ERS Annual Congress Munich

6–10 September 2014

Postgraduate Course 15 Hot topics in paediatric allergy

Saturday, 6 September 2014 14:00–17:30

Room M-1 (B0)

You can access an electronic copy of these educational materials here:

www.ers-education.org/2014pg15 To access the educational materials on your tablet or smartphone please find below a list of apps to access, annotate, store and share pdf documents.

iPhone / iPad

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Adobe Reader - FREE The Android version of Adobe Reader lets you view, annotate, comment, fill out, electronically sign and share documents. It has all of the same features as the iOS app like freehand drawing, highlighting, underlining, etc. http://bit.ly/1deKmcL iAnnotate PDF - FREE You can open multiple PDFs using tabs, highlight the text and make comments via handwriting or typewriter tools. iAnnotate PDF also supports Box OneCloud, which allows you to import and export files directly from/to Box. http://bit.ly/1p2SV00 ez PDF Reader - $3.99 With the ez PDF reader you can add text in text boxes and sticky notes; highlight, underline, or strikethrough texts or add freehand drawings. Add memo & append images, change colour / thickness, resize and move them around as you like. http://bit.ly/1kdxZfT

Postgraduate Course 15 Hot topics in paediatric allergy

AIMS: Asthma and allergies are the most prevalent chronic disorders in children in the western world. In this postgraduate course, experts in the field will discuss the recent advances in four major areas within paediatric allergy, namely, allergic skin diseases, food allergy, anaphylaxis, and drug allergies, in an interactive, case-based manner. HERMES LINKS PAEDIATRIC: Allergic Disorders, Bronchial Asthma and other wheezing disorders. TARGET AUDIENCE: Pulmonologists, respiratory physicians, general practitioners, nurses, allergologists, and trainees. CHAIRS: N. Arends (Rotterdam, Netherlands), A. Barbato (Padova, Italy) COURSE PROGRAMME PAGE 14:00 Preschool wheeze: what is new since the 2008 taskforce? 5 P.L.P. Brand (Zwolle, Netherlands) 14:45 An update on food allergy 38 K. Beyer (Berlin, Germany) 15:30 Break 16:00 Paediatric drug allergy: state of the art 39 M. Duse (Rome, Italy) 16:45 Anaphylaxis in children 43 G. Roberts (Southampton, United Kingdom) Additional course resources 82

Faculty disclosures 83

Faculty contact information 84

Answers to evaluation questions 85

Th e ERS Handbook of Paediatric Respiratory MedicineEdited by Ernst Eber and Fabio Midulla

ISBN 978-1-84984-038-5

Th e ERS Handbook of Paediatric Respiratory Medicine comprises more than 100 sections covering the whole spectrum of paediatric respiratory medicine, from anatomy and development to disease, rehabilitation and treatment.

Th e book is structured to tie in with the paediatric HERMES syllabus, making it an essential resource for anyone interested in the fi eld and the ideal training aid for those wishing to take the European Examination in Paediatric Respiratory Medicine.

Accredited by EBAP for 18 hours of European CME credit

To buy printed copies, visit the ERS Bookshop in Hall A1, stand D.01.

Visit ersbookshop.com

THE ERS HANDBOOK OF paediatric respiratory medicine

Preschool wheeze: what is new since the 2008 taskforce?

Prof. Paul L.P. Brand Consultant paediatrician for respiratory and allergic disease

Princess Amalia Children’s Clinic Isala Klinieken P.O. Box 10400 8000 GK Zwolle

Netherlands p.l.p.brand@isala.nl

Twitter @paulbrandzwolle AIMS • To discuss limitations of distinguishing episodic viral wheeze and multiple trigger wheeze. • To provide evidence based treatment recommendations for preschool children with

troublesome recurrent wheeze. SUMMARY Introduction Wheezing and shortness of breath are very common presenting symptoms in preschool children. Approximately one in three children has at least one episode of wheeze before their third birthday.[1;2] Parents vary considerably in their understanding of the term ‘‘wheeze’’ but wheeze confirmed by a doctor is associated with lower airway obstruction.[3] Even among such children with doctor-confirmed wheeze, considerable clinical heterogeneity exists: children differ considerably in the severity and frequency of wheeze episodes, and in other clinical characteristics. Due to this heterogeneity, and despite its common occurrence, relatively little evidence is available on the pathophysiology and treatment of wheezing in preschool children. Many preschool children with wheeze become symptom-free between the ages of 3 and 8 years .[4] This distinguishes preschool wheeze from the more persistent asthma in later childhood and adulthood, and illustrates the heterogeneity of wheeze in this age group. Until recently, however, international asthma management guidelines did notprovide separate recommendations for preschool children. In 2008, a European Respiratory Society (ERS) Task Force published a report on the classification, diagnosis and management of preschool wheeze, based on a systematic assessment of the available literature at that time.[5] One of the Task Force’s main findings was that ‘‘the evidence on which to base recommendations is limited’’ and that ‘‘The present recommendations are likely to change when more evidence becomes available.’’ In 2008, the Task Force recommended distinguishing between episodic viral wheeze (EVW, wheeze only during or following a viral cold) and multiple trigger wheeze (MTW, wheeze not only in response to viral colds, but also to other triggers) and proposed a differentiated approach to controller therapy (montelukast as first choice treatment for EVW and inhaled corticosteroids (ICS) for MTW).[5] Since 2008, a large number of studies have provided important new evidence which necessitate a reconsideration of the ERS 2008 Task Force recommendations. Because of this, an international group of experts convened at the 2013 ERS Annual Congress to discuss the current state of the art of the classification and management of preschool wheeze, and to formulate a consensus statement on the current value of phenotyping preschool wheezing disorders into EVW and MTW, and the treatment approach associated with it. The group’s report was recently published in the ERJ, and the highlights of this report will be discussed in this presentation.[6]

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Classification The 2014 update of the ERS Task Force Report recognizes that the distinction between EVW and MTW is not as clear-cut, and not as clinically useful, as was proposed in 2008. There are two main reasons for this paradigm shift. First, it was recognized that the temporal pattern of wheeze in relation to triggers (i.e., EVW or MTW) was not the only characteristic that varies between preschool children with wheeze (table 1).[6]In clinical practice, the severity and frequency of wheeze episodes are more important in determining whether a child will be prescribed daily controller therapy than whether the wheeze follows an EVW or MTW pattern. Clinicians also weigh other factors into this decision, such as the presence of allergic comorbidity (eczema, allergic rhinitis, food allergy), and the patient’s family history.[7]

Table 1: reproduced from [6] Second, it has been shown that the EVW and MTW phenotypes are not stable over time in many patients.[8] For example, in a cohort of 109 preschool children followed for one year in an Australian children’s hospital (indicating that these were children with relatively severe wheeze who were referred for specialist care), only 50 (46%) had a stable MTW or EVW phenotype. Thirty-five patients (32%) changed from an EVW to an MTW phenotype or vice versa, and 24 (22%) became wheeze-free during daily controller therapy.[8] This unstability of wheeze phenotypes over time limit sits usefulness for classification purposes and as a basis for prescription of therapy. This is reflected in the 2014 update of the ERS Task Force Report.[6] Treatment The 2008 ERS Task Force Report recommendation for phenotype-directed choice of daily controller therapy was based on limited evidence, with only one randomized controlled trial (RCT) showing a significant, but small, reduction of wheeze symptoms in preschool children treated with montelukast,[9] and a single negative RCT in preschool children with an EVW phenotype.[10] A systematic review of 16 ICS RCTs in preschool children showed a significant and clinically relevant reduction of wheeze episodes and severity in the pooled meta-analysis.[11] Because phenotype descriptions were missing in most of these studies, it was not possible to do a stratified analysis based on wheeze phenotype. To date, a single study has compared ICS to montelukast in preschool children, showing superiority of budesonide (an ICS) over montelukast daily controller therapy.[12] A recent study in the Netherlands showed that adherence to daily ICS controller therapy was the single most important factor in determining asthma control in preschool children followed for one year using electronic assessment of adherence.[13] These observations suggest that ICS daily controller therapy is useful and effective in preschool children with wheeze of sufficient severity to merit referral to a hospital-based paediatric specialist. The 2014 update of the ERS Task Force Report therefore proposes that ICS be used as daily controller therapy not only in children with the MTW phenotype, but also in those children with EVW who have severe or frequent episodes, or when the clinician suspects that interval symptoms are being underreported.[6] Given the favourable natural history of preschool wheezing (at population level, the majority of preschool children with wheeze become symptom-free after the age of 4-6 years), any maintenance treatment should be viewed as a treatment trial, with scheduled follow-up. Daily controller therapy should be tapered down to the lowest effective dose, and should be discontinued when the patient has remained symptom-free for 3-6 months.[6] It should be

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stressed, however, that the favourable history of preschool wheezing has been primarily demonstrated in population-based samples, in which most wheezy children have mild symptoms. Surprisingly few data are available on the long-term outcome of preschool wheezing in children with more severe symptoms, who have been referred to specialist care. In a recent follow-up study of such patients with troublesome EVW, 67% of children remained symptomatic by the age of 5-10 years.[14] Unfortunately, currently available scoring systems are too unreliable to allow meaningful prediction of long-term outcome and treatment response to allow targeted presciption of daily controller therapy.[15] Daily controller therapy of preschool wheezing does not influence the long-term outcome of preschool wheeze, but does reduce troublesome symptoms during the preschool age period. This is why preschool children with recurrent troublesome symptoms deserve a trial of daily controller therapy. REFERENCES 1. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ, Group Health

Medical Associates: Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133-138.

2. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock A, Strachan DP, Shaheen SO, Sterne JA: Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood. Thorax 2008;63:974-980.

3. Lowe L, Murray CS, Martin L, Deas J, Cashin E, Poletti G, Simpson A, Woodcock A, Custovic A: Reported versus confirmed wheeze and lung function in early life. Arch Dis Child 2004;89:540-543.

4. Savenije OE, Kerkhof M, Koppelman GH, Postma DS: Predicting who will have asthma at school age among preschool children. J Allergy Clin Immunol 2012;130:325-331.

5. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Custovic A, de Blic J, de Jongste JC, Eber E, Everard ML, Frey U, Gappa M, Garcia-Marcos L, Grigg J, Lenney W, Le Souef P, McKenzie S, Merkus PJ, Midulla F, Paton JY, Piacentini G, Pohunek P, Rossi GA, Seddon P, Silverman M, Sly PD, Stick S, Valiulis A, Van Aalderen WM, Wildhaber JH, Wennergren G, Wilson N, Zivkovic Z, Bush A: Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008;32:1096-1110.

6. Brand PL, Caudri D, Eber E, Gaillard EA, Garcia-Marcos L, Hedlin G, Henderson J, Kuehni CE, Merkus PJ, Pedersen S, Valiulis A, Wennergren G, Bush A: Classification and pharmacological treatment of preschool wheezing: changes since 2008. Eur Respir J 2014;43:1172-1177.

7. Schultz A, Brand PL: Episodic Viral Wheeze and Multiple Trigger Wheeze in preschool children: A useful distinction for clinicians? Paediatr Respir Rev 2011;12:160-164.

8. Schultz A, Devadason SG, Savenije OE, Sly PD, Le Souef PN, Brand PL: The transient value of classifying preschool wheeze into episodic viral wheeze and multiple trigger wheeze. Acta Paediatr 2010;99:56-60.

9. Bisgaard H, Zielen S, Garcia-Garcia ML, Johnston SL, Gilles L, Menten J, Tozzi CA, Polos P: Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med 2005;171:315-322.

10. Wilson N, Sloper K, Silverman M: Effect of continuous treatment with topical corticosteroid on episodic viral wheeze in preschool children. Arch Dis Child 1995;72:317-320.

11. Castro-Rodriguez JA, Rodrigo GJ: Efficacy of inhaled corticosteroids in infants and preschoolers with recurrent wheezing and asthma: a systematic review with meta-analysis. Pediatrics 2009;123:e519-e525.

12. Szefler SJ, Carlsson LG, Uryniak T, Baker JW: Budesonide inhalation suspension versus montelukast in children aged 2 to 4 years with mild persistent asthma. J Allergy Clin Immunol Pract 2013;1:58-64.

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13. Klok T, Kaptein AA, Duiverman EJ, Brand PL: It's the adherence, stupid (that determines asthma control in preschool children)! Eur Respir J 2014;43:783-791.

14. Kappelle L, Brand PL: Severe episodic viral wheeze in preschool children: High risk of asthma at age 5-10 years. Eur J Pediatr 2012;171:947-954.

15. Fouzas S, Brand PL: Predicting persistence of asthma in preschool wheezers: crystal balls or muddy waters? Paediatr Respir Rev 2013;14:48-52.

EVALUATION 1. Which of the following statements is true?

I. >50% of preschool children with episodic viral wheeze referred to hospital based paediatric care become symptom free by the age of 6 years. II. Episodic viral wheeze does not respond to inhaled corrticosteroids maintenance treatment. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

2. Which of the following statements is true?

I. >25% of preschool children with wheeze change phenotype from EVW to MTW or vice versa within one year. II. The severity and frequency of wheeze episodes are less important than the wheeze pattern (EVW or MTW) in determining the need for daily controller therapy. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

3. Which of the following statements is true?

I. Inhaled corticosteroids (ICS) are effective in reducing wheeze symptoms in preschool children with recurrent wheeze, irrespective of wheeze phenotype (EVW or MTW). II. Adherence to ICS treatment is the main determinant of asthma control in preschool children. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

4. Which of the following statements is true?

I. Daily controller treatment in preschool children with wheeze reduces the long-term risk of persistent asthma in these children. II. Daily controller therapy in preschool children with wheeze should be viewed as a treatment trial, with scheduled follow-up and tapering down medication to the lowest effective dose. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

Please find all answers at the back of your handout materials

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PRESCHOOL WHEEZE: WHAT IS NEW SINCE THE 2008

TASKFORCE?

Paul L P Brand

Princess Amalia Children’s CentreIsala hospital, Zwollethe Netherlands

p.l.p.brand@isala.nl

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Faculty disclosure

• Lecturing, consultancy, travel, and research fees from:– Glaxo Smith Kline– Boehringer Ingelheim– Merck

– Thermo Fisher– Nutricia Research– AbbVie

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AIMS

At the end of this lecture, you will be able to:

• Discuss limitations of distinguishing episodic viral wheeze and multiple trigger wheeze

• Provide evidence based treatment recommendations for preschool children with troublesome recurrent wheeze

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Eur Respir J 2014;43:1172-7

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Naomi: 3rd admission for wheeze/dyspnea with URTIs no interval symptoms; M asthma as child, F hay fever

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Anne: 1st ER visit for acute wheeze with URTI has had mild wheeze repeatedly with cold/mist

parents smoke, not allergic

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The ERS 2008 Guideline

EVW MTW

Wheeze episodes Only with URTIs With URTIs, but also with other triggers

Interval symptoms No Yes, with other triggers

Response to ICS - ++

Response to montelukast + +

Many people think:

Allergy Thought to play no role Important driver/trigger

Long-term outcome Transient wheeze Persistent wheeze

Naomi? Anne?15

The 2014 update

Frequency and severity of episodes determines need for

controller therapy

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STABILITY OF WHEEZE PHENOTYPES

132 2-6 yr old children with “asthma”treated with ICSClassified as EVW or MTW at start of studyFollow-up 1 yr (4 visits)Wheeze during colds only or also apart from colds? classification as EVW or MTW

Acta Paediatr 2010;99:56-6017

38 EVW

71 MTW

22

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12EVW

13 no wheeze

13MTW

Acta Paediatr 2010;99:56-60

Start of study End of study (1 year later)

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EVW USUALLY TRANSIENT?

Eur J Pediatr 2012;171:947-54

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PHENOTYPE DIRECTED TREATMENT?

Sonnappa et al, JACI 2010;126:519-26Significant differences?Or mainly overlap?

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PHENOTYPE DIRECTED TREATMENT

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THE 2014 UPDATE

Limited usefulness of phenotype distinction

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TREATMENT OF PRESCHOOL WHEEZE

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CLASSIFICATION OF PRESCHOOL WHEEZE

Eur Respir J 2008;32:1096-1110

“The present recommendations are likely to change when more evidence becomes

available.”

Based on limited evidence

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ICS FOR RECURRENT PRESCHOOL WHEEZE

Castro-Rodriguez, Pediatrics 2009;123:e519-2525

ICS FOR RECURRENT PRESCHOOL WHEEZE

Castro-Rodriguez, Pediatrics 2009;123:e519-25

ICS are effective in recurrent wheeze in preschool children, irrespective of wheeze

pattern

wheeze pattern not specified in most of these studies

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ICS VS MONTELUKAST

ADC 2010;95:365-70

J Allergy Clin Immunol Pract 2013;1:58-64

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ERS TASKFORCE REPORT ON PRESCHOOL WHEEZE: THE 2014 UPDATE

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THE DUTCH GUIDELINE

• Other key factors:– Questions about validity of EVW-MTW distinction– Excellent long-term safety record of ICS, also for

growth

• Recommendation:– If maintenance treatment is indicated in preschool

children with (troublesome) recurrent wheeze, choose ICS as first line therapy

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THE DUTCH GUIDELINE

• Other key factors:– Questions about validity of EVW-MTW distinction– Excellent long-term safety record of ICS, also for

growth

• Recommendation:– If maintenance treatment is indicated in preschool

children with (troublesome) recurrent wheeze, choose ICS as first line therapy

“The present recommendations are likely to change when more evidence becomes

available.”

Based on limited evidence

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ICS ADHERENCE AND ASTHMA CONTROL

Klok et al, Eur Respir J 2014; 43:783-9132

ICS ADHERENCE AND ASTHMA CONTROL

Klok et al, Eur Respir J 2014; 43:783-91

Long-term asthma control largely determined by ICS adherence.No confounders of this association

Could it be that earlier reports of poor ICS efficacy in preschool children were due to

poor adherence/inhaler technique?

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HIGH ICS ADHERENCE CAN BE ACHIEVED

One-year adherence:84% (median)

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TREATMENT AND LONG-TERM OUTCOME

• ICS treatment of preschool wheeze:– Reduces symptoms– Does not influence natural history (persistence or

remission of wheeze over years)

• Effective treatment and control of symptoms:– Improves parental confidence– Enhances long-term adherence

N Engl J Med 2006;354:1985-97Lancet 2006;368: 754-62Acta Paediatr 2009;98:1939-44

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CONCLUSIONS

• Preschool wheeze complex group of syndromes; lots left to learn

• EVW – MTW distinction not very useful

• Treatment determined by severity/frequency of episodes

• ICS appear to be superior to LTRA in treatment of preschool wheeze

• Daily controller therapy helps to control symptoms

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p.l.p.brand@isala.nl

@paulbrandzwolle

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An update on food allergy

Prof. Dr Kirsten Beyer Charité - Universitätsmedizin Berlin

Augustenburger Platz 1 13353 Berlin

Germany kirsten.beyer@charite.de

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Paediatric drug allergy: state of the art

Prof. Marzia Duse Department of Pediatrics and Pediatric Neuropsychiatry

Sapienza Università di Roma 00161 Rome

Italy marzia.duse@uniroma1.it

AIMS • Adverse drug reactions (ADRs) • Drug Hypersensitivity • Epidemiology • Immunological mechanisms in ADRs • Diagnosis of ADRs (SPT, Patch test, ID, DPT) • Clinical features in pediatric population • DRESS syndrome • Stevens-Johnson Syndrome • Drug Desensitization SUMMARY Adverse drug reactions (ADRs) refer to responses to medicinal products that are noxious and unintended. ADRs divided into predictable, dose-dependent reactions (such as drug toxicity and adverse effects) and unpredictable, dose-independent reactions. The latter are generally not related to the pharmacological actions of the drugs. They occur in genetically predisposed patients and include allergic reactions that require prior sensitization. Several terms have been used to describe non-predictable drug adverse reactions but the term “hypersensitivity” seems to be the most appropriate and follows current international recommendations for nomenclature. [1] ADRs in children represent a serious public health problem. The overall incidence of ADRs is estimated at about 9.5% in hospitalized children and at about 1.5% for outpatient children. [2] Risk factors for adverse drug reactions include prior exposure, previous reactions, root of administration, dose (children are more susceptible than adults to error in drug dosage because of their smaller body size), dosing schedule and genetic predisposition. Antibiotics are most responsible for ADRs. For instance, the incidence of allergy to penicillin is estimated at 1-10% while anaphylaxis to penicillin varies between 0.01-0.05%. Cutaneous reactions to antibiotics, on the other hand, are estimated at 2.2%. [3] Acetylsalicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAID) are the most common causes of ADRs after antibiotics. Drugs that most commonly cause anaphylaxis are anti-inflammatory drugs, antibiotics and local anesthetics. Only 6-10% of ADRs can be attributed to an allergic mechanism. Immunologically-mediated ADRs have been classified according to Gell and Coombs classification. Immediate hypersensitive reactions (type I) occur when a drug or drug metabolite interacts with drug-specific IgE antibodies. The latter are bound to mast cells and/or circulating basophils. The binding of IgE by drug antigens causes the release of mediators such as histamine and leukotrienes that contribute to the clinical development of urticaria, bronchospasm and anaphylaxis. Delayed-type hypersensitivity reactions (type IV) are mediated by T-lymphocytes. Sensitization usually takes place through the topical route of administration and results in allergic contact dermatitis. Cytotoxic antibody reactions and immune complex reactions (types II and III) are also implicated in the immuno-pathogenesis of drug reactions. [4]

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Accurate diagnosis of drug allergy can preempt serious or even life-threatening reactions. In addition, it can avoid useless drug restrictions that lead to increased resistance (e.g. to antibiotics) and healthcare costs. If an ADR is suspected, a complete work-up should be performed. Evaluation will vary according to the drug and mechanisms thought to be involved. It is essential to establish an accurate medical history to evaluate the possibility of a patient’s adverse reaction to a drug. Dosages, root and dates of administration of suspected drugs, as well as previous exposure must be identified. Detailed descriptions of past reactions may indicate the nature of the ADR. [5] Symptoms such as anaphylaxis, bronchospasm, urticaria and angioedema are IgE-mediated and require the Skin Prick Test and intradermal test. Patch tests, on the other hand, should be used as a first line of investigation when there is evidence of contact dermatitis, erythema multiforme, Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis. Skin testing is the most efficient way of relating the presence of IgE to a specific drug allergen. A positive skin test is suggestive of drug-specific IgE antibodies. A negative skin test, however, does not exclude the presence of such antibodies; the proper immunogen may not have been used. In addition, many immunologically-mediated adverse drug reactions are caused by metabolites rather than by parent compounds. [6] The drug provocation test remains the gold standard. It has proven effective especially in children displaying a benign rash while on antibiotics. In addition, graded challenge, or test dosing, can be performed in cases of delayed, non-severe, non-IgE-mediated reactions. [7] ADRs include diverse clinical manifestations, the most serious being anaphylactic reactions. Cutaneous reactions are the most common form of ADRs (20% of all ADR), from minor reactions to potentially life-threatening skin reactions such as SJS and toxic epidermal necrolysis. ADRs can on the other hand mimic other skin diseases of children, especially viral exanthemas. [8] A spectrum of well-characterized clinical manifestations of ADRs in the pediatric population will be addressed during the course, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome and SJS. Hypersensitivity to non-steroidal anti-inflammatory drugs (NSAID) is the second most common cause of drug-induced hypersensitivity reaction in children. Inhibition of the cyclooxygenase enzime-1 (COX-1) is the mechanism proposed. Preliminary studies suggest that cyclooxygenase-2 inhibitors are tolerated most of the time. Both NSAID and aspirin can cause an anaphylactoid reaction and urticaria and/or angioedemea in children and, rarely, asthma in adolescents. In patients with bronchial asthma and nasal polyps, the prevalence of aspirin may reach 25% (aspirin-exacerbated respiratory disease (AERD)), while cutaneous manifestations to NSAIDs include rare and severe diseases like SJS and DRESS syndrome. Once aspirin or NSAID intolerance has been established, options include avoidance or pharmacological desensitization. [9] DRESS syndrome is a severe drug-induced hypersensitivity syndrome that may be observed after the administration of several drugs. Symptoms usually occur within two to eight weeks. Since DRESS syndrome may be life threatening, an early diagnosis is imperative. [10] SJS is a muco-cutaneous disorder, induced by drugs, that causes blisters. Epidermal detachment is under 10%. Symptoms include confluent maculae on face and body, severe mucosal erosions and fever. Eyes, liver, kidneys and lungs may also be affected. Risk of infection is high. No matter what the ADR, withdrawing the drug that provokes symptoms remains the most efficient therapeutic option. The withdrawal should include any cross-reactive molecules. For

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example, patients who have experienced pronounced allergic reactions with penicillins should be properly tested before receiving therapy containing a cephalosporin. [11] Specific desensitization is the only therapeutic alternative for patients with IgE antibodies to a specific drug for whom a replacement drug is not yet available or suitable. Desensitization should be performed in a hospital setting with resuscitation equipment available. Complications are usually mild and responsive to adjustments in the drug dose. More severe reactions can occur during parenteral desensitization. REFERENCES 1. Johansson SGO et al. Position Paper. A Revised Nomenclature for Allergy. An EAACI

Position Statement from EAACI Nomenclature Task Force. Allergy. 2001; 56: 813-824. 2. Gomes ER et al. Epidemiology of Hypersensitivity Drug Reactions. Curr Opin Allergy Clin

Immunol. 2005; 5: 309-316. 3. Ahlstedt S. Penicillin Allergy – Can the Incidence Be Reduced? Allergy. 1984; 39: 151-164. 4. Pichler WJ. Delayed Drug Hypersensitivity Reactions. Ann Intern Med. 2003; 139: 683-693. 5. Greenberger PA. Drug Allergy. J Allergy Clin Immunol. 2006; 117: S464-S470. 6. Rieder M. New Ways to Detect Adverse Drug Reactions in Pediatrics. Pediatr Clin North

Am. 2012 Oct; 59(5): 1071-1092. 7. Vezir E et al. The Evaluation of Drug Provocation Tests in Pediactric Allergy Clinic: A

Single Center Experience. Allergy Asthma Proc. 2014 Mar-Apr; 35(2): 156-62. 8. Noguera-Morel L et al. Cutaneous Drug Reactions in the Pediatric Population. Pediatr Clin

North Am. 2014; 61(2): 403-426. 9. Corzo JL et al. Tolerance to COX-2 Inhibitors in Children with Hypersensitivity to

Nonsteroidal Anti-inflammatory Drugs. Br J Dermatol. 2014 Mar; 170(3): 725-729. 10. Irga N et al. Pediatrician! Do You Know the Symptoms of DRESS Syndrome? A Case Report

of A 4-Year-Old Girl. Pediatr Emerg Care. 2013 Apr; 29(4): 504-507. 11. Caubet JC. Diagnostic Issues in Pediatric Drug Allergy. Curr Opin Allergy Clin Immunol.

2012 Aug; 12(4): 341-347.

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EVALUATION 1. What are the most common clinical manifestations in drug hypersensitivity?

a. DRESS syndrome b. Anaphylaxis c. Cutaneous reactions d. All of the above

2. The gold standard for the diagnosis of IgE-mediated drug hypersensitivity is:

a. Patch test b. Skin Prick test c. Drug Provocation test d. Oral desensitization

3. SJS is:

a. An IgE-mediated drug reaction b. A common ADR in pediatric population c. A life-threatening disease d. None of the above

4. Drug desensitization is:

a. a suitable therapeutic alternative for non-IgE-mediated b. a safe procedure when performed orally c. None of the above d. All of the above

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Anaphylaxis in children

Dr Graham Roberts University of Southampton

Southampton United Kingdom

g.c.roberts@soton.ac.uk AIMS • To be able to correctly diagnose anaphylaxis and its important differential diagnoses. • To know the immediate management of a child presenting with anaphylaxis. • To understand the rationale for the longterm management of children at risk of anaphylaxis

including the prescription of adrenaline. SUMMARY Anaphylaxis is a clinical emergency and all healthcare professionals should be familiar with its recognition and acute and ongoing management. The European Academy of Allergy and Clinical Immunology (EAACI) has recently published Guidelines on Anaphylaxis [1]. The development of these guidelines has been underpinned by two systematic reviews of the literature, both on the epidemiology and on clinical management of anaphylaxis [2,3]. Anaphylaxis is a potentially life-threatening condition whose clinical diagnosis is based on recognition of a constellation of presenting features. First-line treatment for anaphylaxis is intramuscular adrenaline. Useful second-line interventions may include removing the trigger where possible, calling for help, correct positioning of the patient, high-flow oxygen, intravenous fluids, inhaled short-acting bronchodilators, and nebulized adrenaline. Discharge arrangements should involve an assessment of the risk of further reactions, a management plan with an anaphylaxis emergency action plan, and, where appropriate, prescribing an adrenaline auto-injector. If an adrenaline auto-injector is prescribed, education on when and how to use the device should be provided. Specialist follow-up is essential to investigate possible triggers, to perform a comprehensive risk assessment, and to prevent future episodes by developing personalized risk reduction strategies including, where possible, commencing allergen immunotherapy. Training for the patient and all caregivers is essential. There are still many gaps in the evidence base for anaphylaxis. REFERENCES 1. Muraro A et al. Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical

Immunology. Allergy, in press. EAACI 2014 guidelines

2. Panesar SS et al. Allergy 2013;68:1353–1361. Systematic review on the epidemiology of anaphylaxis

3. Dhami S et al. Management of anaphylaxis: a systematic review. Allergy 2014;69:159–167. Systematic review on the management of anaphylaxis

43

EVALUATION 1. A diagnosis of anaphylaxis in children is usually made by:

a. A raised tryptase level at presentation. b. A positive serum specific IgE result. c. A skin prick test wheal that is above the 95% positive predictive value. d. Clinical presentation. e. Paired tryptase measurements.

2. The following are likely to be examples of anaphylaxis:

a. A 2 year old with acute onset stridor after a few days of coryzal illness in a child with eczema.

b. An 8 year old who develops an urtarial mouth at a friend’s house, when his parents arrive, he is wheezy.

c. A 14 year old girl who collapses in clinic during skin prick testing. She has localised erythema and some small wheals at the site of testing. Her respiratory rate is 20 per minutes, there are no added respiratory sounds, heart rate 50 per minute and capillary refill time of less than 2 seconds.

d. 9 year old with peanut allergy accidently eats some chocolate with almonds. He rapidly develops am itchy mouth and complains about difficulty in breathing, throat tightness and pins and needles in his fingers.

e. A 14 year old steps in a wasp nest. He is stung a number of times. Within minutes he develops wide spread urtiaria and angioedema. Shortly afterwards he collapses.

3. The following are indications for self-injectable adrenaline:

a. Previous episode of anaphylaxis to a food, latex or aeroallergen. b. Previous episode of exercise induced anaphylaxis. c. Persistent asthma and a food allergy. d. Previous systemic reaction to wasp or bee venom. e. A history of any allergic reaction to peanut or tree nut.

44

Anaphylaxis in Children

Graham RobertsProfessor & Consultant in Paediatric Allergy & Respiratory MedicineDavid Hide Asthma and Allergy Research Centre, IoW & University of Southampton Faculty of Medicine, UK

45

Anaphylaxis in Children

• Introduction• Clinical presentation and diagnosis • Emergency management of anaphylaxis • Long-term management of anaphylaxis • Future perspectives• Summary

Fatalities still occur from anaphylaxis

46

Aims

1.

To be able to correctly diagnose anaphylaxis and its important differential diagnoses.

2.

To know the immediate management of a child presenting with anaphylaxis.

3.

To understand the rationale for the longterm management of children at risk of anaphylaxis including the prescription of adrenaline.

47

Introduction• Anaphylaxis as a clinical emergency• Incidence

of 1.5-7.9 per 100,000 person-years (10 European);

prevalence

of 0.3% (95% CI, 0.1-0.5) (3 European population- based studies)

• Variable, at times suboptimal management• Generation of the 2014 EAACI anaphylaxis guidelines:

– Used Appraisal of Guidelines for Research & Evaluation (AGREE II) approach

– Wide stakeholder involvement– Systematic reviews of evidence– Formulating recommendations– Peer review– Editorial independence

48

Grading evidence for guidelinesLevel of evidenceI

Systematic reviews, meta-analysis, randomised controlled trial

II

Two groups, non-randomized studies (e.g. cohort, case-control)III One-group non-randomized (e.g. before and after, pre test and

post test)IV

Descriptive studies that include analysis of outcomes (single-subject design, case-series)

V

Case reports and expert opinion that include narrative literature, reviews and consensus statements

Grade of recommendationA

Consistent level I studies

B

Consistent level II or III studies or extrapolations from level I studiesC

Level IV studies or extrapolations from level II or III studies

D

Level V evidence or troublingly inconsistent or inconclusive studies at any level

Oxford Centre for Evidence-based Medicine. Levels of Evidence and Grades of Recommendation.

http://www cebm net/index aspx?o=1025 (accessed 25th March 2013)

49

Clinical presentation and diagnosis: definition

Anaphylaxis is highly likely with any one of the following 3 criteria:1. Acute onset of an illness with involvement of the skin or mucosal tissue

AND AT LEAST ONE OF THE FOLLOWINGa. Respiratory compromise b. Reduced BP or associated symptoms of end-organ dysfunction2. Two or more of the following that occur rapidly after exposure to a likely

allergen for that patient:a. Involvement of the skin-mucosal tissue b. Respiratory compromise c. Reduced BP or associated symptoms d. Persistent gastrointestinal symptoms 3. Reduced BP after exposure to known allergen for that patient

Reproduced with permission from Sampson et al(2006) (C).

better identification of anaphylaxis (Harduar-Morano 2010), excellent sensitivity (97%), good specificity (82%) (Campbell 2012).

50

Diagnostic utility of definition Objective: Assess diagnostic accuracy of the NIAID/FAAN criteria for the diagnosis of anaphylaxis.Methods: Retrospective cohort study of 214 emergency department patients with an allergic reaction or anaphylaxis plus a subset of related diagnoses. Records independently reviewed by 2 allergists.Results:

Campbell JACI 2012 51

Clinical presentation and diagnosis: diagnosis

DiagnosisAnaphylaxis is a clinical diagnosisBest to keep things simple:

Cutaneous signs:UrticariaAngioedema

Second system involvement:Respiratory compromiseSymptoms of hypotensionPersistent gastrointestinal symptoms

= Anaphylaxis

+

52

Clinical presentation and diagnosis: investigations

Retrospectively, these may support a diagnosis: Elevated serum tryptase within a few hours of a reaction when compared with baseline levels; but often normal especially in food-triggered reactions in children (Sala-Cunill 2013). Evidence of IgE sensitization (SPT or spIgE)Where continued diagnostic uncertainty, provocation testing, ideally with any potential co-factors (Cardona 2012)

53

Clinical presentation: case 1

A 9-year-old girl with a history of asthma and peanut allergy is at a birthday party.

She complains of sudden onset wheeze and tightness in her chest.

She continues to be very wheezy despite 4 puffs of salbutamol.

She is brought to the emergency department by ambulance –

paramedics give some nebulised

salbutamol.Anaphylaxis?

Unlikely as no cutaneous involvement. Acute exacerbation of asthma is the likely diagnosis.

And if no respond to more nebulised salbutamol?54

Clinical presentation: case 2

A 4-year-old boy is brought into the emergency department at midnight with acute onset stridor.

He has been unwell for a few days with a cold and has recently developed a cough.

He has severe eczema and there is a strong family history of food allergy.

Anaphylaxis?Unlikely as no cutaneous involvement. Croup (acute

laryngotracheitis) is the likely diagnosis given the preceeding cold symptoms, associated (croupy) cough and lack of cutaneous signs.

55

Clinical presentation: case 3

A 6-year-old boy complains of an itchy mouth whilst at his grandfather’s 60th birthday party.

Fifteen minutes later, he starts to develop an itchy rash on his face -

his parents describe it as being like

a nettle rash.

A short while later, his lips became noticeably swollen and he indicated to his parents that he was having difficulties in breathing.

His parents gave him some chlorpheniramine syrup and called an ambulance.

Anaphylaxis?Yes, satisfies criterion 1 (acute onset with skin

involvement and respiratory compromise)56

Clinical presentation: case 4

A 2-year-old boy is brought into the emergency department one afternoon with acute onset stridor.

He had been well but has a history of developing an urticaria rash with exposure to peanuts the previous weekend.

His mother can offer little history as he had been playing in the kitchen while she was answering the telephone.

Anaphylaxis?Unlikely as no cutaneous involvement. Inhaled foreign

body is the most likely diagnosis.

57

Clinical presentation: case 5

A 16-year-old boy is being investigated with skin prick testing in clinic. He has prick to prick testing with a range of fruits on this left forearm.

As the results are being read, he complains of an itchy arm.

A few minute later his complains of feeling light headed and collapses onto the floor.

Anaphylaxis?Possible but more likely to be a vasovagal reaction.

Are there other clues to confirm this? Bradycardia would suggest a vasovagal reaction,

tachycardia would suggest anaphylaxis. 58

Clinical presentation: case 6

A 16-year-old boy with a history of peanut allergy and asthma is brought into emergency department in a collapse state.

He was at a house party with friends, they are not very forthcoming with history.

On examination he has sturtor, respiratory rate of 20/minute, heart rate of 80/minute and smells of alcohol.

Anaphylaxis?Likely to be alcohol intoxication. Should exclude

diabetic ketoacidosis, head injury and other causes of intoxication.

59

Clinical presentation: case 7

13-year-old girl with tree nut allergy is brought by car into emergency department with breathing problems.

She was at a friends house where she accidently ate some chocolate containing hazel nuts.

Within 20 minutes she developed a wide spread itchy rash and then complained of difficulty in breathing.

She did not have her autoinjector.

On examination she has looks started, has an urticaria rash, a biphasic mid pitch wheeze, respiratory rate of 80/minute and tightness in her throat.

Anaphylaxis?Possible but likely to be a mild allergic reaction plus

hyperventilation and vocal cord dysfunction. 60

Clinical presentation: case 8

13-year-old girl with known white fish allergy is at a party. Usually she avoids all fish and sea food.

She accidently ingests some salad containing tuna.

She rapidly develops oral pruiritis.

Approximately 5-10 minutes later she develops an itchy rash and later facial swelling.

She is rushed to hospital by her parents.

On examination in hospital she has obvious widespread urticaria and gross facial angioedma; she is very anxious.

Anaphylaxis?No as only cutaneous BUT might develop into anaphylaxis.

Does she have any risk factors? 61

Clinical presentation: case 9

17-year-old boy became unwell while eating out at a restaurant; he’d enjoyed some smoked mackerel and a chocolate dessert.

Just after finishing the dessert he developed became very red in the face and felt dizziness and nauseous.

In the emergency department he is alert with normal breath sounds, heart rate of 100/minute, perioral oedema and erythematous facial rash. He is also complaining of abdominal pain.

Anaphylaxis?No this is a classic case of scromboid poisoning.

62

Clinical presentation and diagnosis: differential diagnosis

Differential diagnosisSkin or mucosal: chronic urticaria/angioedma; pollen-food allergy syndromeRespiratory diseases: acute laryngotracheitis, tracheal or bronchial obstruction; status asthmaticusCardiovascular diseases: vasovagal syncope, PE, MI, cardiac arrhythmias, hypertensive crisisPharmacological or toxic reactions:

ethanol, histamine,

opiatesNeuropsychiatric diseases: hyperventilation, panic, epilepsy, cerebrovascular event, psychoses, artifactEndocrinological diseases: hypoglycemia, thyrotoxic crisis, carcinoid syndrome, phaeochromocytoma

63

Clinical presentation and diagnosis: risk factors

Factors increasing the risk of severe allergic reactionsPrevious severe allergic reactionConcomitant disease: asthma (eg Gonzalez-Perez 2010), mast cell disorders (Wimazal 2012), and probably cardiovascular disease (Triggiani 2008). Specific allergens: peanut and tree nuts (Vander Leek 2000)Co-factors: exercise, fever, acute infection, premenstrual status, emotional stress, alcohol, NSAID, beta-adrenergic-blocker, angiotensin converting enzyme (ACE) inhibitor (Hompes 2011).

Level of evidence VERY LOW in general64

Emergency management of anaphylaxis

Immediate assessment using an airway, breathing, circulation, disability and exposure approach.

Treated problems as they are found and a call for help

Cardiopulmonary resuscitation should be immediately instituted if cardiorespiratory arrest occurs.

Further approach:

first-line intervention (adrenaline)

second-line interventions

third-line interventions65

Emergency management of anaphylaxis: first-line

Recommendation Level Grade

Adrenaline must be promptly administered IV C

Earlier adrenaline should be considered when an allergic reaction is

likely to develop into anaphylaxis

V D

Adrenaline should be administered by intramuscular injection into

the mid-outer thigh.

I B

In patients requiring repeat doses of adrenaline, these should be

administered at least 5 minutes apart

V D

With inadequate response to 2 or more doses of intramuscular

adrenaline, adrenaline may be administered as an infusion by

appropriate experienced intensive care, emergency department

and critical care physicians, with appropriate cardiac monitoring

IV D

66

Emergency management of anaphylaxis: second & third-line

Second-line recommendation Level Grade

Trigger of the anaphylaxis episode should be removed V D

Help should be called promptly V D

Positioned supine with elevated lower limbs if circulatory instability,

sitting up if respiratory distress, recovery position if unconscious

V D

High flow oxygen should be administered by face mask V D

Intravenous fluids if cardiovascular instability V D

Third-line recommendation Level Grade

Oral H1- (& H2)-antihistamines may relieve cutaneous symptoms of

anaphylaxis

I B

Systemic glucocorticosteroids may reduce the risk of late phase

respiratory symptoms

V D

67

Emergency management of anaphylaxis: monitoring & discharge

Recommendation Level Grade

Monitor for 6-8 hours with respiratory compromise and 12-24 hours

with circulatory instability.

V D

Before discharge, assess risk of future reactions and prescribe

adrenaline auto-injector if at risk of recurrence.

V D

Provide patients with a discharge advice sheet, including allergen

avoidance measures (where possible) and instructions for the use

of the adrenaline auto-injector.

Specialist and food allergy specialist dietitian (in food anaphylaxis)

follow-up should be organized.

Contact information for patient support groups should also be

provided.

V D

68

If no response in 5-10 minutes:•Repeat I.M. adrenaline•Repeat fluid bolus•Set up adrenaline infusion

If no response in 5- 10 minutes:•Repeat nebulized beta-2-agonist•Consider further I.M. adrenaline •Call for ICU support

If respiratory distress or no response within 5-10 minutes:• I.M. adrenaline• I.V. access

Wheeze•High flow oxygen•Sit up•Nebulized beta-2-agonist

If no response in 5-10 minutes: •Repeat nebulised adrenaline•Consider further I.M. adrenaline

If respiratory distress or no response within 5-10 minutes:•I.M. adrenaline•I.V. access•Call for ICU support

Consider lower threshold for adrenaline if:•Previous severe reaction•Exposure to known/ likely allergen•Co-existent asthma

Hypotension or collapse • High flow oxygen• Lie down, extremities

elevated• Normal saline, 20ml/kg I.V.

or intraosseous• Call for ICU support

Angioedema or urticaria ONLY

•PO anti- histamine •If known to have asthma, give inhaled beta-2- agonist•Observe for 4 hours – as this may be an early presentation of anaphylaxis

Stridor•High flow oxygen•Sit up•Nebulized adrenaline

Treat as per protocol

I.M. adrenaline dose0.01ml/kg adrenaline (1mg/ml) OR•7.5 to 25kg: 0.15mg adrenaline auto-injector •≥25kg: 0.3mg adrenaline auto- injector

EVALUATE Airway, Breathing and Circulation

If possible, remove allergenCall for help

CARDIO-RESPIRATORY ARREST

Observation:Patients with respiratory symptoms or signs should be observed for at least 6 to 8 hours in hospital prior to discharge. Those presenting with hypotension or collapse require close monitoring for 12-24 hours.

Discharge check list:•Assess risk of future anaphylaxis.•Prescribe adrenaline auto-injector if risk of recurrence.•Provide discharge advice sheet: allergen avoidance (if possible), instructions for when and how to use adrenaline auto-injector.•Arrange specialist allergy review and specialist dietitian review if food involved. •Provide contact information for patient support groups.•Discharge letter for the family doctor

Upper airway, lower respiratory or cardiovascular symptoms or signs and anaphylaxis is likely

Give I.M. ADRENALINE

With persistent vomiting and/or abdominal pain

CONSIDERI.M. adrenaline

First-lineSecond-line

Third-line: Consider I.V or P.O. antihistamine to control cutaneous symptomsConsider I.V. or P.O. glucocorticoids to prevent late phase respiratory reactions. 69

Long-term management of anaphylaxis

Confirmation of trigger(s) using validated in-vivo and/or in-vitro tests interpreted in the light of a detailed allergy history

Prevention of recurrence including avoidance, patients reacting to foods should see a dietician (hidden allergens, cross-reactions to other allergens, high risk situations)

Allergen immunotherapy where possible, eg venom anaphylaxis

Education for self-treatment of anaphylaxis recurrence in the community

Management of relevant concomitant diseases 70

Long-term management of anaphylaxis: recommendations

Recommendation Level Grade

Anaphylaxis management plan should be used to prevent future

reactions, and aid recognition and treatment of further reactions

III C

Subcutaneous venom immunotherapy I A

Training

Training in allergen avoidance, recognition and management of

anaphylaxis including when and how to use an auto-injector

V D

May involve more than one session to allow revision, an

interactive scenario-based approach, a standardized program

with manual and educational material and simulation tools.

V D

Psychological principles should be incorporated in educational

interventions, some patients may need more input

V D

71

Long-term management of anaphylaxis: action plans

Individualized anaphylaxis emergency action plan1. Immediately administer adrenaline auto-injector if:

•you think that you are having an anaphylactic reaction

•your throat feels tight or you have wheezing or whistling in your chest or you are finding it difficult to breath

•you feel faint or feel like you are about to collapse

•you have severe stomach symptoms plus sudden onset skin symptoms

2. Call emergency medical services

3. Sit up unless you feel faint or feel you are about to collapse in which case lie down with your feet raised above your chest

4. If you have any swelling of your face or itching, take an antihistamine

5. After 5 minutes, if your breathing problems are worse or no better, or you are still feeling faint, you can use a second adrenaline autoinjector

72

Who should be prescribed an adrenaline autoinjector?

Johnson PAI 2011 Guidelines ↑

NYNN

Y/NNY

Y/NYY

73

Who should be prescribed an adrenaline autoinjector?

NYNN

Y/NNY

Y/NYY

Johnson PAI 2011 Guidelines ↑74

Long-term management of anaphylaxis: autoinjectors

Recommendation Level Grade Absolute indications for at least one adrenaline auto-injector: 1. Previous anaphylaxis triggered by food, latex or aeroallergens IV C

2. Exercise-induced anaphylaxis IV C

3. Idiopathic anaphylaxis IV C

4. Unstable or mod-severe, persistent asthma & food allergy* IV C

5. Venom allergy in adults & children (non-cutaneous for children) systemic reactions

IV C

6. Mast cell disorders or elevated baseline serum tryptase concentrations plus any previous systemic venom reactions

IV C

Consider prescribing:

1. Mild-to-moderate allergic reaction to peanut and/or tree nut* IV C

2. Teenager or young adult with a food allergy* IV C

3. Remote from medical help and previous mild to moderate allergic reaction to a food*, venom, latex or aeroallergens

V D

4. Mild-to-moderate allergic reaction to very small amounts of food* V D*Not pollen-food syndrome 75

Long-term management of anaphylaxis: autoinjectors

How many adrenaline autoinjectors? Ref. Study design Auto-

injectorUsed auto-injector during follow up*

Needed 2nd

adrenaline dose

Noimark 2012

Retrospective clinic

All 4% (41/969) over 12m 32% (13/41)

Gold 2000

Retrospective clinic

All 22% (15/68) over 20m 15% (2/13)

Clark 2008

Prospective clinic

Not all 3% (23/785) over 48m 0% (0/23)

Jarvinen 2008

Prospective clinic

Not all 19% (78/413) over 24m 19% (18/95)

Simons 2009

Patient survey Not all 27% (500/1885) 18% (90/500)

Uguz 2005

Patient survey Not all 35% (22/63) 18% (4/22)

76

Long-term management of anaphylaxis: autoinjectors

How many adrenaline autoinjectors? Suggested indications for prescribing a second auto-injector for the patient to carry include:

Level Grade

Co-existing unstable or moderate to severe, persistent asthma and a food allergy

IV C

Co-existing mast cell diseases or elevated baseline tryptase concentration

IV C

Lack of rapid access to medical assistance to manage an episode of anaphylaxis due to geographical or language barriers

V D

Previous near fatal anaphylaxis V D

If available auto-injector dose is much too low for body weight

V D

77

Future perspectivesTwo EAACI systematic reviews reveal a lack of high quality evidence in this area; gaps include: Large prospective cohort studies of patients at risk of anaphylaxis needed to estimate magnitude of riskPharmacokinetic studies to determine the optimal dose and dosing interval of adrenalineWork on other routes of adrenaline administration RCT to assess the effectiveness of corticosteroids in preventing

late manifestations of anaphylaxis RCT to assess whether the addition of antihistamines improves outcomeEvidence to assess the effectiveness of training and anaphylaxis

management plans in improving outcome in patients

Panesar Allergy 2013; Dhami Allergy 2014 78

Anaphylaxis in Children: Summary

Important clinical emergency

Clinical diagnosis

Allergy testing to identifying the trigger.

First-line treatment is intramuscular adrenaline

Second-line interventions may include: remove the trigger, calling for help, correct positioning, high flow oxygen, intravenous fluids, inhaled short-acting bronchodilators and nebulized adrenaline.

Patients should be monitored after recovery

Before discharge: assess risk of further reactions; prescribe adrenaline auto-injector where appropriate

Training the patient and caregivers is essential

Specialist allergy follow-up is essential

79

Acknowledgements

Anaphylaxis Taskforce

Leads: A

Muraro, G Roberts, M Worm Methodologist:

A Sheikh, S Dhami, SS Panesar

Section leads: MB Bilò, K Brockow, M Fernández Rivas, AF Santos, A Sheikh, Z Zolkipli

Members: A Bellou, C Bindslev-Jensen, V Cardona, AT Clark, P Demoly, AEJ Dubois, A DunnGalvin, P Eigenmann, S Halken, L Harada, G Lack, M Jutel, B Niggemann, F Ruёff, F Timmermans, BJ Vlieg–Boerstra, T Werfel

Administrative help:

Toby Pitts-Tucker, Catherine Crowley

Expert reviewers: Carlos Camargo, James Gardener, Gunilla Hedlin, Mike Levin, Phil Lieberman, Richard Loh, Holger Mosbech, Johannes Ring, Maria Said, Estelle Simons, Jasmeet Soar, Massimo Triggiani

EAACI members who have commented on the draft

EAACI

for funding, EAACI ExCom

for their comments and EAACI

Food Allergy and Anaphylaxis Guidelines Group 80

EAACI Anaphylaxis Guidelines

Now in press in Allergy

Part of compilation book

81

Additional course resources Readings and guidelines

Preschool wheeze: what is new since the 2008 taskforce?

1. Ducharme FM, Tse SM, Chauhan B. Diagnosis, management, and prognosis of preschool wheeze. Lancet. 2014 May 3;383(9928):1593-604. doi: 10.1016/S0140-6736(14)60615-2. Review

2. Belgrave DC1, Buchan I, Bishop C, Lowe L, Simpson A, Custovic A. Trajectories of lung function during childhood. Am J Respir Crit Care Med. 2014 May 1;189(9):1101-9. doi: 10.1164/rccm.201309-1700OC.

An update on food allergy

3. Worm M, Moneret-Vautrin A, Scherer K, Lang R, Fernandez-Rivas M, Cardona V, Kowalski M, Jutel M, Poziomkowska-Gesicka I, Papadopoulos N, Beyer K, Mustakov T, Christoff G, Bilò M, Muraro A, Hourihane J, Grabenhenrich L. First European data from the network of severe allergic reactions (NORA). Allergy. 2014 Jul 2. doi: 10.1111/all.12475. [Epub ahead of print]

4. Sicherer SH, Sampson HA. Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014 Feb;133(2):291-307; quiz 308. doi: 10.1016/j.jaci.2013.11.020. Epub 2013 Dec 31. Review

Paediatric drug allergy: state of the art

5. Zambonino MA, Corzo JL, Muñoz C, Requena G, Ariza A, Mayorga C, Urda A, Blanca M, Torres MJ. Diagnostic evaluation of hypersensitivity reactions to beta-lactam antibiotics in a large population of children. Pediatr Allergy Immunol. 2014 Feb;25(1):80-7. doi: 10.1111/pai.12155. Epub 2013 Dec 13.

6. Matar R, Le Bourgeois M, Scheinmann P, de Blic J, Ponvert C. Beta-lactam hypersensitivity in children with cystic fibrosis: a study in a specialized pediatric center for cystic fibrosis and drug allergy. Pediatr Allergy Immunol. 2014 Feb;25(1):88-93. doi: 10.1111/pai.12154. Epub 2013 Nov 18.

Anaphylaxis in children

7. Worm M, Eckermann O, Dölle S, Aberer W, Beyer K, Hawranek T, Hompes S, Koehli A, Mahler V, Nemat K, Niggemann B, Pföhler C, Rabe U, Reissig A, Rietschel E, Scherer K, Treudler R, Ruëff F. Triggers and treatment of anaphylaxis: an analysis of 4000 cases from Germany, austria and Switzerland. Dtsch Arztebl Int. 2014 May 23;111(21):367-75. doi: 10.3238/arztebl.2014.0367

8. Vanlander A, Hoppenbrouwers K. Anaphylaxis after vaccination of children: review of literature and recommendations for vaccination in child and school health services in Belgium. Vaccine. 2014 May 30;32(26):3147-54. doi: 10.1016/j.vaccine.2014.03.096. Epub 2014 Apr 13.

9. Ma L, Danoff TM, Borish L. Case fatality and population mortality associated with anaphylaxis in the United States. J Allergy Clin Immunol. 2014 Apr;133(4):1075-83. doi: 10.1016/j.jaci.2013.10.029. Epub 2013 Dec 14.

10. Brown SG, Stone SF, Fatovich DM, Burrows SA, Holdgate A, Celenza A, Coulson A, Hartnett L, Nagree Y, Cotterell C, Isbister GK. Anaphylaxis: clinical patterns, mediator release, and severity. J Allergy Clin Immunol. 2013 Nov;132(5):1141-1149.e5. doi: 10.1016/j.jaci.2013.06.015. Epub 2013 Aug 1.

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Faculty disclosures Prof. Paul L.P. Brand has received lecturing, consultancy, travel, and research fees from Glaxo Smith Kline, Boehringer Ingelheim, Merck, Thermo Fisher, Nutricia Research and AbbVie. Prof. Dr Kirsten Beyer has received grants and research support from the European Union, the German Research Foundation, Thermo Fisher, Danone, DST and the Foundation for the Treatment of Peanut Allergy. Dr Beyer has also received honoraria and consultation fees from Danone, MEDA Pharma, ALK, Novartis, Unilever, Allergopharma, MedUpdate, Phadia and HAL.

83

Faculty contact information Dr Nicolette Arends Division of Endocrinology Department of Pediatrics Sophia Children’s Hospital / Erasmus MC PO Box 2060 3000 CB Rotterdam NETHERLANDS n.arends@erasmusmc.nl Prof. Dr Kirsten Beyer Charité - Universitätsmedizin Berlin Augustenburger Platz 1 13353 Berlin GERMANY kirsten.beyer@charite.de Prof. Marzia Duse Department of Pediatrics and Pediatric Neuropsychiatry Sapienza Università di Roma 00161 Rome ITALY marzia.duse@uniroma1.it

Prof. Angelo Barbato Dipartimento Salute Donna Bambino (SDB) Università degli Studi di Padova Via Giustiniani 3 35128 Padova ITALY barbato@pediatria.unipd.it Prof. Paul L.P. Brand Consultant paediatrician for respiratory and allergic disease Princess Amalia Children’s Clinic Isala Klinieken P.O. Box 10400 8000 GK Zwolle NETHERLANDS p.l.p.brand@isala.nl Twitter @paulbrandzwolle Dr Graham Roberts University of Southampton Southampton UNITED KINGDOM g.c.roberts@soton.ac.uk

84

Answers to evaluation questions

Please find all correct answers in bold below Preschool wheeze: what is new since the 2008 taskforce? – Prof. Paul L.P. Brand

1. Which of the following statements is true?

I. >50% of preschool children with episodic viral wheeze referred to hospital based paediatric care become symptom free by the age of 6 years. II. Episodic viral wheeze does not respond to inhaled corrticosteroids maintenance treatment. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

2. Which of the following statements is true?

I. >25% of preschool children with wheeze change phenotype from EVW to MTW or vice versa within one year. II. The severity and frequency of wheeze episodes are less important than the wheeze pattern (EVW or MTW) in determining the need for daily controller therapy. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

3. Which of the following statements is true?

I. Inhaled corticosteroids (ICS) are effective in reducing wheeze symptoms in preschool children with recurrent wheeze, irrespective of wheeze phenotype (EVW or MTW). II. Adherence to ICS treatment is the main determinant of asthma control in preschool children. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

4. Which of the following statements is true?

I. Daily controller treatment in preschool children with wheeze reduces the long-term risk of persistent asthma in these children. II. Daily controller therapy in preschool children with wheeze should be viewed as a treatment trial, with scheduled follow-up and tapering down medication to the lowest effective dose. a. Both statements are true. b. Statement I is false, statement II is true. c. Statement I is true, statement II is false. d. Both statements are false.

Paediatric drug allergy: state of the art – Prof. Marzia Duse

Please ask the faculty member on site.

Anaphylaxis in children – Dr Graham Roberts

Please ask the faculty member on site.

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