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http://www.ideacongress.it/firenze2013/
DIPARTIMENTO DI SCIEN ZE DELLA SALUTE SEZIONE DI PEDIATRIA Viale Pieraccini 24, 50139 Firenze Tel.05543 4710 Fx. 0554221012
MASTER 2° LIVELLO
Allergologia ed Immunologia Clinica 2013-2014
12 mesi / 360 ore formative
Adverse drug reaction(ADR)
World Health Organization, 1998
Adverse drug reactions (ADRs) are defined by the World Health Organization as any noxious,
unintended, and undesired effect of a drug that occurs at doses used for prevention, diagnosis, or
treatment
CLASSIFICATION OF ADR
Effetti collaterali Effetti secondari Effetti da sovradosaggio Interazioni farmacologiche
Reazioni da idiosincrasia Reazioni da intolleranza Reazioni allergiche o da
ipersensibilità Reazioni pseudo-
allergiche (anafilattoidi)
REAZIONI DA IPERSENSIBILITA’
Gell and Coombs classification ( Pichler WJ et al, Med Clin North Am 2010)
Haptenization• A hapten in this case would
be a particular drug, which would be immunogenic in protein-conjugated but not free form.
• An example would be penicillins and other betalactams that bind covalently to proteins.
Drugs may be complete antigens (eg insulin), but many drugs are of low molecular weight, and need to form a bond with a macromolecule, and when linked, the simple chemical (hapten) or one of its active metabolites becomes
immunogenic and generates a specific immune response
Hapten and p-i mechanism of drug recognition by T-cells (Pichler Br J Pharmacol 2011)
Abacavir specicicity to HLA B 5701
Positive and negative predictive values and the number needed to test to prevent one specific
drug reaction
Craig MR et al, Clin Biochem Rev 2013;34:15-38
Drug metabolizing enzyme polymorphisms and development of
drug induced MPE
- Association between cytocrome P 450 polymorphism and cutaneous adverse reaction induced by diphenylhydantoin (Lee AY et al 2004)
- Association between NAT 2, CYP29C, CYP2C19, CYP2EI genetic polymorphisms in anti-TB drug induced maculopapular eruption ( Kim SH et al 2011)
Reazioni avverse a farmaci dipendono da:
• Genetica• Infezioni (EBV, HH6)• Risposta immunologica• Metabolismo• Durata trattamento (malattie croniche= HIV
e FC)
INFEZIONI CHE POSSONO CAUSARE ORTICARIA
INFEZIONI CHE POSSONO CAUSARE ORTICARIA
• Infezioni parassitarie ?
•Infezioni virali (adenovirus, rhinovirus, enterovirus, parvovirus, EBV, HIV, HCV, HAV, CMV)
•Infezioni batteriche (H. Pilory, Streptococchi, Stafilococchi, Yersinia)
INCIDENCE OF DRUG ALLERGY
HOSPITALIZED ADULTS 10-20%
CHILDREN 1.0% (outpatients) 10.9 (hospitalized)
Gomes et al Curr Opin Allergy Clin Immunol 2005;5:309-16
GENERAL POPULATION 7%
MORTALITY 0.09/1000 hospitalizations
Thong BY et al Ann Allergy Asthma Immunl 2003;90:342-47
Clavenna A et al Arch Dis Child 2009;94:724-8
• Urticaria 149• Maculopapular exanthema (MPE) 96• Erytema multiforme (EM) 6• Pruritus 4• Angioedema and urticaria 4• Angioedema alone 4• Serum sickness 4• Laringeal edema 2• Bronchospasm, abdominal pain, porpora, vomit 4
Pichichero ME and Pichichero DM, J Pediatrics 1998;132:137-43
CLINICAL MANIFESTATIONS OF ANTIBIOTIC REACTIONS IN 247 CHILDREN
Systemic symptoms of ADR
Asthma/BronchospasmIntestitial pneumonitis
Rhinitis and conjunctivitisNasal obstruction
Sneezing
Peripheral neuropathies
TachycardiaHypotensionCollapseArrythmias
Interstitial nephritisGlomerulonephritis
Abdominal painDiarrhoeaEmesisAcute HepatitisJaundice
Haemolytic anemia,Agranulocytosis,
Thrombocytopenia, CytopeniasIDC
Serum sicknessFever
Lupus-likeDRESS (drug rash with eosinophilia and and systemic symptoms), SJS, TEN,AGEP
SINGLE ORGAN INVOLVMENT OF HYPERSENSITIVITY DRUG REACTIONS
- Hepatitis - Pancreatitis
- Nephritis
• Distinct form tha incorporate the liver as single organ of HSR
• Without a accompanying rash or fever• Driven by metabolic, immune and
genetic factors• Associated with beta-lactams,
tetracycline, anti-tubercolous agents.
DILI (drug-induced liver injury)
Allergies to foods, additives, excipients
Segal et al, Pediatrics 2007;120:e1082-96
Appearance
Differential diagnosis
Time from drug administration to onset
Edematous papules and plaques (wheals) are markedly pruritic
The generalized urticarial reaction pattern can last for weeks from single dose of medication or resolve within hours
Develops within hours to days of drug administration
Childhood hives (acute urticaria)
Transient and effervescent, the individual lesions do not last> 24 h in 1 location on the skin
Viral infections, Vasculitis
URTICARIA
Characteristics
Localized urticaria-angioedema
- Foot and auricle oedema 12 hours after amoxicillin administration
MACULOPAPULAR DRUG ERUPTIONS (MPE)
Characteristics
Appearance
•Morbilliform
•Scarlattiniform
Differential diagnosis
Time from drug administration to onset
Begin as macules, can develop into papules.
Recurs on rechallenge
Onset during the first 2 wk of drug therapy;
Drug specific reaction involving Th2 cells
Viral exanthems
Generalized eruption of erythematous macules and papules progressing centripetally
Erythematous patches develop sandpaper-like texture then desquamate;often with mucous membrane involvement
Shah, K. N. et al. Pediatrics 2007;119:e1177-e1183
-Typical annular and polycyclic morphology -Transient, ecchymotic skin changes may be present
Erythema multiforme
Shah, K. N. et al. Pediatrics 2007;119:e1177-e1183
Erythema multiforme
- Target like lesions
SEVERE DRUG-INDUCED SKIN REACTIONS
- Stevens- Johnson Syndrome (SJS)- Toxic Epidermal Necrolysis (TEN)- Hypersensitivity syndrome (HSS)/ Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)- Acute Generalized Exanthematous Pustolosis (AGEP)
SUMMARY OF FINDINGS COMPARING SJS/TEN &DRESS
Mockenhaupt M. JDDG 2009;7:142-62
Changes SJS/TEN AGEP HSS/DRESS
Onset of reaction after taking medication 1-3 weeks A few days 2-6 weeks
Typical duration of reaction 1-3 weeks Ca. 1 week Several weeks
Fever +++ +++ +++
Facial edema - ++ +++
Pustules - +++ +
Blisters +++ +* +*
Target lesions +++ +/- +/-
Mucosal involvement +++ +/- +/-
Histological changes in the skin Epidermal necrosis Subcorneal pustules Lymphocyte infiltrate
Lymph node enlargement - + +++
Lymph node histology - - Lymphoid hyperplasia
Hepatitis ++ ++ +++
Other organ involvement ++*** + +++**
Neutrophils ↓ ↑↑↑ (↑)
Eosinophils - ↑ ↑↑↑
Atypical lymphocytes - - +
*Tension blisters;**interstitial pneumonia, interstitial nephritis;***tracheobronchial necrosis, tubular nephritis.
1) Generalized maculopapular exanthema involving the face, trunk, palms and soles.Labial oedema 2) Fever 3) Generalyzed lymphadenopathy. 4) Eosinophilia.5) Elevated ALTThe maculopapular eruption progressed to exfoliative eriytroderma.
Drug Reactions Eosinophilic Systemic Symptoms (DRESS)
Pustules in AGEP in detail.
Acute generalized exanthematous pustulosis (AGEP)
Mockenhaupt M. J Dtsch Dermatol Ges. 2009 Feb;7(2):142-60
- Several dozen of small, usually non follicular pustoles on a background of widespread edematous erythema- Fever > 38°- elevated PMN in peripheral blood- spontaneous resolution of pustoles in < 15 days with a characteristic desquamation
Valutazione allergologica nel bambino con sospetta allergia a farmaci
Anamnesi1
Test cutanei:(prick, intradermo,patch)2
Test in vitro (IgE sieriche, BAT, LTTElispot)
3
Test di tolleranza ,quando indicato 4
N° dosi assunte
L’Anamnesi nella allergia ai farmaci
tipo di farmaco
formulazione (sciroppo, cpr ecc)presenza di additivi
terapia effettuata ed effettoterapia effettuata ed effetto
sintomi simili in assenza di assunzione del farmacosintomi simili in assenza di assunzione del farmaco
tipo , gravità, durata dei sintomi
intervallo di tempo fra assunzione e sintomi
precedenti assunzioni e reazioni
condizioni favorenticondizioni favorenti
ADRs are distinguished in
• Immediate – within 1 hr (seldom within few minutes)
• Non-immediate – within 1- 72 hr (or more)
Drug hypersensitivity reactions: Inconsistency in the use of the classification of immediate and nonimmediate reactions
Bircher AJ et al JACI 2012
Several factors influence the elicitation period:1)The initial signs of the reaction often unreliable2) Methods od administration (oral, parenteral)3) Drug metabolites formation4) Cofactors (effort, food intake, comedications)
Drug hypersensitivity reactions: Inconsistency in the use of the classification of immediate and nonimmediate reactions
Bircher AJ et al JACI 2012
We propose that the term ‘‘immediate’’ for likely IgEmediatedor pseudoallergic reactions presenting with urticaria,
angioedema, bronchospasm, or anaphylaxis should encompassalso these manifestations occurring at up to several hours (eg, <_6
hours) and the term ‘‘delayed’’ be used for maculopapular andmore severe exanthemas, which can start as early as 12 hours,
even if many are mediated by T cells.
What about children ?
What about children ?
Cutaneous tests are dangerous
Allergologic work-up is time consuming
Offending drugs are age dependent
Skin tests: Risk of adverse reactions
• Adults 13/148 with positive ST (8.8%)
• Children* 6/227 with positive ST (2.6%)
* Only mild reactions
(Co-Minh HB et al, 2006)
(Ponvert C et al, 2011)
Skin tests: Risk of adverse reactions
• In a 4 years period (2008-2011) we tested 518 children (382 for betalactams, 17 with positive ST) and we had no systemic reactions.
Mori F et al, al submitted
Adverse drug reactions among children over a 10-years period.
Le J et al, Pediatrics. 2006;118:555-62.
- 1087 adverse reactions - Drugs more commonly involved : antibiotics (33%) analgesics (12%) anticonvulsivants (11%)
List of the 10 most used active substances in the population study ordered by % of treated
children
Piovani D et al BMC Pediatrics 2013
-Amoxicillin clavulanate 41.6-Beclometasone 23.5-Clarithromycin 18.5-Amoxicillin 18.2-Salbutamol 14.8-Cefixime 13.8-Azythromycin 12.8-Betametasone 9.7-Cefaclor 8.0-Cetirizina 5.9
* drug prescription patterns in Italian children in an extra-hospital setting
Amoxicillin reactions
• 382 children evaluated for suspected beta-lactams in a 5 year period
• 200 (56%) to amoxicillin (+- AC)
Mori F et al, al submitted
Skin tests in diagnosis of amoxicillin hypersensitivity
• 52 children (mean age 7.48 years) with history of mild-moderate cutaneous adverse reactions following the ingestion of Amoxicillin. Patients underwent skin tests (Skin Prick Test and Intradermal Test), determination of total and specific serum IgE with an immunoassay method (UNICAP) and with the epoxy-activated sepharose 6 B radioimmunoassay. All children underwent the Oral Provocation Test (OPT) with Amoxicillin.
• 13/52 children (25%) had history of immediate reaction after taking Amoxicillin, and in 2 cases (15.4%) the diagnosis was confirmed by a positive OPT. 3 children (23%) had positive response to immediate reading of cutaneous tests
• 5 out of 39 children (12.8%), reporting a not immediate reaction after taking Amoxicillin, had a positive OPT. None of those 32 subjects who took the skin tests, had a positive response to delayed reading of the
intradermal test. Tubili F et al, al submitted
Diagnosis of benign non immediate beta lactam reactions
Caubet J, Eingenmann A: Curr Opin Infect Dis 2012
http://www.ideacongress.it/firenze2013/
GRAZIE PER L’ATTENZIONE
DIPARTIMENTO DI SCIEN ZE DELLA SALUTE SEZIONE DI PEDIATRIA Viale Pieraccini 24, 50139 Firenze Tel.05543 4710 Fx. 0554221012
MASTER 2°LIVELLO
Allergologia ed Immunologia Clinica
2013-2014
Multiple drug hypersensitivity
• Pathogenetic mechanisms:- The first drug hypersensitivity reaction lower the treshold
of T-cell reactivity to drugs and facilitate the immune response to the second drug (Daubner et al 2012)
- Autoreactivity (ASST/APST positive responses)
(Asero et al 2003, 2008)
ANAMNESI E TEST IN VITRO
ID con PPL/MDM/farmaco sospetto (1)
Prick con PPL/MDM/farmaco sospetto
ALLERGICO
NON ALLERGICO
Test in vitro -
Test in vitro +
DPT con il farmaco indice Ripetere valutazione dopo 2-4 settimane (2)
--
+
++
+
+
(1) Se cronologia sconosciuta o incerta controllare lettura a 48-72 ore
(2) Se storia clinica suggestiva e lungo intervallo prima della valutazione
- -
Algoritmo per diagnosi di RAF di tipo immediato da antibiotici beta-lattamici (Torres 2003)
Late intradermalreading
Patchreading
or
Immediatehypersensitivity
First evaluationFirst evaluation(1(1stst day) day)
Patch with BP, AP and any suspect BL
Intradermal with PPL, MDM and BP
+
-
and
+
-
-
Second evaluationSecond evaluation(3(3rdrd day) day)
Third evaluationThird evaluation(5(5thth day) day)
2nd patch and BP determinant late
intradermal reading
AP and any suspect BL late intradermal reading
Perform challenge with the suspect BL
Suspect BL therapymay be advised
Undeterminedpathogenic mechanism
Advise avoidance ofpositive BL therapy
-
Intradermal with APand any suspect BL
ImmediateImmediatehypersensitivityhypersensitivity
+
+
+
and
-
+
BP= benzylpenicillinAP= aminopenicillins (ampicillin and amoxicillin)BL= β-lactam
20 min
20 min
DelayedDelayedhypersensitivityhypersensitivity
A Romano et al, Allergy 2004;59:1153-60A Romano et al, Allergy 2004;59:1153-60
Algorithm for a in vivo allergologic work-up of non immediate reactions to beta-lactams
CONSTITUTIONAL AND ACQUIRED FACTORS IN ADR
InfectionsDietetc.
SUSCEPTIBLE PATIENT DRUG - dose(drug metabolism, immune response) - duration
- number
RRI, HIV, FC, H Pilory ecc
Common diagnosting problems in diagnosing delayed drug hypersensitivity reactions
• No established gold standard for the diagnosis • Even challenge tests are not an unequivocal
gold standard• Lack of knowledge of the number of true-
positive results
Schnyder B et al J All Clin Immunol 2012
Certa Convincente Possibile Dubbia Nessuna
■ Scala che esprime la probabilità del rapporto di causalità tra
farmaco e reazione:
RELAZIONE
Adverse drug reactions among children over a 10-years period.
Le J et al, Pediatrics. 2006;118:555-62.
- 1087 adverse reactions - Drugs more commonly involved : antibiotics (33%) analgesics (12%) anticonvulsivants (11%)
http://www.ideacongress.it/firenze2013/
DIPARTIMENTO DI SCIEN ZE DELLA SALUTE SEZIONE DI PEDIATRIA Viale Pieraccini 24, 50139 Firenze Tel.05543 4710 Fx. 0554221012
MASTER 2° LIVELLO
Allergologia ed Immunologia Clinica 2013-2014
12 mesi / 360 ore formative
4
Adverse drug reaction(ADR)
World Health Organization, 1998
Adverse drug reactions (ADRs) are defined by the World Health Organization as any noxious,
unintended, and undesired effect of a drug that occurs at doses used for prevention, diagnosis, or
treatment
5
CLASSIFICATION OF ADR
Effetti collaterali Effetti secondari Effetti da sovradosaggio Interazioni farmacologiche
Reazioni da idiosincrasia Reazioni da intolleranza Reazioni allergiche o da
ipersensibilità Reazioni pseudo-
allergiche (anafilattoidi)
REAZIONI DA IPERSENSIBILITA’
Gell and Coombs classification ( Pichler WJ et al, Med Clin North Am 2010)
7
Haptenization• A hapten in this case would
be a particular drug, which would be immunogenic in protein-conjugated but not free form.
• An example would be penicillins and other betalactams that bind covalently to proteins.
Drugs may be complete antigens (eg insulin), but many drugs are of low molecular weight, and need to form a bond with a macromolecule, and when linked, the simple chemical (hapten) or one of its active metabolites becomes
immunogenic and generates a specific immune response
Hapten and p-i mechanism of drug recognition by T-cells (Pichler Br J Pharmacol 2011)
Abacavir specicicity to HLA B 5701
Positive and negative predictive values and the number needed to test to prevent one specific
drug reaction
Craig MR et al, Clin Biochem Rev 2013;34:15-38
Drug metabolizing enzyme polymorphisms and development of
drug induced MPE
- Association between cytocrome P 450 polymorphism and cutaneous adverse reaction induced by diphenylhydantoin (Lee AY et al 2004)
- Association between NAT 2, CYP29C, CYP2C19, CYP2EI genetic polymorphisms in anti-TB drug induced maculopapular eruption ( Kim SH et al 2011)
Reazioni avverse a farmaci dipendono da:
• Genetica• Infezioni (EBV, HH6)• Risposta immunologica• Metabolismo• Durata trattamento (malattie croniche= HIV
e FC)
INFEZIONI CHE POSSONO CAUSARE ORTICARIA
INFEZIONI CHE POSSONO CAUSARE ORTICARIA
• Infezioni parassitarie ?
•Infezioni virali (adenovirus, rhinovirus, enterovirus, parvovirus, EBV, HIV, HCV, HAV, CMV)
•Infezioni batteriche (H. Pilory, Streptococchi, Stafilococchi, Yersinia)
INCIDENCE OF DRUG ALLERGY
HOSPITALIZED ADULTS 10-20%
CHILDREN 1.0% (outpatients) 10.9 (hospitalized)
Gomes et al Curr Opin Allergy Clin Immunol 2005;5:309-16
GENERAL POPULATION 7%
MORTALITY 0.09/1000 hospitalizations
Thong BY et al Ann Allergy Asthma Immunl 2003;90:342-47
Clavenna A et al Arch Dis Child 2009;94:724-8
15
• Urticaria 149• Maculopapular exanthema (MPE) 96• Erytema multiforme (EM) 6• Pruritus 4• Angioedema and urticaria 4• Angioedema alone 4• Serum sickness 4• Laringeal edema 2• Bronchospasm, abdominal pain, porpora, vomit 4
Pichichero ME and Pichichero DM, J Pediatrics 1998;132:137-43
CLINICAL MANIFESTATIONS OF ANTIBIOTIC REACTIONS IN 247 CHILDREN
However, the majority of clinical manifestations involve the skin. In this pediatric study, only few NON cutaneous clinical manifestations of antibiotic reactions have been reported…………..
16
Systemic symptoms of ADR
Asthma/BronchospasmIntestitial pneumonitis
Rhinitis and conjunctivitisNasal obstruction
Sneezing
Peripheral neuropathies
TachycardiaHypotensionCollapseArrythmias
Interstitial nephritisGlomerulonephritis
Abdominal painDiarrhoeaEmesisAcute HepatitisJaundice
Haemolytic anemia,Agranulocytosis,
Thrombocytopenia, CytopeniasIDC
Serum sicknessFever
Lupus-likeDRESS (drug rash with eosinophilia and and systemic symptoms), SJS, TEN,AGEP
17
SINGLE ORGAN INVOLVMENT OF HYPERSENSITIVITY DRUG REACTIONS
- Hepatitis - Pancreatitis
- Nephritis
Sometimes, cutaneous drug reactions may be severe as in SJS, TEN . AGEP is very rare in children. DRESS is not uncommon
• Distinct form tha incorporate the liver as single organ of HSR
• Without a accompanying rash or fever• Driven by metabolic, immune and
genetic factors• Associated with beta-lactams,
tetracycline, anti-tubercolous agents.
DILI (drug-induced liver injury)
19
Allergies to foods, additives, excipients
Segal et al, Pediatrics 2007;120:e1082-96
Appearance
Differential diagnosis
Time from drug administration to onset
Edematous papules and plaques (wheals) are markedly pruritic
The generalized urticarial reaction pattern can last for weeks from single dose of medication or resolve within hours
Develops within hours to days of drug administration
Childhood hives (acute urticaria)
Transient and effervescent, the individual lesions do not last> 24 h in 1 location on the skin
Viral infections, Vasculitis
URTICARIA
Characteristics
Urticaria is characterized by typical , marked pruritic wheals…
20
Localized urticaria-angioedema
- Foot and auricle oedema 12 hours after amoxicillin administration
Amoxicillin can also induce late reactions with localized oedema
21
MACULOPAPULAR DRUG ERUPTIONS (MPE)
Characteristics
Appearance
•Morbilliform
•Scarlattiniform
Differential diagnosis
Time from drug administration to onset
Begin as macules, can develop into papules.
Recurs on rechallenge
Onset during the first 2 wk of drug therapy;
Drug specific reaction involving Th2 cells
Viral exanthems
Generalized eruption of erythematous macules and papules progressing centripetally
Erythematous patches develop sandpaper-like texture then desquamate;often with mucous membrane involvement
The appearance of EDR begin with papules, that can develop into macules.
22
Shah, K. N. et al. Pediatrics 2007;119:e1177-e1183
-Typical annular and polycyclic morphology -Transient, ecchymotic skin changes may be present
Erythema multiforme
23
Shah, K. N. et al. Pediatrics 2007;119:e1177-e1183
Erythema multiforme
- Target like lesions
24
SEVERE DRUG-INDUCED SKIN REACTIONS
- Stevens- Johnson Syndrome (SJS)- Toxic Epidermal Necrolysis (TEN)- Hypersensitivity syndrome (HSS)/ Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)- Acute Generalized Exanthematous Pustolosis (AGEP)
Sometimes, cutaneous drug reactions may be severe as in SJS, TEN . AGEP is very rare in children. DRESS is not uncommon
25
SUMMARY OF FINDINGS COMPARING SJS/TEN &DRESS
Mockenhaupt M. JDDG 2009;7:142-62
Changes SJS/TEN AGEP HSS/DRESS
Onset of reaction after taking medication 1-3 weeks A few days 2-6 weeks
Typical duration of reaction 1-3 weeks Ca. 1 week Several weeks
Fever +++ +++ +++
Facial edema - ++ +++
Pustules - +++ +
Blisters +++ +* +*
Target lesions +++ +/- +/-
Mucosal involvement +++ +/- +/-
Histological changes in the skin Epidermal necrosis Subcorneal pustules Lymphocyte infiltrate
Lymph node enlargement - + +++
Lymph node histology - - Lymphoid hyperplasia
Hepatitis ++ ++ +++
Other organ involvement ++*** + +++**
Neutrophils ↓ ↑↑↑ (↑)
Eosinophils - ↑ ↑↑↑
Atypical lymphocytes - - +
*Tension blisters;**interstitial pneumonia, interstitial nephritis;***tracheobronchial necrosis, tubular nephritis.
Respect to SJS/TEN, DRESS have some some differential features.
1) Generalized maculopapular exanthema involving the face, trunk, palms and soles.Labial oedema 2) Fever 3) Generalyzed lymphadenopathy. 4) Eosinophilia.5) Elevated ALTThe maculopapular eruption progressed to exfoliative eriytroderma.
Drug Reactions Eosinophilic Systemic Symptoms (DRESS)
Pustules in AGEP in detail.
Acute generalized exanthematous pustulosis (AGEP)
Mockenhaupt M. J Dtsch Dermatol Ges. 2009 Feb;7(2):142-60
- Several dozen of small, usually non follicular pustoles on a background of widespread edematous erythema- Fever > 38°- elevated PMN in peripheral blood- spontaneous resolution of pustoles in < 15 days with a characteristic desquamation
Valutazione allergologica nel bambino con sospetta allergia a farmaci
Anamnesi1
Test cutanei:(prick, intradermo,patch)2
Test in vitro (IgE sieriche, BAT, LTTElispot)
3
Test di tolleranza ,quando indicato 4
N° dosi assunte
L’Anamnesi nella allergia ai farmaci
tipo di farmaco
formulazione (sciroppo, cpr ecc)presenza di additivi
terapia effettuata ed effettoterapia effettuata ed effetto
sintomi simili in assenza di assunzione del farmacosintomi simili in assenza di assunzione del farmaco
tipo , gravità, durata dei sintomi
intervallo di tempo fra assunzione e sintomi
precedenti assunzioni e reazioni
condizioni favorenticondizioni favorenti
30
ADRs are distinguished in
• Immediate – within 1 hr (seldom within few minutes)
• Non-immediate – within 1- 72 hr (or more)
Drug hypersensitivity reactions: Inconsistency in the use of the classification of immediate and nonimmediate reactions
Bircher AJ et al JACI 2012
Several factors influence the elicitation period:1)The initial signs of the reaction often unreliable2) Methods od administration (oral, parenteral)3) Drug metabolites formation4) Cofactors (effort, food intake, comedications)
Drug hypersensitivity reactions: Inconsistency in the use of the classification of immediate and nonimmediate reactions
Bircher AJ et al JACI 2012
We propose that the term ‘‘immediate’’ for likely IgEmediatedor pseudoallergic reactions presenting with urticaria,
angioedema, bronchospasm, or anaphylaxis should encompassalso these manifestations occurring at up to several hours (eg, <_6
hours) and the term ‘‘delayed’’ be used for maculopapular andmore severe exanthemas, which can start as early as 12 hours,
even if many are mediated by T cells.
What about children ?
What about children ?
Cutaneous tests are dangerous
Allergologic work-up is time consuming
Offending drugs are age dependent
Skin tests: Risk of adverse reactions
• Adults 13/148 with positive ST (8.8%)
• Children* 6/227 with positive ST (2.6%)
* Only mild reactions
(Co-Minh HB et al, 2006)
(Ponvert C et al, 2011)
Skin tests: Risk of adverse reactions
• In a 4 years period (2008-2011) we tested 518 children (382 for betalactams, 17 with positive ST) and we had no systemic reactions.
Mori F et al, al submitted
37
Adverse drug reactions among children over a 10-years period.
Le J et al, Pediatrics. 2006;118:555-62.
- 1087 adverse reactions - Drugs more commonly involved : antibiotics (33%) analgesics (12%) anticonvulsivants (11%)
In children, antibiotics are the more common cause of ADR
38
List of the 10 most used active substances in the population study ordered by % of treated
children
Piovani D et al BMC Pediatrics 2013
-Amoxicillin clavulanate 41.6-Beclometasone 23.5-Clarithromycin 18.5-Amoxicillin 18.2-Salbutamol 14.8-Cefixime 13.8-Azythromycin 12.8-Betametasone 9.7-Cefaclor 8.0-Cetirizina 5.9
* drug prescription patterns in Italian children in an extra-hospital setting
In children, antibiotics are the more common cause of ADR
Amoxicillin reactions
• 382 children evaluated for suspected beta-lactams in a 5 year period
• 200 (56%) to amoxicillin (+- AC)
Mori F et al, al submitted
Skin tests in diagnosis of amoxicillin hypersensitivity
• 52 children (mean age 7.48 years) with history of mild-moderate cutaneous adverse reactions following the ingestion of Amoxicillin. Patients underwent skin tests (Skin Prick Test and Intradermal Test), determination of total and specific serum IgE with an immunoassay method (UNICAP) and with the epoxy-activated sepharose 6 B radioimmunoassay. All children underwent the Oral Provocation Test (OPT) with Amoxicillin.
• 13/52 children (25%) had history of immediate reaction after taking Amoxicillin, and in 2 cases (15.4%) the diagnosis was confirmed by a positive OPT. 3 children (23%) had positive response to immediate reading of cutaneous tests
• 5 out of 39 children (12.8%), reporting a not immediate reaction after taking Amoxicillin, had a positive OPT. None of those 32 subjects who took the skin tests, had a positive response to delayed reading of the
intradermal test. Tubili F et al, al submitted
Diagnosis of benign non immediate beta lactam reactions
Caubet J, Eingenmann A: Curr Opin Infect Dis 2012
http://www.ideacongress.it/firenze2013/
GRAZIE PER L’ATTENZIONE
DIPARTIMENTO DI SCIEN ZE DELLA SALUTE SEZIONE DI PEDIATRIA Viale Pieraccini 24, 50139 Firenze Tel.05543 4710 Fx. 0554221012
MASTER 2°LIVELLO
Allergologia ed Immunologia Clinica
2013-2014
Multiple drug hypersensitivity
• Pathogenetic mechanisms:- The first drug hypersensitivity reaction lower the treshold
of T-cell reactivity to drugs and facilitate the immune response to the second drug (Daubner et al 2012)
- Autoreactivity (ASST/APST positive responses)
(Asero et al 2003, 2008)
ANAMNESI E TEST IN VITRO
ID con PPL/MDM/farmaco sospetto (1)
Prick con PPL/MDM/farmaco sospetto
ALLERGICO
NON ALLERGICO
Test in vitro -
Test in vitro +
DPT con il farmaco indice Ripetere valutazione dopo 2-4 settimane (2)
--
+
++
+
+
(1) Se cronologia sconosciuta o incerta controllare lettura a 48-72 ore
(2) Se storia clinica suggestiva e lungo intervallo prima della valutazione
- -
Algoritmo per diagnosi di RAF di tipo immediato da antibiotici beta-lattamici (Torres 2003)
Late intradermalreading
Patchreading
or
Immediatehypersensitivity
First evaluationFirst evaluation(1(1stst day) day)
Patch with BP, AP and any suspect BL
Intradermal with PPL, MDM and BP
+
-
and
+
-
-
Second evaluationSecond evaluation(3(3rdrd day) day)
Third evaluationThird evaluation(5(5thth day) day)
2nd patch and BP determinant late
intradermal reading
AP and any suspect BL late intradermal reading
Perform challenge with the suspect BL
Suspect BL therapymay be advised
Undeterminedpathogenic mechanism
Advise avoidance ofpositive BL therapy
-
Intradermal with APand any suspect BL
ImmediateImmediatehypersensitivityhypersensitivity
+
+
+
and
-
+
BP= benzylpenicillinAP= aminopenicillins (ampicillin and amoxicillin)BL= β-lactam
20 min
20 min
DelayedDelayedhypersensitivityhypersensitivity
A Romano et al, Allergy 2004;59:1153-60A Romano et al, Allergy 2004;59:1153-60
Algorithm for a in vivo allergologic work-up of non immediate reactions to beta-lactams
47
CONSTITUTIONAL AND ACQUIRED FACTORS IN ADR
InfectionsDietetc.
SUSCEPTIBLE PATIENT DRUG - dose(drug metabolism, immune response) - duration
- number
RRI, HIV, FC, H Pilory ecc
Common diagnosting problems in diagnosing delayed drug hypersensitivity reactions
• No established gold standard for the diagnosis • Even challenge tests are not an unequivocal
gold standard• Lack of knowledge of the number of true-
positive results
Schnyder B et al J All Clin Immunol 2012
Certa Convincente Possibile Dubbia Nessuna
■ Scala che esprime la probabilità del rapporto di causalità tra
farmaco e reazione:
RELAZIONE
50
Adverse drug reactions among children over a 10-years period.
Le J et al, Pediatrics. 2006;118:555-62.
- 1087 adverse reactions - Drugs more commonly involved : antibiotics (33%) analgesics (12%) anticonvulsivants (11%)
In children, antibiotics are the more common cause of ADR