Drug allergy in children

Eva Rebelo Gomes

CHUP – Porto - Portugal

Greek Paediatric Allergy Society

1. Epidemiology

2.1 Prevalence/Incidence

2.2 Drugs involved

2. Clinical presentation

3.1 Anamnesis

3.2 Examination

3. Diagnosis

3.1 in vitro

2.2 in vivo

3.3 betalactams

3.4 NSAIDs

4. Follow-up

ADR in paediatric patients(102 studies from 1964 - 2010)

Incidence rates for ADRs causing hospital admission ranged

from 0.4% to 10.3% of all children

ADR occur in 0.6% to 16.8% of all children exposed to a drug

during hospital stay

From 0.0% to 11.0% of children evaluated in ambulatory settings

Smyth RMD. PLoS ONE 2012

ADR more frequent among young children

Antibiotics and NSAIDs are frequently

associated with ADRs in pediatric outpatient

3.472.183 ADR reports

7.7% concerned children (268.145 reports)

ADR reported (children/adults)

Cutaneous reactions (35% vs 23%)

Drug classification groups (children/adults)

Antibiotics (33% vs 15%), respiratory (15% vs 5%)

and dermatological drugs (12% vs 7%)

Star K et al. Suspected ADR reported for children worldwide. Drug Saf 2011

Suspected ADR in children worldwide

(WHO-VigiBase database)

“a noxious and unintended response to a drug that occurs at a

dose normally used for therapeutical or diagnostic purposes”

Report of a WHO meeting. World Health Organ Tech Rep Ser. 1972

Allergy is an hypersensitivity reaction initiated by immunologic

mechanisms (antibody or cell-mediated)

Johansson S G O. Allergy 2001

Systematic review of 53 studies on self reported drug allergy (126.306 participants)

8.3% of the participants (10% adults, 5% of the children) reported a drug allergy.

Cutaneous manifestations were the most frequent (68% of the participants)

more common in children than in adults (72% VS 67%)

Anaphylactic and systemic reactions were reported by 10.8% of the participants

less frequently reported in pediatric studies (7.6%)

Antibiotics, NSAIDs and anaesthetics were the most frequently reported culprit

drug classes.

Sousa-Pinto B. Ann Allergy Asthma Immunol. 2017

Self reported dug allergy(53 studies – 126.306 participants)

1426 questionnaires - 10.2% reported previous ADR - 6% reported a drug

allergy (52% betalactams) Portugal, Gomes E, 2008

1447 questionnaires - 7.5% reported ADR - 4.2% history of drug allergy

(70% betalactams) Germany, Lange L, 2008

2855 questionnaires (6-9y) - 2.8% reported drug allergy Turkey, Orhan F, 2008

3222 questionnaires - 7.9% reported a drug allergy (4.5% antibiotics)

Lituania, Kvedariene V, 2018

Self reported dug allergy(cross sectional pediatric studies)

5 to 10% of the children questioned had at least one ADR

3 to 8% of them report a drug allergy

Betalactams involved in up to 70% of the reactions

Implicated drugs in pediatric DH

reactions

Antibiotics/AntinfectivesBeta-lactam

Macrolides

Sulfonamides

Anti-inflammatory drugsParacetamol

Ibuprofen

Aspirin

Anesthetics

Anticonvulsants

Vaccines

Respiratory drugs

RCM

Antineoplastic

Biologicals

Clinical HistoryDemoly P. Drug hypersensitivity: questionnaire. Allergy 1999

Which kind of reaction? Cutaneous?

Respiratory? Digestive? Anaphylaxis?

Detailed description of the lesions, distribution,

pruritus, pain, mucosal, evolution, resolution?

When? Which circumstances (infection, exercise,

meal,..)

Time to reaction after exposure? Immediate?

All drugs taken at the time of the reaction

Time line to resolution. Spontaneous? Under

medication? Treatment stopped/changed?

Severity of the reaction

Previous/posterior treatments

Comorbidities

Clinical manifestations

Maculopapular exanthema

Urticaria / Angioedema

FDE

Serum Sickness like disease

SJS/TEN, DRESS, AGEP

Cutaneous

Respiratory

Gastrointestinal

Anaphylaxis

Immediate Reactions

Non-immediate Reactions

Physical exam - observation

Describe the lesions and the locations

Make photos!

Vital signs

Respiratory distress signs

Neurologic signs / conscientiousness

Lymph nodes and Liver enlargement

Mucosal involvement

Joints

Skin lesions / Residual skin lesions

Sequels

After the clinical history

Is it a possible drug hypersensitivity?

Culprit drug? Culprits?

Do I need to do anything?

Which kind of reaction?

Immediate/non immediate/delayed

Looks like IgE mediated?

Severe or mild?

Acute phase

Hemogram with full count

ESR

PCR

Liver and kidney function

Urinalysis

virus/bacteria infection

Tryptase

Specific IgEs

In Vitro assays

Later on

Specific IgEs

Beta-lactams, muscle relaxants

Basophil Activation Test

Antibiotics

Lymphocyte Transformation Test

Antibiotics, anti tuberculous drugs, antiviral,

anticonvulsants, allopurinol

In Vivo studies - Skin Tests

Immediate reactions

• skin prick tests – easy, low sensitivity

• intradermal tests – painful, IV formulations, standardization

In Vivo studies - Skin Tests

Non Immediate and delayed

• intradermal tests with late reading up tp 7 days

• skin patch tests – easy, low sensitivity except…

In Vivo studies - Provocation Tests

Contra-indications and limitationsAberer W et al. Allergy. 2003

Gold standard for the diagnosis of drug hypersensitivity

Lack of in vitro reliable diagnostic tests Basophil activation test – SNIUAA

Cellular allergen stimulation test

Skin tests have low sensitivityMetamizole, paracetamol

Diagnostic provocation tests are usually

needed

Provocation tests to look for safe alternatives

NSAID hypersensitivity

Cross intolerant type (non allergic HS – NERD, NECD, NIUAA) –

urticaria, angioedema, dyspnea, rhinitis, conjuntivitis, anaphylaxis –

minutes/hours after exposure – COX-1 inhibition

Non Cross intolerant (allergic reactions)

•Selective NSAID induced urticaria, angioedema, anaphylaxis

(SNIUAA) – less than 1 hour – IgE mediated

•Selective NSAID induced delayed reactions (SNDR) – MPE, FDE,

SCARs, internal organ damage – »24 hours – Tcell mediated.

Kidon M et al. Pediatric Allergy Immunology 2018

The classification of NSAID hypersensitivity reactions is important

to plan the allergological work-up and is crucial for management

of pediatric patients

Anti-inflammatory drugs and anti pyretic

Paracetamol and Ibuprofen

Aspirin («12y)

Naproxen (»5y for RA)

Diclofenac («12y for RA)

Indometacin («12Y for RA)

Preferential /Selective COX2 inhibitors

(»12 or 16y)

119 patients included with a suspected NSAID hypersensitivity (median age 9y)

44% of the patients were atopic. 40% reported more than one previous reaction

Ibuprofen was the commonest implicated NSAID (79%)

71% reported only cutaneous manifestations (mostly urticaria/angioedema) and

15% had systemic symptoms

NSAID hypersensitivity was confirmed in only nine (7.6%) patients

after a provocation test

Anaphylaxis represented a relative risk to NSAID hypersensitivity confirmation.

No association was found for atopy and the number of previous reactions.

Patients with diagnostic confirmation were older than patients with exclusion

Alves C et al. NSAID hypersensitivity in children. Allergol Immunopathol 2017

693 children with a history of NSAIDs reactions

(Serbia, Italy, Switzerland, Spain, Portugal)

Atopy in 29% (n=203/693), asthma 9.5% of patients, urticaria in 6%

Reactions – cutaneous reactions (707/814, 87%) (mainly angioedema and/or

urticarial) followed by respiratory manifestations

There were 70/814 (9%) systemic reactions - 61% occurred in children «10

years and 38% in the group »10 years (p= 0.44)

70% of the reactions occurred within the first 6 hours

526 DPTs were performed with the culprit NSAID

Mori F et al. accepted JACI in practice

The diagnosis was confirmed in 19.6% (103/526) of children

526 DPTs were performed with the culprit NSAID

The proportion of positive DPT was similar for patients with paracetamol as

culprit (19.4%) or NSAID as culprit (19.8%)

There were 19% positive DPTs in the group of children with history of reaction to

a single NSAID and 22 % in children with reaction to multiple NSAIDs

The rate of positive provocations increased with age being only around 7% in

children with less than 2 years (7/94)

Atopy did not influence the results of the provocation test

Antibiotic hypersensitivity

Outpatient studies of cutaneous ADR estimate that 2.5% of

children who are treated with a drug, and up to 12% of children

treated with an antibiotic, can have a cutaneous reaction

Segal AR et al. Cutaneous reactions to drugs in children. Pediatrics 2007

General clinicians and pediatricians often face a diagnostic

dilemma when children taking antibiotics present with a rash.

“Allergy” – exclude the drug from future treatments

16% of 1431 children with BL allergy Ponvert C, 2011

5% of 732 children with BL allergy Ibañez MD, 2018

58% of 1170 children with BL immediate allergy Atanaskovic M, 2005

7% of 1026 children with non immediate reactions to BL Atanaskovic M, 2016

8% of 783 children with BL allergy (13 vs 7%) Zambonino MA, 2014

7% of 88 children with non immediate skin reactions to BL Caubet JC, 2011

11% of 550 children with non immediate reactions to BL Lezmi G, 2017

14% of 146 children with BL allergy Azevedo J, 2018

6% of 117 children with reported immediate DH Erkoçoğlu M, 2013

5% of 186 pre-school children with BL allergy Gomes E, 2016

11% of 176 children with BL allergy Arnold A, 2019

Urticaria/Angio 39 (11.0) 316 (89.0) 206 (14.4) 1222 (85.6)

MPE 5 (3.1) 157 (96.9) 68 (12.8) 463 (87.2)

Anaphylaxis 17 (22.4) 59 (77.6) 117 (20.5) 454 (79.5)

Anaph shock 7 (31.9) 15 (68.2) 96 (29.2) 233 (70.8)

Total 70 (10.6) 588 (89.4) 537 (16.5) 2719 (83.5)

Positive C/C Negative C/C Positive A/A Negative A/A

Rubio M et al. Results of drug hypersensitivity evaluations in a large group of

children and adults. Clin Exp Allergy 2012

3275 patients evaluated for suspected drug allergy (658 children)

Clinical presentation - urticaria/angioedema/pruritus (45%), MPE (18%),

anaphylaxis (16%), anaphylactic shock (8%)

14.9% of the pediatric patients had a suspected drug induced anaphylaxis

Overall DH confirmation was 15.2% (16.5% in adults / 10.6% in children)

The rate depended on the type of reaction under study

Beta-lactams 31 (9.6) 292 (90.4) 207 (20.2) 820 (79.9)

NSAIDs 29 (18.5) 128 (81.5) 105 (15.7) 563 (84.3)

Other ABs 5 (7.8) 59 (92.2) 97 (24.7) 296 (75.3)

Paracetamol 2 (5.6) 34 (94.4) 25 (12.6) 174 (87.4)

Positive C/C Negative C/C Positive A/A Negative A/A

Overall DH confirmation was 15.2% (16.5% vs 10.6%)

The rate depended also on the drug class under evaluation

Among children the mean age at suspicion was significantly higher for the

ones with confirmation than for the group with negative results (p«0.001)

Workup of drug hypersensitivity in children Gomes ER et al. Drug hypersensitivity in children: report from the pediatric task force of

the EAACI Drug Allergy Interest Group. Allergy 2016

Mill C et al. Assessing diagnostic properties of DPT for diagnosis of immediate and

non immediate reactions to amoxicillin in children JAMA Pediatr. 2016

818 children - reaction to amoxicilin either immediate or non

immediate (SCARs excluded) – Direct Drug ProvocationTest

94% tolerated the drug - 4% had nonimmediate reactions (MPE,

urticaria/angioedema, SSLR)

2% (17) had immediate reactions (urticaria) – Skin Tests 3 months

later and only one was positive

94%

2% 4%

NPV 90%

Jaoui A et al. Safety and cost effectiveness of supervised ambulatory DPT in

children with mild non-immediate reactions to beta-lactams. Allergy 2019

446 children (mean age 2y) - mild non-immediate reactions to BL – Ambulatory DTP

91% tolerated the drug and 39 children reacted (9%)

reactions were mainly urticaria and maculopapular exanthema

most were similar to the previous reaction and occurred earlier or at the same

chronology of the index reaction

Most reactions were similar or milder to the initial one, 15% the extent was greater

Documentation for patients - Brockow K et al. Drug allergy passport and

other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug

Allergy Interest Group Position Paper. Allergy 2016

Messages to take home

3 to 6 % of the parents report their children to be allergic to drugs

Betalactam antibiotics and NSAIDs are the most suspected drugs

Cutaneous reactions as the maculopapular exanthema and

urticaria are the most common clinical presentations

Most reactions are non immediate.

Only around 10% of the suspected drug reactions can be

confirmed after a full clinical investigation. Drug provocation tests

are the most helpful tools for diagnostic confirmation or exclusion

The value of the laboratory tests and skin testing is limited

Thank’s for your attention