lack the /3-lactam side chain, and would therefore be safer. are: Cefazolin.
Cefuroxime, Cefdinir, Cefixime, Ceftibuten.
We should be aware that cephalosporin cross-reactivity in a penicillin allergic patient is not
necessarily a class effect. Dispensing of a prescription in a penicillin-allergic patient should be
evaluated based on the type of allergic manifestations and the drug prescribed [26]. The other side of
:\.; 20 I 5 Klinicki <.:en tar Srbiic. Beograd .p
the discussion is whether those allergic to cephalosporins can safely receive penicillin. Anaphylactic
reactions to cephalosporins are much less common than anaphylaxis associated with penicillin. Persons
who make lgE in response to cephalosporins seem to produce it only in response to a particular
cephalosporin. whereas persons who make clinically significant IgE in response to penicillin tend to
react to core penicillin break-down products. Thus, in a patient with a history of a serious, potentially
IgE-mediated reaction to a cephalosporin, it is critical to avoid reexposure to the same cephalosporin,
to a cephalosporin that shares the same side chain, and even to other ~-lactams that share the same
side chain (such as ceftazidime and aztreonam). Another thing to remember when thinking about
medication for patients with a penicillin allergy is that there is a three-fold increased coincidental risk
of adverse reactions to even an unrelated drug. Penicillin-allergic patients are more likely to react to
any class of drug, so extra care is required [28, 29].
USE OF CEPHALOSPORINS- A RELATIVE CONTRAINDICATION
IF PENICILLIN "ALLERGIC"
It has become common practice by some physicians to avoid cephalosporins if a patient claims
to be allergic to penicillin. In most situations this is unnecessary and again leads to the overuse of
extended spectrum antibiotics. The common reactions to cephalosporins are listed below (Table 3).
The most common reaction is a maculopapular or morbilliform skin eruption [6]. The incidence of
cross-reactivity for patients who are allergic to penicillin is now estimated to be between 6-8% [30].
Approaches to patients with penicillin allergy who could be given cephalosporins: a) avoid all
~-lactams - a common approach that leads to increased cost and increased use of vancomycin; 6) test
patients with skin testing- test for penicillin allergy then give the cephalosporin if negative. This
approach may be used in certain situations with patients who have a strong indication for cephalosporin
use but a history of a serious penicillin reaction.
Table 3. Common reactions to cephalosporins
Type of Reaction Frequency
Dermatologic 1.0-2.8%
Positive direct antiglobulin test 1.0-2.0%
Anaphylaxis 0.0001-0.1%
Fever 0.5-0.9%
Eosinophilia 2.7-8.2%
CEPHALOSPORIN USE IN PATIENTS WITH A HISTORY
OF CEPHALOSPORIN ALLERGY
A patient who has had an allergic reaction to a specific cephalosporin should avoid that
cephalosporin. If an alternative cephalosporin is desired, the Joint Task Force on Practice Parameters
[ 16] recommends one of the following: I) perform a graded dose challenge with an alternative
cephalosporin with a different side chain determinate or 2) consider skin testing with desired
cephalosporin.
4X L 2015 Klinicki centar Srbiie. Beograd
CONCLUSION
Clinicians commonly encounter patients with a history of allergy to penicillin and other ~-lactam
antibiotics. However. it is knm\ n that about 90°/cJ of these patients are not truly allergic and could safely
receive ~-lactam antibiotics. The seriousness of the problem posed by drug allergies is perhaps
overblown in part because of the loose use of the \\·ord "allergy." to refer to all immunologically
mediated reactions. When assessing an allergy to penicillin the first issue is to establish whether or not
a true allergic IgE mediated reaction has taken place. Instead, these patients are often treated
unnecessarily with an alternate broad spectrum antibiotic. which could increase costs and contribute
to the development and spread of multiple drug-resistant bacterThe frequently cited figures of l 0%
cross reactivity between penicillin and cephalosporin is perhaps an overestimate. The degree of cross-
reactivity between cephalosporins and penicillins depends on the generation of cephalosporins, being
higher with earlier generation cephalosporins. Cross reactivity between penicillin and second and third
generation cephalosporin is low and may be lower than the cross reactivity between penicillin and
unrelated antibiotics. In addition, the frequency of immediate allergic reactions to cephalosporins is
considerably lower compared to penicillins, and cross-reactivity among cephalosporins is lower
compared to cross-reactivity between penicillin and cephalosporins [ 12. 27, 31].
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I. Weiss M.E, Adkinson N.F., Jr. f3-Lactum Allergy. In: Mandell G.L, Bennett J.E, Dolin R, editors.
Douglas and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill
Livingstone; 2000.
2. Wright AJ. The penicillins. Mayo Clin Proc 1999: 74:290-307.
3. Kerr JR. Penicillin allergy: a study of incidence as reported by patients. Br J Clin Pract 1994; 48:5-7.
4. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin
"allergy" in hospitalized patients: A cohort study. J Allergy Clin lmmunol 20 14; 133(3 ):790-6.
5. Anderson J. Penicillin allergy. Current therapy in allergy, immunology and rheumatology-3, ed.
F.A. Lichtenstein LM. 1988, Toronto: BC Delker, Inc. 68-76.
6. Kelkar PS, Li JT. Cephalosporin allergy.[see comment]. New England Journal of Medicine
200 I ;345( II): 804-9.
7. Lin R Y. A perspective on penicillin allergy. Archives of Internal Medicine 1992; 152(5):930-7.
8. Levine BB. Immunologic mechanisms of penicillin allergy: a haptenic model system for the study
of allergic diseases in man. N Eng! J Med 1966;275: 1115-1125.
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medicine 2003, vol 70, No4:331-326
10. Greenberger P. Drug Allergy. Part B: Allergic Reactions to Individual Drugs: Low Molecular Weight.
Patterson's Allergic Diseases, ed. G.L.a.G. PA. 2002, Philadelphia: Lippincott Williams and Wilkins.
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nosis and therapy. Int J Immunopathol Pharmacal 2003; 16:19-23.
12. Atanaskovic-Markovic M, Medjo B, Gavrovic-Jankulovic M, eta!. Immediate allergic reactions to
cephalosporins and penicillins and their cross-reactivity in children. Pediatr Allergy lmmunol 2005;
16(4):341-347.
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 13. Petz LD. Immunologic reactions of humans to cephalosporins. Post grad Med J 197 I: 47:64-69.
14. Lockey RF. Bukantz SC. Bousquet J. Allergens and allergen immunotherapy. Informal Health Care.
2004.
15. Warrington R. and Sih iu-Dan F. Drug allergy.AIIergy Asthma& Clinical Immunology 20 II. 7
(Suppl I ):S I0.
16. Anonymous, Executive summary of disease management of drug hypersensitivity: a practice pa-
rameter. Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma and
Immunology, the American Academy of Allergy, Asthma and Immunology, and the Joint Council
of Allergy, Asthma and Immunology. Annals of Allergy, Asthma, & Immunology, 1999:83( 6 Pt
3 ):665-700.
17. Salden AEO, Rockmann H, Verheij JMT,and Broekhuizen LOB. Diagnosis of allergy against beta-
lactams in primary care: prevalence and diagnostic criteria. Family Practice 2015, 1-6.
18. Gadde J, et al. Clinical experience with penicillin skin testing in a large inner-city STD clinic. JAMA
1993:270(20): 2456-63.
19. Sogn DD, et al. Results of the National Institute of Allergy and Infectious Diseases Collaborative
Clinical Trial to test the predictive value of skin testing with major and minor penicillin derivatives
in hospitalized adults. Archives of Internal Medicine 1992:152(5): I025-32
20. Thethi AK. Van Dellen RG. Dilemmas and controversies in penicillin allergy. Immunology & Al-
lergy Clinics of North America 2004:24(3 ):445-61.
21. Wide L. Juhlin L. Detection of penicillin allergy of the immediate type by radioimmunoassay of
reagins (lgE) to penicilloyl conjugates. Clinical Allergy 1971:1 (2): 171-7.
22. Norrby SR. Side effects of cephalosporins. Drugs 1987;34 Suppl 2: I05-20.
23. Novalbos A, et al. Lack of allergic cross-reactivity to cephalosporins among patients allergic to
penicillins. Clinical & Experimental Allergy 200 I J I(3):438-43.
24. Daulat S, et al., Safety of cephalosporin administration to patients with histories of penicillin al-
lergy.[see comment]. Journal of Allergy & Clinical Immunology 2004:113(6 ): 1220-2.
25. Pumphrey RS. Davis S. Under-reporting of antibiotic anaphylaxis may put patients at risk. Lancet
1999: 353(9159):1157-8
26. Macy. E. Drug allergies: What to expect, what to do. Modern medicine, 2006.
27. Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic patients: a
meta-analysis. Otolaryngol Head Neck Surg 2007: 136:340-347.
28. Madaan A, Li JT. Cephalosporin allergy. Immunol Allergy Clin.North Am 2004: 24(3):463-476.
29. Ulman K. AANP: Certain Cephalosporins may be safe for patients with penicillin allergies. Modern
medicine, 2007.
30. Apter AJ. et al. Is there cross-reactivity between penicillins and cephalosporins? American Journal
of Medicine 2006:119(4):354 e11-9.
31. Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin
"allergy" in hospitalized patients: A cohort study. J Allergy Clin Immunol2014: 133(3):790-6.
50 \CT\ Cl.i'\IC.\ \'oL 15 .\c.~ c :'Ill" Klinic·ki cl'ntar Srhiie. lkourad
j 51
-I
ALERGIJSKE REAKCIJE IZAZYANE LEKOVIMA
NEIMUNOLOSKI POSREDOVANA PREOSETLJIVOST NAASPIRIN
Mirjana Bogie
lv!edicinskifakultet, L'nh·ecitet u Beogradu
Klinika ::a alergologij'u i imunologij'u. Klinicki centar Srbij'e
Adresa autora:
Profesor l'vfirjana Bogie,
Klinika ::a a/ergologij'u i imuno/ogij'u,
Koste Todorovica 2, II 000 Beograd
E-mail: bogic.miljanal@gmail.com
SAZETAK
Nesteroidni antiintlamatorni lekovi - NSAIL, trenutno su najcesci izazivaci preosetljivosti na lekove,
prevazilazeci beta-laktamske antibiotike kao vodece uzrocnike alergijskih reakcija na Iekove. Preosetljivost
na aspirin, srece se kod okvirno 2-23% pacijenata sa astmom i kod 21-30% pacijenata sa hronicnom
urtikarijom i/ili angioedemom. Klinicke manifestacije preosetljivosti na aspirin obuhvataju dve grupe
organa: 1) kozu- urtikarija/angioedem izazvan aspirinom (Aspirin induced urticaria/angiooedema- AIU)
i 2) respiratorni trakt- aspirinska astma (Aspirin exacerbated respiratory disease- AERO/Aspirin induced
asthma- AlA), a retko se javljaju u kombinaciji. Aspirinska astma je posebni fenotip astme sa
koegzistirajucim hronicnim rinitisom, polipima u nosu i preosetljivoscu na aspirin i druge nesteroidne
antiintlamatorne lekove. AERO karakterise povisen rizik za obolevanje donjih i gornjih disajnih puteva.
Pacijenti sa AERO-om zahtevaju sveobuhvatan i multidisciplinarni dijagnosticki pristup. Kontrolisanje
astme i rinitisa kod tih pacijenata je slicno kao i kod ostalih oblika ovih bolesti. Aspirinska desenzibilacija
maze biti efikasan tretman za neke pacijente sa AERO-om.
Kljucne reci: preosetljivost na aspirin, aspirinska astma
Aspirin iii acetilsalicilna kiselina (acetylsalicylic acid- ASA) je jedan od najcesce prepisiva-
nih nesteroidnih antiinflamatornih lekova (nonsteroidal antiinflammatory drugs- NSAIDs) kod
odraslih osoba [ 1]. Visoka doza aspirina (>300m g) preporucuje se za kontrolu akutnog koronarnog
sindroma i ishemijskog mozdanog udara, dok se niza doza aspirina (75-1 OOmg) preporucuje za
primarnu i sekundarnu prevenciju kardiovaskularnih bolesti (cardiovascular disease - CVD) u za-
visnosti od internaciolnih vodica [2]. Rastuci su i dokazi koji demonstriraju da aspirin takode mo.Ze
prevenirati kancer- specifican mortalitet potencijalno podstice siru upotrebu u opstoj populaciji [3].
Nesteroidni antiinflamatorni lekovi trenutno su najcesci izazivaci preosetljivosti na lekove,
prevazilazeci beta-laktamske antibiotike kao vodece uzrocnike alergijskih reakcija na lekove [4].
Preosetljivost na aspirin, srece se kod okvirno 2-23% pacijenata sa astmom i kod 21-30% pacijenata
sa hronicnom urtikarijom i/ili angioedemom [5].
Klinicke manifestacije preosetljivosti na aspirin obuhvataju dve grupe organa: 1) kozu-
urtikarija/angioedem izazvan aspirinom (Aspirin induced urticaria/angiooedema - AIU) i
2) respiratorni trakt - aspirinska astma (Aspirin exacerbated respiratory disease - AERO/ Aspirin Tabela I. Klinic~ke karakteristike AERD-a
induced asthma- AlA), a retko se javljaju u kombinaciji. Ova HLA alela ito, HLA-OPBI*0301 za
AlAi ORBI* 1302-DQBI*0609 za AIU. mogu se koristiti za razlikovanje dva glavna fenotipa I

~----
Uzajamna reakcija sa inhibitorima ciklooksigenaze-1 (COX-I)
preosetlj ivosti na aspirin [6]. • Tolerancija inhibitora ciklooksigenaze-2 (COX-2)

Hronicni rinosinuzitis sa polipima u nosu

PATOGENEZA PREOSETLJIVOSTI NA ASPIRIN/NSAIL
Mehanizam preosetljivosti na aspirin i NSAIL kod pacijenata sa astmom nije imunoloske prirode,
vee je povezan sa inhibicijom enzima COX-1 koji pretvara arahidonsku kiselinu u prostaglandin,
tromboksan i prostacilin. Kod osoba sa aspirinskom astmom, aspirin inhibira COX-1 podizuci nivo
arahidonske kiseline metabolisane posredstvom lipoksigenaze (LTA4, LTB4, LTC4, LT04 i LTE4).
Ovo pak podize nivo proinflamatornih cisteinil leukotriena (LTC4 i LT04) i smanjuje nivo
antiinflamatomih prostaglandina (PGE2) time izazivajuci bronhokonstrikciju [7]. Ovaj efekat javlja
se sa drugim NSAIL-om koji inhibira COX-1. Nasuprot tome, osobe sa aspirinskom astmom kod kojih
se javlja respiratoma reakcija kao odgovor na aspirin ili COX-1 inhibiran NSAIL-om, izgleda dobro
podnose COX-2 inhibitore [8].
Neimunoloski posredovana preosetljivost na NSAIL podrazumeva nekoliko razlicitih klinickih
manifestacija [9]: aspirinska astma; urtikarija izazvana aspirinom kod pacijenata sa hronicnom,
idiopatskom urtikarijom; i urtikarija i/ili angioedem izazvan kombinacijom NSAIL-a kod pacijenata
bez prethodno prisutne hronicne urtikarije/angioedema. Ova poslednja grupa je daleko najbrojnija
i Cini je 62% svih reakcija na NSAIL [ 10]. Test oslobadanja medijatora nakon nazalne provokacije
aspirinom podrzava razlicite fenotipe kod osoba preosetljivih na NSAIL. Koncentracija eozinofilnih
katjonskih proteina i triptaze u nosnom sekretu visa je kod pacijenta sa aspirinskom astmom u
poredenju sa pacijentima bez prethodno prisutne hronicne urtikarije. Znacajan porast eikosanoida
PGE2, PG02, LT04 i LTE4 primecen je kod pacijenata sa aspirinskom astmom, aline i kod
pacijenata bez prethodno prisutne hronicne urtikarije [ 11]. Podaci podrzavaju zapazanje da iako obe
grupe pacijenata imaju isti odgovor na COX inhibitore, u pitanju su razliCiti fenotipovi [ 12].
Medutim, moze se javiti preosetljivost zavisna od IgE, pracena anafilaksom [13, 14].
Osnovne abnormalnosti metabolizma arahidonske kiseline (nedostatak PGE2 i prekomerna
proizvodnja leukotriena), upome virusne infekcije, enterotoksini Staphylococcus aureus i genetska
predispozicija mogu imati znacajnu ulogu u patogenezi hronicne eozinofilne upale tipicno prisutne u
sluznici gomjih i donjih disajnih puteva kod pacijenata sa aspirinskom astmom [15].
ASPIRINSKA ASTMA- AERD
Aspirinska astma je pose ban klinicki sindrom primecen kod 5-10% pacijenata sa astmom.
Karakterise je istorija akutne dispneje obicno pracene simptomima rinoreje i/ili nazalne kongestije.
Ovi pacijenti pate od hronicnog, obicno tezeg oblika rinosinuzitisa sa cestom pojavom nazalnih polipa
i nemaju toleranciju na druge nesteroidne antiinflamatorne lekove koji su snazni inhibitori
ciklooksigenaze-1 (tabela 1). Nekada je ovaj sindrom bio poznat kao ,aspirinski tries". Pacijenti sa
aspirinskom astmom veoma se mogu razlikovati u pogledu ozbiljnosti astme, prisustva atopije (do
70% moze biti atopicno) [16] kao i opste reakcije na tretman. Medutim, AERD se uobicajeno povezuje
sa teskim oblicima astme, cestim pogorsanjima i iznenadnom smrcu.
• Hiperplasticni sinuzitis
• Polipi u nosu koji se iznova javljaju
• Hiposmija
Astma
• Tezi oblik od uobicajene astme
• Teza za kontrolu
• Povecan rizik od smrti
DIJAGNOZA PREOSETLJIVOSTI NA NSAIL
Kod vecine pacijenata, dijagnoza preosetljivosti na aspirin/NSAIL moze biti zasnovana na
istorij i respiratornih simptoma izazvanih upotrebom aspirina ili nekog drugog NSAIL-a. Kod
nekih pacijenata moze biti neophodna potvrda i to, kontrolisanim izlaganjem aspirinu. Oralna
provokacija aspirinom jeste zlatni standard kod uspostavljanja dijagnoze [ 17], ali bronhijalna ili
nazalna provokacija lizin-acetilsalicilatom moze predstavljati dragocenu dijagnosticku alternativu
[ 18, 19].
LECENJE ASPIRINSKE ASTME
Pazljivo izbegavanje aceti1salicilne kiseline i ostalih NSAIL-a, snaznih COX-I inhibitora, je
neophodno kako bi se sprecili teski napadi astme. Kao alternativa NSAIL-u, preporucuju se
selektivni COX-2 inhibitori [20] (tabela 2).
Lecenje astme i rinosinuzitisa kod pacijenata sa AERO-om je slicno kao i kod drugih formi
ovih bolesti, te se trebaju pratiti internacionalni vodici i smernice za lecenje [21]. Inhalacija
kortikosteroida u adekvatnim dozama,,cesto u kombinaciji sa beta-2 agonistima sa produzenim
delovanjem, efikasan je tretman za kontrolu simptoma astme. Medutim, kod nekih pacijenta moze
biti neophodan tretman prednizonom oralno [22].
Oodavanje antagonista leukotrienskih receptora poput montelukasta standardnoj terapiji moze
olaksati simptome i popraviti respiratornu funkciju pacijenata sa AERO-om, ali je stepen
poboljsanja slican kao i kod astmaticara tolerantnih na aspirin [23].
. Prednost u kontroli rinosinuzitisa imaju topikalni steroidi koji mogu usporiti ponovnu pojavu
~~hpa u. nosu [24]. Hirurske procedure (polipektomija, funkcionalna endoskopska sinusna hirurgija
th etm01dektomija) su najcesce neophodne u odredenom stadijumu bolesti [9].

<' 201" Klinicki centar <;;rt>ije. Reograd ~ 2015 Klinicki ccntar Srbiie. Beotrrad \CT\ U 1'\IC.\ \'ol. 15 .\': 0
52 AliAlLINllA \ol. ISJii"J
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No vi selektivni COX-2 inhibitori (etorikoksib) nasal aspirin provocation supports different phenotypes in subjects \vith hypersensitivity reaction
to NSAIDs. Allergy 2013;68:1001-7.
12. Caimmi S, Caimmi D, Bousquet PJ, Demoly P. How can we better classify NSAIDs hypersensiti\-
DESENZIBILIZACIJA NA ASPIRIN ity reactions?Valididations from a large database:lnt Arch Allergy Immunol 2012:59:306-12.
Poseban pristup ovim pacijentima predstavlja desenzibilizacija na acetilsalicilnu kiselinu [25]. 13. Picaud J, Beudouin E, Renaudin JM, Pirson F, Metz-Favre C. Dron-Gonzalvez M ct al. Anaphy-
Kod pacijenata kod kojihje obavljena desenzibilizacija na aspirin uocenaje smanjena pojava hronicnih laxis to diclofenac:nine cases reporeted to the Allergy Vigilance Network in France. Allergy 20 l.f:
simptoma gomjih i donjih disajnih puteva, smanjen broj hospitalizacija i hitnih prijema kao i smanjena 69:1420-3.
potreba za hirurskim intervencijama nosa/sinusa. 14. Sen I, Mitra S, Gombar KK. Fatal anaphylactic reaction to oral diclofenac sodium. Can J Anaesth
Posle uspesno obavljene desenzibilizacije na aspirin treba otpoceti terapiju sa 2x650mg aspirina 200 I ;49:421.
dnevno, a posle mesec dana smanjiti dozu na 2x325mg, ako je moguce [26]. 15. Mastalerz L, Celejewska-Wojcik N, Wojcik K, Gielciz A, Januszek R, Cholewa A et al. Induced
Ipak, samo mali deo pacijenata sa AERO-om ce imati korist od desenzibilizacije, a trenutno nije sputum eicosanoids during aspirin bronchial challenge of asthmatic patients with aspirin h~ persen-
moguce predvideti njihovu reakciju [27]. sitivity. Allergy 20 14;69: 1550-9.

54 Al lA l LINil A \ol. 15 Jlid < ?OJ' Klini<'ki cent;;r <;rhije. Beograd <· 2015 Klinicki centar Srhije.lko~rad
p
16. Chang JE, White A, Simon RA, Stevenson DO. Aspirin-exacerbated respiratory disease: burden of
disease. Allergy Asthma Proc 20 12;33: 117-21.
17. Nizankowska-mogilnicka E, Bochenek E, Mastalerz L, Swierczynska M, Picado C. Sccading Get
a!. EAACI/GA2LEN guideline:aspirin provocation test for diagnosis of aspirin hypersensitivity.
Allergy 2007;62: II I 1-8.
18. Agache L Silo M, Braunstahl GJ, Delgado L, Demoly P, Eigenmann Pet a!. In vivo diagnosis of
allergic disease-alergen provocation tests position paper. Allergy 20 15;70:355-65.
19. Scadding G, He! lings P, Alobid I, Bachert C, Fokkens W, van Wijk RG eta!. Diagnosis tools in
Rhinology EAACI postion paper. Clin Trans! Allergy 2011; I :2.
20. Lee RU, Stevenson DO. Aspirin exacerbated respiratory disease:evaluation and management. Al-
lergy Asthma Immunol Respir 20 II ;3:3-1 0.
21. Erikkson J, Ekerlung L, Bossios A, Bjerg A, Wennergren G, Ronmark E eta!. Aspirin-intolerant
asthma in the population:prevalence and important determinants. Clin Exp Allergy 2015;45:211-9.
22. Stevenson DO, Szczeklik A. Clinical and pathological perspectives on aspirin sensitivity and asthma.
J Allergy Clin Immunol 2006; 118:773-86.
23. Dahlen S, Micheletto C. Improvement of aspirin intolerant asthma by montelukast. Am J Respir Crit
Care Med 2002:165:9-14.
24. Holmberg K, Scadding G. Fluticasone propionate aqueous nasal spray in the treatment of nasal
polyposis. Ann Allergy Asthma Immunol 1997;78:270-6.
25. Berges-Gimeno MP, Simon RA, Stivenson DO. Treatment with aspirin desenzitization-treatment of
aspirin sensitive asthmatic patients:clinical outcomes studies. J Allergy Clin lmmunol2003; Ill: 180-6.
26. Lee JY, Stevenson DO. Selection of aspirin dosages after aspirin desenzitization treatment in patients
with aspirin-exacerbated respiratory disease. J Allergy Clin lmmunol 2007; 119:157-64.
27. Berges-Gimeno MP, Simon RA, Stivenson DO. Early effects of aspirin desenzitization treatment in
asthma patients with aspirin exacerbated respiratory disease. Ann Allergy Asthma Immunol
2003;90:338-41.
56 ACTA CLINIC A Vol. 15 ll(u-; L 2015 Klinicki centar Srhiie. Beograd
DRUG ALLERGY
NONIMMUNOLOGICALLY MEDIATED HYPERSENSITIVITY TO ASPIRIN
Mirjana Bogie
.Medical Faculty, University a./Belgrade
Clinic for allergy and immunology, Clinical Centre of' Serbia, Belgrade
Author's address:
Pro_f'essor Mirjana Bogie,
Clinic for allergy and immunology,
Koste Todorovica 2, 11000 Belgrade, Serbia
E-mail: bogic.mirjana1@gmail.com
ABSTRACT
Nonsteroidal anti-inflammatory drugs are currently the medicines most freqvently involved in
hypersensitivity reactions to drugs,surpassing beta-lactam antibiotics as the leading cause of drug allergy.
Aspirin hypersensitivity occurs in approximately 2-23% of asthmatic patients and 21-30% of chronic
urticaria and/or angioedema patients. The clinical manifestations of aspirin hypersensitivity can affect
two major target organs, the skin called as aspirin hypersensitivity urticaria/angioedema (AIU). and the
respiratory tract called as aspirin hypersensitivity intolerant asthma (AlA), though these rarely occur in
combination. Aspirin exacerbated respiratory disease is a distinct phenotype of asthma with coexisting
chronic rhinosinusitis, nasal polyps and hypersensitivity to aspirin and to other non-steroidal anti-
inflammatory drugs. AERO is characterized by an increased risk for uncontrolled upper and lower airway
disease. Patients with AERO require comprehensive and multidisciplinary diagnostic approach.
Management of asthma and rinosinusitis in a patient with AERO is similar to other forms of asthma and
rhinosinusitis. Aspirin desenzitization may be an effective treatment option for some AERO patients.
Key words: Aspirin hypersensitivity, aspirin exacerbated respiratory disease
Aspirin (acetylsalicilic acid-ASA) is one of the most commonly prescribed nonsteroidal
antiinflammatory drugs (NSAIDs) kod odraslih osoba [I ].High dose aspirin (>300mg)is recommended
for the management of acute coronary syndrome and ischaemic stroke,and low dose aspirin (75-1 OOmg)
is recommended for the primary and secondray prevention of cardiovascular disease (CVD) depending
on international guidelines [2]. Increasing evidence demonstrates that aspirin may also prevent cancer-
specific mortality potentially prompting wider use among the general population [3].
Nonsteroidal anti-inflammatory drugs are currently the medicines most freqvently involved in
hypersensitivity reactions to drugs, surpassing beta-lactam antibiotics as the leading cause of drug
allergy [4]. Aspirin hypersensitivity occurs in approximately 2-23% of asthmatic patients and 21-30%
of chronic urticaria and/or angioedema patients [5].
The clinical manifestations of aspirin hypersensitivity can affect two major target organs .the skin
called as aspirin hypersensitivity urticaria/angioedema (AIU), and the respiratory tract called as aspirin
hypersensitivity intolerant asthma (AlA), though these rarely occur in combination. Two HLA allele
~ 2015 Klinicki centar Srhiie. Beograd
markers. namely. HLA-DPBI*030 I for AlA and ORB!* 1302-DQBI*0609 for AIU. can be used for atopic) [ 16] and general responsiveness to teratment. However. on average AERO is associated with
differentiating two major phenotypes of aspirin hypersensiti\ ity [6 ]. increased risk for se\ ere asthma. frequent excerbations and sudden death.

Tah!l! 1. Clinicul clwractaistics ojA.ERD

PATHOGENESIS OF HYPERSENSITIVITY TO ASA/NSAIDS
•Cross reacti\ ity with COX-I inhibitors l
The mechanism of hypersensiti\ity to ASA and NSA!Ds in asthmatic patients is non
immunologicaLbut is related to inhibition of COX-I .an enzym that converts arachidonic acid into •General tolerance of COX-2 inhibitors
prostaglandins,thromboxanes and prostacyclin.In people with AlA, aspirin inhibits COX-I increasing Chronic rhinosinusitis with nasal polyps
the levels of arachidonic acid metabolized via the lypoxygenase pathway ( LTA4,LTB4.LTC4,LTD4
•Hyperplastic pansinusitis
and LTE4 ). This in turn increases the levels of pro-inflammatory cysteinylleukotrienes (LTC4 and
LTD4) and reduces the levels of anti-inflammatory prostaglandins (PGE2) tipping the balance towards •Recurrent nasal polyps
bronchoconstriction in asthma [7]. This effect occurs with other NSAIDs that inhibit COX-1. In •Hyposmia
contrast,COX-2 inhibitors appear well tolerated in people with AlA experiencing respiratory reactions
Asthma
in response to aspirin or COX-I -inhibiting NSA!Ds [8].
Nonimmunologically mediated hypersensitivity to NSAIDs include several entities with •More severe than average
1-----
very distinct and varied clinical manifestations [9]: aspirin-axacerbated respiratory disease •More difficult to control
(AERO); aspirin-exacerbated cutaneous disease (AECD) in patients with chronic idiopathic •Increased death risk
urticaria; and multiple NSAID-triggered urticaria and/or angioedema in patients without pre-
existing chronic urticaria/angioedema (MNSAID-UA). This last group is by far the
largest,accounting for 62% of all hypersensitivity reactions to NSA!Ds [ 10]. Mediator release DIAGNOSIS OF NSAID HYPERSENSITIVITY
after nasal aspirin provocation supports different phenotypes in subjects with hypersensitivity In the majority of patients the diagnosis of ASA/NSAID hypersensitivity can be based on a
reactions to NSAIDs. Eosinophil cationic protein and tryptase levels in nasal lavages were higher history of respiratory symptoms induced by the ingestion of aspirin or other NSAIDs. Confirmation
in AERO compared with MNSAID-UA. Significant increases of eicosanoids PGE2, PGD2, LTD4 by controlled aspirin challenge may be necessary in some patients. Oral aspirin provocation is the gold
and LTE4 were observed in AERO but not in MNSAID-UA[ 11]. Data support the observation standard for the diagnosis [ 17],but bronchial or nasal provocation with lysine-ASA may be valuable
that MNSAID-UA, although sharing a common response with AERO to COX inhibitors, seems alternative diagnostic tools [ 18, 19].
to have a distinctive phenotype [ 12].
However, IgE-dependent hypersensitivity may occur, with clinical presentation of anaphylaxis
MANAGEMENTOFAERD
[13,14].
Baseline abnormalities of arachidonic acid metabolism (PGE2 deficiency and overproduction Careful avoidance of ASA and other NSAIDs,which are strong COX-I inhibitors.is necessary
of leukotrienes ), persistent viral infections,Staphylococcus aureus enterotoxins and underlying genetic to prevent severe asthma attacks.As alternative to NSAIDs selective COX-2 inhibitors are
predisposition may have important role in the pathogenesis of chronic eosinophylic inflammation recommended [20] (table2).
typically present in the upper and lower airway mucosa of AERO patients [ 15]. Management of asthma and rhinosinusitis in AERO is similar to other forms of asthma and
rhinosisnusitis and international treatment guidelines should be followed [21 ]. Inhaled corticosteroids
in appropriate doses,often in combination with long acting beta 2 agonists are effective in controlling
ASPIRIN EXACERBATED RESPIRATORY DISEASE asthamtic inflammation and symptoms,but in some patients chronic treatment with oral prednisone
Aspirin exacerbated respiratory disease is a distinct clinical syndrome observed in 5-l 0% of may be necessary [22].
patients with asthma and characterized by history of acute dyspnea usually accompanied by nasal Addition of a leukotriene receptor antagonist such as montelukast to standard anti-inflammatory
symptoms (rhinorrhoea and/or nasal congestion). These patients suffer from chronic, ussualy severe therapy may be effective in relieving symptoms and improving respiratory function in some patients
rhinosinusitis with recurrent nasal polyps and do not tolerate other non-steroidal antiinflammatory with AERD,but the degree of improvement is similar to ASA tolerant asthmatic [23].
drugs (NSAIDs ), which are strong cyclooxigenase-1 inhibitors (table 1). The syndrom has been Topical nasal steroids are preffered for controlling symptoms of rhinosinusitis and may slow
previously called ,Aspirin-triad" or ,Aspirin sensitive asthma with polyps". Patients with AERO are down recurrence of nasal polyps [24]. Surgical procedures (polypectomyJunctional endoscopic sinus
quite hetrogeneous with respect to asthma severity,presence of atopic sensitization (up to 70% may be surgery or ethmoidectomy) are usually needed at certain stage of the disease [9].

58 \CT.\ CL!'-:JC.\ \'ol. 15 :-;,_; c 201'1 Klinicki ccntar <;rhiic.lknl!rad t 2015 Klinicki cent"r <;rhije. llengrad

I
\l J..\ l 1.1:'-.ll A \ol. 15 -'',-"-'
 Table 2. lv'SA!Ds tolerance in patients with AERD* REFERENCES:
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clasijfication. diagnosis and management rnrier ol rhe EAA C/IE.\ DA and CIA .c.LE.\; HA .\\A A 1/ergy
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Meloxicam ity phenotypes. Allergy 2009;64: 1384-92.
7. Mastalerz L, Sanak M, Gawlewicz-Mroczka A, Gielicz A, Cmiel A. Szczeklik A. Prostaglandin E2
Nimesulide
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Acetaminophen 8. Morales DR, Guthrie B, Lipworth BJ, Jackson C, Donnan PT, Santiago VH. Safety risk for patients
with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-in-
Meloxicam flammatory drugs and COX-2 inhibitors: meta analysis of controlled clinical trials. J Allergy Cliun
Nimesulide Immunol 2014;134:40-5.
9. Kowalski ML, Makowska JS, Blanca M, Bavbek S, Bochenek G, Bousquet Jet a!. Hypersensitivity
Selective COX-2 inhibitors( celecoxib, rofecoxib)
to nonsteroidal anti-inflammatory drugs(NSAIDs )-classification, diagnosis and management:review
Group C:NSAIDs well tolerated by all hypersensitive patients( single cases of hypersensitivity have of the EAACIIENDA and GA2LEN/HANNA. Allergy 2011 ;66:818-29.
been reporeted)
10. Dona I, Blanca-Lopez N. Corneja-Garcia JA, Torres MJ, Laguna JJ, Fernandez Jet a!. Characteris-
Rhinitis/asthma type tics of subjects experiencing hypersensitivity to non-steroidal anti-inflammatory drugs:patterns of
Selective COX-2 inhibitors( celecoxib) response. Clin Exp Allergy 2011 ;41 :86-95.

Urticaria/angioedema type
New selective COX-2 inhibitors( etoricoxib)
ASPIRIN DESENZITIZATION
The special approach for these patients is ASA desenzitization [25]. The alleviation of chronic
upper and lower airway symptoms, reduction in hospitalization and emergency room visits and
decreased need for nasal/sinus surgery is observed in desenzitized patients.
After successful aspirin desensitization, it is necessary to start daily aspirin therapy (2x650mg),
and after a month, if possible, reduce dose to 2x325mg [26].
However, only a fraction of patients with AERO will benefit from aspirin desenzitization and at
present it is not possible to predict the responders [27].
11. Campo P, Ayunso P, Salas M, Plaza MC, Cornejo-Garcia JA, Dona I eta!. Mediator release after
nasal aspirin provocation supports different phenotypes in subjects with hypersensitivity reaction
to NSAIDs. Allergy 2013;68:1001-7.
12. Caimmi S, Caimmi D, Bousquet PJ, Demoly P. How can we better classify NSAIDs hypersensitiv-
ity reactions?Valididations from a large database:Int Arch Allergy Immunol 20 12;59:306-12.
13. Picaud J, Beudouin E, Renaudin JM, Pirson F, Metz-Favre C, Dron-Gonzalvez M eta!. Anaphy-
laxis to diclofenac:nine cases reporeted to the Allergy Vigilance Network in France. Allergy
20 14;69: 1420-3.
14. Sen I, Mitra S, Gombar KK. Fatal anaphylactic reaction to oral diclofenac sodium. Can J Anaesth
2001;49:421.
15. Mastalerz L, Celejewska-Wojcik N, Wojcik K, Gielciz A, Januszek R. Cholewa A eta!. Induced
sputum eicosanoids during aspirin bronchial challenge of asthmatic patients with aspirin hypersen-
sitivity. Allergy 20 14;69: 1550-9.

60 r· ?01" Klinicki cent~r <;rf-ije. Re<>grad ID 2015 Klinicki cent~r <;rf-ije. Beograd
61

I
Al lA lll'-<ll!\ \ol. 15 -'""-'
 r
16. Chang JE. White A. Simon RA. Stevenson DO. Aspirin-exacerbated respiratory disease: burden of
disease. Allergy Asthma Proc 2012;33: 117-21.
17. Nizankowska-mogilnicka E. Bochenek E. Mastalerz L Swierczynska M. Picado C. Sccading Get
al. EAACI/GA2LEN guideline:aspirin provocation test for diagnosis of aspirin hypersensiti\·ity.
Allergy 2007;62: 1111-8.
18. Agache L Bilo M. Braunstahl GJ, Delgado L, Demoly P, Eigenmann Petal. In vivo diagnosis of
allergic disease-alergen provocation tests position paper. Allergy 20 15;70:355-65.
19. Scadding G, Hellings P. Alobid I, Bachert C. Fokkens W, van Wijk RG et al. Diagnosis tools in
Rhinology EAACI postion paper. Clin Trans! Allergy 2011; 1:2.
20. Lee RU. Stevenson DO. Aspirin exacerbated respiratory disease:evaluation and management. Al-
lergy Asthma Immunol Respir 2011 ;3 :3-1 0.
21. Erikkson J, Ekerlung L, Bossios A, Bjerg A, Wennergren G. Ronmark E et al. Aspirin-intolerant
asthma in the population:prevalence and important determinants. Clin Exp Allergy 20 15;45:211-9.
22. Stevenson DO. Szczeklik A. Clinical and pathological perspectives on aspirin sensitivity and asthma.
J Allergy Clin lmmunol 2006; 118:773-86.
23. Dahlen S. Micheletto C. Improvement of aspirin intolerant asthma by montelukast. Am J Respir Crit
Care Med 2002;165:9-14.
24. Holmberg K. Scadding G. Fluticasone propionate aqueous nasal spray in the treatment of nasal
polyposis. Ann Allergy Asthma lmmunol 1997;78:270-6.
25. Berges- Gimeno MP, Simon RA, Stivenson DO. Treatment with aspirin desenzitization-treatment
of aspirin sensitive asthmatic patients:clinical outcomes studies. J Allergy Clin lmmunol
2003; 111:180-6.
26. Lee JY. Stevenson DO. Selection of aspirin dosages after aspirin desenzitization treatment in patients
with aspirin-exacerbated respiratory disease. J Allergy Clin lmmunol2007; 119:157-64.
27. Berges-Gimeno MP, Simon RA, Stivenson DO. Early effects of aspirin desenzitization treatment in
asthma patients with aspirin exacerbated respiratory disease. Ann Allergy Asthma lmmunol
2003;90:338-41.
•· ~ll I' K linick i cent:tr <;rrije. lkngmd
62 ,\L IAL 1.1'-.ILA \ol. 15.\e.l
ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA
ALERGIJSKE REAKCIJE ~A LEKOVE U PERIOPERATIVNO!VI PERIODU
I TOKOM DIJAGNOSTICKIH PROCEDURA
OPSTI ANESTETICL MISICNI RELAKSANSI I LATEX
Aleksandra Peric-Popadic:I. 2
1
A1edicinskifakultet L'niver~iteta u Beogradu
: Klinika ~a alergologiju i imunologiju. Klinicki centar Srbije
Adresa autora:
PrC!f'esor Aleksandra Peric-Popadic
Klinika ~a alergolog[ju i imunologiju,
Koste Todorovi(·a 2. 11 ()()()Beograd, Srbija
E-ma i1: popealeksandra(l~J ·alwo. com
SAZETAK:
Anestezija predstavlja farmakoloski jedinstvenu situaciju u toku koje je pacijent izlozen mnogobrojnim
stranim supstancama ukljucujuci anestetike, koji mogu dovesti do ranih hipersenzitivnih reakcija iii anafilakse.
Na srecu. anafilakticke reakcije na anestetike su retke. I na 5. 000 do 25. 000 slucajeva. Tezine reakcija mogu
varirati. a ispoljavaju se kao ras. urtikarija. bronhospazam. hipotenzija. angioedem. pmracanje. Anafilaksa
tj anatilakticki sok je najteza forma rano nastale reakcije; najcesce nastaje nakon ponovne ekspozicije
speciticnom antigenu. Anatilaktoidne reakcije nastaju kroz direktno. ne-lgE posredmano oslobadjanje
medijatora iz mast celija iii kroz aktivaciju komplementa. Alergenski agensi nisu ograniceni samo na
intravenske lekove iii tecnosti, vee obuhvataju i druge supstance koje se koriste u toku operacije kao sto su
kozni deziticijensi. rukavice od lateksa i kateteri. Misicni relaksansi i lateks cine najcesce uzrocnike anatilakse
tokom perioperativnog perioda. Biage reakcije se tesko mogu razlikovati od nezeljenih efekata lekm a iii
anestezije per se; npr, prolazno crvenilo na kozi iii hipotenzija \ idjena kod upotrebe mivacuriuma. Medjutim.
ako postoji sumnja, neophodno je pacijenta podHgnuti ispitivanju. jer bi ponmna ekspozicija mogla dm esti
do katastrofe. Pacijent sa sumnjom na alergijsku reakciju semora ispitati radi pokusaja utHdji\anja pravog
uzrocnika reakcije. Ukoliko je neophodno. mogu se raditi provokacioni iii kozni testm i pod nadzorom
imunologa/alergologa. Anatilakticke reakcije je neophodno brzo prepoznati i tretirati. a pacijentu se savetuje
nosenje medicinske dokumentacije sa upozorenjima o tipu preosetljivosti na odredjene agense.
Kljucne reci: anestetici, misicni relaksansi, opioidi. lateks, hipnotici
UVOD
Reakcije rane preosetljivosti su prepoznate kao najcesci uzrocnici morbiditeta i sm11nih ishoda
u anestezioloskoj praksi [I]. Ove reakcije mogu biti iii imunski posredovane (alergijske) iii neimunski
posredovane (pseudoalergijske iii anafilaktoidne) [2]. Oko 60% -70% reakcija rane preosetljivosti koje
se odvijaju tokom anestezije su posredovane imunoglobulinima E ( IgE ). Mortalitet udruzen sa ovim
tipom reakcije varira od 3% do 9%. Neuromisicni blokatori cine 63% reakcija. lateks 14%. hipnotici
'\: 2015 Klinick1 ccntar Srhiic. llc<ll!rad
7%. antibiotici 6%, zamenici plazme 3%, i morfinu slicne supstance 2%. Reakcije kasne preosetljivosti
uzrokovane agensima koji se koriste tokom anestezije su manje zastupljene. One su opisane uglavnom
kod primene lokalnih anestetika. heparina, antibiotika. antiseptika. i supstanci kao sto su jodna
r lntravenski anestetici- sporodelujuCi Benzodiazepini (BZ)
kontrastna sredstva.
Klasifikacija agenasa koji se koriste tokom opste anestezije je prikazana na Tabeli 1.
Pre same anestezije (preoperativno ), u zavisnosti od vrste operacije. koriste se antiholinergici
kao sto su atropin sui fat iii skopolamin, radi redukcije salivacije i bronhosekrecije. Atropin se takodje
moze koristiti i po zavrsetku operacije, u kombinaciji sa neostigminom, za otklanjanje paralize izazvane
neuromisicnim blokatorima koji se daju po uvodu u anesteziju. Smatra se da je prevalence teskih
alergijskih reakcija na atropin veoma niska. Alergijsko testiranje se moze vrsiti subkutanim injekcijama,
patch testom iii drugim metodama [3].
Tabela 1. Klasifikacija
Opsta anestezija anesthesia
~--------------------~------------------
Anafilaksa na benzodiazepine ( BZ) je ekstremno retka. Diazepam je rastvoren u propilen
glikolnoj bazi. cineci ga verovatno vecim prouzrokovacem anafilakse u odnosu na midazolam.
Metabolit desmetildiazepam je odgovoran za ukrstenu reaktivnost sa drugim benzodiazepinima.
Midazolam nema metabolite, i smatra se imunoloski najsigurnijim benzodiazepinom.
Opioidi
Anafilakticke reakcije na opioide su retke [5]. Tercijarna aminska struktura morfina, kodeina i
meperidina predisponira mast celijsku degranulaciju sa oslobadjanjem histamina. pri cemu je meperidin
najcesci prouzrokovac ovih reakcija. To moze dovesti u zabunu tumacenje rezultata koznog testa
prilikom trazenja okrivljenog opioida. Ipak, IgE antitela na morfin i meperidin su bila detektovana, a
i kozni test je bio pozitivan. Medjutim, morfin i meperidin uzrokuju oslobadjanje hi stamina kada se
apliciraju u kozu, te mogu dovesti u zabunu rezultate pozitivnog koznog testa.
Fentanil pripada grupi fenilpiperidina i ne uzrokuje neimunolosko oslobadjanje histamina, a
postoji i par prijavljenih slucajeva sa IgE posredovanom anafilaksom na fentanil. Ukrstena reaktivnost
izmedju razlicitih opioida iste familije postoji, ali ne izmedju derivata fenilpiperidina (fentanil,
sufentanil, alfentanil, ramifentanil).
Kozni prick test se nije pokazao korisnim za validaciju alergije na opioide. Placebo kontrolisane
provokacije se moraju koristiti za pomoc u dijagnozi.
Brzodelujuci intravenski anestetici kao sto je etomidat, imidazolski derivat: i sporodelujuci kao
sto su ketamin, fenilciklidinski derivat, isto kao i midazolam, kratkodelujuci imidazolbenzodiazepin.
su retki izazivaci alergijskih reakcija [6].

Neuromisicni relaksansi (blokatori) (NMB)

Etar
Halotan NMB mogu ucestvovati u reakcijama rane preosetljivosti. Oni su podeljeni u tri grupe:
Enfluran depolarizirajuce (suksametonijum), nedepolarizirajuce (benzilizokinolinium: atrakurijum,
Isofluran Propofol
cisatrakurijum, d-tubokurarin) i aminosteroidalne agense (rokuronijum, pankuronijum). Prema
Destluran Etomidat
Sevotluran Droperidol ucestalosti alergijskih reakcija koje mogu izazvati, neuromisicni blokatori se dele na one sa visokom
Metoxyf1urane frekfencom alergijskih reakcija, ukljucujuci suksametonijum i rokuronijum: one sa srednjom
frekfencom kao sto su vekuronijum i pankuronijum: kao i one sa niskom ucestaloscu alergijskih
reakcija ukljucujuci atrakurijum, mivakurijum i cisatrakurijum [7]. Iako prva ekspozicija NMB moze
prouzrokovati senzibilizaciju sa tipom I reakcije u toku sledece izlozenosti, vecina reakcija na NMB
Intravenski indukcioni anestetici- brzodelujuCi se desava i bez prethodne izlozenosti specificnom agensu. Siroko rasprostranjene kucne hemikalije
Propofol (alkilfenol) je odgovoran za 1. 2% do 2% svih peri-operativnih anafilaktickih reak- (samponi, deterdzenti, paste za zube ), cak i opioidi, dele kvaternernu amonijum grupu u odgovarajucoj
cija. Sadasnji pripravci u emulziji od sojinog ulja, album ina jaja i glicerola mogu sugerisati oprez molekularnoj strukturi jezgra, koja je odgovorna za ukrstenu senzitivnost sa neuromisicnim
kod pacijenata sa alergijom na jaja iii soju, ali ne postoji evidencija koja pokazuje povecani rizik relaksansima. U Norveskoj, gde je pholocodeine (opioid koji suprimira kasalj) direktno dostupan (bez
od anafilakse u ovoj populaciji. Izopropil grupe prisutne u produktima za negu koze mogu indu- lekarskog recepta), postoji neuobicajeno visoka incidence alergija na NMB [8].
kovati IgE senzibilizaciju sa posledicnom ukrstenom reakcijom sa izopropil grupom molekula Ukrstena preosetljivost izmedju razlicitih relaksanasa je cesta. Studije koje su proucavale
propofo la [4]. strukturu molekula, ustanovile su da kvaternerni i tercijarni amonijum joni predstavljaju glavne
Incidenca alergije na hipnoticki agens tiopenton (kratkodelujuci barbiturat) je 1:30000, ali kako komponente alergenskih mesta na reaktivnim lekovima. Prisustvo specificnih IgE na kvaternerne
se sve redje koristi, izvestaji o reakcijama su vrlo retki. Ukrstena reaktivnost sa drugim barbituratima amonijum jone se moze detektovati nekoliko godina nakon reakcije rane preosetljivosti na NMB [9].
kao sto je pentobarbiton, fenobarbiton, barbiton i metoheksital moze biti prisutna. lgE na kvaternerni amonijum jon se detektuje kod 3%-10% tolerisucih pacijenata/kontrola bez

c 201 'i Klinicki ccntar Srhiie. Reograd ~ 2015 Klinicki centar Srhije. Beograd ()5
ACTA CLI:\IC A Vol. 15 XcJ

I

prethodnih reakcija. sto ogranica\ a specificnost. S druge strane. pokazano je da 65%-88% pacijenata
sa hipersenzitivnim reakcijama imaju 0\ a anti tela.
Dijagnoza reakcija rane preosetljivosti se bazira na kombinaciji klinickih znakova ..m~renJU
.
r
I
medijatora (kao sto je mast celijska triptaza. koja dostize S\Oj najvisi ni\ o u plazmi nakon pnbhzno 1
h). i izvodjenjem a1ergijskog koznog testa. laboratorijskih testova, i kada je moguce. provokacionog
testa. Za anesteziologa. alergijski test kao zlatni standard se ne moze normalno sprovesti zbog
fannakoloskih efekata O\ ih lekova. Stoga je jedino moguce pokazati senzibilizaciju na lek indirektno,
npr pozitivnim koznim testom ili prisustvom specificnih IgE bez konacne potnde. Oetekcija IgE
antitela na kvaternerne amonijum jone ostaje veoma korisna za dijagnozu. ali ovaj esej nije zamena
za kozno testiranje. Rane hipersenzitivne reakcije na anesteticke lekove se otkrivaju koriscenjem
koznog prick testa (KPT), intradennalnog testa (lOT), ili oba. sa komercijalnim ra~tvorima. Oni mogu
biti cisti ili razblazeni u tizioloskom rastvoru ili feno1u. Senzitivnost KPT je manJa u odnosu na lOT.
Rezultat KPT vodi izboru prve koncentracije za lOT. Kada je KPT negativan, lOT testiranje zapocinje
sa 1/1000 razblazenja datog NMB. Ukoliko je lOT negativan, naredna koncentracija ( 10 puta jaca) se
koristi u 20 minutnim intervalima izmedju svakog testa. Maksimalna koncentracija se ne sme
prekoraciti zbog izbegavanja lazno pozitivnog nalaza. Pozitivan rezultat ~~Ts~ definise kao ~ojav~,
nakon 20 minuta. papule dijametra 3 mm veceg od negativne kontrole III dtJametar od naJmanJe
polovine dijametra papule pozitivne kontrole. Intradermalni test se Hsi ubrizgavanjem 0. 02 do 0, 05
ml razblazenog komercijalnog preparata u derm. Ovo je dovoljno da izazove injekcionu papulu ne
vecu od 4 mm. Kriterijum za pozitivan 10 test je pojava papule (otoka) dijametra najmanje 8 mm
nakon 20 min uta, a koja je takodje najmanje dvostruko veca od otoka izazvanog injekcijom.
Postoji obaveza ispitivanja ukrstene senzitivnosti sa drugim neuromisicnim blokatorima u slucaju
pozitivnog KPT ili lOT za doticni neuromisicni blokator. Potencijalna ukrstena senzibilizacija se moze
ispitati upotrebom s\ ih drugih komercijalnih dostupnih NMB, uzimajuci u obzir potrebu za
izbegavanjem maksimalne preporucene koncentracije leka. Preporuka je ispitati ukrstenu senzitivnost
sa novim neuromisicnim blokatorima u slucaju prethodne anafilakticke reakcije na NMB tokom
anestezije, obezbedjujuci potvrdu rezultatima pozitivnog koznog testa [ 10].
Aktuelni dostupni celularni eseji (testovi) su testovi aktivacije bazofila (pomocu flow citometrije ),
test oslobadjanja histamina iz leukocita, test oslobadjanja leukotrijena (celijski antigen stimulacioni
test). Celularni eseji se izvode kada su rezultati koznog testa teski za interpretaciju (kao sto je slucaj
sa pacijentima koji imaju dermografizam, veoma mladi i stariji pacijenti. pacijenti sa izrazenim
atopijskim koznim lezijama, ili pacijenti koji uzimaju lekove sa antihistaminergickim efektima, kao
sto su antidepresivi i antihistaminici koji sene mogu obustaviti). U slucaju rane hipersenzitivne reakcije
na NMB, celularni eseji mogu potvrditi odgovornog agensa, cak i kada je kozni test negativan. Postoji
teskoca za definitivnom identitikacijom leka odgovornog za ne-IgE posredovanu reakciju zbog toga
sto nema odgovarajuceg dostupnog testa.
Medju NMB, benzilizokvinoliniumi kao sto su atrakurijum i mivakurijum predstavljaju histamin-
oslobadjajuce lekove. Zbog mogucnosti sistemskog prosirivanja reakcije, pametno je izbegavati ove
lekove kod osoba sa atopijom. Medjutim cisatrakurijum, izomer atrakurijuma, nije povezan sa
oslobadjanjem hi stamina, iako deli istu benzilisokvinoliniumsku strukturu [ 11].
Ukoliko pacijent ima deticijenciju pseudoholinesteraze, jedan od agenasa koji se koriste tokom
anestezije, kao sto jc sukcinilholin. se moze razgradjivati veoma sporo. i moze trajati vrlo dugo, satima,
umesto minutima, ali to ne znaci postojanje preosetljivost tj alergije na taj agens.
< l()l.; Klinit'ki ccntar <;rhiic. lk<H!rad
66 ACTA CLI~ICA Vol. 15 X".~
,
LATEKS
Lateks je mlecni biljni sok dobijen iz kaucukovog drveta (Hevea brasiliensis). Primamo se sastoji
od cis- I. 4- poliizoprena. benignog organskog polimera koji doprinosi jacini i elasticnosti lateksa.
I
Takodje se sastoji od velikog broja secera. lipida. nukleinskih kiselina, i visoko alergenih proteina.
Nakon sakupljanja se centrifugira radi dobijanja 60% su\ e gume. Yulkanizacija, dodavanje
antioksidansa kao i drugih supstanci preveniraju koagulaciju. i daju lateksu elasticitet [ 12]. Lateks je
fleksibilan, elastican i relativno jeftin material koji se koristi u brojnim zdravstvenim i potrosackim
produktima. On formira efikasnu barijeru protiv infektivnih organizama. i koristi se u medicinskim
proizvodima kao sto su hirurske rukavice. delovi katetera. ventilacioni baloni. respiratorni i intravenski
kateteri. Takodje se koristi i za druge proizvode ukljucujuci balone. kondome. dijafragme, rukavice,
djonova za tenske patike. cucle, igracke, gumena creva i automobilske gume.
Prirodni lateks predstavlja potentni alergen (njegovi alergeni variraju u alergenskom potencijalu),
koji godinama unazad predstavlja vazan zdravstveni problem. Sastoji se od panalergena i konstitutivnih
alergena. Takodje se alergeni stvaraju tokom procesa prerade gume. Do danas su utvrdjeni sledeci
alergeni Hev b l i 3- glavni alergeni kod spine bitide: Hev b 5 i 6- glavni alergeni kod zdra\·stvenih
radnika: Hev b 2, 4. 7. i 13- sekundarni ali relevantni alergeni kod zdravstvenih radnika: Hev b 6. 02
i 7- verifikovani kod ukrstene reaktivnosti sa vocem: Hev b 8, 11. i 12- panalergeni sa nepoznatom
ukrstenom reaktivnoscu na voce [ 13 ).
Preosetljivost na lateks je drugi po redu uzrocnik intraoperativne anatilakse, posle misicnih
relaksanasa. Alergija na lateks je prisutna kod 1-5% opste populacije. Osobe sa povecanim rizikom za
razvoj alergije na lateks ukljucuju: zdravstvene radnike kao i one koji cesto nose rukavice od lateksa
(prevalenca 8-12% ), osobe sa prethodnim visestrukim operacijama ( 10 iii vise). dec a sa spinom
bitidom (prevalenca 20-68%), osobe cesto izlozene prirodnom gumenom lateksu. ukljucujuci radnike
u proizvodnji gume ( 10%), osobe sa drugim alergijama, (kao sto je alergijski rinitis) iii alergija na
odredjenu hranu [ 14].
Preosetljivost na lateks nastaje kao rezultat direktnog kontakta sa proizvodima od prirodne gume.
Inhalacija cestica lateksa je cest nacin nastajanja senzibilizacije. Mnoge medicinske rukavice su
oblozene talkom, sto im omogucava lakse stavljanje i skidanje. Talk absorbuje protein lateksa. potom
ih raznosi vazduhom do disajnih puteva, a preosetljivost je cesca kod osoba sa atopijskom konstitucijom.
Rani ili I tip preosetljivosti su reakcije koje nastaju imunoglobulinima E (lgE)-posredovanim odgovorom
na protein lateksa. i mogu se rangirati od urtikarije do anafilakse (soka). Tip I reakcije semora razmotriti
kod pacijenata koji imaju rane kozne promene nakon kontakta sa rukavicama od lateksa. Kada imunski
sistem detektuje alergen, dolazi do produkcije antitela iz klase IgE, uz zapocinjanje oslobadjanja
hemijskih supstanci unutar organizma. Jedna od supstancije je histamin. Histamin je delimicno
odgovoran za crvenilo, svrab i oticanje koje se desava u kozi tokom alergijske reakcije. i dovodi do
pojave simptoma urtikarije, rasa, curenja iz nosa, otoka kapaka. Histamin takodje moze dovesti do
ote.lanog disanja, au najtezim slucajevima i do soka sa padom krvnog pritiska, ubrzanog pulsa i oticanja
tkiva. Alergijske reakcije na 1ateks se rangiraju od blagih do veoma ozbiljnih. Svake godine postoji
stotine slucajeva anafilakse, po zivot opasne alergijske reakcije, zbog alergije na lateks. Tezina alergijske
reakcije na lateks se moze pogorsavati sa ponavljanim izlaganjem supstanci.
Kasni tip (tip IV) hipersenzitivne reakcije (Langerhansove celije procesuju antigene i prezentuju
ih kutanim T celijama),je obicno uzrokovan hemikalijama, akcelerantima i antioksidantima u rukavicama.
a ne samim lateksom. Ovo dovodi do kasnije pojave simptoma kontaktnog dermatitisa (nekoliko sati do
67
.\CT.\ Cll'\lC.\ Vol. 15 .'\·.'
 r

48 sati nakon kontakta), sto je tipicno za tip IV reakcije. Prikazi slucajeva sa IV tipom preosetljivosti na obezbediti vestacko disanje i intravenski pristup u uslovima bez lateksa. Neophodna je dobra edukacija
Jateks su retki. Procenjeno je da oko 50% !judi sa alergijom na lateks ima i druge tipove alergija. radi izbegavanja buzducih ekspozicija. Izbegavati hranu koja ima ukrstenu reaktivnost sa lateksom [ 16].
Reakcije na produkte lateksa prikazani su na Tabeli 1. Tip I reakcije se tretira kao i bilo koja druga sistemska alergijska reakcija. Kamen temeljac
Tabefa -·7 Reakcije na produkte lateksa tretmana je upotreba epinefrina (adrenal ina) i H 1 antihistaminika. Sistemskikortikosteroidi i H2
blokatori mogu biti od koristi.
Tip reakcije I
Simptomi uzrocnik Vreme pojavljivanja
Za sada nema specificne imunoterapije koja se pokazala efikasnom, te su potrebna dopunska
Urtikarija istrazivanja.
(lokalna iii generalizovana),
Rana preosetljivost Ran a Tip IV reakcije (lokalizovani kontaktni dermatitis) se moze tretirati topikalnim steroidima i
nauzeja, povracanje, omaglica, Lateks
(tip I) (unutar minuta) edukacijom radi izbegavanje buducih ekspozicija.
rinitis, konjunktivitis, bronhos-
pazam, anafilakticki sok
Kasna preosetljivost iii Odlozena-kasna (nekoliko LITERATURA:
Papulami. pruriticni ras: Hemikalije
kontaktni dermatitis sati do 48 sati nakon
vezikule; bule u lateksu I. Mertes PM, Laxenaire M. Allergy and anaphylaxis in anaesthesia. Minerva Anestesiol 2004;
(tip IV) kontakta)
Iritantni kontaktni dermatitis Hemikalije Postepeno 70:285-91.
Suva, ispucala, iritirana koza
(neimunski) u lateksu (za nekoliko dana) 2. Birnbaum J, Porri F, Prada! M, Charpin D, Vervloet D. Allergy during anaesthesia. Clinical and
Experimental Allergy 1994; Volume 24: pages 915-921.
Odredjeno voce i povrce kao sto su banana, kesten, kivi, avokado i paradajz, mogu prouzrokovati 3. Robenshtok E, Luria S, Tashma Z, Hourvitz A. Adverse Reaction to Atropine and the Treatment of
alergijske simptome kod nekih osoba sa preosetljivoscu na lateks (poznato kao lateks-voce sindrom). Organophosphate Intoxication. IMAj 2002; Vol 4: 535-539. 4. Dippenaar JM, Naidoo S. Allergic
Zbog potencijalno veoma ozbiljnih alergijskih reakcija, adekvatna dijagnoza na lateks je od reactions and anaphylaxis during anaesthesia. Review Article. Current Allergy & Clinical Immunol-
velikog znacaja. · ogy March 20 15; Vo128: No 1.
Dijagnoza: ne postoji standardizovani protokol za testiranje preosetljivosti na lateks. Kompletna 5. Baldo BA, Pham NH. Histamine-releasing and allergenic properties of opioid analgesic drugs: resolv-
anamneza je veoma vazna i od velike pomoci, ali nije dovoljna za dijagnozu preosetljivosti I tipa na ing the two. Anaesth Intensive Care. 2012 Mar; 40(2):216-35.
lateks. Kozni prick testje najsenzitivniji test koji potvrdjuje ranu preosetljivost (tip I reakcije) [15]. 6. Stephanie SF Fischer. Anaphylaxis in anaesthesia and critical care. Current Allergy & Clinical im-
Standardizovani ekstrakti mogu obezbediti senzitivnost od 93% sa specificnoscu od 100%. munology August 2007; Vol 20: No. 3
Merenje in vitro nivoa lateks-specificnih serumskih IgE se smatra najkorisnijim testom za
7. Porri F, Lemiere C, Birnbaum. J, Guilloux J, Lanteaume L, Didelot Ret a!. Prevalence of muscle
potvrdu suspektne teske alergije, jer ne postoji rizik od nastajanja anafilakse. Senzitivnost i specificnost relaxant sensitivity in a generalpopulation: implications for a preoperative screening. Clinical and
IgE testiranjaje varijabilna (50 do 90% i 80 do 87% ). Experimental Allergy 1999; Volume 29: pages 72-75.
Provokacioni test sa rukavicom- "rukavica provokacioni test, "iako nije test prvog izbora, je
8. Florvaag E, Johansson SG, Irgens A, de Pater GH. IgE-sensitization to the cough suppressant phol-
koristan kada je anamneza neusaglasena sa rezultatom IgE. U toku testa, pacijent nosi jedan prst od codine and the effects of its withdrawal from the Norwegian market. Allergy 20 II: 66:955-60.
lateks rukavice dok lekar posmatra reakciju. Ukoliko nema urtikarije nakon 15 minuta, povecava se
9. Chacko T, Ledford D. Peri-anesthetic anaphylaxis. Immunol Allergy Clin N Am 2007; 27: 213-230.
zona (povrsina) ekspozicije. Test se zakljucuje ili kao pozitivan, ukoliko se javi urtikarija, ili kao
I0. Mertes PM, Malinovsky JM, Jouffroy L, and the Working Group of the SFAR and SFA and W Ab-
negativan ukoliko je pacijent u mogucnosti da nosi celokupnu rukavicu u toku 15 minuta bez reakcije.
erer, I Terreehorst, K Brockow, P Demoly, for ENDA and the EAACI Interest Group on Drug.
Zbog varijacija sadrzaja lateksa u rukavici, ovaj test ima razliCitu senzitivnost i moze biti nebezbedan
Reducing the Risk of Anaphylaxis During Anesthesia: 2011 Updated Guidelines for Clinical Prac-
u izrazito preosetljivih osoba. tice. Allergy J Investig Allergol Clin Immunol20 11; Vol. 21 (6): 442-453.
Kozni patch test je senzitivan za dijagnostikovanje tipa IV kasne preosetljivosti na aditive u gumi
11. Ebo D, Fisher M, Hagendorens M, eta/. Anaphylaxis during anaesthesia: diagnostic approach. Al-
(npr. hemijski akceleratori, antioksidansi). Izvodi se nanosenjem uzorka alergena na intaktnu kozu lergy 2007; 62: 471-487.
prekrivenog zastitnom oblogom. Nakon uklanjanja uzorka, proverava se reakcija na kozi pacijenta na
12. Subramaniam A. The chemistry of natural rubber latex. In: Latex Allergy. Ed: Fink NJ. Immunol
30 minuta, 24 sata, i 48 sati.
Allergy Clin N Am 1995; 15:1-21.
Specificni bronhijalniprovokacioni test se izvodi razlicitim metodana, konjunktivalni I nazalni
provokacioni test se takodje koriste, mada su generalno od manjeg znacaja. 13. Krurup Vp, Fink JN. The spectrum of immunologic sensitization in latex allergy. Allergy 200 I; 56: 2-12.
Tretman: uporiste terapije kod alergije na lateks je u tretmanu prisutne reakcije i prevenciji buduCih 14. Hepner DL, Castells MC. Latex allergy: an update. Anesth Analg 2003; 96:1219-29.
reakcija. Ukoliko postoji sumnja na tip I preosetljivosti na lateks, sve procedure treba da se izvode sa 15. Turjanmaa k. diagnosis of latex allergy. Allergy 200 I; 56: 810-3.
instrumentima i uredjajima bez lateksa kao i sa dgovarajucom zastitnom odecom. Radi smanjivanja 16. Agustin P, Blanco C, Cabailes N, Dominguez J, de Ia Hoz B, Igea JM, eta!. Latex Allergy: Position
rizika za pacijenta koristiti visoko kvalitetne rukavice bez lateksa. Za visoko rizicne pacijente je potrebno Paper. J Investig Allergol Clin Immunol 2012; Vol. 22(5): 313-330.

AliA l LINilA \ol. 15 Jli~.l <· 201' Klinicki centar <irhije. Reograd © 20 IS Klinicki centar Srbiie. Beograd
.\lT\ CLI:\IC.\ \ol. 15 .\',;
 DRUG ALLERGY r
i Noeuromuscular bl~ckers (NMBs) account for 63% of reactions, latex 14%, hypnotics 7%, antibiotics
6%, plasma substit~tes 3%, and morphine-like substances 2%. Delayed hypersensitivity reactions
DRUG-INDUCED ALLERGIC REACTIONS IN PERI OPERATIVE PERIOD caused ~y anesth.etic agents are less frequent. They are reported mostly association with local
anesthetics, hepann, antibiotics, antiseptics, and substances such as iodine contrast media.
AND DURING DIAGNOSTIC PROCEDURES
Classification of agents used during anesthesia is present on Table 1.
GENERAL ANESTHETICS, MUSCLE RELAXANTS AND LATEX Before ~he anesthesia (preoperative), depending on the type of surgery, are used anticholinergics
such as atropme sulfate or scopolamine, for decreasing the production of saliva and secretions of the
Aleksandra Peric-Popadic 1· 2
ainvay. ~tr~pin~ can also be used, and upon completion of the operation, in combination with neostigmine,
1
Medical Facul(r University qfBelgrade
for the ehmmat10n of the paralysis induced by neuromuscular blockers are administered after the induction
-' Clinicfor Allergology and Immunology, Clinical Centre of'Serbia
of anes~hesi~. Since the prevale~ce of severe allergy to atropine is probably very low, screening of large
Author:\· address: populations m order to trace patients with this allergy is not warranted. Allergy testing for atropine can be
done by subcutaneous injection of atropine solution, patch tests, or other testing methods [3].
Associate Prolessor Aleksandra Peric-Popadic
Clinicfor Allergology and Immunology, Tahlc /. Classification olagcnts used during anesthesia
Koste Todorovica 2. II 000 Belgrade, Serbia
E-mail: popealeksandra@yahoo.com
General anesthesia
ABSTRACT

Anesthesia represents a pharmacologically unique situation, during which patients are exposed to ~------------------ ---

multiple foreign substances including anesthetics, which can produce immediate hypersensitivity reactions
or anaphylaxis. Anaphylaxis reaction to anesthetic agents is fortunately rare, ranging from 1 in 5, 000 to lnhalational
Intravenous
25, 000 cases. The severity of the reaction may vary but features may include rash, urticaria, bronchospasm, ------ __l_ _______ --
hypotension, angioedema, and vomiting. Anaphylaxis is the most severe immune-mediated reaction; it
generally occurs on reexposure to a specific antigen. Anaphylactoid reactions occur through a direct non-
Slower acting Inducing agents
immunoglobulin E-mediated release of mediators from mast cells or from complement activation. Allergenic
raoidlv acting
agents are not limited to intravenous drugs or fluids, but include other substances used in the operating I I
room such as skin disinfectants, latex gloves and catheters. Muscle relaxants and latex account for most Nitrous Ether Dissociative Opioid Benzodiazepines
cases of anaphylaxis during the perioperative period. Mild reactions may be difficult to distinguish from oxide rlnrJIQesirJ Thiopentone sod_
Halothane anesthesia
well-described side-effects of drugs, or anaesthesia per se; for example, the transient skin flushing or
Zenon Methohexital sod
hypotension seen with mivacurium. However, where doubt exists, it would seem prudent to refer these
patients for investigation as subsequent re-exposure may be disastrous. Patients who are suspected of an
Enflurane

lsoflurane
Ketamine I .. I_F_e_nt-an_v_l..... Diazepam
Propofol
allergic reaction should be referred for further investigation to try to determine the exact cause. If necessary, Lorazepam
Etomidate
this may involve provocation testing or skin prick testing and patients should be referred to local Desflurane
Midazolam
immunologists. Anaphylaxis needs to be promptly recognised and managed and patients should be advised Droperidol
Sevoflurane
to wear a medical emergency identification bracelet or similar once they recover.
MPtoxvflurrJn
Key words: anesthetics, muscle relaxants, opioids, latex, hypnotics

INTRODUCTION Intravenous (inducing) rapidly acting anaesthetics

Immediate hypersensitivity reactions have been recognized as one of the most common causes Propofol (alkyl phenol) is responsible for I. 2% to 2% of all peri-operative anaphylactic reactions.
of morbidity and death in anesthesiology practice [I]. They can be either immune mediated Current formulation in an emulsion of soy oil, egg albumin and glycerol may suggest cautious use in
(allergic) or non-immune mediated (pseudoallergic or anaphylactoid reactions) [2]. About 60%- patients with egg or soy allergy, but there is no evidence to show increased risk of anaphylaxis in this
70% of the immediate hypersensitivity reactions that occur during anesthesia are mediated by population. Isopropyl groups present in skin care products may induce IgE sensitisation '' ith
immunoglobulin lgE. The mortality associated with this type of reactions varies from 3% to 9%. subsequent cross reaction with the isopropyl groups of the propofol molecule [4].
I
l. 70 ACTA CLINICA \'ol. 15 N~3 < 2015 Klinicki centar Srbije. Beograd L 2015 Klinicki centar Srhijc_ Hcngrad
\l 1.\ ll.l\ll .-\ \ol. 15 su;
 The incidence of hypnotic agent thiopentone (a short-acting barbiturate) allergy is 1:30000, but
since it is rarely used these days, reports of reactions to it are very rare too. Cross-reactivity with other
barbiturates such as pentobarbitone. phenobarbitone, barbitone and methohexital may be present.
Intravenous slower acting anesthetics Benzodiazepines (BZ)
Anaphylaxis to benzodiazepines (BZ) is extremely rare. Diazepam is dissolved in a propylene
glycol base, making it more likely to cause anaphylaxis than midazolam. The desmethyldiazepam
metabolite is responsible for cross reactivity with other BZ's. Midazolam has no metabolites, and is
considered the immunologically safest BZ.
Opioids
Anaphylactic reactions to opioids are rare [5]. The tertiary amine structure of morphine, codeine
and meperidine predisposes to mast cell degranulation with histamine release, with meperidine being
the most common offender. This may confound the results of skin testing when searching for an
offending opioid. IgE antibodies to morphine and meperidine have been detected, and skin tests have
been reported to be positive. However, morphine and meperidine cause histamine release when applied
to the skin and may confound the results of positive skin tests.
Fentanyl belongs to the phenylpiperidine group and does not cause nonimmunological histamine
release, but there are a few reported cases of IgE mediated anaphylaxis to fentanyl. There is cross-
reactivity between different opioids of the same family, but not between phenylpiperidine derivatives
(fentanyl, sufentanil, alfentanil, remifentanil).
Skin-prick testing has not been found to be useful for validating opioid allergy. Placebo controlled
challenges can be utilised to aid diagnosis.
Intravenous rapidly acting anesthetics like etomidate, an imidazole derivative, and slower acting
like ketamine, a phenylcyclidine derivative, as well as midazolam, a short-acting imidazobenzodiaz-
epine, are rarely implicated in allergic reactions [6].
Neuromuscular relaxants (blockers) (NMBs)
NMBs may precipitate an immediate hypersensitivity reaction. They are divided in three groups:
depolarizing (suxamethonium), non-depolarizing (benzylisoquinolinium: atracurium, cisatracurium,
d-tubocurarine) and aminosteroidal agents (rocuronium, pancuronium). In terms of the number of
subjects exposed to NMBs, the drugs can be divided in those associated with a high frequency of
allergic reactions, including suxamethonium and rocuronium; those associated with an intermediate
frequency of allergy, including vecuronium and pancuronium; and those associated with a low
frequency of allergy, including atracurium, mivacurium and cisatracurium [7]. Although uneventful
first exposure to an NMBs may cause sensitisation with type I reaction at next exposure, most reactions
to NMBs occurs without previous exposure to the specific agent. Common household chemicals
(shampoo, detergents, toothpaste) and even opioids share the quaternary ammonium group in their
respective core molecular structure responsible for cross-sensitisation of the immune system. In
Norway, where pholocodeine (opioid cough suppressant)is available as an over-the-counter medicine,
there is an unusually high incidence of allergies to NMBs [8].
72· ACTA CLINICA Vol. 15 NQ3 L 2015 K1inicki centar Srbiie. Beo!!rad
Cross-sensitivity between different relaxants is frequent. Structure-activity studies have
established that quaternary and tertiary ammonium ions were the main component of the allergenic
sites on the reactive drugs. The presence of specific IgE to quaternary ammonium ions can be detected
several years after an immediate hypersensitivity reaction to a neuromuscular blocker [9]. IgE to
quaternary ammonium ions has been detected in 3%-10% of tolerating controls/patients with no
previous reactions. thus limiting specificity. On the other hand, 65%-88% of patients with
hypersensitivity reactions have been shown to have these antibodies.
The diagnosis of an immediate hypersensitivity reaction is based on a combination of clinical
signs, measurement of mediators (as mast cell tryptase, that after degranulation reach its peak level
in the plasma after approximately 1 h), and the performance of allergy skin tests, laboratory tests,
and, where possible, challenge tests. For anesthetics, gold standard allergy test cannot normally be
used because ofthe pharmacological effects of these drugs. Thus, it is only possible to demonstrate
sensitization to a drug indirectly, eg, by a positive skin test result or demonstration of specific IgE
with no final confirmation. Detection of IgE antibodies to quaternary ammonium ions remains very
helpful in diagnosis, but this assay is not a substitute for skin testing. Immediate hypersensitivity
reaction to anesthetic drugs is investigated using skin prick test (SPT), intradermal test (lOT), or
both, with commercial solutions. These may be pure or diluted in saline or phenol. The sensitivity
of SPT is inferior to that of IDT. The result of an SPT guides the choice of the first concentration
tested with IDT. When the SPT is negative, IDT testing starts at a I /1000 dilution of the stock
solution for neuromuscular blocking agents. If the IDT is negative, the subsequent concentration
( 10 times stronger) is used with a 20-minute interval between each test. The maximum
concentrations should not be exceeded in order to avoid the false positives featured. A positive SPT
result is defined as the appearance, after 20 minutes, of a wheal that has a diameter 3 mm greater
than that of the negative control or a diameter of at least half the diameter of the positive control
wheal. For IDT is necessary to ensure that the IDT extract is injected into the dermis in 0. 02 to 0.
05 ml of a diluted commercial solution in order to create a postinjection wheal of up to 4 mm in
diameter. The criterion for a positive IDT result is the appearance after 20 minutes of an
erythematous wheal (often pruritic), the diameter of which is at least equal to twice that of the
postinjection wheal.
It is mandatory to investigate cross-sensitivity with other neuromuscular blocking agents in the
case of a positive SPT or IDT result for a particular neuromuscular blocking agent. Potential cross-
sensitization should be investigated using all other commercially available neuromuscular blocking
agents, taking into account the need to avoid exceeding the maximum recommended concentrations.
It is recommended to investigate cross-sensitivity with the newer NMBs in the case of a previous
anaphylactic reaction to a neuromuscular agent during anesthesia, providing that this has been
confirmed by positive skin test results [10].
The currently available cellular assays are the histamine release assay, the basophil activation
test (by flow cytometry), and the leukotriene release test (cellular antigen stimulation test). Cellular
assays are performed when skin test results are difficult to interpret (as in patients with dennographism,
very young and elderly patients, patients with extensive atopic skin lesions, or patients on medication
with antihistaminergic effects, such as antidepressants and antihistamines which cannot be stopped).
In the case of an immediate hypersensitivity reaction to a NMBs, cellular assays may confirm
the responsibility of the agent, even when the skin tests are negative.
~· 2015 K1inicki ccntar Srbije. Beograd 71,
 It is difficult to definitively identify the drugs responsible for non-IgE mediated reactions because named immunoglobulin E ( IgE) is produced, triggering the release of chemicals within the body.
there are no specific tests available. Among the NMBs, benzylisoquinoliniums such atracurium and One chemical is histamine. Histamine is partly responsible for the redness, itching and swelling that
mivacurium are histamine-releasing drugs. This may extend systemically as welL so it is prudent to can occur in the skin during an allergic reaction. and it produces symptoms of hives, rashes, a runny
avoid these drugs in the atopic population. whereas cisatracurium, an isomer of atracurium, is not nose,. and \Vatery, swollen ~yes. Hista1_11ine can also lead to breathing difficulties and a severe allergic
associated with histamine release, even though it shares the same benzylisoquinolinium structure [II]. reactiOn called anaphylaxis that can mclude a sudden drop in blood pressure, an increase in pulse,
If patient knows to have pseudocholinesterase deficiency, it means that one of the agents used and tissue swelling. Allergic reactions to latex range from mild to very severe. Every year, there are
during anesthesia, called Succinylcholine, are broken down very slowly and may last for many, many hundreds of cases of anaphylaxis, a life-threatening allergic reaction, due to latex allergy. The
hours instead of minutes, but is not allergic to anesthetic agents. severity of allergic reactions to latex can worsen with repeated exposure to the substance.
Delayed type IV hypersensitivity reactions (Langerhans cells process the antigens and present
Latex them to cutaneous T cells), are usually caused by chemicals, accelerants, and antioxidants in the gloves
and not by the latex itself. This leads to a later onset of contact dermatitis symptoms (several hours to
Latex is a milky sap produced by rubber trees (Hevea brasiliensis). It is composed primarily
48 hours after contact), that are typical of type IV reactions. Case reports of delayed type IV reaction
of cis -I, 4-polyisoprene. a benign organic polymer that confers most of the strength and elasticity
to latex are rare. Approximately 50% of people with latex allergy have a history of another type of
of latex. It also contains a large variety of sugars, lipids, nucleic acids, and highly allergenic
allergy. Reactions to latex products are present on Table 2.
proteins. After harvesting (extracted by making cuts in the tree bark), the latex is centrifuged to
obtain 60% dry rubber. Vulcanization accelerators, antioxidants, and other substances are then Table 2. Reactions to Latex Products
added, to prevent it from coagulating [ I2], and to give latex its elastic quality. Latex is a flexible, Type of reaction Symptoms Cause Time of onset
elastic and relatively inexpensive material used in a number of healthcare and consumer products. Urticaria !
Immediate
It forms an effective barrier against infectious organisms, and is used to make hospital and medical (local or generalized), nausea, vomiting, Immediate
hypersensitivity Latex
items, such as surgical and examination gloves and some parts of anesthetic tubing, ventilation faintness, rhinitis, conjunctivitis, (within minutes)
(type I)
bags, respiratory tubing and intravenous lines. It is used in making other products, including bronchospasm. anaphylactic shock
balloons, condoms, diaphragms, rubber gloves, tennis shoe soles, nipples for baby bottles, toys, Delayed hypersensitivity Delayed
or contact dermatitis Papular, pruritic rash; vesicles; blisters Chemicals
(several hours to
rubber hoses and tires. (type IV) in latex 1

48 hours atter contact) i

Natural rubber latex represents a potent allergen (their proteins vary in their allergenic Chemicals
potential), which for many years had an important impact on occupational health problems. It has Irritant contact dermatitis Gradual
Dry, cracked, irritated skin
i

(nonimmune) in latex or I

panallergens and constitutive allergens. In addition, allergens are generated during the manufacturing
process. The allergens characterized to date are as follows: Hev b I and 3- main allergen in spina
bifida; Hev b 5 and 6- main allergen in health care workers; Hev b 2, 4, 7, and 13- secondary but
relevant allergen in health care workers; Hev b 6. 02 and 7- verified cross-reactivity with fruits; Hev
b 8, II, and 12- panallergens with unknown cross-reactivity with fruits [ I3]. A latex allergy is the
second cause of intraoperative anaphylaxis after muscle relaxants. Allergy on latex is present in
1-5% of the general population. People who are at higher risk for developing latex allergy include:
Health care workers and others who frequently wear latex gloves (prevalence 8-I2%), people who
have had multiple surgeries ( 10 or more), such as children with spina bifida (prevalence 20-68%),
people who are often exposed to natural rubber latex, including rubber industry workers ( 10%),
people with other allergies, such as hay fever (allergic rhinitis) or allergy to certain foods (14].
People can become sensitized to latex as a result of direct contact with natural rubber products.
Inhaling latex particles is a common way for health care workers to become sensitized to latex.
Many medical gloves are coated with cornstarch to make them easier to pull on and off. Cornstarch
absorbs the latex proteins, and then carries them into the air where they can be inhaled, with an
increased prevalence in atopic individuals. Immediate type I hypersensitivity reactions are
immunoglobulin E (lgE)-mediated responses to latex proteins, and can range from urticaria to
anaphylaxis. Type I reactions should be considered in patients who have immediate skin symptoms
on contact with latex gloves. When the immune system detects the. allergen, a type of antibody
hand washing (over several days)
Certain fruits and vegetables, such as bananas, chestnuts, kiwi, avocado and tomato can cause
allergic symptoms in some latex-sensitive individuals (it calls latex-fruit syndrome).
Given the potential for a very serious allergic reaction, proper diagnosis of latex allergy is
important.
Diagnosis: There is no standardized testing protocol for diagnosing latex allergy. A complete
history is important and often very helpful, but may not be sufficient for diagnosing a type I latex
allergy. Skin prick testing is the most sensitive test and would be considered the preferred test for
diagnosing type I immediate hypersensitivity [ 15]. Standardized extracts can provide a sensitivity of
93% with a specificity of I00% .
A measurement in vitro of latex-specific serum IgE levels is considered the most useful test for
confirming suspected severe allergy because there is no risk of anaphylaxis. The sensitivity and
specificity of IgE testing is variable (50 to 90 percent and 80 to 87 percent, respectively).
Glove provocation testing, or "glove challenge test, " is useful when the patient's clinical history
is incongruent with IgE results, although it is not considered a first-line test. During the test, the
patient wears one finger of a latex glove while the physician watches for a reaction. If there is no
urticarial reaction after 15 minutes, the exposed surface area is increased. The test concludes when
an urticarial response is identified (i. e., a positive provocation test), or when the patient is able to

74 ACTA CLINIC A \"ol. 15 Nu1 < 2015 Klinicki ccntar Srbiic. Beograd ~ 2015 Klinicki centar Srbije. Beograd 7::.
wear the full glove for 15 minutes with no reaction (i.e., a negative provocation test). Because of the
variation of latex content in gloves. this test has a varied sensitivity and could be unsafe in highly
sensitized persons.
Skin patch testing is a sensitive test for diagnosing type IV delayed reactions to rubber additives
(e. g.. chemical accelerators. antioxidants). It is performed by applying allergen samples to intact skin
and covering them with a dressing. After the patch is removed. the patient is checked for skin reaction
at 30 minutes, 24 hours. and 48 hours.
Specific bronchial challenge tests have been performed using different methods, and conjunctival
challenge and nasal challenge have also been used, although they are generally of little value.
Management: The mainstays of management oflatex allergy are treatment of the present reaction
and prevention of future reactions. If type I latex allergy is suspected, all procedures should be
performed with latex-free instruments, devices, and protective clothing. Use powder-free latex gloves
or, ideally, high-quality nonlatex gloves to minimize risk to patients. Latex-free resuscitation and
intravenous access equipment should be available for high-risk patients [16].
Latex allergies are best treated with patient education to avoid further exposure. Avoidance of
foods with cross-reactivity to latex. Type I reactions are treated as any other systemic allergic reaction.
The cornerstones of treatment are epinephrine and HI antihistamines. Systemic corticosteroids and
H2 blockers may be useful.
Specific immunotherapy must be further developed (no specific immunotherapy has been shown
to be effective).
Type IV reactions (localized contact dermatitis) can be treated with topical steroids and patient
education to avoid further exposures.
10. Mertes PM, Malinovsky JM, Jouffroy L, and the Working Group of the SFAR and SFA and W Ab-
erer. I Terreehorst. K Brockow, P Demoly, for ENDA and the EAACI Interest Group on Drug.
Reducing the Risk of Anaphylaxis During Anesthesia: /011 Updated Guidelines for Clinical Prac-
tice. Allergy J Investig All ergo! Clin lmmunol20 11; Vol. 21 (6): 442-453.
II. Ebo D, Fisher M, Hagendorens M, et al. Anaphylaxis during anaesthesia: diagnostic approach. Al-
lergy 2007; 62:471-487.
12. Subramaniam A. The chemistry of natural rubber latex. In: Latex Allergy. Ed: Fink NJ. Immunol
Allergy Clin N Am 1995; 15:1-21.
13. Krurup Vp, Fink JN. The spectrum of immunologic sensitization in latex allergy. Allergy 2001; 56:
2-12.
14. Hepner DL, Castells MC. Latex allergy: an update. AnesthAna1g 2003; 96:1219-29.
15. Turjanmaa k. diagnosis of latex allergy. Allergy 2001; 56: 810-3.
16. Agustin P, Blanco C, Cabanes N, Dominguez J, de Ia Hoz B, Igea JM, eta!. Latex Allergy: Position
Paper. J Investig Allergol Clin Immunol 20 12; Vol. 22(5): 313-330.

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2. Birnbaum J. Porri F, Prada] M, Charpin D, Vervloet D. Allergy during anaesthesia. Clinical and
Experimental Allergy 1994; Volume 24: pages 915-921.
3. Robenshtok E, Luria S, Tashma Z, Hourvitz A. Adverse Reaction to Atropine and the Treatment of
Organophosphate Intoxication. IMAj 2002: Vol 4: 535-539.
4. Dippenaar JM, Naidoo S. Allergic reactions and anaphylaxis during anaesthesia. Review Article.
Current Allergy & Clinical Immunology March 20 15; Vol 28: No 1.
5. Baldo BA, Pham NH. Histamine-releasing and allergenic properties of opioid analgesic drugs: re-
solving the two. Anaesth Intensive Care. 2012 Mar; 40(2):216-35.
6. Stephanie SF Fischer. Anaphylaxis in anaesthesia and critical care. Current Allergy & Clinical im-
munology August 2007; Vol20: No.3
7. Porri F, Lemiere C, Birnbaum. J, Guilloux J, Lanteaume L, Didelot Ret a!. Prevalence of muscle
relaxant sensitivity in a generalpopulation: implications for a preoperative screening. Clinical and
Experimental Allergy 1999; Volume 29: pages 72-75.
8. Florvaag E, Johansson SG, Irgens A, de Pater GH. IgE-sensitization to the cough suppressant phol-
codine and the effects of its withdrawal from the Norwegian market. Allergy 2011; 66:955-60.
9. Chacko T, Ledford D. Peri-anesthetic anaphylaxis. Immunol Allergy Clin N Am 2007: 27: 213-230.

76 '\CT'\ Cl I"JIC". Vol. I~'"'' ~: 2015 Klinicki centar Srhiie. Heograd 02015 Klinicki centar Srhiie. Reograd 77
ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA
ALERGIJSKE REAKCIJE IZAZVANE MEDIKAMENTIMA
U PERIOPERATIVNOM PERIODU I TOKOM DIJAGNOSTICKIH PROCEDURA
JODNA KONTRASTNA SREDSTVA
Mirjana Bogie
lvfedicinski.fakultet. Univer::itet u Beogradu
Klinika ::a alergologij"u i imunologij"u, Klini{ki centar Srbij"e
Adresa autora:
Profesor lvfi1jana Bogie
Klinika ::a alergologiju i imunologiju
Koste Todorovica 2. 11000 Beograd
E-mail: bogie. mil_jana1~gmail. com
ABSTRAKT
Sva jodna kontrastna sredstva (J KS) su poznata po tome sto mogu izazvati rane (<I sata) i kasne (>I sata)
hipersenzitivne reakcije. lako kod vecine ranih reakcija alergijska preosetljivost ne moze biti dokazana,
nedavne studije pokazuju da rana ozbiljna reakcija moze biti IgE posredovana, dok se cini da je vee ina kasnih
reakcija-egzantema, posredovana limfocitima. Pacijentima koji iskuse takvu reakciju se savetuje alergoloska
procena. Nekoliko istrazivaca je potvrdilo da je kozni test koristan u potvrdivanju preosetljivosti na JKS, pre
svega kada su u pitanju pacijenti sa kasnim koznim erupcijama. Ukoliko je pacijenta kod kojeg je potvrdena
alergija, neophodno ponovo izlagati JKS-u, moze se pokusati sa premedikacijom. Medutim, nijedna od ovih
mera predostroznosti, nije garancija da se reakcija nece ponoviti. Stoga je jasna potreba za vecim brojem
istrazivanja fokusiranih na patoloske mehanizme, dijagnosticko testiranje i premedikaciju kako bi se u
buducnosti sprecila preosetljivost uzrokovana jodnim kontrastnim sredstvima.
Kljucne reci: jodna kontrastna sredstva, rana reakcija, kasna reakcija, premedikacija, kozni testovi
UVOD
Nezeljeni efekti JKS-a mogu biti podeljeni na tri razlicita tipa: a) alergijske i b) nealergijske
hipersenzitivne reakcije prema definiciji Evropske akademije za alergologiju i klinicku imunologiju
[1] i c) toksicne reakcije [2].
Hipersenzitivne reakcije su iii rane reakcije koje se ispoljavaju do jednog sata po prijemu JKS-a,
iii kasne reakcije koje nastupaju nakon vise od jednog sata po izlaganju JKS-u [3]. Prijavljeno je da
se oko 70% ranih simptoma ispoljava 5 minuta nakon izlaganja JKS-u [4].
PREVALENCA REAKCIJA NA KONTRASTNA SREDSTVA
Blaga nezeljena dejstva kod ranog tipa pogadaju 3, 8-12, 7% pacijenata nakon i. v. aplikacije
visoko osmolarnog jonskog kontrasnog sredstva i 0, 7-3, 1% pacijenata poi. v. aplikaciji nisko
osmolamog nejonskog JKS [4]. Teske reakcije kod ranog tipa, prijavljene su kod 0, 1-0, 4% pacijenta
.\CTA CLI:-.:IC.\ \'ol. 15 Xc3
gd~ su ~potrebljena jonska kontrastna sredstva i kod 0, 02-0, 04% pacijenata u slucaju primene
neJonskih kontrastnih sredstava [4].
, lako su nezel~ena ~ejstva -~~d primene nejonskih JKS obicno manje teska nego u slucaju jonskih
JKS, s.topa.mort.aiiteta Je raziic1ta" za .o:·e dve \TSt~.kontrastnih sredstava. Procenjuje se da stopa
mortahteta Iz.nosi I: I 0~ 00~.[5]. Teske 1tatal.ne.reakciJe predstavljaju ozbiljan problem, imajuci u vidu
da se tokom Jedne godme, s1rom sveta oban nse od 70 miliona aplikacija JKS-a [6].
PATOFIZIOLOGIJA
Rane reakcije su barem delimicno povezane sa oslobadanjem histamina iz bazofila i mastocita
[7]. Do oslobadanja histamina dolazi zbog: a) direktnog efekta membrane na koji uticu osmolamost
JKS rastvora iii he~ijska struktura JKS molekula: b) aktivacije sistema komplemenata iii c) IgE
posredovanog mehamzma. Dokazi za lgE posredovane reakcije uglavnom se srecu kod retkih slucajeva
teskih reakcija [8].
Vecina kasnih reakcija koje se odnose na kozne erupcije, izgleda su povezane sa alergijskim
reakcijama posredovane limfocitima sto dokazuju: a) cesti pozitivni epikutani testovi i odgodene
reakcije intradermalnih testova [9]. b) prisustvo dermal nih limfocitnih infiltrata [I OJ, c) ponovna pojava
erupcija nakon provokacijskog testiranja [ I1], i sposobnost JKS-a da stimulise proiiferaciju perifemih
iimfocita kod pacijenata sa erupcijama izazvanim JKS-om [II].
FAKTORI RIZIKA
Najznacajniji faktori rizika u slucaju ranih reakcija preosetljivosti na JKS su prethodne rane
reakcije. Osoba koja je prethodno reagovala, ima 2I-60% povecan rizik za ponavljanje reakcije
prilikom ponovnog izlaganja istom iii slicnom jonskom JKS-u [ 12]. Kada pacijent sa prethodnom
reakcijom na jonsko kontrastno sredstvo posle toga bude izlozen nejonskom, zabelezeno je desetostruko
smanjivanje incidence teskih ponovljenih reakcija [ I2].
Ostali faktori rizika za teske, rane reakcije jesu teski slucajevi alergije, bronhijalna astma. srcanc
bolesti i tretman beta blokatorima [ 13].
Prijavljeni predisponirani faktori za kasne kozne reakcije su: prethodne nezeljene reakcije
izazvane JKS-om, nivo kreatinina u serumu >2. Omg/dl i istorija kontaktnih i alergija na lekove [ 14 ].
Drugi potencijalni faktori koji mogu uticati na tezinu reakcije su mastocitoza, virusne infekcije
u vreme izlaganja JKS-u, kao i autoimune bolesti poput sistemskog eritemskog lupusa [ 15]. .
KLINICKI SIMPTOMI
Klinicki simptomi hipersenzitivnih reakcija na JKS su nabrojani u tabelama I i 2. Pruritus i blaua
urtikarija su najcesce rane manifestacije, koje obuhvataju do 70% pogodenih pacijenata [ 16]. Tete
reakcije zahvataju respiratorni i kardiovaskularni sistem, dok su fatalne reakcije neposredne
anafilakticke reakcije [ 17].
Najucestalije kasne reakcije izavane JKS-om su makulopapulami ras koji se javlja u vise od 50<%
slucajeva [ 18]. Ostale ceste kasne reakcije su: eritem, urtikarija, angioedem, makulozni egzantem iii
kozna erupcija koja se siri [ 18]. Kasne reakcije su po tezini obicno blage do umerene, prolazne i
samoogranicavajuce. Medutim, u slucaju teskih koznih reakcija, poput Stivens-Dzonsonovog sindroma.
prijavljeni su slucajevi toksicne dermalne nekrolize i koznog vaskuiitisa [ 19].
~; 2015 Klinicki centar Srhiie. lko11rad
\l J..\LLI:--Jl,\ \ul. 15.\c_,
DIJAGNOZA RANIH HIPERSENZITIVNIH REAKCIJA atopicnih osoba, . nego . . nisu. atopicni [25] ·. Jos uvek niJ·e defin1·sana u1oga testova u kOJ1ma
. kod .onih koji ··
Utvrdivanje preosetlji\osti podrazumeva detaljnu istoriju bolesti i lekarski pregled, pracen nekom se os I.o.badaJKS
hIstamm kao 1ostahh m vitro testova akttvaci1·e bazofila u d1··Jagnos t"k · l ··
1 ovanJu a erg1JS 1
k"h
rea kCIJa na .
od sledecih procedura: laboratorijska ispitivanja, kozni testovi ina kraju provokacijski testovi [20].
In vivo testovi
Precizna identifikacija agensa odgovornog za preosetljivost je od presudnog znacaja za buduce
tretmane, kako bi se izbeglo dozivotno etiketiranje nekog kao ,alergicnog" bez valjanog razloga. .. Kozni . testovi.. Prick
. . kozni testovi
. . . i intradermalni
.. testovi se vee god1·nama konste · pn·1·k1 om
dtjagnostikovanJa
. • .
ramh• .
htpersenZitivmh
..
reakciJa na JKS '
ali su retko priJ·av11·1·van· ·t· ·
1 pozt tvm rezu 1tatt
·
Tahela I. Simptomi rane hipersen::.itirne reakcije na JKS 1to samo u slucaJu teskth reakciJa [24, 25].
Pruritus . . Provokacijski
d d". . . .Provokacijski
testovi. .. test na
.. lek predstavlJ. a kontrolisanu adm 1·n1·straCIJU·· 1eka sa
Urtikarija ct 1Jem a se IJagnost~kuje htpersenzi~.Ivna rea~ctJa na lek. ~pr~?s svojim ogranicenjima, provokacijski
Angioedem
test se smatra· ,zlatmm Tk standardom
. kako b1 se ustanovtla th odbacila preoseu1·ivost na odre denu

k1
su p~t.akncu, Je:~se pr~.~ om nJe~a ne is~?ljavaju sa~o alergijski simptomi vee i sve druge nezeljene
Ras
Ime e mamtestactJe
. k)" . .
bez obZira na nJthov mehamzam [26]. Medutim, provokaciJ. ski test Se lZVO · d.1
Mucnina, dijareja, grcevi u stomaku
IS JUCtvo ukohko neke druge, manje opasne metode ne daju relevantni zakljucak i uko1iko bi rezultat
Rinitis (kijanje, rinoreja)
testa mogao da razjasni inace nepoznato patolosko stanje [26]. Stoga se i uzima u obzir tek nakon
Promuklost, kasalj razmatranja odnosa rizika i koristi za svakog pojedinacnog pacijenta.
Dispneja (bronhospazam, edem larinksa)
Hipotenzija, tahikardija, aritmija
DIJAGNOSTIKOVANJE KASNIH HIPERSENZITIVNIH REAKCIJA
Kardiovaskularni sok
Srcani zastoj Tokom ispoljavanja, iii neposredno po ispoljavanju reakcije
Prestanak disanja
. Hematologija i klinicka hemija. Kod pacijenta kod kojih se ispoljavaju kasne kozne reakcije
tzazvane JKS-om, mogu reagovati i drugi organi [27]. Tokom akutne faze teskih reakcija trebalo bi
Tokom ispoljavanja, iii neposredno po ispoljavanju reakcije
razmotri~i i lab~ratorijske testove poput onih za utvrdivanje funkcije bubrega i jetre kao i diferencijalnu
In vitro testovi krvnu shku radt moguce eozinofilije.
Koncentracija histamina i triptaze. Poviseni histamin i triptaza u serumu se srecu u nekim, ali Biopsija koie. Povremeno se sprovodi histoloski pregled uzoraka u slucaju kasnih koznih
ne u svim slucajevima teske iii fatalne rane reakcije, i ne kod onih pacijenata sa blazim simptomima
erupcija.
[21 ]. Stoga ostaje da se ustanovi korist ovih markera za potrebe dijagnostikovanja.
Zna se da nivo histamina u plazmi dostize svoj vrhunac 5-10 min uta po pojavi simptoma, a kod Tabela 2. Simptomi kasne hipersenzitivne reakcije na JKS
pacijenata sa reakcijama nizeg stepena tezine, nivo hi stamina se za < 1h vraca na nivo normalnih Pruritus
vrednosti [21]. Iz ovog razloga, uzorke krvi radi analize hi stamina, treba uzeti sto je moguce ranije po Urtikarija
ispoljavanju reakcije. Preporucuje se da se uzorkovanje krvi radi analize nivoa triptaze obavi 1-2 sata
Angioedem
po pojavi simptoma [21 ]. Kako bi bilo moguce poredenje sa normalnim vrednostima, nove uzorke bi
Egzantem (makulozni, makulopapulozna erupcija)
trebalo prikupiti 1-2 dana nakon reakcije.
Eritem multiforrne
Nakon oporavka Fiksne erupcije
In vitro testovi Stiven-Dzonsonov sindrom
Specificna IgE antitela. Zabelezena ucestalost pozitivnih rezultata testova veoma varira. Dok su Toksicna epidermalna nekroliza
japanski istrazivaci kod 47% pacijenata sa ran om reakcijom otkrili specificna IgE anti tela na joksaglat Vaskulitis
[22], francuski istrazivaCi su samo kod 2-3% pacijenata sa teskim simptomima pronasli specifican lgE
na joksaglat ili joksitalmat [23]. Nakon oporavka
Ne postoji nijedan komercijalni test za merenje nivoa JKS- specificnih IgE antitela u serumu, i
tek ostaje da se utvrdi vrednost takvog testa u dijagnostici teskih ranih reakcija. .. Koini testovi. Cini se da su epikutani i intradermalni testovi sa JKS-om posebno korisni u
Aktivacija bazofila. U zavisnosti od doze, doslo je do direktnog oslobadanja histamina kada su dt]agnostikovanju alergije kod kasnih koznih reakcija.
leukociti perifeme krvi 30-60 minuta bili inkubirani na 30 Co u prisustvu visoke koncentracije JKS-a Li'!ifocit ~~~ns.forn:acioni test (LTT). Iako se ovaj test povremeno koristi za dijagnostikovanje
(20-400mM) [24]. Leukociti su oslobadali vise histamina nakon izlaganja kontrastnim sredstvima kod kasne htpersenztttvnostt on ne moze biti preporucen kao rutina.

c. 2015 Klinicki centar Srhije. Beograd C> 2015 Klinicki centar Srbiie. Beoszrad .\CT.\ CLI:'-:IC.\ Vol. 15 Sc.i S!
80
PROFILAKSA
Prevencija ranih reakcija
J:::hor kontrastnog sredstra. Kod pacijenata kod kojih postoje faktori rizika poput bronhijalne
astme ili prethodne nezeljene reakcije. radiolozi koriste nisko osmolarno kontrastno sredstvo zbog nize
incidence ukupnih reakcija [27]. Ukoliko je pacijenta sa prethodnom ranom hipersenzitivnom
reakcijom neophodno ponovo izlagati JKS-u nikako sene sme koristiti kontrastno sredstvo koje je
tada korisceno. Ponovno izlaganje JKS-u mora biti izbegnuto kod pacijenata sa prethodnom teskom
reakcijom.
Premedikacija. Kod pacijenata sa istorijom umerenih do teskih reakcija, uobicajena je
premedikacija kortikosteroidima, samostalno ili u kombinaciji sa H 1 i!ili H2 antihistaminicima [28].
Prevencija kasnih reakcija
/:::bor kontrastnog sredstva. Kod pacijenata sa prethodnom kasnom reakcijom postoji rizik od
nastanka nove erupcije ukoliko se ponovo izloze istom kontrastnom sredstvu [ 16]. Prema tome.
neophodno je izabrati drugo kontrastno sredstvo. Zbog ucestalog uzajamnog delovanja izmedu
razlicitih JKS-a, promena kontrastnog sredstva nije garancija da se nezeljena reakcija nece ponoviti.
Premedikacij"a. U najnovijim smernicama Komiteta za bezbednu upotrebu kontrastnih sredstava
pri Evropskom udruzenju urogenitalne radiologije navedeno je da je pacijentima sa prethodnim teskim
kasnim nezeljenim reakcijama pre novog izlaganja kontrastnim sredstvima neophodno dati profilaksu
oralnim steroidima [28].
LITERATURA:
I. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C. Dreborg S, Haatela T et al. A
revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task
force. Allergy 200 I;56:813-24.
2. Almen T. The etiology of contrast medium reactions. Invest Radio! 1994;29:S37-45.
3. Munechika H, Hiramatsu Y, KudoS, Sugimura K, Hamada Cyamaguci Ketal. A prospective survey
of delayed adverse reactions to iohexol in urography and computed tomography. Eur Radio!
2003:13:185-194.
4. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes.
Lancet 1977;1 :466-9.
5. Wolf GL, Arenson RL, Cross AP. A prospective trial of ionic vs nonionic contrast agents in routine
clinical practice:Comparison of adverse effectts. Am J Roentgenol 1989; 152:939-44.
6. Christiansen C. X-ray contrast media-an overview. Allergologie 2004;27: 165-70.
7. Laroche D. Aimone -Gastin I, Dubois F, Huet H, Gerard P, Vergnaud M-C et al. Mechanisms of
severe, immediate reactions to iodinated contrast media. Radiology 1998;209: 183-90.
8. Laroche D, Dewachter P, Mouton-Faivre C, Clement 0. Immediate reactions to iodinated contrast
media: The CIRTACI study. Allergologie 2004;27: 165-70.
9. Vernassiere C, Trechot P, Commun N, Schmutz JL, Barbaud A. Low negative predictive value of skin
tests in investigating delayed reactions to radio-contrast media. Contact Dermatitis 2004;50:359-66.
82
I0. Romano A, Artesani MC. Andriola M, Viola M, Pettinato R. Vecchioli-Scaldazza A. EtTective pro-
phylactic protocol in delayed hypersensitivity to contrast media:report of a case involving lymhocyte
transformation studies with different compounds. Radiology 2002;225:466-7o.
II. Sanchez-Perez J. Villaltta MG. Ruiz SA, Garcia Diez A. Delayed hypersensitivity reaction to the
non-ionic X-ray contrast media. Contact Dermatitis 2003;48: 167-70.
12. Wolf GL, Mishkin MM. Roux SG, Halpern EF, Gottlieb J, Zimmerman Jet al. Comparison of the
rates of adwrse drug reactions. Ionic contrast media, ionic media combined with steroids and non-
ionic media. Invest Radio! 1991 ;26:404-1 0.
13. Bettman MA, Heeren T, Greenfield A, Goudey C. Adverse events with radiographic contrast agents:
results of the SCVI R contrast agent registry. Radiology 1997 ;203 :611-20.
14. Aoki Y, Takemura T. Allergies correlated to adverse reactiuons induiced by non-ionic monomeric
and ionic dimeric contrast media for contrast enhanced CT examination. Jpn J Radio! Techno!
2002;58: 1245-51.
15. Pichler WJ. Yawalkar N, Britschgi M, Depta J, Strasser JI, Schgmid Setal. Celular and molecular
pathophysiology of cutaneous drug reactions. Am J Clin Dermatol2002;3:229-38.
16. Katayama H, Yamaguchi K, Kozuka T. Takashima T, Seez P. Matsuura K. Adverse reactions to
ionic and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast
Media. Radiology 1990;175:621-8.
17. Carro JJ, Trindade E, McGregor M. The risks of death and of severe nonfatal reactions with high-vs
low-osmolality contrast media:a meta-analysis. Am J Roentgenol 1991; 156:825-323.
18. Hosoya T, Yamaguchi K, Akutsu T, Mitsuhashi Y, Kondo S, Sugai Yet al. Delayed adverse reactions
to iodinated contrast media and their risk factors. Radiat Med 2000; 18:39-45.
19. Christiansen C, Pichler WJ, Skotland T. Delayed allergy-liker reactgions to X-ray contrast
media:mechanistic considerations. Eur Radio! 2000; I0:1965-75.
20. Abberer W, Bircher A, Romano A. Blanca M, Campi P. Fernandez Jet al. Drug provocation testing
in the diagnosis of drug hypersensitivity reactions:general considerations-position paper. Allergy
2003;58:854-63.
21. Laroche D, Vergnaud MC, Sillard B. Soufarapis H, Bricard H. Biochemical markers of anaphylactoid
reactions to drugs. Comparison of plasma histamine and tryptase. Anesthesiology 1991 ;75 :945-9.
22. Mita H. Tadokoro K. Akiyama K. Detection ogf IgE antibody to a radio-contrast medium. Allergy
1998;53: 1133-1140.
23. Sweeney MJ, Klotz SO. Frequency of IgE mediated radio contrast dye reactions. J Allergy Clin
Immunoll983;71:147-50.
24. Kvedariene V, Martins P, Rouanet L, Demoly P. Diagnosis of iodinated media hypersensitivity: results
of a 6-year period. Clin Exp Allergy 2006;36: I072-7.
25. Demoly P, Adkinson NF, Brockow K, Castells M, Chiaric AM, Greenberger PA et al. International
consensus on drug allergy. Allergy 20 14;69:420-37.
26. Yoon S H, Lee SY, Kang HR, Kim JY, Hahn S, Park CM et al. Skin test in patients with hypersen-
sitivity reaction to iodinated contrast media. Allergy 20 15;70:625-37.
27. Egbert RE, De Cecco CN. Joseph-Schoeph U, McQuiston A, Meine FG, Katzberg RW. Delayed adverse
reactions to the parenteral administration of iodinated contrast media. AJR 2014:203: 1163-70.
28. Morcos SK, Thomsen HS, Webb JA. Prevention of generalized reactions to contrast media: a con-
sensus report andguidelines. Eur Radio! 200 I: 11: 1720-8.
AliAll.INilA \'oi.ISN~3
DRUG ALLERGY
DRUG-INDUCED ALLERGIC REACTIONS IN PERI OPERATIVE PERIOD
AND DURING DIAGNOSTIC PROCEDURES
IODINATED CONTRAST MEDIA
Mirjana Bogie
lvfedical Faculty, University o{Belgrade
Clinicfor allergy and immunology, Clinical centre of Serbia, Belgrade
Author's address:
Professor Mirjana Bogie
Clinic for allergy and immunology,
Koste Todorovica 2, 11000 Belgrade, Serbia
E-mail: bogic.mit:jana1@gmail.com
ABSTRACT
All iodinated contrast media (I CM) are known to cause both immediate (< 1h) and nonimmediate (> 1h)
hypersensitivity reactions. Although for most immediate reactions an allergic hypersensitivity cannot be
demonstrated, recent studies indicate thtat the severe immediate reactions may be IgE-mediated, while most of
the non immediate exanthematous skin reactions, appear to be T-cell mediated. Patients who experience such
hypersensitivity reactions are therefore adivesed to undergo an allergologic evaluation. Several investigators
have found skin testing to be useful in confirming a ICM allergy, especially in patients with nonimmediate skin
eruptions. Ifa patient with confirmed allergy to a ICM needs a new exposure, a skin test negative ICM should
be chosen and premedication may be tried. However, none of these precautional measures is a guarantee against
a repeat reaction. More research focusing on pathomechanisms, diagnostic testing and premedication is therefore
clearly needed in order to prevent ICM-induced hypersensitivity reactions in the future.
Key words: iodinated contrast media, diagnosis, immediate reactions, nonimmediate reaction,
premedication, skin tests
INTRODUCTION
The adverse events seen after contrast media (ICM) administration may be divided into three
different types: a) allergic and nonallergic hypersensitivity reactions as defined by the European
Academy of Allergy and Clinical Immunology [1] and b) toxic reactions [2].
Hypersensitivity reactions are either immediate reactions, which occur within 1h after ICM
administration, or nonimmediate reactions, which become apparent more than 1 h after ICM exposure [3].
About 70% of the immediate symptoms are reported to start within the first 5 min ofiCM administration [4].
PREVALENCE OF CONTRAST MEDIUM REACTIONS
Mild adverse reactions of the immediate type occur in 3, 8-12, 7% of patients receiving
intravenous injections of high-osmolar, ionic ICM and in 0, 7-3, 1% of patients receiving low-osmolar
84 .,. 201' Klinicki centar <;rhije. Rengrad
nonionic ICM (4). Severe immediate reactions have been reported to occur with a frequency of 0, 1-0.
4% for ionic ICM and with a frequency ofO, 02-0.04% for nonionic ICM [4].
Although ther adverse reactions observed with the nonionic ICM are ussualy less severe than
reactions induces by the ionic ICM, the death rates for the two types of products are not significantly
different. The mortality rate has been estimated to be in the range of l in l 00 000 examinations [5].
Severe and fatal reactions represent a serious problem in regard to the more than 70 million applications
ofiCM per year worldwide [6].
PATHOPHYSIOLOGY
Immediate hypersensitivity reactions to ICM are at least in part associated with histamine release
from basophils and mast cells [7]. Histamine release may be due to: a) a direct membrane effect related
to the osmolarioty of the ICM solution or the chemical structure of the ICM molecule; b) an activation
of the complement system or c) an IgE-mediated mechanism. Evidence for an lgE-mediated reaction
has mainly been found in the rare cases of severe reaction [8].
Most of the ICM-induced nonimmediate skin eruptions appear to beT-cell mediated allergic
reactions as shown by: a) the frequently reported positive patch tests and delyed intradermal tests to the
culprit ICM in previous reactors [9], b) the presence of dermal infiltrates ofT cells in affected skin and
positive skin test sites [10], c) the reappearance of the eruption after provocation testing [ ll ], and the ability
ofiCM to stimulate proliferation of peripheral T cells from patients with ICM-induced skin eruptions [11].
RISK FACTORS
The most significant risk factors for an immediate hypersensitivity reaction is a previous
immediate reaction. Previous reactor have a 21-60% risk of a repeat reaction when re-exposed nto the
same or a similar ionic ICM [12]. When patients with a previous reaction to an ionic ICM are
subsequently given a nonionic ICM, an up to l 0-fold reduction in the incidence of severe repeat
reactions has been reported [12].
Other risk factors for more severe immediate reactions are severe allergy, bronchial asthma,
cardiac disease and treatment with beta-blockers [ 13].
Reported predisposing factors for nonimmediate skin reactions are a previous lCM-induced
adverse reaction, serum creatinine level >2. Omg/dl and history of drug and contact allergy [ 14].
Other potential factors that may influence the severity of a ICM reaction include mastocytosis,
viral infection at time of ICM exposure and autoimmune disease, such as systemic lupus
erythematosus [ 15].
CLINICAL SIMPTOMS
Clinical symptoms of hypersensitivity reactions to ICM are listed in table 1 and table 2. Pruritus
and mild urticaria are the commonest immediate manifestations, occuring in up to 70% of affected
patients [16]. More severe reactions involve the respiratory and cardiovascular systems, and most fatal
hypersensitivity reactions to ICM are immediate anaphylactic reactions [17].
The most frequent ICM-induced nonimmediate reaction is maculopapular rash, observed in more
than 50% of nonimmediate reactors [ 18]. Other frequently occuring nonimmediate reactions include
erythema, mticaria, angioedema, macular exanthema or scaling skin eruption [18]. The non immediate
© 2015 Klini~ki centar Srbije, Beograd
\CTA.Cli'\JIC\ \'ol.15.'{n1
 skin reactions are usually mild to moderate in severity and transient and self-limiting. However, cases . N_o commercial assa~ is avai~abl~ for r?uti~e mea~ureme~t of serum levels of ICM-specific IgE
of severe skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis and cuateneous antibodies, and the value of the test m diagnosis of severe Immediate rwactions remains to be established.
vasculitis have been reporeted [ 19]. Basophil activation. Dose-dependent. direct histamine release was demonstrated when human
peripheral blood leukocytes were incubated for 30-60 min at 37 C in presence of rather high concentrations
DIAGNOSIS OF IMMEDIATE HYPERSENSITIVITY REACTIONS ofiCM (20-400mM) [24]. Leukocytes from atopic individuals were reported to release more histamine
upon ICM exposure than leukocytes from nonatopics [25]. The role of the histamine release test and
The work-up of a suspected drug hypersensitivity includes a detailed clinical hystory and physical
other in vitro basophil activation tests in the allergy diagnosis of reactions to ICM is not yet defined.
examination, followed by one or more of the following procedures:laboratory tests, skin tests and
ultimately provocation tests [20]. Accurate identification of the responsible agent is important for future
treatments to avoid labeling somebody as being"allergic"for life witout good reason. Tests in vivo
Tahle 1. Symptoms of'immediate lnpersensitiritr reactions to /CJ1 Skin tests. Skin prick tests (SPT) and intradermal tests (lOT) have been performed for many
Pruritus
years in the diagnosis of immediate hypersensitivity reactions to ICM, but positive tests have only
rarely been reported and only in patients with severe reactions [24, 25].
Urticaria
Provocation test. A drug provocation test (OPT) is the controlled administration of a drug in
Angioedema order to diagnose drug hypersensitivity reactions. In spite of its limitation, OPT is widely considered
Rush to be"gold standard"to establish or exclude the diagnosis of hypersensitivity to a certain substance, as
Nausea, diarrohea, cramin it not only reproduces allergic symptoms but also any other adverse clinical manifestation irrespective
Rhinitis(sneezing, rhinorrhea) of the mechanism [26]. But OPT should be performed only if other, less dangerous test methods do
Hoarseness, cough not allow relevant conclusions and if the outcome might thus help clarify an otherwise obscure
Dyspnea(bronchospasm, laryngeal edema) pathologic condition (26]. However, OPT should only be considered after balansing the risk-benefit
Hypotension, tachycardia. arrhythmia
ratio in the individual patient.
Cardiovascular shock
Cardiac arrest DIAGNOSIS OF NONIMMEDIATE HYPERSENSITIVITY REACTIONS
Respiratory arrest
During or immidiately after the reaction
Hematology and clinical chemistry. In patients with ICM-induced nonimmediate skin eruptions.
During or immediately after the reactions other organs may be involved [27]. Thus, during the acute phase of more severe reactions, laboratgory
Tests in vitro tests such as liver and renal function tests as well as differential blood cell counts to look for
Plasma hystamin and tr;ptase. Elevated serum levels of histamine and tryptase have been found eosinophilia should be considered.
in some but not all patients with severe or fatal immediate reactions but not in those with milder Skin biopsy. Histological examination of biopsy samples from nonimmediate skin eruptions has
symptoms [21 ]. The usefulness opfthese markers for diagnostic purposes remains to be established. occasionally been conducted.
Plasma histamine concentration is known to peak within 5-l 0 min after onset of symptoms, and for Table 2. Symptoms of non immediate hJpersensitirity reactions to /CM
patients with reactions of lower severity grade, histamine may return to baseline level in < 1h [21]. Pruritus
Consequently, blood samples for histamine analysis should be drawn as soon as possible after the reactions.
Urticaria
For, tryptase, blood sampling l-2h after onset of symptoms has been recommended [21 ]. The enable
Angioedema
comparison with baseline levels, new blood samples should be collected 1-2 days after the reactions.
Exanthema( macular, maculopapular eruption)
Erythema multi forme minor
After recovery
Fixed drug eruption
Tests in vitro
Steven-Johnson syndrome
Specffic lgE antibodies. The reported frequency of positive tests results varies widely. While a Japanese
Toxic epidermal necrolysis
group detected ICM- specific IgE to ioxaglate in 47% of immediate reactors (22], a French group found ICM
-specific IgE to either ioxaglate or ioxithalamate only in teh 2-3% of rectors with severe symptomy [23]. Vasculitis

86 ACTA CLINIC A Yol. 15 N":> c 2015 Klinicki centar Srhiie. Hcograd © 2015 Klinicki ccntar Srbije, Heograd X7

~
.

.I
J!
After recovery
Skin tests!.__patch tests (PT) and IDT with ICM appear to be specific and useful in allergy diagnosis
of non immediate skin reactions to ICM.
Lymphocyte tran~formation test. Although LTT has occasionaly been used in diagnosis of
nonimmediate hypersensitivity, this test cannot be recommended for routine use at present.
PROPHYLAXIS
Prevention of immediate reactions
Contrast medium selection. In patients with risk factors such as bronchial asthma or previous
ICM-induced immediate adverse reaction, radiologists have routinely administered low-osmolar ICM
because of their lower incidence of total reactions [27]. If a patient with a previous immediate
hypersensitivity reaction to a ICM needs a new ICM exposure, the ICM that caused the reaction should
not be readministered. New exposure to ICM should be avoided in patients with previous severe ICM-
induced immediate reaction.
Premedication. It has been common practice to use premedication with corticost~roids either
alone or in combination with H !-antihistamines and/or H2-antihistamines in patients with a history of
moderate or severe immediate reaction to ICM [28].
Prevention of nonimmediate reaction
Contrast medium selection. Patients with previous ICM-induced nonimmediate skin eruption
are at risk for developing new eruptions ifre-exposure to the same ICM takes place [16]. Consequently,
another ICM products should be chosen ifre-exposure is required. Because of frequent cross-rectivity
between different ICM, change of ICM is no guarantee against a repeat reaction.
Premedication. In the recent guidelines from the Contrast Media Safety Commitee of the
European Society of Urogenital Radilogy, it is stated that patients with previous serious nonimmediate
adverse reactions can be given oral steroid prophylaxis if new ICM exposure is required [28].
REFERENCES:
1. Johansson SG, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haatela T et al. A
revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task
force. Allergy 2001 ;56:813-24.
2. Almen T. The etiology of contrast medium reactions. Invest Radio! 1994;29:S37-45.
3. Munechika H, Hiramatsu Y, KudoS, Sugimura K, Hamada Cyamaguci Ketal. A prospective survey
of delayed adverse reactions to iohexol in urography and computed tomography. Eur Radio!
2003;13:185-194.
4. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes.
Lancet 1977; 1:466-9.
5. Wolf GL, Arenson RL, Cross AP. A prospective trial of ionic vs non ionic contrast agents in routine
clinical practice:Comparison of adverse effectts. Am J Roentgenol 1989:152:939-44.
6. Christiansen C. X-ray contrast media-an overview. Allergologie 2004;27: 165-70.
'\CTA CI l"l!C!\ Vol. 15 ."1"~3 2015 Klinicki centar Srhiie. Beograd
7. Laroche D, Aimone -Gastin L Dubois F, Huet H, Gerard P, Vergnaud M-C et al. Mechanisms of
severe, immediate reactions to iodinated contrast media. Radiology 1998;209: 183-90.
8. Laroche D. Dewachter P. Mouton-Faivre C. Clement 0. Immediate reactions to iodinated contrast
media:The CIRTACI study. Allergologie 2004:27:165-70.
9. Vernassiere C, Trechot P, Commun N, Schmutz JL, Barbaud A. Low negative predictive value of
skin tests in investigating delayed reactions to radio-contrast media. Contact Dermatitis
2004;50:359-66.
10. Romano A, Artesani MC, Andriola M, Viola M, Pettinato R, Vecchioli-Scaldazza A. Effective
prophylactic protocol in delayed hypersensitivity to contrast media:report of a case involving
lymhocyte transformation studies with different compounds. Radiology 2002;225:466-7o.
11. Sanchez-Perez J, Villaltta MG, Ruiz SA, Garcia Diez A. Delayed hypersensitivity reaction to the
non-ionic X-ray contrast media. Contact Dermatitis 2003:48:167-70.
12. WolfGL, Mishkin MM, Raux SG, Halpern EF, Gottlieb J, Zimmerman Jet al. Comparison of the
rates of adverse drug reactions. Ionic contrast media, ionic media combined with steroids and
nonionic media. Invest Radio! 1991 ;26:404-1 0.
13. Bettman MA, Heeren T, Greenfield A, Goudey C. Adverse events with radiographic contrast
agents:results of the SCVIR contrast agent registry. Radiology 1997 ;203 :611-20.
14. Aoki Y, Takemura T. Allergies correlated to adverse reactiuons induiced by non-ionic monomeric
and ionic dimeric contrast media for contrast enhanced CT examination. Jpn J Radio! Techno!
2002;58: 1245-51.
15. Pichler WJ, Yawalkar N, Britschgi M, Depta J, Strasser JI, Schgmid Setal. Celular and molecular
pathophysiology of cutaneous drug reactions. Am J Clin Dermatol2002;3:229-38.
16. Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K. Adverse reactions to ionic
and nonionic contrast media. A report from the Japanese Committee on the Safety of Contrast Media.
Radiology 1990; 175:621-8.
17. Carro JJ, Trindade E, McGregor M. The risks of death and of severe nonfatal reactions with high-vs
low-osmolality contrast media:a meta-analysis. Am J Roentgenol 1991; 156:825-323.
18. Hosoya T, Yamaguchi K, Akutsu T, Mitsuhashi Y, Kondo S, Sugai Y et al. Delayed adverse reactions
to iodinated contrast media and their risk factors. Radiat Med 2000; 18:39-45.
19. Christiansen C, Pichler WJ, Skotland T. Delayed allergy-liker reactgions to X-ray contrast
media:mechanistic considerations. Eur Radio! 2000; 10:1965-75.
20. Abberer W, Bircher A, Romano A, Blanca M, Campi P, Fernandez Jet al. Drug provocation testing
in the diagnosis of drug hypersensitivity reactions:general considerations-position paper. Allergy
2003;58:854-63.
21. Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H. Biochemical markers of anaphylactoid
reactions to drugs. Comparison of plasma histamine and tryptase. Anesthesiology 1991 ;75:945-9.
22. Mita H, Tadokoro K, Akiyama K. Detection ogf lgE antibody to a radio-contrast medium. Allergy
1998;53:1133-1140.
23. Sweeney MJ, Klotz SO. Frequency of lgE mediated radio contrast dye reactions. J Allergy Clin
Immunol1983;71:147-50.
24. Kvedariene V, Martins P, Rouanet L, Demoly P. Diagnosis of iodinated media hypersensitivity:results
of a 6-year period. Clin Exp Allergy 2006;36: 1072-7.
© 2015 Klinicki centar Srbiie. Beograd ACTA Cl IN!CA Vol. 15 ."foi X9
 25. Demoly P, Adkinson NF, Brockow K, Castel isM, Chiaric AM, Greenberger PA eta!. International ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA
consensus on drug allergy. Allergy 20 14;69:420-3 7.
26. Yoon S H. Lee SY, Kang HR, Kim JY. Hahn S, Park CM et al. Skin test in patients with
hypersensitivity reaction to iodinated contrast media. Allergy 2015;70:625-37. ALERGIJSKE REAKCIJE IZAZVANE LOKALNIM ANESTETICIMA
27. Egbert RE, De Cecco CN, Joseph-Schoeph U, McQuiston A, Meine FG, Katzberg RW. Delayed
adverse reactions to the parenteral administration of iodinated contrast media. AJR 2014: Vojislav Durie
203:1163-70. Medicinskifakultet u Beogradu, Univerzitet u Beogradu
28. Marcos SK, Thomsen HS, Webb JA. Prevention of generalized reactions to contrast media:a Klinika za a/ergo/og(ju i imuno/og(ju, Klinicki centar Srhije
consensus report andguidelines. Eur Radio! 200 I; II: 1720-8.
Adresa autora:
Profesor Vojis/av Djuric
Klinika za a/ergologiju i imuno/ogUu
Koste Todorovica 2, 11000 Beograd
E-mail: vojadj@eunet.rs

SAZETAK
Alergijske reakcije na lokalne anestetike su retke, verovatno je samo oko 1% neze1jenih dejstava na
ove medikamente posredovano imunskim sistemom. Lokalni anestetici se dele na esterske i amidne. Rede
se javljaju alergijske reakcije I tipa a cesce IV tipa. U slucaju reakcije na lokalni anestetik potreban je opis
reakcije i podatak koji je lokalni anestetik upotrebljen. Alergolosko testiranje se sastoji od prick. intrader-
malnih, patch testova i dozno provokacionog testa. Laboratorijski testovi koji se koriste dijagnosticke
svrhe su i merenje specificnog IgE i test limfocitne transformacije.
Kljucne reci: 1oka1ni anestetik, a1ergijska reakcija, a1ergo1osko ispitivanje

Lokalni anestetici su otkriveni 1884 godine, kada je oftalmolog Carl Koller u tu svrhu upotrebio kokain,
prvo na samom sebi. U stomatologiji gaje prvi upotrebio Hall. Kokain se dobija iz lista koke, u EHopuje
uveden u 19 veku ijedinije prirodni lokalni anestetik. Kasnije, 1904 je Einhorn sintetisao prokain (Novokain).
Mook je prvi opisao alergijsku reakciju tj kontaktni dermatitis na rukama koji je izazvao apotezin kod jednog
zubara 1920 godine, ko:Zna proba je u ovom slucaju bila pozitivna a dermatitis se povukao kada je pacijent
prestao da koristi apotezin. Prvi amidni lokalni anestetik je sintetisao Lofgren 1943 godine [I].
Lokalni anestetici se sastoje od lipofilnog aromatskog prstena vezanog za hidrofilnu amino grupu. Na
osnovu veze izmedu njih dele se na esterske i amidne lokalne anestetike. U esterske spadaju kokain. prokain.
tetrakain, benzokain i hloroprokain i svi su derivati para- aminobenzojeve kiseline. Cesto se u lokalni anestetik
dodaju vazokonstriktori kao sto su adrena1in, ili noradrenalin kao i prezervativi kao sto su metilparaben,
propilparaben, sulfiti. Metilparaben se dodaje zbog njegovog antimikrobnog delovanja, a sulfiti se dodaju
da sprece oksidaciju adrenalina. Amidni su lidokain, mepivakain, bupivakain, etidokain, prilokain dibukain
(u imenu sadrZe dva puta slovo i). Deluju tako sto reverzibino vefu za natrijumske kanale u membrani nervne
celije tako da sprecava nastanak akcionog potencijala. Na ovaj naCin se blokira aferentni prenos signala
nervnim putevima. Lokalni anestetik difuzijom prolazi kroz celijsku membranu I to u nejonizovanom obliku.
Estarski lokalni anestetici se metabolisu hidrolizom nespecificnim holinesterazama u plazmi. Izuzetak
je kokain koji se sporo metabolise ujetri. Jedan od metabolite je para amino benzojeva kiselina (PABA) koja
I sama moze biti alergen. Amidni lokalni anestetici podlefu metabolizmu u jetri i izlucuju se preko bubrega.

90 ACTA CLINICA Vol. 15 N23 c 2015 Klinicki centar Srhije. Beograd ~ 2015 Klinicki centar Srbijc. Beograd ACTA CLINICA Vol. 15 -""-' 91
ALERGIJSKE REAKCIJE
Na osnovu klinicke slike kod 71 pacijenata, Incaudo I saradnici su podelili reakcije u rane
generalizO\ ane reakcije 15%. lokalan otok na mestu ubrizga\anja 25%. nespecificni sistemski
simptomi 42%. i ostali 17% [2]. Lokalni anestetici su male molekulske mase i sami nisu antigeni, vee
se kao hapteni vezuju za proteine domaeina, nosac a onda kompleks hapten nosac stimulise imunski
system. U novije neme je pronadeno da neki lekovi a medu njima i lokalni anestetici lidokain I
mepivakain mogu direktno da se vezu za T eelijski receptor (TCR) nekovalentnim, van der Waalsovim
silama, sto ce naziva farmakoloska interakcija saT eelijskim receptorom, tzv p-i koncept. U ovom
mehanizmu lek se ne vezuje za nosac, niti je obraden od antigen prezentujuee eelije, nema faze
senzibiizacije. pa je alergijska reakcija moguea i pri prvoj upotrebi leka.
Alergijske reakcije na lokalne anestetike su retke, verovatno da je samo oko I% svih reakcija
posredovano imunskim sistemom . Na osnovu patch testova smatra se da izmedu esterskih lokalnih
anestetika postoji unakrsna reaktivnost, dok izmedu esterskih i amidnih kao ni izmedu samih amidnih
ne postoji unakrsna reaktivnost. Reakcije na amidne lokane anestetike su rede nego na esterske, U stvari,
od kako su 1950 ih godina amidni lokalni anestetici poceli da se vise koriste, broj reakcija se smanjio.
Alergijske reakcije su rane, I tipa i cesee, kasne, IV tipa po Coombsu I Gellu .. Reakcije I tipa su
posredovane imunogloblinom E i mogu biti blage, u vidu koprivnjace iii teze sa angioedemom,
bronhospazmom i arterijskom hipotenzijom. Alergoloski testovi kod osoba za koje postoji podatak da su
imale reakcije na lokalni anestetik su retko pozitivni Troiso i saradnici su izvrsili prick, intradermalne
kozne probe i dozno- provokacioni test kod 386 pacijenata sa podatkom o reakciji na lokalni anestetik.
Prick kozna proba je bila pozitivna kod I 0 pacijenata a intradermalna je bila pozitivna kod 3 pacijenta
[3]. U 197 slucajeva alergijske reakcije na lokalni anestetik gde su izvrseni prick, intradermalna proba i
dozno provokacioni test i izmeren specificni IgE radioalergosorben testom (RAST) utvrdeno je da su
samo 3 dozno provokaciona testa bila pozitivna ito u dva slucaja reakcija je bila rana au jednom kasna.
Pri tom nisu nadena specificna IgE na lokalni anestetik [4]. Retko su nalazeni slucajevi rane reakcije gde
je nadena I pozitivna prick kozna proba I specifCni IgE na lidokain [5]. Bohle i saradnici su pregledom
literature na engleskom jeziku nasli 29 slucaja IgE posredovane reakcije na lokalni anestetik kod ukupno
2978 pacijenata [6]. Smrtni slucajevi se desavaju sa ucestaloseu od oko 1 pacijent na I.5 milion pacijenata.
Ponekad pacijenti imaju ranu reakciju na metilparaben koji se nalazi kao aditiv u lokalnom anestetiku.
Kasne reakcije kako na esterske tako i amidne lokalne anestetike se desavaju verovatno cesee
nego reakcije ranog tipa. Javlja se kontaktni dermatitis, najcesee kod zubara, lekara i medicinskih
sestara, mada je i za mnoge slucajeve koprivnjace i angioedema posle potkoznog davanja lokalnog
anestetika pokazano da su posredovani limfocitima T na osnovu patch testa i testa transformacije
limfocita [7]. U ovom radu je kod pacijenata koji su imali koprivnjacu sa iii bez angioedema posle
potkozno primljenog lokalnog anestetika intradermalna proba bila pozitivna kod samo 2 od 20
pacijenata, tj I 0% dok je patch bio pozitivan kod 6 pacijenata tj 30% a test limfocitne transformacije
je bio pozitivan kod 60% pacijenata.
Velika veeina reakcija na lokalne anestetike nisu alergijske vee se tokom upotrebe anestetika javlja
anksioznost, toksicne reakcije, idiosinkraticke, vazovagalna sinkopa (koja se klinicki razlikuje od
anafilakticke reakcije po tome sto je prisutna bradikardija a ne tahikardija i sto nema koprivnjace ). Toksicno
dejstvo lokalnih anestetika nastaje zbog predoziranja iii intolerancije, i ispoljava se na nervnom i
kardiovaskulamom sistemu. U pocetku nastaje stimulacija nervnog sistema, euforija nervoza, uzbudenje,
mucnina, konvulzije, posle cega dolazi do depresije pa nastaje koma, srcana insuficijencija, hipotenzija i
A.CT<\. Cl I"JICA. Vol. I~"~""' c 2015 Klinicki centar Srhiie. Hco~rad
ponekad smrt. Verovatno u nekim slucajevima navodne reakcije ponekad dolazi do slucajnog
intravaskulamog ubrizgavanja lokalnog anestetika. Ovako ubrizgan lokalni anestetik moze dovesti do
aritmija. a ako se u lokalnom anestetiku nalazio i adrenalin moze doei do arterijske hipertenzije i tahikardije.
ALERGOLOSKO ISPITIVANJE
U slucaju sumnje na alergijsku reakciju na lokalni anestetik potrebni su detaljni podaci od lekara
iii zubara o reakciji, koji je lokalni anestetik upotrebljen, kako je reakcija izgledala tj kakva je bila klinicka
slika kao i vremenski razmak izmedu primanja lokalnog anestetika i pojave pojednih simptoma i znakova.
Treba voditi racuna I o tome da se ponekad radio alergijskoj reakciji na lateks a ne na lokalni anestetik.
U slucaju da su podaci o reakciji na esterski lokalni anestetik ubedljivi Savet za alergologiju
astmu I imunologiju (Joint Council of Allergy, Asthma and Immunology- JCAAI) preporucuje da se
testira amidni lokalni anestetik, dok se u slucaju reakcije na amid preporucuje testiranje sa esterom iii
sa drugim amidom [8,9, 10]. Alergolosko testiranje se sastoji od kozne probe, prvo prick metodom sa
cistim lokalnim anestetikom koji ne sadrzi adrenalin kao ni prezervative pa zatim intradermalnim
metodom i to prvo sa razblazenjem l: i 00, pa sa 1: 10, pa sa cistim lokalnim anestetikom. Ako su kozne
probe negativne sprovodi se dozno provokacioni test. Ako je dozno provokaconi test negativan. lokalni
anestetik se moze upotrebiti kod pacijenta. Testiranje na konzervanse kao sto su parabeni I sulfiti se
rutinski ne radi, mada sui na ove supstance zabelezene alergijske reakcije. Patch test je takode veoma
koristan kako je to ranije pokazano. Merenje specificnog IgE na Iokalni anestetik kao i test
transformacije limfocita se takode koriste, mada nisu lako dostupni.
LITERATURA:
I. Boren E. Teuber SS Naguwa SM, Gershwin ME. A critical review of local Anesthetic Sensiti\ ity.
Clinical Reviews in Allergy and Immunology 2007; 32 : 119-127.
2. Incaudo G, Schatz M, Patterson R, Rosenberg M, Yamamoto F, Hamburger RN. Administration of local
anesthetics to patients with history of prior adverse reaction.J Allergy Clin Immunol 1978;61: 339-45.
3. Troise C, Voltolini S, Minale P, Modeni P, Negrini AC. Management of patients at risk of adverse
reactions to local anesthetics: analysis of 386 cases. J Invest Alerg Clin Immunol 1998: 8. 172-75.
4. Gall H, Kaufmann R, Kalverman CM. Adverse reactions to local anesthetics: analysis of 197 cases.
J Allergy Clin Immunol 1996: 97: 933-37.
5. Noormalin A, Shanaz Rosmilah M, Mujahid SH, Gendeh BS. IgE- mediated hypersensitivity reaction
to lignocaine -a case report. Trop Biomed 2005 22, 179-83.
6. Bhole MY, Manson AL, Seneviratne SV, Misbah SA. lgE mediated allergy to local anaesthetics:
separating facts from perception: a UK perspective. Br J Anasthesiol 2012 108 (6): 903-911. 7. Orasch
CE, Helbing A, Zanni MP, Yawakar N, Hari J, Pichler WJ. T cell reaction to local anesthetics,
relationship to angioedema and urticaria after subcutaneous application- patch testing and LTT in
patients with adverse reactions to local anaesthetics. Cin Exp Allergy Immunol 1999; 29( 11 ): 1549-54.
8. JCAAI The diagnosis and management of anaphylaxis- XVIII Local anesthetics. J Allergy Clin
Immunol 1998; 101: S465-S528.
9. JCAAI Prototypes of immunologically mediated drug hypersensitivity. Ann Allergy 1999: 83: 665-700.
10. DeShazo RS and Nelson HS. An approach to patient with history of local anesthetics hypersensitivity:
experience with 90 cases. J Allergy Clin Immunol 1979; 63: 387-394.
© 2015 Klinicki centar Srhiie. Beo~rad

DRUG ALLERGY
ALLERGIC REACTIONS TO LOCAL ANAESTHETICS
Vojislav Durie
Medical Faculty, University of'Belgrade
Clinic of allergology and immunology, Clinical Centre of Serbia
Authors address:
Professor Vojislav Djuric
Clinic for allergy and clinical immunology
Koste Todorovica 2, II 000 Belgrade. Serbia
E-mail: vojadj@eunet.rs
ABSTRACT
Allergic reactions to local anesthetics are rare, probably only I% of adverse events are
immunologically mediated. Local anesthetics are divided to esters and amides. Allergic reactions are rarely
type I, more frequently IV type. In case of allergic reaction detailed history is needed. Allergologic
investigation consists prick, intradermal, patch and challenge test. Laboratory tests are measurement of
specific IgE and lymphocyte transformation test.
Key words: local anaesthetics, allergy, allergologic evaluation
Local aneasthetics were discovered in 1884 when ophtalmologist Carl Koller used cocaine. Hall
used cocaine in dentistry. Later, in 1904 Einhorn synthesized procaine. Mook described in 1920 an
allergic reaction to apothesin as contact dermatitis on the hands of a dentist, skin test was positve and
dermatitis resolved when exposure to apothesin ceased. The first amide local aneshetic was synthesized
by Lofgren in 1943 [ 1].
Local anesthetics consist of lipophilic aromatic ring and hydrophilic amine. The bond between
ring and amine can be ester or amide. Based on this bond local anesthetics are divided in esters and
amids. Esters are cocaine, procaine, tetracaine, benzocaine, chloroprocaine, amids are lidocaine,
mepivacaine, etidocaine, prilocaine, bupivacaine, dibucaine. Esters are hydrolized by cholinesterase.
One of the metabolites is para amino benzpoc acid (PABA) which can be an allergen. Exception is
cocaine which is metabolized in the liver. Amides are metabolized in liver with renal excretion.
ALLERGIC REACTIONS
Based on history Incaudo et al has divided reactions to immediate generalized in 15%, local
sweeling at the site of administration, 25%, nonspecific systemic symptoms 42% and others 17% [2].
Local anesthetics are of low mollecular weight and are not immunogenic, so they are haptens which
must bind to host peptides (carrier) and make hapten -carrier complex. Recently another mechanism
was postulated, so called pharmacollogical interaction with T cell receptor or p i concept when the
drug is noncovalently binds with van der Waals forces toT cell receptor. In such mechanism there is
no sensibilisation phase, so reaction is possible even after the first exposure to the drug.
':015 Klinicl.i ccnt.u Srbijc.
94 ACTA CLINIC A Vol. 15 No3
,
. Aller~ic reactions to local anesthetis are rare, probably only 1% of all reported reactions are
~mmunologtcally mediated. Based on patch testing there is cross reactivity between esters while there
IS no cross reactivity amids and esters or between individual amids. Reactions to amids are less
frequent. In fact since amids were used in 1950s more frequently, reactions became less prevalent.
Allergic reactions are immediate (or type I) and more frequently, late (or type IV). Immediate reactions
are IgE mediated and t~ey can be ~ilder. present.ing as urticaria only, or severe, with angioedema,
bronchospas~ ~nd arte~Ial hypotensiOn. Aller~olo~Ic testing in patients with history of allergic reaction
are rarely positive. Tr01so et al performed pnck, mtradermal and challenge tests in 386 patients with
history of allergic reaction to local anesthetics. Prick test was positive in 10 patients, and intradermal
was positive in 3 patients [3]. In 197 cases of allergic reaction to local anesthetic prick intradermal,
challenge test ~:ere pe.rforme? and spe~ific IgE was measured and it was found that only 3 challenge
tests were positive, 2 Immediate reaction and one late reaction. Specific IgE to local anesthetic was
not found [4]. Cases of immediate reaction with positive prick test and specific llgE were rarely found
[5]. Bohle et al reviewed literature in English and found 29 cases of IgE mediated reaction to local
anesthetic out of 2978 patients [6]. Fatalities happened with frequency of 1 in 1.5 million patients.
Sometimes patients have allergic reaction to methylparaben.
Late reactions to esters and amides are probably more prevalent than immediate reactions.
Contact dermatitis occurs in doctors, dentists and nurses, although for many cases of urticaria and
angioedema after subcutaneous administration of local anethetic it was shown that they were
lymphocyte T mediated based on patch testing and lymphocyte transformation test. [7] In this paper
patients who had urticaria with or without angioedema after subcutaneous administraion of local
anesthetic intradermal test was positive in only 2 out of 20 patients ( 10%) while patch was positive in
6 patients (30%) and lymphocyte transformation test was positive in 60% patients.
Overwhelming majority of reactions are not allergic, but are due to anxiety. toxic reactions.
idiosyncratic reactions, vasovagal syncope (clinicall different from anaphylactic reaction bradicardia
ant not tachycardia and absence of urticaria). Toxic effect oflocal anesthetic can occur as a consequence
of overdose or intolerance and manifests on nervous and cardiovascular system. At first, stimulation
of nervous system occurs, manifested as euphoria, excitement, nervousness, convulsions. later
depression of brain and heart functions may lead to coma, heart failure, hypotension and sometimes
death. In some cases probably accidental intravascular injection may lead to arrhythmias. Adrenaline
that is present in preparation, may cause hypertension and tachyacardia.
Al/ergologic evaluation
In case of possible allergic reaction to local anesthetic detailed history of reaction is needed tl'om
physician or dentist, with information which local anesthetic was used and the time interval between
administraion of anesthetic and appearence of symptoms and signs. It is necessary to consider the
possibility of latex allergy.
In cases of convincing history of reaction to ester anesthetic, Joint Council of Allergy Asthma
and Immunology (JCAAI) recommends that amide should be tested first, while in the case of
reaction to amide anesthetic, testing with another amide or with ester is recommended [8.9.1 0].
Allergologic testing consists of skin test first prick with neat local anethetic without pre sen atives
and adrenaline, and than intradermal, first 1: 100 dilution, and than 1:10 than with neat locval
anesthetic. If skin tests are negative, challenge test is performed. If the challenge test is negati\ e,
~ 2015 Klinicki ccntar '\rhiic. lkoerad
Ikugr~J
local anethetic can be safely used. Testing to parabens and sulfites is not performed routinely.
although allergic reacions were reported to these substances. Patch test is also very useful, as
pereviously mentioned. Specific IgE to local anethetics and lymphocyte transformation tests are
also used, although they are often not available.
REFERENCES:
1. Boren E. Teuber SS Naguwa SM, Gershwin ME. A critical review of local Anesthetic Sensitivity.
Clinical Reviews in Allergy and Immunology 2007; 32 : 119-127.
2. Incaudo G, Schatz M, Patterson R, Rosenberg M, Yamamoto F, Hamburger RN. Administration of
local anesthetics to patients with history of prior adverse reaction. J Allergy Clin Immunol 1978;61:
339-45.
3. Troise C, Voltolini S, Minale P, Modeni P, Negrini AC. Management of patients at risk of adverse
reactions to local anesthetics: analysis of 386 cases. J Invest AI erg Clin Immunol 1998; 8, 172-75.
4. Gall H, Kaufmann R, Kalverman CM. Adverse reactions to local anesthetics: analysis of 197 cases.
J Allergy Clin Immunol 1996: 97: 933-37.
5. Noormalin A, Shanaz Rosmilah M, Mujahid SH, Gendeh BS. IgE- mediated hypersensitivity reaction
to lignocaine -a case report. Trop Biomed 2005 22, 179-83.
6. Bhole MY, Manson AL, Seneviratne SV, Misbah SA. lgE mediated allergy to local anaesthetics:
separating facts from perception: a UK perspective. Br J Anasthesiol 2012 108 (6): 903-911.
7. Orasch CE, Helbing A, Zanni MP, Yawakar N, Hari J, Pichler WJ. T cell reaction to local
anesthetics, relationship to angioedema and urticaria after subcutaneous application- patch testing
and LTT in patients with adverse reactions to local anaesthetics. Cin Exp Allergy Immunol 1999;
29(11 ): 1549-54.
8. JCAAI The diagnosis and management of anaphylaxis- XVIII Local anesthetics. J Allergy Clin
Immunol 1998; 101: S465-S528.
9. JCAAI Prototypes of immunologically mediated drug hypersensitivity. Ann Allergy 1999; 83:
665-700.
10. DeShazo RS and Nelson HS. An approach to patient with history oflocal anesthetics hypersensitivity:
experience with 90 cases. J Allergy Clin Immunol 1979; 63: 387-394.
96 <\ClACIIl\JIC<\ Vol. 15.t.f.. 1 ,;; 2015 Klinicki centar Srbiie. Beograd
ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA
REAKCIJA NA LEKOVE SA EOZINOFILIJOM I SISTEMSKIM SIMPTOMIMA
Sanvila Raskovic
JV!edicinskifakultet, Univer::itet u Beogradu
Klinika za alergologiju i imunologiju, Klinicki Centar Srbije
Adresa autora:
Profesor Sanvila Raskovic
Klinika za alergologiju i imunologiju,
Koste Todorovica 2, 11000 Beograd
E-mail: sanvilar28@gmail.com
SAZETAK
Reakcija na lekove pracena eozinofilijom i sistemskim simptomima (DRESS) opisana je prvobitno
u toku lecenja antikonvulzivnim lekovima. Ovi lekovi mogu prouzrokovati DRESS sa incidencijom od 1
na 5000-10 000 ekspozicija. Mnoge druge klase lekova takodje mogu izazvati DRESS, koji se klinicki
prezenzuje velikom heterogenoscu, ali uobicajeno sa febrilnoscu, morbiliformnim rasom, limfadenopatijom,
eozinofilijom i disfunkcijom jetre. Patogeneza ukljucuje citavu mre:Zu metabolita leka, specificnih HLA
alela, delovanja herpes virusa i aktivacije imunskog sistema. Laboratorijski poremecaji su: eozinofilija koja
je prisutna u vecini slucajeva, moze se videti limfocitoza iii limfopenija, kao i parametri holestatskog iii
hepatocelularnog tipa ostecenja jetre. Virusna reaktivacija moze se dokazati pomocu PCR. Patch testiranje
je preporuceno kao metod potvrde suspektnog leka u DRESS-u koji je uzrokovan antiepilepticima. U
lecenju DRESS-a se koriste sistemski kortikostertoidi i intravenski imunoglobulini.
Kljucne reci: DRESS, preoset1jivost na 1ek, eozinofilija, lezija jetre, febri1nost
Epidemiologija: Reakcija na lekove pracena eozinofilijom i sistemskim simptomima [DRESS]
prvobitno je opisana u toku lecenja antiepilepticima, najcesce karbamazepinom [C8Z), ali sledstveno
i u toku primene mnogih drugih klasa lekova [I], sto je prikazano na TA8ELI I. Antiepileptici mogu
uzrokovati DRESS sa incidencom od I slucaj prema 5 000-I 0 000 ekspozicija [2]. Nekoliko drugih
naziva su u toku godina usvojeni: lekom uzrokovan pseudolimfom, hipersenzitivni sindrom, i odskora.
lekom indukovani odlozeni multi-organski hipersenzitivni sindrom.
Faktori rizika: dva vrha manifestacija DRESS-a uzimajuci u obzir starosno doba, su izmedju
2I-40 godina i izmedju 6I-70 godina [3]. Srednje trajanje izlozenosti leku iznosi oko 28 dana. sto je
unutar perioda od 2-8 nedelja. Mono iii politerapija nije povezana sa pojavom DRESS-a. Specificni
HLA aleli koji izgleda da su povezani sa DRESS-om su sledeci: karbamazepin sa HLA-8*I5:02, a
abacavir sa HLA-8*57:0I alelom. Sadasnja preporuka od strane FDAje geneticki skrining pomenutih
HLA alela, pre nego se zapocne terapija sa ova dva leka [4].
Patogeneza: Mehanizam DRESS-a jos uvek nije kompletno shvacen, on ukljucuje mrezu
matabolita leka, specificnih HLA alela, herpes virusa i aktivacije imunoloskog sistema [I).
Postoje dva dobro definisana modela aktivacije CD4+ T celija putem leka: to su haptenski
koncept i p-i koncept, ali je skoro ustanovljena i, hipoteza alteracije peptidog repertoara".
© 2015 Klinicki centar Srbije, Beograd
 -HAPTENACIJA: njen prvi korak moze biti defektna detoksikacija leka, sa produkcijom
reaktivnih metabolita, koji okidaju imunski sistem putem stvaranja haptena. Za CBZ, opisano je
stvaranje reaktivnih arenskih oksidnih metabolita.
-P-1 KONCEPT: implicira farmakolosku stimulaciju T celija putem direktne stimulacije
T celijskog receptora i imunskog odgovora ( za CBZ, lamotrigin, sulfametoksazol).
-ALTERACIJA PEPTIDNOG REPERTOARA: u ovom modelu, interreakcija leka sa specificnim
MHC- peptid kompleksom rezultuje u generisanju neo-antigena.
-Reaktivacija herpes virusa: Sledstvena reaktivacija herpes virusa (EBV, CMV, HHV-6) koji
proliferisu preferencijalno u CD4+ celijama aktivisanim lekom, pracena nekontrolisanim anti-viralnim
CDS+ celijskim odgovorima, doprinosi generalizovanoj inflamaciji u DRESS-u. Amoksicilin ima
direktni efekat na HHV i EBV replikaciju u in vitro uslovima. lnkriminisani lek takodje inhibira
aktivnost 8 celija, prouzrokujuci tranzitornu hipogamaglobulinemiju.
TABELA 1. Grupe lekom koje mogu izazvati DRESS
Aromaticni antikonvulzivi-carbamazepin, fenobarbiton, fenitoin
Ne-aromaticni antikonvulzivi-valproicna kiselina, lamotrigin, rufinamid
Nesteroidni antiinlamacioni agensi-ibuprofen, fenilbutazon, celecoxib
Antiretrovirusni agensi-abacain, nevirapine, raltegravir
Antibiotici-beta laktami, sulfonamidi, monociklin, ciprofloksacin, azitromicin, linezolid
Antituberkulotici-rifampiciin, amikacin
Inhibitori protonske pumpe
Imunomodulatori- ciklosporin, letlunomid, dapson, sulfasalazin
Statini-atorvastatin
Antihipertenzivi-spironolaktoni
Hipourikemici-alopurinol
Antikoagulanti-acenokumarol, enoxaparin
Hipoglikemici-sitagliptin
KLINICKA SLIKA: Klinicka heterogenost DRESS-a komplikuje napore da se ustanovi set
dijagnostickih kriterijuma [5]. U velikoj evaluaciji 216 pacijenata u Francuskoj [6] klinicki slika je
obicno bila sledeca: febrilnost, ras, limfadenopatija, eozinofilija i lezija jetre, ali to nisu bile
konzistentne manifestacije kod svih bolesnika.
Kozne manifestacije: prvi znaci su obicno febrilnost visokog stepena (3S-40°C), uporedo sa
morbiliformnim rasom. Ras je pleomorfan, moze biti i pustulozan [6], ali generalno bez bula ili erozija.
Edem lica sa centralnim eritemom moze pogresno biti smatran angioedemom. Histopatologija koze
pokazuje superficijalne perivaskularne limfocitne infiltrate i, redje, vaskulitis.
Visceralne manifestacije: ostecenje jetre je najcesca visceralna manifestacija (u oko 60%
pacijanata). U studiji 72 slucaja DRESS-a [7], distribucija hepaticnih lezija bila je sledeca: holestatski
tip 37%, mesoviti tip 27% i hepatocelularni tip 19%. Lezija jetre moze biti odlozenog pocetka, sa
produzenim vremenom oporavljanja. Limfadenopatija je takodje uobicajena. Sistemske manifestacije
\' 2015 Klinicki centar Srhije, Heograd
'\CT<\ Cl l"'IC '\Vol. 15 '"''
mogu ukljuciti i sledece: miokarditis, kolitis, akutni intersticijalni nefritis (alopurinol), pneumonitis.
manifestacije CNS-a, retinopatija.
Laboratorijski poremecaji: eozinofilija ranga preko 1.5x 109/L je prisutna u 30-90% slucaje\ a.
Ona je cesto odlozena, cak se moze pojaviti i nakon normalizacije transaminaza. Takodje, moze se
javiti atipicna limfocitoza iii limfopenija. Poviseni nivoi Interleukina- 5 (11-5), produkovanog od strane
aktivisanih CD4+ celija. doprinose znacajnoj eozinofiliji u sklopu DRESS-a. Osim toga, skretanje od
predominantnog CD4+, Th-2 imunskog profila ka CDS+ citotoksicnom odgovoru, kao i visoki nivoi
IFN- gama i TNF- alfa mogu biti detektovani, sto traje do tri meseca. Viralna reaktivacija HHV-6
I ostalih herpes virusa moze se dokazati putem PCR.
Dijagnoza: RegiSCAR sistem skoriranja je predlozen u cilju pojednostavljenja dijagnostike [S],
ali ovaj sistem nije bio ukljucio reaktivaciju virusa HHV-6. Osavremenjeni dijagnosticki pristup sa
9 parametara razvila je Japanska konsenzus grupa (J-SCAR) (TABELA 2).
DOKAZIYANJE LEKA KAO UZROCNIKA REAKCIJE:
Kozni testovi: Vrednost kutanih testova jos uvek nije jasno razgranicena. Patch testovi [PT] sa
nekim od lekova, ukljucujuci CBZ, su reproducibilno reaktivni. Pocetne koncentracije od 0,1-1% su
preporucene (odnosno do I0%, ako su prethodne negativne) [9]. Rang pozitivnost testa za CBZ iznosi
70-100%.
Ostali lekovi sa visokom frekvencijom pozitivnosti PT su: beta laktami [amoksicilin],
trimetoprim-sulfametoksazol, benzodiazepini. Patch test je izgleda sigurna i korisna metoda potvrde
kauzalnosti inkriminisuceg leka u DRESS-u uzrokovanom antiepileptickim lekovima, ali ima malu
vrednost u DRESS-u izazvanom alopurinolom. Intradermalno testiranje je veoma kontraverzno u
DRESS-u.
Sto se tice in vitro testova, test transformacije limfocita (LLT) moze da potvrdi kauzalnost
leka, s tim sto je pozitivan rezultat mnogo korisniji nego negativan. LLT je pozitivan u periodu od
5-7 nedelja posle nastanka alergijske reakcije na lek.
TABELA 2. Dijagnosticki kriterijumi za DRESS [7 iii vi.5e i5punjenih]
Makulopapularni ras nastao bar 3 nedelje posle ekspozicije leka
Prolongiranje klinickih simptoma i posle ukidanja suspektnog leka
Febrilnost preko 38°C
Poremecaj hepatograma (ALT > IOOU/L) iii drugog organa
Limfadenopatija
Poremecaj broja leukocita ( ::::1 ):
- Leukocitoza
- Atipicna limfocitoza
- Eozinofilija
HHV-6 reaktivacij
'{:; 2015 K!inicki centar Srhije, Heograd
l)l)
LECENJE:
1. Obustava leka: blagi slucajevi se mogu resiti samom obustavom leka i suportivnom terapijom
2. Sistemski kortikosteroidi: ako su simptomi ozbiljniji. prednizon je indikovan u pocetnoj dozi
l-2mg/kg. Vaznost veoma postepenog smanjivanja doze kortikosteroida je podvucena mnogobrojnim
izvestajima o egzarberbaciji simptoma u fazi smanjivanja steroida [10].
3. Intravenski imunoglobulini ( IVIG) koriste se u tezim slucajevima. Mehanizam delovanja
IVIG-a, smatra se, rezultat je blokiranja T-celijskog imunskog odgovora uzrokovanog toksickim
metabolitima leka, ili delovanjem u smislu antivirusnog IgG u slucajevima viralne reaktivacije.
4. Antivirusna terapija sa valganciklovirom, koja pogadja HHV-6 I HHV-7 moze biti indikovana
u DRESS-u pracenom virusnom reaktivacijom, ali za sada ovo jos nije klinicki potvrdjeno.
Prognoza: DRESS je potencijalno zivotno ugrozavajuci sa utvrdjenim mortalitetom od oko 10%,
uglavnom u slucajevima pracenim nekrozom jetre. Autoimunske bolest, kao sto je S~E, dijabe~es tipa
I, autoimunski tireoiditis, mogu biti dugorocne posledice DRESS-a, zbog produkctJe autoantttela, u
oko 12% pacijenata, sto se desava mesecima ili godinama nakon DRESS-a. [ 11 ]. Povisen rizik za
autoimunitet je primecen kod pacijenata koji nisu bili leceni visokim dozama glikokortikoida dovoljno
dugo, kao i u mladjih pacijenata.
LITERATURA:
1. Kuruvilla M, Khan D. Eosinophilic Drug Allergy. Clinic Rev Allerg Immunol. Published on-line,
26 May 2015
2. Chaudhary S, Me Lead M, Torchia D, Romanelli P. Drug reaction with eosinophyllia and systemic
symptoms [DRESS] syndrome. J ClinAesteth Dermatol. 2013; 6[6]:31-7.
3. De Silva Pereira N, Piquioni P, Kochen S, Saidon P. Risk factors associated with DRESS syndrome
produced by aromatic and non-aromatic anti epileptic drugs. Eur J Clin Pharmacal . 2011 ;67 :463-70.
4. Chung WH, Hung SI, Hong HS, Hsih MS eta!. Medical genetics: a marker for Stevens-Johnson
syndrome. Nature 2004; 428[6982]:486.
5. Walsh S.A, Creamer D. Drug reaction with eosinophylia and systemic symptoms (DRESS): a
clinical update and review of current thinking. Clinic and Experimental Dermatol 2010: 36, 6-11.
6. Cacoub P, Musette P, Descamps V, Meyer 0 eta!. The DRESS syndrome: a literature rewiev. Am
J Med 2011; 124(7):588-97.
7. Lin CI, Yang HC, Strong C, Yang CW, Cho YT eta!. Liver injury in patients with DRESS: A clini-
cal study of 72 cases. JAm Acad Derma to!. Published on-line, March 22, 2015
8. Kardaun SH, Sekula P, Valeyre-Allanore L, Liss CY, Creamer D, Sidoroff A et all. Drug reaction
with eosinophilia and systemic symptoms ( DRESS): an original multisystem adverse drug reac-
tion- Results from the prospective RegiSCAR study. British J Dermatol 20 13; 169: 1071-1080.
9. BarbaudA. Drug patch testing in systemic cutaneous drug allergy. Toxicology 2005; 209(2):209-16.
10. Shiohara T, Inaoka M, Kano Y. Drug induced hypersensitivity syndrome [DIHS] : a reaction induced
by a complex interplay anong herpesviruses and antiviral and antidrug immune responses. Allergol
lnt 2006;55( 1): 1-8.
II. Ushigome Y, Kana Y, Ishida T, Hirakara K eta!. Short and long-term outcomes of 34 patients with
drug-induced hypersensitivity syndrome in a single institution. Am J Acad Dermatol 2013;
68[5]:721-8.
,: 2015 Klinicki centar Srbije, Beograd
100 ACTA CI.I~IC\ \'ol. 15 Xd
DRUG ALLERGY
DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS
Sanvila Raskovic
Medical Faculty, University a./Belgrade
Clinic a./Allergology and Immunology, Clinical Center o.l Serbia
Authors address:
Pro.f'essor Sanvila Raskovic
Clinic o.l Allergology and Immunology
Koste Todorovica 2, II 000 Belgrade, Serbia
E-mail: sanvilar28@gmail.com
ABSTRACT
Drug reaction with eosnophilia and systemic symptoms (DRESS) was first described during the
tretment with anticonvulsant drugs. These drugs can cause DRESS with an incudence of I per 5 000-10
000 exposures. Many other medication classes can also induce DRESS, which is presented with wide
clinical heterogenity, but usually with fever, morbiliform rush, lymphadenopathy, eosinophilia and liver
disfunction. The pahogenesis involves a net-work of drug metabolities, specific HLA allels, herpes viruses
and activation of immune system. Laboratory abnormalities: eosinophylia is present in major of cases,
lymhocytosis or lymhopenia can be seen, also the parametars of cholestatic or hepatocellular liver injuru.
Viral reactivation of herpes viruses is assessed by PCR. Patch testing is recomanded as a method of
confirming culprit drug in DRESS induced by antiepileptic drugs. In therapy of DRESS, systemic steroids
and IVIG are used.
Key words: DRESS, drug allegy, eosinophilia, hepatic lesion, fever
Epidemiology: Drug reaction with eosinophillia and systemic symptoms was first described
during treatment with anticonvulsant drugs, most commonly carbazepine (CBZ) and subsequently
with a multitude of medication classes [ 1] (Table 1). Antiepileptic drugs cause DRESS with an
incidence of 1 per 5 000-10 000 exposures. [2]. Several other acronyms were adopted over the years:
drug induced pseudolymphoma, hypersensitivity syndrome, and recently, drug induced delayed multi-
organ hypersensitivity syndrome.
Risk factors : two peaks of DRESS manifestations with respect of age are between 21-40 years
and between 61-70. [3]. The average drug exposure is 28 days, witch is within the period of2-8 weeks.
Mono or po1ytherapy is not related to DRESS. Specific HLA allels apear to be associated wih DRESS:
carbamazepine with HLA-8*15:02, abacavir with HLA-8*57:01 allele. The FDA currenty recomends
genetic screening for the respective HLA allels prior to instituting therapy with these two drugs (4].
Pathogenesis: The mechanism of DRESS is not competely understood, it involves a net-work of
drug metabolites, specific HLA alleles, herpes viruses and immune system activation [I]
-T-cell activation: There are two well defined models for CD+ T cell activation by drugs : the
hapten concept and the p-i concept, but recently there is also ,altered peptid repertoire hypothesis"
C 2015 Klinicki centar Srbije, Beograd
I 01
 T
-HAPTENATION: the first step may be defective detoxyfication of drugs, with production of
reactive metabolites, which trigger immune system via haptenation. For carbamazepin, generation of
reactive arene oxide metabolites was described.
-P-1 CONCEPT: It implies a pharmacologic stimulation ofT-cells via direct stimulation ofT-cell
receptor, with immune response ( for CBZ, lamotrigin, sulfamethoxasole ).
-ALTERED PEPTID REPERTOIRE: In this model, drug interaction with specific MHC peptide
complexes results in generation of neo-antigen.
-Herpesvirus reactivation: A subsequent reactivation ofherpesviruses ( EBV, CMV, HHV-6) that
proliferate preferentially in drug activated CD4+ cells, followed by uncontrolled antiviral CD8+ cell
responses, contribute to the generalized inflammation in DRESS. Amoxicillin has a direct effect on
HHV and EBV replication in vitro. Culprit medications also inhibit 8 cell activity, producing transient
hypogammaglobulinemia.
Table 1 Medications reported to cause DRESS
Aromatic anticonvulsants- carbamazepine, phenobarbital, phenytoin
Non-aromatic anticonvulsants- valproic acid, lamotrigine, rufinamide
1
NSAIDs- ibuprofen, phenylbutazone, celecoxib
Antiretroviral agents -abacavir, nevirapine, raltegravir
Antibiotics- beta lactams, sulfonamides, minocycline, ciprofloxacin, azytromycin, linezolid
Antituberculotics- rifampin, amikacin
Proton pump inhibitors
Immunomodulators -cyclosporine, leflunomide, dapson, sulfasalazine
Statins- atorvastatin
Antihypertensives- spironolactone
] Hypouricemics- allopurinol
Hypoglicemic agents- sitagliptin
CLINICAL PRESENTATION The clinical heterogeneity in DRESS complicates the efforts to
define a set of diagnostic criteria [5]. In major review of cases in France [6], fever, rush,
lymphadenopathy, eosinophilia and liver disfunction occurred commonly, but were not a consistent
feature in all cases.
Cutaneous manifestations: the first signes are usually fever of high grade (38-40°C) along with
morbilliform rush. The rush is pleomorphic and can be pustular [6], but generally without blisters or
erosions. An erythematous central facial swelling can be mistaken for angioedema. Histopathology of
skin demonstrates superficial perivascular lymphocytic infiltrates, rarely vasculitis.
Visceral manifestations: hepatic injury is the most common visceral involvement (in 60% of
patient with DRESS). In study of 72 cases [7], the distribution of hepatic lesions was: cholestatic type
37%, mixed type 27%, hepatocellular type 19%. Liver lesion can be delayed in onset, with prolong
time to recovery. Lymphadenopathy is also common feature. Also, systemic manifestations can include:
myocarditis, colitis, acute interstitial nephritis (allopurinol), pneumonitis, CNS involvement,
retinopathy.
10~ '\CT'\ CII"JIC.'\ Vol. IS >ofo< c 2015 K1inicki centar Srbijc, Heograd
Laboratory abnormalities: Eosinophilia in the presence of more than 1.5 x 109/L in 30-90%
cases. It may often be delayed even occurring after resolution of transaminitis. Also. atypical
lymhocytosis or lymphopenia can occur. Elevated levels of Inerleukin-5, produced by activated CD4_.__
cells contribute to significant eosinophilia. Also, shift from predominantly CD4+. Th2 immunity to
CD8+ cytotoxic T cells and high levels of IFN gamma and TNF alfa can be measured and last up to
3 months. Viral reactivation of HHV-6 and other herpes viruses is assessed by PCR.
Diagnosis: the RegiSCAR scoring system was proposed to simplify the approach to diagnosis
[8], but this system did not include HHV-6 reactivation. An updated diagnostic tool with 9 parameteres
was developed by a Japanese consensus group ( J-SCAR). (Table 2)
ASSEASMENT OF DRUG CAUSALITY
Skin testing: The value of skin testing has not been clearly delineated. Patch testing [PT] with
some medications, including CBZ have reproduced cutaneous reactions. Starting concentration of
0,1-1% is recommended ( up to 10% if negative) [9]. The positive rate for CBZ is 70-100%.
Other drugs with high frequency of positive PTs are: beta-lactams [amoxicillin ], trimethoprim-
sulfamethoxasole, benzodiazepines. PT appears to be safe and useful method of confirming the culprit
drug in DRESS induced by antiepileptic drugs, but it has little value in DRESS caused by allopurinol.
Intradermal testing is controversial in DRESS.
In vitro testing: LLT -lymphocyte transformation test may support causality, the positive results
are more useful! than negative. LLT is positive at 5-7 weeks after onset of drug reaction.
Table 2. Diagnostic criteria for DRESS (seven or more required)
Maculopapular rash developing >3 weeks after drug exposure
Prolonged clinical symtoms after discontinuation of the causative drug
Fever>38° C
Liver abnormalities (ALI> 100 UIL) or other organ involvement
Limphadenopathy
WBC abnormalities (~1 ):
- Leukocytosys
- Atypicallymhocytosys
- Eosinophilia
HHV-6 reactivation
TREATMENT
1. Drug discontinuation: mild cases may be menaged by drug withdrawal and supportive therapy.
2. Systemic corticosteroids: if symptoms are more severe, prednison is indicated at a dose of 1-2
mg/kg. The importance of graduated steroid taper is highlighted by multiple reports of symptom flare
during taper [10].
3. Intravenous immunoglobulins (IVIG) are used in severe cases. The mechanisam of IVIG is
thought to result by blocking the T cell-mediated immune response in toxic metabolites, or by acting
as a antiviral IgG in cases of viral reactivation.
2015 Klinicki centar Srbije, Beograd
ACTA Cl INICA Vol. IS No'
 4. Antiviral therapy with valgancyclovir, targeting HHV-6 and HHV-7 could be indicated for
DRESS with viral reactivation, but cllinicaly this has not been confinned yet.
Prognosis: DRESS is potentially life-threatening with an estimated mortality of about 10%.
mostly in cases with liver necrosis. Autoimmune diseases such as SLE, diabetes mellitus type I,
autoimmune thyreoiditis can be long-tenn sequele, because of autoantibody production, in about 12%
of cases. months or years after DRESS [ 11 ]. An increased risk for autoimmunity is observed in patients
who were not treated with high-dose prolonged courses of corticostertoids and in younger patients.
REFERENCES:
1. Kuruvil1a M, Khan D. Eosinophilic Drug Allergy. Clinic Rev Allerg Immunol. Published on-line,
26 May, 2015
2. Chaudhary S, Me Leod M, Torchia D, Romanelli P. Drug reaction with eosinophyllia and systemic
symptoms (DRESS) syndrome. J ClinAesteth Dermatol2013; 6(6):31-7.
3. De Silva Pereira N, Piquioni P, Kochen S, Saidon P. Risk factors associated with DRESS syndrome
produced by aromatic and non-aromatic antiepileptic drugs. Eur J Clin Pharmacal . 2011 ;6 7:463-70.
4. Chung WH, Hung Sl, Hong HS, Hsih MS eta!. Medical genetics: a marker for Stevens-Johnson
syndrome. Nature 2004; 42(6982):486.
5. Walsh S.A, Creamer D. Drug reaction with eosinophylia and systemic symptoms (DRESS): a
clinical update and review of current thinking. Clinic and Experimental Dermatol 2010: 36, 6-11.
6. Cacoub P, Musette P, Descamps V, Meyer 0 eta!. The DRESS syndrome: a literature rewiev. Am
J Med 2011; 124 (7):588-97.
7. Lin CI, Yang HC, Strong C, Yang CW, Cho YT eta!. Liver injury in patients with DRESS: A clini-
cal study of 72 cases. JAm Acad Dermato!. Published on-line, March 22, 2015
8. Kardaun SH, Sekula P, Valeyre-Allanore L, Liss CY, Creamer D, Sidoroff A et all. Drug reaction
with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction-
Results from the prospective RegiSCAR study. British J Dermatol 20 I3; 169: 107I-I 080.
9. Barbaud A. Drug patch testing in systemic cutaneous drug allergy. Toxicology 2005; 209[2] :209-16.
I0. Shiohara T, lnaoka M, Kano Y. Drug induced hypersensitivity syndrome (DIHS): a reaction induced
by a complex interplay anong herpesviruses and antiviral and antidrug immune responses. Allergol
Int 2006;55( I): I-8.
II. Ushigome Y, Kano Y, Ishida T, Hirakara K eta!. Short and long-term outcomes of 34 patients with
drug-induced hypersensitivity syndrome in a single institution. Am J Acad Dermatol 20I3;
68(5):721-8.
~ 2015 Klinicki centar Srbije, Heograd
104 \CT.\ CLI~IC\ Vol. 15 -'~""'
ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA
LEKOVIMA IZAZVAN LUPUS
Sanvila Raskovic
Medicinskifakultet, Univerzitet u Beogradu
Klinika za alergologiju i imunologiju, Klinicki Centar Srbije
Adresa autora:
Profesor Sanvila Raskovic
Klinika za alergologiju i imunologiju,
Koste Todorovica 2, 11000 Beograd
E-mail: sanvilar28@gmail.com
SAZETAK
Lekovima indukovani lupus (OIL) je autoimunski fenomen koji je iniciran primenjenim lekom, a
rezultira u sindromu koji ima neke zajednicke karakteristike sa sistemskim eritemskim lupusom (SLE).
Lekovi kao sto su prokainamid i hidralazin su cvrsto povezani sa razvojem DIL, ali u toku protekle dekade,
prijavljeni su slucajevi DIL-a koji su povezani sa davanjem bioloske terapije, uglavnom sa anti TNF- alfa
agensima. Bolesnici sa DIL obicno se prezentiraju febrilnoscu, artralgijama, mijalgijama i serozitisom.
Zahvatanje bubrega i nervnog sistema je izuzetno retko. Prepoznate su tri klinicke forme: sistemska,
subakutna kozna i hronicna kozna forma. Seroloske karakteristike DIL-a su: prisustvo antinukleusnih
antitela, anti-histonska antitela u do 95% slucajeva. Medjutim, anti TNF- alfa indukovani OIL moze se
prezenovati znacajnim titrom anti dsDNA anti tela i snizenom incidencom anti-histonskih anti tela. U tezim
slucajevima, osim ukidanja inkriminisuceg leka, neophodna je terapija kortikosteroidnim lekovima.
Kljucne reCi: lupus, preoset1jivost na lek, anti histonska antitela, bioloski agensi
Lekom indukovani lupus (DIL) je podgrupa bolesti koje se odnose na lupus. Prvi put je opisan
u toku terapijske primene sulfadiazina 1945.godine, a zatim i I952. kod izvesnog broja pacijenata
lecenih hidralazinom. [I]. Prokainamid je lek koji je najcesce povezan sa razvojem ovog sindroma.
Medjutim, danas se smatra daje OIL povezan sa primenom vise od 80 razlicitih lekova (TABELA I).
Relativna incidenca OIL je oko 20% godisnje za prokainamid, 5-8% za hidralazin, manje od 1% za
kinidin a znatno je niza za ostale lekove.
Postoji nekoliko razlika izmedju idiopatske fonne SLE i OIL-a. Idiopatski SLE se javlja u odnosu
7: I do 9: I posmatrajuCi ucesce zenskog i muskog pola, dok je u OIL podjednako. Ucesce starosne
dobi pacijenata u OIL-u reflektuje udeo primene suspektnog leka u samoj populaciji. Znaci, dok je
idiopatski SLE vise prisutan u mladjoj populaciji, OILje vise zastupljen u starijoj dobi pacijenata, kod
kojih je izlozenost lekovima veca. Incidenca lupusa izazvanog lekovima je I5-20 000 slucajeva
godisnje, bela rasa je pogodjena sest puta cesce, a faktori rizika su i stanje usporene acetilizacije,I
prisustvo alela HLA-OR4, HLA-OR030I iii nultog alela za C4 komponentu komplementa.
Klinicki OIL se cesto manifestuje artralgijama, mijalgijama, serozitisom, febrilnoscu i koznim
manifestacijama, koje su razlicite od malamog rasa, fotosenzitivnosti i oralnih ulceracija [2]. Retko
~ 2015 Klinicki centar Srbi ie. Reo grad ACTACLll\illA \ol.i5J;"_; 105
je zahvatanje centralnog nervog sistema i bubrega, kao i alopecija, diskoidne promene i oralne Hipoteza ~irektn~ citotoksicnosti: Izvesni metaboliti Ieka mogu direktno prouzrokovati celijsku
ulceracije. Medju subakutnim koznim lezijama u DIL-u, vidjaju se na kozi donjih ekstremiteta: s~rt putem ne-.~~~ns.ki pos~edova~og pro_cesa. Metaboliti Ieka takodje mogu izmeniti degradaciju iii
purpura. nodozni eritem i urtikarijalni \askulitis. Hronicne kozne lezije nadjene u DIL-u ukljucuju klirens ~poptot1~mh celiJa. sto vod1 u gub1tak tolerancije za sopstvene antigene [7].
diskoidne promene i retko lupus tumidus, koji se obicno odnosi na primenu tluorouracila i anti TNF H~poteza hmfocitne aktivacije: Misji splenociti izlozeni prokainamidu iii hidraiazinu in vitro.
lekova [3]. pokaz~Ju_ povisen ~r~Ii~~r~tiv~i odgovo~ pre~a autolognim antigen-prezentirajucim celijama.
Medju laboratorijskim poremecajima, poviseni titar antinukleusnih antitela (ANA) je univerza- Adopt1vm transfer t1h celiJa Izaziva lupus-like smdrom u miseva.
lan u DIL-u, kao i u idiopatskom SEL-u, uglavnom sa homogenim tipom tluorescencuije u DIL-u. . P_re~id centralne ii_Tiunske tolerancije: U murinom modelima, intra-timicna injekcija Jupus-
Antihistonska antitela (At) se otkrivaju u oko 75% u DIL-u, ali ipak ona nisu patognomonicna za OIL. mdukuJU~Ih lekova rezul_I:a u produzenoj proizvodnji anti-hromatinskih At. Ovi Jekovi interferiraju sa
Antihromatinska (antinukleozomna) At su takodje nadjena i u idiopatskom SLE i u DIL-u. Kao kon- uspostav!Jenom toleranciJOm na endogene self-antigene [8].
trast, antitela protiv dvo-lancane DNA (anti-ds DNA) se nalaze u 50- 70% pacijenata sa idiopatskim
SLE, dok se pojavljuju u manje od 5% slucajeva OIL-a. Cesto se mogu naci antitela na jedno-lancanu
BIOLOSKI AGENSI I OIL
DNA (anti-ssDNA) u DIL-u. Prisustvo anti-Smith (anti-Sm) At je ekskluzivno za idiopatski SLE.
Antifosfoiipidna At, kao i lupusni antikoagulans (LAC) opisani su samo u retkim slucajevima OIL-a. Anti-TNF al~a:_ Poc~vsi od uvodjenja u lecenje TNF-alfa antagonista 1998.godine, vise slucajeva
Ali, kod 75% pacijenata lecenih hlorpromazinom nadjeno je prisustvo LAC [4]. Hematoloske mani- TNF-alfa antagomst1ma mdukovanog lupusnog sindroma (TAILS) je prijavljeno. Ova grupa Jekova
festacije, odnosno citopenije, koje su prisutne u idiopatskom SLE, mogu se javiti u DIL-u, ali obicno ukljucuje intliximab, etanercept, i adaiimumab [9]. Intliximab je najimunogeniji, sto se zasniva na
su blage, dok je sedimentacija eritrocita obicno ubrzana. Lupus izazvan lekovima je predominantno njeg~~oj him~rickoj strukturi i sposobnosti da dostigne visoku koncentraciju u tkivu. Pacijenti na
normo-komplementemijska bolest. terapiJI sa anti TNF-alfa mogu produkovati anti tela [I 0]. Zapazena je pojava ANA u 73% bolesnika
Sledece preporuke za OIL cesto se koriste u praksi [ 1]: sa Reumatoidnim artritisom i u 52% bolesnika sa Ankilizirajucim spondilitisom, a takodje i pojava
-Lecenje suspektnim lekom bar u toku mesec dana anti- DNA anti tela. Incidenca TAILS-a je niska, izmedju 0.5-1%. U nekoliko serija pacijenata,
-Simptomi /zahvatanje organa: artralgija, mijalgija, febrilnost, serozitis i ras. najucestaliji simptomi su bili: artritis, miozitis I serozitis. U TAILS-use Anti ds DNA At pronalaze
-Laboratorija: ANA, anti-histonska AT, u odsustvu drugih specificnih At cesce, u 72-92%, ali za razliku od SLE, ona su obicno IgM subtipa. Medjutim, anti-histonska At u
-Poboljsanje simptoma u toku nekoliko dana/nedelja posle obustavljanja leka. pacijenata sa TAILS su nadjena u samo 17-57%. Kod nekih slucajeva, predpostavlja se da anti TNF
Tri forme OIL-a su prepoznate 1) Sistemska forma 2) Subakutna kozna forma, cesca u zena, uz samo "demaskira" idiopatski SLE kod bolesnika.
ANA. anti-histonska AT, Ro i La At 3) Hronicna kozna formaje retka i obicno povezana sa primenom Pretpostavljeni mehanizmi delovanja kod TAILS su : indukcija celijske apoptoze sa
tlorouracila. osiobadjanjem antigenih partikula, zatim imunosupresija koja dovodi do bakterijske infekcije sa
pojavom poliklonalnih B limfocita, kao i supresija Th-1 imunskog odgovora I favorizovanje Th-2
Tahela 1. Lekori koji izazivaju DIL
odgovora.
! Definitivno Pretpostavljeno Moguce Noviji izvestaji Lecenje pacijenata sa TAILS i blazom klinickom slikom zahteva prekid bioloske terapije, dok
Hidralazin Sulfasalazin Antibiotici Infliximab oni sa TAILS i tezom klinickom slikom, osim prekida primene bioloskog agensa zahtevaju uvodjenje
Antikonvulzivi Nesteroidni agensi Etanercept oralnih kortikosteroida .
Prokainamid
Interferoni: Incidenca OIL-a medju pacijentima lecenim razlicitim tipovima humanih Interferona
lzonijazid Tireosupresivi Antihipertenzivi Interleukin-2
(IFN), je najvisa kod primene IFN -a! fa i procenjena je na oko 0.15-0.7% [II]. Ovi slucajevi se
Metildopa Statini Litijum Zafirlukast karakterisu vecim ucescem kutanih I renalnih manifestacija, uz produkciju anti DNA.
Kinidin Terbinafin Interferoni Clobazam
Minociklin Penicilamin Soli zlata Tocainid LITERATURA:
Hlorpromazin Fluorouracil Beta-blokeri Lisinopril ', l. Sarzi-Puttini P, Arzeni F, Capsoni F, Lubrano E, Doria A. Drug-induced lupus erythematosus. Au-
toimmunity 2005;38:507-18.
2. Katz U, Zandman-Goddard G. Drug-induced lupus: An update. Autoimmunity Reviews 201 O; 10:
MEHANIZAM RAZVOJA LEKOM IZAZVANOG LUPUSA 46-50.
Haptenska hipoteza: predpostavijeni mehanizam ukijucuje metabolite Ieka koji mogu deiovati 3. Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: an update on its dermatologic aspects. Lupus
kao hapteni za lekom izazvani T celijski odgovor [5]. Sam lek iii metabolit vezuje se za protein, sto 2009; 18:935-40.
pokrece imunski odgovor protiv haptena iii moguce sopstvenog antigena, preko molekulske mimikrije 4. Zarrabi MH, Zucker S, Miller F, Derman RM, Romano GS, Hartnett JA et al. Immunologic and
iii prerade anti gena koja rezultuje u prezentaciji skrivenog anti gena [6] coagulation disorders iun chlorpromazine-treated patients. Ann Intern Med 1979:91: 1949 ....

106 \lT\ ll.l'iiC '\Vol. I~-"~"' L 2015 Klinicki ccntar Srbiie. Beograd c, 201' Klinicki ccnt3r Srhijc. llcograJ
AC lA CI.INICA \"of. 15 -""-' 107
 5. Vasoo S. Drug-induced lupus: an update. Lupus 2006;15:757-61.
6. Griem P, Wulferink M, Sachs B, Gonzales JB, Gleichmann E. Allergic and autoimmune reactions
T
I DRUG ALLERGY

to xenobiotics:how do they arise.Immunol Today 1998:19:133-41.

7. Williams DP, Pirmohamed M, Naisbitt OJ, Uetrecht JP, Park BK. Induction of metabolism-depen-
DRUG-INDUCED LUPUS
dent and independent neutrophil apoptosis by clozapine. Mol Pharmacal 2000:58;207-16. Sanvila Raskovic
8. Kretz-Rommel A, Rubin RL. Disruption of positive selection of thymocyte causing [autoimmunity. Medical Faculty~ University of Belgrade
Nat Med 2000:6;298-305 Clinic ofAllergology and Immunology, Clinical Center of Serbia
9. Fenandez-Araujo S, Lana-Ahijon M, Isenberg DA. Drug-induced lupus: Including anti-tumour
necrosis factor and interferon induced. Lupus 2014:23:545-53. Authors address:
1o. Wetter DA, Davis MD. Lupus -like syndrome attributable to anti-tumor necrosis factor alfa thera- Professor Sanvila Raskovic
py in 14 patients during an 8- year period at Mayo clinic. Mayo Clin Proc 2009;84:979-84. Clinic ofAllergology and Immunology
11. Antonov o, Kazandijeva J, Etugov 0 at a!. Drug-induced lupus erythematosus. Clin Dermatol Koste Todorovica 2, 11000 Belgrade, Serbia
2004,22:157-66. E-mail: sanvilar28@gmail.com

ABSTRACT

Drug-induced lupus (OIL) is an autoimmune phenomenon triggered by a given drug and resulting a
syndrome sharing several features of systemic lupus erythematosus (SLE). Drugs like procainamid and
hydralazine are strongly associated with OIL, but during the past decade, cases of OIL related to biologic
therapy were reported, mostly with anti TNF alfa agents. Patients with OIL commonly present with fever,
arthralgia, myalgia and serositis. Renal and neurologic involvment is rare. Three forms of OIL are
recognized: systemic, subacute cutaneous and chronic cutaneous form. Serological featers of OIL are: the
presence of antinuclear antibodies, anti-histone antibodies in up to 95%. Anti-TNF induced OIL may present
with significant anti ds-DNA antibody titers and a decreased incidence of anti-histone antibodies. In severe
cases, cessation of incriminating drug and corticosteroid therapy is essential.
Key words: lupus, drug allergy, anti- histone antibodies, biological agents

Drug-induced lupus (DIL) is a subset oflupus related deseases. It was first described in following
the treatment with sulfadiazin in I945, and than I952 in a number of patients treated with hydralazin
[I] . Procainamid is the most frequent involved drug. But, nowadays, OIL is associated with more than
80 different medications.( Table I). The relative incidence of DIL is about 20% per year for procainamid,
5-8% for hydralazine, less than I% for quinidine, and much less for other drugs.
Several differences exist between the idiopathic form of SLE and OIL. Idiopathic SLE has a
female:male ratio of 7:1 to 9:1. OIL has a gender ratio reflecting the relative use of suspected drug.
Idiopathic SLE is present in younger patients, while OIL apperas in older, with greater exposure to drugs.
Estimasted OIL incidence is 15 000-20 000 cases per year, whites may be affected up to six times more
frequently, risk factors are slow acetylator status, HLA-DR4, HLA-DR0301, complement C4 null allele.
In clinical presentation, OIL occurs frequently with arthralgia, myalgia, serositis, fever and
cutaneous manifestations, which are different from malar rash, photosensitivity and oral ulcers.[2].
Renal and central nervous system involvement are rare, such as alopecia, discoid rash and oral
ulcerations. Among subacute cutabneous lesions in OIL, purpura, erythema nodosum, urticarial
vasculitis can be found usually on lower extremities, and these lesions are realated with ACE inhibitors,
calcium channel blockers and anti-TNF drugs. Chronic cutaneous lesions found in OIL include discoid
lesions and rarely lupus tumidus, usually related to fluorouracil and to anti TNF drugs. [3].

:e, 20 IS K linicki centar Srhije. Reograd 16,2015 K!inicki centar Srhije. Rengrad ACTA CLINICA Vol. IS N~3 109
I 08 ACT,\ CL!~IC\ Vol. 15 Xd
 Among laboratory abnonnalities, elevated titers of antinuclear antibodies (ANA) are universal in BIOLOGICAL AGENTS AND OIL
OIL, as in idiopathic SLE, generally with a homogenous pattern in OIL. Anti-histone antibodies (Abs) are
detected in 75% in OIL. but however they are not patognonomic for OIL. Anti-chromatin [antinucleosome] Anti TNF-alfa: Since the introduction ofTNF-alfa antagonists in 1998. several cases ofTNF-alfa
Abs are also found in both idiopathic SLE and OIL. In contrast, anti-double stranded DNA (anti-ds DNA) ~nt~g_onist induced lupus syn~rome (TAILS)_ h_ave been reported. This group of drugs includes
Abs are found in 50-70% cases of idiopathic SLE, while they apper in less than 5% of patients with OIL. mtliximab, etancercept and adahmumab [9] · Inthxnnab · is the most 1'mmunogeni·c , base d on 1·t s c1mnenc
· ·
It is frequent to find Abs to single-stranded DNA (anti ss-DNA) in OIL. The presence of anti-Smith (anti- structure a~d a~ility to reach high tissue concentrations. Patients on treatment with anti TNF -alfa
Sm) Abs is exclusive for idiopathic SLE. Antiphospholipid Abs as well as lupus anticoagulants (LAC) deve_lop a~tibo~Ies [ 1O,J_. It can_ i~~uce the a~~e~rance of A~A in :3% patients with rheumatoid arthritis
were described in several cases of OIL. LAC was reported in 75% patients treated w'ith chlorpromazine and m 52 Y~ patients \\ Ith ankiiizmg spondiiitis.,and also It can mduce anti DNA Abs. The incidence
[4]. Hematological abnonnalities typical for idiopathic SLE are usually present, but mild, and erythrocyte of hTAILS
.. Is low,
. . between 0.5-1%. In several patients series the most common symptoJn s \\ere . ..
sedimentation rate is frequently elevated. OIL is predominantly a nonno-complementic disease. art ntis, myositis and serositis. Anti ds- DNA Abs are found more frequently, 72-92%, but unlike SLE
The following guidelines for OIL are commonly used [ 1] they are usually. o~ IgM sybtipe. But a~ti-histone Abs in patients with TAILS are found in only 17-57%:
Treatment with the suspected drug of at least one month In some cases, It Is suspected that anti-TNF agents underline idiopathic SLE.
- Symptoms /organ involvement: arthralgia, myalhia, fever, serositis and rash. . Pro~able mechanism_of acti~n of TAILS are: inducing cell apoptosis with relase of antigenic
- Laboratory: ANA, anti-histone, in the absence of other antibody specificities particles: ImmunosuppressiOn which leads to bacterial infection with polyclonal 8-lymhocites. and
- Improvement of symptoms within days /weeks after drug discontinuation suppressiOn ofTh- 1 immune response and favouring a Th-2 response.
Three forms of OIL have been recognized 1) The systemic form; 2) The subacute cutaneous Treatment: Patients with TAILS and mild features need cessation of therapy, but patients with
fonn, more common in females, with ANA, antibodies to histone, Ro and La; 3) The chronic cutaneous TAILS and severe features,need cessation of biological agent and the initiation of oral co 11icosterids.
fonn is rare and usually related to florouracil compounds. . IFN :_The incidence of OIL, among the patients treated with different types of human IFNs, is
Table 1. Drugs implicated in the derelopment of DIL highest With IFN-alfa estimated to be 0,15-0,7% [11]. These cases lead to a higher incidence of
Definite Probable Possible Recent reports cutaneous and renal involvement, with the development of anti DNA.
Hydralazine Sulphasalazine Antibiotics lnfliximab
Procainamide Anticonvulsants Non-steroidal agents Etanercept REFERENCES:
Isoniasid Anti-thyroid Antihipertensives Interleukin-2 I. S~rzi-Put_tini P, Arzeni F, Capsoni F, Lubrano E, Doria A. Drug-induced lupus erythematosus. Au-
Methyldopa Statins Lithium Zafirlukast tOimmumty 2005;38:507-18.
Quinidine Terbinafirie Interferons Clobazam 2. Katz U, Zandman-Goddard G. Drug-induced lupus: An update. Autoimmunity Reviews 2010:10: ~6-50.
Minocycline Penicillamine Gold salts Tocainide 3. Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: an update on its dermatologic aspects. Lupus
2009; 18:935-40.
Chlorpromazine Fluorouracil agents Beta-blockers Lisinopril
4. Zarrabi ~H, ~ucker ~' Miller F, Derman RM, Romano GS, Hartnett JA et al. Immunologic and
coagulatiOn disorders wn chlorpromazine-treated patients. Ann Intern Med 1979:91:194-9.
MECHANISMS FOR THE DEVELOPMENT OF DRUG-INDUCED LUPUS [5]
5. Vasoo S. Drug-induced lupus :an update. Lupus 2006:15:757-61.
Hapten hypothesis: Proposed mechanisms include drug metabolities that may act as haptens for
6. Griem P, Wulferink M, Sachs B, Gonzales JB, Gleichmann E. Allergic and autoimmune reactions
drug-driven T-cell response. Either drug or its metabolite binds to protein, thus incites an immune
to xenobiotics:how do they arise. Immunol Today 1998:19:133-41.
response against the hapten or possibly self antigens by molecular mimicry or antigen processing,
resulting in presentation of criptic antigens [6] 7. Williams_DP, Pinnohamed M, Naisbitt OJ, Uetrecht JP, Park BK. Induction of metabolism-depen-
Direct cytotoxicity hypothesis: Certain drug metabolites may directly cause cell death via a non- dent and mdependent neutrophil apoptosis by clozapine. Mol Phannacol2000:58:207-16.
immune mediated process. Drug metabolites also can alter degradation and clearence of apoptotic cells 8. Kretz-Rommel A, Rubin RL. Disruption of positive selection of thymocyte causing autoimmunity.
which can lead to the loss of tolerance for self antigens [7]. Nat Med 2000:6;298-305
Lymphocyte activation hypothesis: Murine splenocytes exposed to procainamid or hydralazine 9. Fenandez-Araujo S, Lana-Ahijon M, Isenberg DA. Drug-induced lupus: Including anti-tumour
in vitro demonstrate an increased proliferative response to autologous antigen-presenting cells. necrosis factor and interferon induced. Lupus 2014:23:545-53. .__
Adoptive transfer of such cells induce a lupus-like syndrome in mice. I0. Wetter DA, Davis MD. Lupus ~like syndrome attributable to anti-tumor necrosis factor alta thera-
Disruption of central immune tolerance: In murine models, intra-thymic injections of lupus- py in 14 patients during an 8- year period at Mayo clinic. Mayo Clin Proc 2009:84:979-84.
inducing drugs result in a sustained production of anti-chromatin Abs. These drugs interfered with the 11. Antonov D, Kazandijeva J, Etugov Datal. Drug-induced lupus erythematosus. Clin Dermatol
establishment of tolerance to endogenous self-antigens [8]. 2004,22:157-66.

110 ACT\ CU\:JC.\ \'ol. IS .\c] ,. 201" Klinicki ccntar Srhijc. Beograd t· 2015 Klinic·!..i celllar Srb1je. Beograd
Ill
T
ALERGIJSKE REAKCIJE IZAZVANE LEKOVIMA

UPUTSTVO AUTORIMA

Urednistvo casopisa ,Acta Clinica" moli autore da se prilikom pripreme i obrade tekstova pri-
drzavaju sledecih uputstava.
Casopis je namenjen lekarima opste medicine~ specijalistima pojedinih medicinskih grana i
strucnjacima iz drugih biomedicinskih oblasti. Casopis objavljuje strucne i naucne radove po pozivu
gosta urednika za svaki tematski broj. Radovi treba da budu pripremljeni u formi preglednih radova.
Gost urednik kontaktira saradnike tematske sveske tokom procesa pripreme tekstova, vrsi stilsko i
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Gost urednik dostavlja urednistvu casopisa i korigovane verzije radova prema zahtevima recenzent-
skog tima.
Radovi se dostavljaju u dva primerka, na srpskom i engleskom jeziku, odstampani na laserskom
stampacu, samo na jednoj strani bele hartije formata A4, dvostrukim proredom sa najvise 30 redova
po strani i sa marginom od najmanje 3 em. Dozvoljeni obim rukopisa koji ukljucuje sazetak, sve pri-
loge i spisak literature treba da iznosi do 15 stranica. Pored stampane verzije, tekstualna verzija rada
se salje u obliku elektronske forme, na CD-u za PC kompatibilne racunare uz koriscenje Word for
Windows programa za obradu teksta.
Prilozi u obliku tabela, crteza~ grafikona i sl. trebalo bi da budu izradeni u nekom od PC kom-
patibilnih programa, snimljeni u nekom od uobicajenih grafickih formata i odstampani na laserskom
stampacu. Svaki prilog treba da bude pripremljen na posebnom listu papira, odnosno snimljen u po-
sebnom dokumentu na CD-u koja sadrzi tekstualnu verziju rada. Na poledini svakog odstampanog
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originali slika (fotografije, slajdovi, rentgenski, CT i MR snimci, itd). Troskove stampanja kolor slika
u radu snosi sam autor teksta.
Prva strana rukopisa sadrzi Naslov rada koji treba da bude kratak, jasan i bez skracenica. Zatim
slede puna imena i prezimena autora~ bez titula iii akademskih zvanja. U sledecem redu se navode
ustanove u kojima pojedini autori rade uz njihovo povezivanje sa odgovarajucim imenima autora bro-
jevima u superskriptu. U dnu stranice se navodi ,Adresa autora" uz navodenje imena i prezimena
prvog autora, titule, pune postanske adrese i e-mail adrese.

~ 2015 Klinicki centar Sroi_ie. Reograd AL lA LLINIL A \ol. 15 N~3 113

 Sazetak duzine do 250 reci predstavlja sledecu stranu rukopisa. Na kraju ove strane se navodi Rad u zborniku radova:
do pet kljucnih reci. Harley ~H. Comparing radon daught~r dosimetric and risk models. U: Gammage RB, Knye SV.
Predlaze se da sadrzaj rukopisa bude podeljen odgovarajucim podnaslovima na manje celine. eds. Indoor a1~ and human health. Proceedmgs of the Seventh Life Sciences Symposium: 1984 Oct
Ukoliko se u tekstu rada koriste skracenice, potrebno je da se pri prvom njihovom pominjanju u tekstu 29-31; Knoxville (TN). Chelsea (Ml): Lewis, 1985: 69-78.
ispisu punim nazivom. Predlaze se koriscenje generickih naziva lekova, a ukoliko je neophodno, zas-
Disertacije i teze:
ticena imena lekova u tekstu navoditi velikim slovima. Predlaze se koriscenje SI mernih jedinica
ukoliko nije medunarodno drugacije prihvaceno. . Cairns ~B. I~frared spectroscopis studies of solid oxygen. Disertacija. Berkley, California: Uni-
versity of California, 1965.
Literatura se u tekstu oznacava arapskim brojevima u srednjoj zagradi prema redosledu poja-
vljivanja, npr. [23]. U popisu literature na kraju teksta, citirane literature podatke poredati po redosle- Rukopisi koji ukljucuju sve priloge u papirnoj formi i elektronskoj formi na CD kao i originate
slika, salju se na adresu: '
du po kojem se prvi put pojavljuju u tekstu. Nazivi casopisa se skracuju kao u Index Medicusu. Kori-
stiti Vankuverski stil citiranja (za detalje videti N Engl 1 Med 1997; 336 (4): 309-15). Ukoliko je
preko sest autora, navesti prvih sest i dodati ,et al".
Urednistvo ACTA CLINICA
Klinicki centar Srbije
Cianci u casopisima: Pasterova 2
Originalni rad: 11000 Beograd
Williams CL, Nishihara M, Thalabard J-C, Grosser PM, Hotchkiss J, Knobil E. Corticotropin-
releasing factor (CRF) inhibits gonadotropin-releasing hormone pulse generator activity in the rhesus Rukopisi i ostali prilozeni materijali se ne vracaju autorima.
monkey. Neuroendocrinology 1990; 52: 133-7.

Uvodni rad:
Tomkin GH. Diabetic vascular disease and the rising star of Protein Kinase C (editorial). Dia-
betologia 2001; 44: 657-8

Volumen sa suplementom:
Magni F, Rossoni G, Berti F. BN-52021 protects guinea pig from heart anaphylaxis. Pharmacal
Res Commun 1988; 20 Suppl 5: 75-8.

Sveska sa suplementom:
Myers BD. Pathophysiology of proteinuria in diabetic glomerular disease. 1 Hypertens 1990; 8
(I Suppl): 41 S--46S

Sazetak u casopisu:
Fuhrman SA, Joiner KA. Binding of the third component of complement C3 by Toxoplasma
gondi (abstract). Clin Res 1987; 35: 475A.

Knjige i druge monogra.fije:

Jedan iii vise autora:
Eisen HN. Immunology: an introduction to molecular and cellular principles of the immune
response. 5th ed. New York: Harper and Row, 1974: 406.
Poglavlje u knjizi:
Weinstein L, Shwartz MN. Pathologic properties of invading microorganisms. U: Soderman WA
Jr, Soderman WA, eds. Pathologic physiology: mechanisms of disease. Philadelphia: Saunders,1974:
457-72.

114 Al rA CLil\iiCA \'ol. 15 }'i"3 ""101' Klinicki centRr "rhije. Reograd © 2015 Klinicki centRr \;rhije. ReogrRd
ALIA CLINICA \ol. 15 N2J j j5
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tacts coauthors of the thematic issue during process of manuscript preparation, does stylistic and
technical coordination according to requirements in journal instructions, and delivers them to the
editorial board. Guest editor delivers to the editorial board manuscript versions corrected according
to the requirements of reviewers team.
Manuscripts should be submitted in duplicate, in Serbian and English language, printed by
laser printer, on one side of paper format A4, double space with at most 30 lines per page and at
least 3 em margin. Manuscripts including abstract, all the appendixes and references should be
no longer than 15 pages. Besides printed version, textual version of the manuscript should be
submitted in electronic form, on CD for PC compatible computers using Word for Windows text
processor. . .
Appendixes in the form of tables, drawings, graphs etc. should be done m PC compatible pro-
gram, saved in usual graphic format and printed by laser printer. Each appendix should be submitted
on separate sheet of paper, and saved in separate document on CD which contains textual version of
manuscript. Number which appendix will carry in the manuscript, as well as manuscript title should
be written on the back side of each printed appendix. Titles and legends of each appendix are given
on a separate sheet of paper, printed with double space. Each table should be prepared on a separate
sheet of paper, with double space, including title which is preceded by serial table number. Position
of the appendix in the manuscript should be marked. Original images are submitted with manuscript
(photographs, slides, x-rays, CT and MR images etc.). Expenses for color images printing are covered
by author of the manuscript.
First page of the text should contain Title of the manuscript which should be short and clear
without abbreviations. It is followed by full author's names and surnames, without titles and academic
positions. In the next line institutions affiliations are written, with their linking with corresponding
authors names by superscript numbers. At the bottom of the page ,Author address" is given in with
name and surname of the first author, title, full mailing address and e-mail address.
Abstract, length up to 250 words represents next page of the manuscript. At the bottom of this
page up to five key words are given.
. It is sug~e~tested that manuscript should be divided by subtitles into smaller parts. If abbreYia-
tiOns are used It Is necessary that they are given by full term by their first appearance in the manuscript.
It is suggested that generic drug names should be used, if necessary registered drug names should be
given i~ capital letters. Usage of SI measurment units is recommended, if internationally not accepted
otherwise.
Literature is marked in the manuscript by arabic numbers in the middle parenthesis according
to the. order o.f appearance, i.e. [23], and listed in the same numerical order at the end of the manuscript.
The titles of Journals should be abbreviated according to the style used in the Index Medicus. Vanco-
uver style of citing is used (for detailes seeN Engl J Med 1997; 336 (4): 309-15). If more than six
authors, first six are cited followed by ,et a!".
Papers published in Journals:
Original paper:
Williams CL, Nishihara M, Thalabard J-C, Grosser PM, Hotchkiss J, Knobil E. Corticotropin-
releasing factor (CRF) inhibits gonadotropin-releasing hormone pulse generator activity in the rhesus
monkey. Neuroendocrinology 1990; 52: 133-7.
Editorial:
Tomkin GH. Diabetic vascular disease and the rising star of Protein Kinase C (editorial). Dia-
betologia 200 I; 44: 657-8
Volume with supplement:
Magni F, Rossoni G, Berti F. BN-52021 protects guinea pig from heart anaphylaxis. Pharmacol
Res Commun 1988; 20 Suppl5: 75-8.
Issue with supplement:
Myers BD. Pathophysiology of proteinuria in diabetic glomerular disease. J Hypertens 1990; 8
(1 Suppl): 41 S-46S
Abstract in journal:
Fuhrman SA, Joiner KA. Binding of the third component of complement C3 by Toxoplasma
gondi (abstract). Clin Res 1987; 35: 475A.
Books and other monographs:
One or more authors:
Eisen HN. Immunology: an introduction to molecular and cellular principles of the immune re-
sponse. 5th ed. New York: Harper and Row, 1974: 406.
Chapter in book:
Weinstein L, Shwartz MN. Pathologic properties of invading microorganisms. U: Soderman WA Jr,
Soderman WA, eds. Pathologic physiology: mechanisms of disease. Philadelphia: Saunders, 1974: 457-72

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ACTA CLINICA \'ol. IS N~3

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 Paper in digest:
Harley NH. Comparing radon daughter dosimetric and risk models. U: Gammage RB, Knye SV,
eds. Indoor air and human health. Proceedings of the Seventh Life Sciences Symposium: 1984 Oct
29-31; Knoxville (TN). Chelsea (Ml): Lewis, 1985: 69-78.

Dissertation and thesis:

Cairns RB. Infrared spectroscopis studies of solid oxygen. Disertacija. Berkley, California: Uni-
versity of California,1965.
Manuscripts and all the appendixes in paper and electronic form on CD, as well as original ima-
ges, are posted to the address:

Editorial board ,Acta Clinica"

Clinical Center of Serbia
Pasterova 2
11000 Belgrade Serbia

Manuscripts and other enclosed materials are not returned to the authors.

Klinicki centar Srbije, Beograd

ACTA CLINICA
Volumen 15, Broj 3
decembar 2015.

ISSN 1451-1134

Tiraz: 500 primeraka

Stampa: JP Sluzbeni glasnik, Beograd

Stampano u Srbiji

II~ ACTA CLINICA Vol. 15 .N~3 ,{', 201 'i Klinicki centar Srhiie. Rengrad