The European Academy of Allergy & Clinical Immunology s Allergen Immunotherapy Guidelines

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1 The European Academy of Allergy & Clinical Immunology s Allergen Immunotherapy Guidelines Professor Aziz Sheikh OBE BSc, MSc, MD, FRCGP, FRCP, FRCPE, FFPH, FACMI, FRSE, FFCI, FMedSci Director, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Director, Asthma UK Centre for Applied Research Director, Scottish Allergy & Respiratory Academy Director, NIHR Global Respiratory Health (RESPIRE) Unit Danish Society of Pediatric Allergology and Pulmonology, Kolding, 20 January 2018

2 Overview History of allergen immunotherapy (AIT) From European Academy of Allergy & Clinical Immunology (EAACI) Position Papers to Guidelines Developing guidelines the AGREE II approach EAACI AIT Guidelines Examples of key findings and recommendations from EAACI AIT Guidelines Allergy prevention Food allergy Allergic rhinitis Asthma Venom Implementation considerations Conclusions Discussion/Q&A

3 First things first

4 Potential conflicts of interest EAACI Asthma UK Centre for Applied Research (AUKCAR) Scottish Allergy and Respiratory Academy (SARA)

5 Definition of and synonyms for AIT Definition: Repeated allergen exposure at regular intervals to modulate immune response to reduce symptoms and the need for medication for clinical allergies and to prevent the development of new allergies. Synonyms: Allergen specific immunotherapy Allergy shots Allergy vaccination Desensitisation therapy Hypo-sensitisation therapy, etc. Delivery routes: Epicutaneous immunotherapy (EPIT) Intra-lymphatic immunotherapy (ILIT) Intra-nasal immunotherapy (INIT) Oral immunotherapy (OIT) Subcutaneous immunotherapy (SCIT) Sublingual immunotherapy (SLIT)

6 A Potted History of AIT

7 Larche M et al. Nature Rev Immunol, 2006

8 Some landmarks in Allergy 1819: First description of catarrhus aestivus (summer catarrh) by John Bostock (Medico- Chirurgical Transactions) 1905: Hygienist William Philipps Dunbar extracted from pollen what he considered to be the active toxic substance (J Hygiene). 1906: Clemens von Pirquet defines allergy (Munch Med Wochenschr)

9 Some landmarks in AIT 1908: Alfred T. Schofield publishes case report of curing egg poisoning (Lancet) 1911: Leonard Noon publishes case series of prophylactic vaccination against hay fever (Lancet)

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11 Innovation in immunotherapy 1930: John Freeman introduces rush SCIT given every few hours or every day (Lancet) 1938: Hymen L Naterman uses lanolin and olive oil as adjuvants of ragweed pollen SCIT (NEJM) 1939: Albert R Zoss et al use alum depot adjuvant for SCIT ragweed pollen (JACI)

12 Concerns around safety : There were a number of cases of AIT-triggered anaphylaxis which proved fatal this resulted in greater regulation of AIT in the UK with the Committee on Safety of Medicines (CSM) recommending: "that these treatments should be restricted to those patients who have not responded to anti-allergy drugs (UK CSM) 1992: Trial of subcutaneous immunotherapy for peanut allergy abandoned because of unacceptable risks of anaphylaxis (JACI, 1997)

13 Understanding of mechanisms and establishing post-treatment effects 1966: Discovery of IgE by Hans Bennich and Gunnar Johansson; and Kimishige and Teruko Ishizaka (WHO Bulletin, 1969) 1999: Establishing the long-term clinical effectiveness of grasspollen immunotherapy by Durham and Walker (NEJM)

14 Evolution of AIT AIT now available for a range of scenarios/conditions *Prevention *Food *Allergic rhinitis *Asthma *Venom allergy Eczema Pet allergy Drug allergy Range of preparations/routes of delivery now available for example: Epicutaneous (EPIT) Intra-lymphatic (ILIT) Oral Intra-nasal (INIT) Subcutaneous (SCIT) Sublingual (SLIT)

15 From EAACI Position Papers to Guidelines

16 Position Papers Strengths: Provide clinically important summaries to frontline clinicians with a view to aiding delivery of safe, effective and cost-effective care Relatively quick, straightforward and cheap to produce EAACI has considerable track record in producing Position Papers Limitations Limited stakeholder engagement May miss important literature High risk of bias Increasingly seen as passé/suboptimal by policymakers/clinicians Limited ability to influence care processes

17 Defining CPGs Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioners and patient decisions about appropriate health care for specific clinical circumstances. (BMJ, 1999) CPGs are statements that include recommendations intended to optimize patient care that are informed by a systematic review of the evidence and an assessment of the benefits and harms of alternative care options. (NGC, AHRQ, 2014)

18 Rationale for developing CPGs Considerable variations in the standards of clinical care Sub-optimal care leads to potentially avoidable morbidity, harm and expenditure The volume of evidence now being generated is too voluminous and complex for practitioners to read, interpret and clinically apply in day-today care Carefully developed, evidence-based recommendations can support clinicians in delivering high quality care doing the right thing, at the right time, on every occasion

19 Limitations of CPGs CPGs should be seen as supporting provision of high quality care; they are not a substitute for professional decision making CPGs are a means to an end, not an end in themselves The ultimate goal is to support implementation/knowledge translation and through so doing improve care guideline development without adequate implementation is therefore of very limited value

20 Other reasons for developing CPGs Policy: Increases potential for decision makers to expect standards of care and has the potential for incentives/penalties to follow to support implementation Professional: Raising the standing of professional bodies

21 Evolving approach to developing CPGs Began with expert opinion pronouncements Moved to more consensus-based approaches Following the emergence of evidence-based medicine, increasing recognition of the need to systematize the process using robust, transparent and reproducible techniques

22 Developing CPGs the AGREE II approach

23 Key methodological considerations Aim is to develop unbiased recommendations that have the potential to be implemented in routine care Requires an appreciation of clinical subject expertise, epidemiology/statistics and health services research in order to: Identify, select and critically appraise the literature Appropriately interpret it Identify approaches to support implementation and evaluation Process needs to be as transparent as possible, both to instil confidence/trust and also facilitate assessment of why different CPGs may come to different conclusions

24 Current state-of-the-art Just as CONSORT is now the gold standard for reporting clinical trials and PRISMA is the standard for reporting systematic reviews, the AGREE approach is regarded as the gold standard for reporting and critically appraising CPGs AGREE has the additional role of being an internationally accepted and widely used tool to support the development of CPGs The NIH, SIGN and NICE approaches are other well respected approaches, but these have most currency in the US and the UK

25 A brief history of AGREE II AGREE stands for Appraisal of Guidelines Research and Evaluation Developed by methodologists and health services researchers from Manitoba, Canada PI is Melissa Brouwers Has been the subject of ongoing methodological development and evaluation AGREE was published in 2003; current version is AGREE II, which was launched in 2009 Used by professional bodies internationally A manual, and variety of training and support tools have also been developed available from:

26 Aims of AGREE II A tool to support development, reporting and critical appraisal of CPGs Considering development, CPGs have focused: Mainly on treatment considerations They have also been used to address questions of: Screening Investigations Diagnosis Eligibility for treatment Referral Prognosis More health policy questions e.g. commissioning

27 AGREE II Domain 1: Scope and purpose Domain 2: Stakeholder involvement Domain 3: Rigor of development Domain 4: Clarity of presentation Domain 5: Applicability Domain 6: Editorial independence

28 Domain 1: Specific questions 1. The overall objective(s) of the guideline is (are) specifically described. 2. The health question(s) covered by the guideline is (are) specifically described. 3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.

29 Domain 2: Stakeholder involvement 4. The guideline development group includes individuals from all relevant professional groups. 5. The views and preferences of the target population (patients, public, etc.) have been sought. 6. The target users of the guideline are clearly defined.

30 Domain 3: Ensuring rigour 7. Systematic methods were used to search for evidence. 8. The criteria for selecting the evidence are clearly described. 9. The strengths and limitations of the body of evidence are clearly described. 10. The methods for formulating the recommendations are clearly described. 11. The health benefits, side effects, and risks have been considered in formulating the recommendations. 12. There is an explicit link between the recommendations and the supporting evidence. 13. The guideline has been externally reviewed by experts prior to its publication. 14. A procedure for updating the guideline is provided.

31 Domain 4: Clarity of presentation 15. The recommendations are specific and unambiguous 16.The different options for management of the condition or health issue are clearly presented 17.Key recommendations are easily identifiable

32 Domain 5: Applicability 18.The guideline describes facilitators and barriers to its application. 19.The guideline provides advice and/or tools on how the recommendations can be put into practice. 20.The potential resource implications of applying the recommendations have been considered. 21.The guideline presents monitoring and/or auditing criteria.

33 Domain 6: Editorial Independence 22.The views of the funding body have not influenced the content of the guideline. 23.Competing interests of guideline development group members have been recorded and addressed.

34 Two final over-arching questions Rate the overall quality of the guideline (1-7) I would recommend this guideline for use (Yes, Yes with modifications, No)

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37 EAACI AIT Guidelines

38 EAACI AIT Guidelines EACCI AIT Guidelines project began in June 2015 Five key subject areas chosen: 1. Allergy Prevention 2. Food Allergy 3. Allergic Rhinitis 4. Venom Allergy 5. Allergic Asthma First 4 CPGs completed; asthma still in progress

39 Development process Produced according to AGREE II framework, which involved: Multi-disciplinary expert working groups Systematic reviews of the underpinning evidence External peer-review of draft recommendations

40 Systematic reviews: summary of methods We searched 9 international biomedical databases for published, inprogress and unpublished evidence Studies eligible for inclusion included some/all of the following: o Effectiveness: Systematic reviews (SR), randomized controlled trials (RCT), quasi- RCTs, controlled clinical trials (CCT), controlled before-after (CBA) studies, and interrupted time series (ITS) analyses o Health economics: Cost-effectiveness and cost-utility analysis o Safety: SR, RCT, non-randomized studies and case series (>300 patients) Studies were independently screened against pre-defined eligibility criteria and critically appraised using established instruments by 2 reviewers Data were descriptively summarized and, where possible and appropriate, meta-analysed using fixed effect/random effects meta-analyses

41 A long journey... 1 Considering possible approaches Agree-II approach 2 3 Deciding on scope and purpose Creating Task Forces and ensuring relevant stakeholder involvement Key questions that need to be answered were identified by the Task Forces 4 Brainstorming of possible questions and mapping into overarching systematic reviews 5 Team of methodologists identified Working closely with Task Force leads

42 6 Protocols of SRs prepared, iterated and signed-off Registered in PROSPERO and published in CTA 7 8 SRs finalized Developed guidelines using evidence from systematic reviews and elsewhere Systematic grading of quality of evidence and strength of recommendations Peer review 9 Identification of audit criteria, barriers, facilitators and resource implications to implement recommendations 10 Development of tools to support implementation, assess progress and updating of guidelines

43 EAACI AIT Guidelines: Summary of Findings & Key Messages

44 AIT for Allergy Prevention: Outcomes of Interest Primary outcomes The development of the first allergic manifestation in healthy individuals, or of a new allergic manifestation in those with a previous allergic condition (e.g. development of asthma in patients with atopic eczema/dermatitis (AD) or AR, assessed over the short term (< 2 years) or the longer term ( 2 years) post-ait Secondary outcomes The development of new allergic sensitization(s), spreading of allergic sensitization(s) from one allergen to other non-related allergen(s), spreading of allergic sensitization(s) at molecular level, from one allergenic molecule to other molecules The development of previously non-existent oral allergy syndrome (OAS) Safety as assessed by local and systemic reactions in accordance with the World Allergy Organization s (WAO) grading systems of local and systemic side-effects Health economic analysis from the perspective of the health system/payer as reported in studies

45 AIT for Allergy Prevention: Summary of Findings 32 studies satisfied the inclusion criteria Prevention of allergic sensitization Evidence that the risk of new sensitization was reduced over the short-term (within 2 years of completion of AIT), but this was not confirmed in the sensitivity analysis: RR = 0.72; 95% CI: There was no clear evidence of any longer-term (i.e. 2 years post-completion) reduction in the risk of sensitization: RR = 0.47; 95% CI: Prevention of first allergic disease Meta-analysis found no conclusive evidence that AIT reduced the risk of developing a first allergic disease over the short-term: RR = 0.30; 95% CI: No randomized controlled evidence in relation to the longer-term benefits of AIT Prevention of progression from allergic rhinitis to asthma Evidence of reduced risk of developing asthma over the short-term: RR = 0.40; 95% CI: , with this finding being robust to a pre-specified sensitivity analysis. Inconclusive evidence that this benefit was maintained over the longer-term: RR = 0.62; 95% CI: Safety: AIT appeared to have an acceptable side-effect profile. Health economics: No relevant health economic data identified

46 AIT for Allergy Prevention: Key Recommendations Prevention of allergic sensitization: AIT cannot currently be recommended Prevention of first allergic disorder: AIT cannot currently be recommended Prevention of progression from allergic rhinitis to allergic asthma: A 3-year course of SCIT or SLIT AIT can be recommended for children and adolescents with moderate-to-severe allergic rhinitis (AR) triggered by grass/birch pollen allergy to prevent asthma for up to 2 years post-ait; this may in addition improve AR outcomes leading to a reduction in AR symptoms and medication use.

47 AIT for Food Allergy: Outcomes of Interest Primary outcomes Desensitization (i.e. the ability to safely consume foods containing the allergen in question whilst on AIT) Sustained unresponsiveness (i.e. the ability to safely consume foods containing the allergen in question after discontinuing AIT) at food challenge Changes in disease-specific quality of life (QoL) using a validated instrument. Secondary outcomes Safety as assessed by local and systemic reactions in accordance with the WAO grading system of side-effects Health economic analysis from the perspective of the health system/payer as reported in studies.

48 AIT for Food Allergy: Summary of Findings 31 studies met our inclusion criteria Effectiveness Consistent evidence that oral AIT may be effective in raising the threshold of reactivity to cow s milk, hen s eggs and peanuts in patients with IgE-mediated food allergy whilst receiving OIT (i.e. desensitization) and post-discontinuation of OIT. This evidence came mainly from studies in children, and it is therefore still unclear if OIT is effective for adults. Only 1 study assessed impact on QoL, which reported no comparative results between OIT and the control group Limited body of evidence investigating other routes of delivery of AIT Safety Pooling of the safety data demonstrated an increased risk of local and systemic reactions with AIT. No fatalities were reported during AIT. Health economics No data investigating the cost-effectiveness of AIT in patients with food allergy.

49 AIT for Food Allergy: Key Recommendations OIT AIT can be recommended for persistent cow s milk, hen s egg and peanut allergy for children from around 4-5 years of age on the basis of its ability to increase the threshold of exposure required to trigger clinical reactions whilst on AIT At present, there are insufficient data to be able to recommend AIT for other foods and for adults outside clinical trials In view of the risk of triggering anaphylaxis, AIT should only be performed in research centers or in clinical centers with extensive experience in AIT and proficiency in recognizing and managing anaphylaxis. SLIT/SCIT/EPIT Insufficient data to recommend alternative routes of delivery

50 AIT for Allergic Rhinitis: Outcomes of Interest Primary outcomes Effectiveness, both short-term (i.e., during treatment) and long-term (i.e., at least a year after discontinuation of AIT), as assessed by symptom and/or medication scores. Secondary outcomes Disease-specific QoL Threshold of allergen exposure to trigger symptoms on allergen challenge or in an environmental exposure chamber Safety as assessed by local and systemic reactions in accordance with the WAO grading system of side-effects Health economic analysis from the perspective of the health system/payer

51 AIT for Allergic Rhinitis: Summary of Findings 160 studies met our inclusion criteria Short-term effectiveness: symptom scores We were able to pool data from 58 SCIT and SLIT studies assessing the effectiveness of AIT by symptom scores. This showed a standardized mean difference (SMD) of 0.53 (95% CI 0.63, 0.42) this suggesting a moderate effect in favor of AIT Long-term effectiveness: symptom scores Four trials at low risk of bias found a beneficial effect on the longterm effectiveness of AIT on symptom scores.

52 AIT for Allergic Rhinitis: Summary of Findings Medication scores Short-term effectiveness We were able to pool data from 45 SCIT and SLIT trials. This showed an overall SMD of 0.38 (95% CI 0.49, 0.26), this suggesting a smallto-medium effect in favor of AIT in improving medication scores Long-term effectiveness There were three low ROB trials that assessed this outcome: one SCIT and two SLIT. Overall, one trial found a benefit of AIT (SCIT) on longterm medication scores; the two other SLIT trials did not show a sustained effect.

53 AIT for Allergic Rhinitis: Summary of Findings Secondary outcomes: Disease specific QoL: Pooling data from the six SCIT studies with suitably reported data derived from the original and standardized RQLQ instruments found a SMD of 0.35 (95% CI 0.74, 0.04), this corresponding to a likely small-tomedium improvement in the AIT group when compared to placebo Allergen challenge models in AIT: No clear conclusions could be drawn Cost-effectiveness: The seven key studies identified suggested that SLIT and SCIT treatment would be considered cost-effective in the patient population in England at the standard NICE cost-effectiveness threshold of ( ) per QALY. However, the quality of the studies and the general lack of attention to characterizing uncertainty and handling missing data need to be taken into account when interpreting these results Safety: AIT increased the risk of adverse events for both SCIT and SLIT, but no fatalities occurred.

54 AIT for Allergic Rhinitis: Key Recommendations AIT should be considered when all of these criteria are met: Symptoms strongly suggestive of AR, with or without conjunctivitis Evidence of IgE sensitization (positive skin prick test and/or serumspecific IgE) to one or more clinically relevant allergen Experience moderate-to-severe symptoms which interfere with usual daily activities or sleep despite regular and appropriate pharmacotherapy and/or avoidance strategies AIT may also be considered in less severe AR where a patient wishes to take advantage of its long-term effect on AR and potential to prevent asthma with grass pollen AIT

55 AIT for Allergic Rhinitis: Key Recommendations SCIT and SLIT should be considered for the short-term treatment benefits in both seasonal and perennial AR, particularly for those with troublesome disease that is inadequately controlled by pharmacotherapy The strongest evidence for long-term benefits is for grass pollen AIT To achieve long-term benefits, a minimum of 3 years of AIT is recommended

56 AIT for Venom: Outcomes of Interest Primary outcomes Short- and long-term efficacy assessed by tolerated sting challenge or field sting; long-term was defined as sustained clinical efficacy after discontinuation of VIT. Secondary outcomes Disease-specific QoL Safety as assessed by local and systemic reactions in accordance with the WAO grading system of side-effects Health economic analysis from the perspective of the health system/payer.

57 AIT for Venom: Summary of Findings 17 studies met our inclusion criteria Effectiveness of VIT as judged by the risk of systemic sting reactions Evidence suggests that VIT is effective in reducing subsequent systemic sting reactions in both children and adults Meta-analysis demonstrated an overall substantial protective effect of VIT against subsequent systemic reactions (OR = 0.08, 95% CI ) However, this conclusion is based on low quality, non-trial evidence

58 AIT for Venom: Summary of Findings Impact on disease-specific quality of life VIT was found to be associated with a significant improvement in quality of life Meta-analysis of two RCTs demonstrated an improvement in disease-specific quality of life (1.41, 95% CI Safety The available data suggest that although adverse events occurred during both the build-up and maintenance phases, the vast majority were relatively mild with adrenaline only being needed very infrequently No fatalities were recorded Health economic analysis We found no primary evidence on the cost-effectiveness of VIT; the one modelling study found that VIT would be cost-effective in high-risk groups or if disease-specific QoL was taken into consideration.

59 AIT for Venom: Key Recommendations Venom immunotherapy (SCIT) may be indicated in venom-allergic children and adults to prevent further moderate-to-severe systemic sting reactions, particularly if there is an impact on QoL Conventional regimes appear to be best tolerated, while rush and ultrarush protocols are more frequently associated with adverse events Duration Some studies have concluded that VIT for three years may be sufficient, particularly in patients with only mild-to-moderate initial sting reactions Most studies concluded that a minimum of five-years treatment is superior for longterm effectiveness Lifelong VIT may be recommended in highly exposed patients with honeybee venom allergy, patients with very severe initial sting reactions (Muller grade IV or grades III- IV according to Ring & Messmer), and patients with systemic side-effects during VIT as they are major risk factors for relapse

60 AIT for Allergic Asthma: Summary of Findings Primary outcomes Effectiveness, both short-term (i.e. during treatment) and long-term (i.e. at least a year after discontinuation of AIT), as assessed by symptom and/or medication scores Secondary outcomes Asthma control Asthma-specific QoL Asthma attacks Lung function Response to environmental exposure chamber or bronchial allergen challenge Safety as assessed by local and systemic reactions Health economic analysis from the perspective of the health system/payer

61 AIT for Allergic Asthma: Summary of Findings 98 studies met our inclusion criteria Short-term effectiveness Symptom scores: Meta-analysis showed that AIT improved symptom scores with a standardized mean difference (SMD) of 1.11 (95% CI 1.66, 0.56), these suggesting a large effect of AIT Medication scores: Meta-analysis found evidence that AIT improved medication scores (i.e. reduced medication use) with an SMD of 1.21 (95% CI 1.87, 0.54), this corresponding to a large effect Combined symptom and medication score: Pooling of data was possible for two studies, this showing no clear evidence of benefit: SMD of 0.17 (95% CI 0.23, 0.58)

62 AIT for Asthma: Summary of Findings Long-term effectiveness No studies reported on the long-term effectiveness of AIT on individual symptom score or medication score One SLIT study at low ROB reported on this combined symptom and medication scores over 5 years: SLIT was found to have a significant improvement in combined asthma symptom and medication scores when compared to placebo over the entire five-year period (P=.049).

63 Asthma: Summary of Findings Asthma control Seven SLIT studies reported on a measure of asthma control We were unable to pool data due to the differences in reporting of results. The one study at low ROB found that AIT did not improve asthma control. We found no evidence to assess whether SCIT is effective in improving asthma control in allergic asthma patients Disease specific QoL Three SCIT studies, all judged to be at low ROB, reported significant improvements in disease-specific QoL. Pooled data from two of these trials showed a large treatment effect with an SMD of 0.83 (95% CI 1.19, 0.47) in favor of SCIT Seven SLIT trials reported on disease-specific QoL. We were unable to pool data from these studies for meta-analysis due to the variable reporting of results The one low ROB trial of SLIT showed no significant improvement in disease-specific QoL.

64 Asthma: Summary of Findings Exacerbations The trials at low ROB, the one SCIT trial failed to demonstrate evidence of a reduction in exacerbations in those treated with AIT compared with those treated with placebo Two SLIT trials reported a positive effect of AIT on asthma exacerbations, one in the context of reducing the dose of inhaled corticosteroids Lung function The evidence identified from meta-analysis evaluating the effect of AIT on lung function in allergic asthma supports the effectiveness of AIT on small airways (FEF 25%-75%), but with no clear evidence of benefit on improving PEFR or FEV1

65 AIT for Allergic Asthma: Summary of Findings Safety AIT was associated with a moderate increased risk of adverse events, both for SCIT and SLIT. Severe systemic AEs were observed, but these were uncommon and mainly occurred with SCIT. No fatalities were reported. Cost-effectiveness Limited evidence on cost-effectiveness was mainly available for SLIT and this suggested that SLIT may be cost-effective.

66 AIT for Allergic Asthma: Recommendations

67 Implementation Considerations

68 Implementation is challenging Barriers and facilitators Audit criteria Resource implications Particularly helpful Ownership/leadership Organizational resources Links with CPD Computerized clinical decision support Developing indicators Monitoring, benchmarking and nudge-based approaches

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70 Conclusions AIT has now been used for over 100 years Over this time there has been considerable progress in developing a range of standardized products for a range of clinical indications delivered through a number of delivery routes according to a variety of delivery protocols There is a growing evidence base, but this is overall methodologically weak using sub-optimal study designs, a range of health outcomes, studying mainly short-term outcomes, and very limited study of health economic outcomes The new EAACI AIT Guidelines have helped to clarify evidence-based indications for AIT and highlighted important gaps in the literature that need to be addressed

71 EAACI AIT Steering Group Task Forces Methodologists Patient representatives Acknowledgments

72 Further reading

73 Further details:

74 Tak skal du have!

75 The European Academy of Allergy & Clinical Immunology s Allergen Immunotherapy Guidelines Professor Aziz Sheikh OBE BSc, MSc, MD, FRCGP, FRCP, FRCPE, FFPH, FACMI, FRSE, FFCI, FMedSci Director, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Director, Asthma UK Centre for Applied Research Director, Scottish Allergy & Respiratory Academy Director, NIHR Global Respiratory Health (RESPIRE) Unit Danish Society of Pediatric Allergology and Pulmonology, Kolding, 20 January 2018