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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