Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).

Tolerance development in cow's milk-allergic children receiving amino acid-based formula with synbiotics: 36-Months follow-up of a randomized controlled trial (PRESTO Study).

The objective of the present study is to assess the rates of acquired tolerance to cow's milk (CM) after 36 months in subjects who consumed amino acid-based formula with synbiotics (AAF-S) or amino acid-based formula without synbiotics (AAF) during a 1-year intervention period in early life as part of the PRESTO study (Netherlands Trial Register number NTR3725). Differences in CM tolerance development between groups were analysed using a logistic regression model. Results show that the proportion of subjects (mean [±SD] age, 3.8 ± 0.27 years) who developed CM tolerance after 36 months was similar in the group receiving AAF-S (47/60 [78%]) and in the group receiving AAF (49/66 [74%]) (p = 0.253), that is, figures comparable to natural outgrowth of CM allergy. Our data suggest that the consumption of AAF and absence of exposure to CM peptides do not slow down CM tolerance acquisition.

Anaphylaxis Refractory to intramuscular adrenaline during in-hospital food challenges: A case series and proposed management.

BACKGROUND: Anaphylaxis is a severe, systemic hypersensitivity reaction that can be potentially life-threatening. Anaphylaxis during oral food challenge is not uncommon and can usually be effectively managed with intramuscular adrenaline as first line treatment. Although very rare, fatal anaphylaxis during in-hospital food challenge has been reported. OBJECTIVE: We describe our experience of cases of refractory anaphylaxis at in-hospital challenge and propose a framework for escalation of treatment in such cases using intravenous infusion of adrenaline which has been adopted for widespread use elsewhere. METHODS: We present four patients who all experienced severe life-threatening anaphylaxis, refractory to intramuscular adrenaline treatment, during supervised oral food challenges. Patient data were collected from contemporaneous notes, and patient consent was obtained. RESULTS: In all four cases, the anaphylaxis reactions were amenable to treatment with low-dose intravenous adrenaline, with no reported adverse effects. CONCLUSION AND CLINICAL RELEVANCE: These cases demonstrate the need for clinicians undertaking higher risk allergen challenges to be able to manage cases of severe anaphylaxis refractory to intramuscular adrenaline, and to consider a framework for managing these reactions. While peripheral intravenous adrenaline infusions should always be initiated only in conjunction with expert input, the protocol suggested is simple enough to be undertaken within the hospital environment while more experienced support is obtained.

Severity and threshold of peanut reactivity during hospital-based open oral food challenges: An international multicenter survey.

BACKGROUND: Peanut allergy is classically managed by food avoidance. Immunotherapy programs are available at some academic centers for selected patients reacting to small amounts of peanut during food challenge. We aimed to determine and compare reaction thresholds and prevalence of anaphylaxis during peanut oral challenges at multiple specialist allergy centers. METHODS: A retrospective, international survey of anonymized case records from seven specialist pediatric allergy centers from the UK and Ireland, as well as the Australian HealthNuts study. Demographic information, allergy test results, reaction severity and threshold during open oral peanut challenges were collated and analyzed. RESULTS: Of the 1634 children aged 1-18 years old included, 525 (32%) failed their peanut challenge. Twenty-eight percent reacted to 25 mg, while 38% only reacted after consuming 1 g or more of whole peanut. Anaphylaxis (55 [11%]) was 3 times more common in teenagers than younger children and the likelihood increased at all ages as children consuming more peanut at the challenge. Children who developed anaphylaxis to 25-200 mg of whole peanut were significantly older. Previous history of reaction did not predict reaction threshold or severity. CONCLUSIONS: More than a third of the children in this large international cohort tolerated the equivalent of one peanut in an oral challenge. Anaphylaxis, particularly to small amounts of peanut, was more common in older children. Tailored immunotherapy programs might be considered not only for children with low, but also higher reaction thresholds. Whether these programs could prevent heightened sensitivity and anaphylaxis to peanut with age also deserves further study.

In vitro rapid diagnostic tests for severe drug hypersensitivity reactions in children.

BACKGROUND: Previous reports have demonstrated the utility of T-cell proliferation and cytokine release assays as in vitro diagnostic tests for drug causation in drug hypersensitivity reactions (DHR). However, data from pediatric populations are scarce compared with data in adults. OBJECTIVE: To compare the lymphocyte proliferation assay (LPA) with combination cytokine assays in the pediatric population and to identify its potential use in the acute and postrecovery phases. METHODS: A total of 18 in vitro tests were undertaken ex vivo to compare drug-specific proliferation and cytokine release (interferon-γ [IFN-γ] and interleukin-4 [IL-4]). The study included 16 patients with DHR: 7 children tested in the acute phase, 7 tested after recovery, and 2 tested during both the acute and postrecovery phases. RESULTS: The sensitivity of the LPA was better during the acute stage of DHR in children. Cytokine assays revealed a higher frequency of positive drug-specific responses compared with LPA in both the acute (LPA, 77.8%; IFN-γ, 88.9%; IL-4, 100%) and postrecovery phases (LPA, 33.3%; IFN-γ, 66.7%; IL-4, 66.7%). Combination cytokine assays (IFN-γ and IL-4) produced higher positive drug-specific responses in identifying culprit drugs compared with LPA in both the acute and postrecovery phases. CONCLUSION: In vitro drug-induced T-cell proliferation and cytokine release assays are useful for identification of the causative drug in children with DHR. Cytokine assays (IFN-γ and IL-4) were better than LPA, but when combined, they offer even greater utility in the diagnosis of acute and postrecovery DHR. Cytokine detection is rapid and does not involve radioactivity. These novel in vitro assays may offer a significant advancement in our future management of DHR in children.

Safety of live attenuated influenza vaccine in atopic children with egg allergy.

BACKGROUND: Live attenuated influenza vaccine (LAIV) is an intranasal vaccine recently incorporated into the United Kingdom immunization schedule. However, it contains egg protein and, in the absence of safety data, is contraindicated in patients with egg allergy. Furthermore, North American guidelines recommend against its use in asthmatic children. OBJECTIVE: We sought to assess the safety of LAIV in children with egg allergy. METHODS: We performed a prospective, multicenter, open-label, phase IV intervention study involving 11 secondary/tertiary centers in the United Kingdom. Children with egg allergy (defined as a convincing clinical reaction to egg within the past 12 months and/or >95% likelihood of clinical egg allergy as per published criteria) were recruited. LAIV was administered under medical supervision, with observation for 1 hour and telephone follow-up 72 hours later. RESULTS: Four hundred thirty-three doses were administered to 282 children with egg allergy (median, 4.9 years; range, 2-17 years); 115 (41%) had experienced prior anaphylaxis to egg. A physician's diagnosis of asthma/recurrent wheezing was noted in 67%, and 51% were receiving regular preventer therapy. There were no systemic allergic reactions (upper 95% CI for population, 1.3%). Eight children experienced mild self-limiting symptoms, which might have been due an IgE-mediated allergic reaction. Twenty-six (9.4%; 95% CI for population, 6.2% to 13.4%) children experienced lower respiratory tract symptoms within 72 hours, including 13 with parent-reported wheeze. None of these episodes required medical intervention beyond routine treatment. CONCLUSIONS: In contrast to current recommendations, LAIV appears to be safe for use in children with egg allergy. Furthermore, the vaccine appears to be well tolerated in children with a diagnosis of asthma or recurrent wheeze.

Validation of the Paediatric Food Allergy Quality of Life Questionnaire (PFA-QL).

BACKGROUND: The Paediatric Food Allergy Quality of Life Questionnaire (PFA-QL) was the first tool to be developed for assessing health-related quality of life (QoL) in children with food allergy. It has been used in a number of published studies, but has not been validated. OBJECTIVE: The aim of the current study was to validate child (PFA-QL) and parent-proxy (PFA-QL-PF) versions of the scale in a specialist allergy clinic and in parents of children with food allergy. METHODS: For the clinic sample, a generic QoL scale (PedsQL) and the PFA-QL were completed by 103 children (age 6-16 yrs) with peanut or tree nut allergy; test-retest reliability of the PFA-QL was tested in 50 stable patients. For the non-clinical sample, 756 parents of food allergic children completed the PFA-QL-PF, the Child Health Questionnaire (CHQ-PF50), Food Allergy Quality of Life Parental Burden Scale (FAQL-PB) and a Food Allergy Impact Measure. RESULTS: The PFA-QL and PFA-QL-PF had good internal consistency (α's of 0.77-0.82), and there was moderate-to-good agreement between the generic- and disease-specific questionnaires. The PFA-QL was stable over time in the clinic sample, and in both samples, girls were reported to have poorer QoL than boys. CONCLUSIONS: The PFA-QL and PFA-QL-PF are reliable and valid scales for use in both clinical and non-clinical populations. Unlike other available tools, they were developed and validated in the UK and thus provide a culture-specific choice for research, clinical trials and clinical practice in the UK. Validation in other countries is now needed.

Food protein-induced enterocolitis syndrome in the British Isles.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a delayed type of food allergy, most often seen in infancy. We aimed to estimate its incidence, to describe common food triggers and the patient journeys of this rare but serious condition. DESIGN: We undertook a prospective epidemiological survey of FPIES using the British Paediatric Surveillance Unit. SETTING: UK and Ireland. PARTICIPANTS: A survey of all paediatricians over 13 months between January 2019 and February 2020. MAIN OUTCOME MEASURES: 204 cases were reported, 98 (48%) meeting case definition, giving an incidence of 0.006% for England based on 93 cases. RESULTS: 98 patients reported 135 trigger foods, 27% (26 of 98) had multiple food triggers. Common food triggers included cow's milk (24%, 33 of 135), fruits and vegetables (19%, 26 of 135), hen's egg (16%, 22 of 135) and fish (14%, 19 of 135). In 46% (41 of 90), the initial trigger food had been ingested three or more times before diagnosis, with a median diagnostic delay of 7.9 months (3.0, 17.3). Half (50 of 98) were admitted, yet only 5% (5 of 98) received appropriate acute treatment with ondansetron. Most cases were diagnosed by an allergy specialist (74 of 98, 76%), within a median of 7.5 (3.0, 13.3) miles from home. CONCLUSION: The incidence of FPIES was significantly lower than expected across the whole of the British Isles. Most reports were of cases local to specialist allergy centres, with delays in diagnosis. This suggests under-recognition of FPIES in frontline clinical setting where education of healthcare professionals is required to improve recognition, earlier diagnosis and treatment.

Management of nut allergy influences quality of life and anxiety in children and their mothers.

Nut allergy is known to impact on the quality of life (QoL) and anxiety of both the allergic child and their parents, but little is known about how the management of food allergy is associated with these variables. To investigate the impact of nut allergy on QoL and anxiety in mothers and children with nut allergy in order to identify management strategies that may influence these factors. Forty-one nut allergic children (age 6-16 yrs) and their mothers completed questionnaires to assess maternal and children's QoL (PedsQL, WHOQOL-BREF, FAQL-PB), anxiety (SCAS, STAI) and perceived stress scale (PSS). Children also completed a nut allergy specific QoL questionnaire. Demographic data, details of previous reactions, test results and management plans were collected using parent-report questionnaires and hospital notes. Children with nut allergy had poorer emotional (p = 0.004), social (p = 0.043), and psychological (p = 0.006) QoL compared to healthy normative data. Maternal and child QoL and anxiety were not influenced by the severity of previous reactions. Mother and child reported lower anxiety (p = 0.043 and p < 0.001 respectively) when the child was prescribed an epinephrine auto-injector. Anxiety was not associated with whether the child carried the auto-injector or whether they strictly avoided traces of nuts in foods. Prescribing auto-injectors is associated with reduced anxiety for food allergic children and their mothers, but is not associated with improved adherence with medical management or reduced risk-taking behavior.

Efficacy and safety of oral immunotherapy with AR101 in European children with a peanut allergy (ARTEMIS): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Peanut allergy is the leading cause of food-related anaphylaxis. Current management options can negatively affect food allergy-related quality of life. We aimed to investigate the efficacy of an investigational oral biologic drug (AR101). METHODS: The AR101 Trial in Europe Measuring Oral Immunotherapy Success in peanut-allergic children (ARTEMIS) trial was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial done at 18 hospitals in Ireland, France, Germany, Italy, Spain, Sweden, and the UK. Children and adolescents with peanut allergy, aged 4-17 years, who developed dose-limiting symptoms to 300 mg or less peanut protein (equivalent to approximately one peanut kernel) during a double-blind placebo-controlled food challenge test at study entry were enrolled. Participants were randomly assigned (3:1) to receive daily doses of either AR101 oral immunotherapy (AR101 group) or a taste-masked placebo (placebo group). All participants, investigators, and care providers were masked to treatment allocation until the study was completed. Doses were increased every 2 weeks over 6 months until a dose of 300 mg was reached and maintained for 3 months. The primary endpoint was the proportion of participants in the intention-to-treat or safety population (defined as those participants who had been randomly assigned and had received at least one dose of the assigned drug) who could consume a single dose of 1000 mg (cumulative dose 2043 mg) peanut protein without developing dose-limiting allergic symptoms at an exit double-blind placebo-controlled food challenge after 9 months of treatment. Additional endpoints included safety (ie, the frequency and severity of adverse events) and changes in food allergy-related quality of life, assessed by use of age-appropriate Food Allergy Quality of Life Questionnaires (FAQLQs) and the Food Allergy Independent Measure (FAIM). The study is registered with ClinicalTrials.gov, NCT03201003, and is completed. FINDINGS: Between June 12, 2017, and Feb 15, 2018, 227 patients were screened, of whom 175 were randomly assigned to the AR101 group (n=132) and the placebo group (n=43). All primary and secondary endpoints were met. 77 (58%) of 132 participants in the AR101 group tolerated 1000 mg peanut protein at the exit food challenge versus one (2%) of 43 participants in the placebo group (AR101-placebo treatment difference 56·0% [95% CI 44·1-65·2], p<0·0001). Adverse events were reported by almost all participants. The maximum severity of adverse events reported was mild or moderate for most participants who received AR101 (mild, 66 [50%] of 132 participants; moderate, 63 [48%]; and severe, one [1%]) or placebo (mild, 24 [56%] of 43 participants; moderate, 18 [42%]; severe, none). Participants aged 8-12 years in the AR101 group reported improvements that exceeded the minimum clinically important difference between the two groups across all FAQLQ domains. Additionally, participants in the AR101 group and their caregivers reported improvements that exceeded the minimum clinically important difference in FAIM domains related to the perceived likelihood and outcomes of a severe allergic reaction. INTERPRETATION: AR101 oral immunotherapy treatment led to rapid desensitisation to peanut protein, with a predictable safety profile that improved with treatment, and an associated improvement in self-reported and caregiver-reported food allergy-related quality of life. These patient-oriented outcomes provide invaluable data to help physicians, patients, and caregivers make informed, shared decisions on the management of peanut allergy. FUNDING: Aimmune Therapeutics.

Safety of live attenuated influenza vaccine in young people with egg allergy: multicentre prospective cohort study.

STUDY QUESTION: How safe is live attenuated influenza vaccine (LAIV), which contains egg protein, in young people with egg allergy? METHODS: In this open label, phase IV intervention study, 779 young people (2-18 years) with egg allergy were recruited from 30 UK allergy centres and immunised with LAIV. The cohort included 270 (34.7%) young people with previous anaphylaxis to egg, of whom 157 (20.1%) had experienced respiratory and/or cardiovascular symptoms. 445 (57.1%) had doctor diagnosed asthma or recurrent wheeze. Participants were observed for at least 30 minutes after vaccination and followed-up by telephone 72 hours later. Participants with a history of recurrent wheeze or asthma underwent further follow-up four weeks later. The main outcome measure was incidence of an adverse event within two hours of vaccination in young people with egg allergy. STUDY ANSWER AND LIMITATIONS: No systemic allergic reactions occurred (upper 95% confidence interval for population 0.47% and in participants with anaphylaxis to egg 1.36%). Nine participants (1.2%, 95% CI 0.5% to 2.2%) experienced mild symptoms, potentially consistent with a local, IgE mediated allergic reaction. Delayed events potentially related to the vaccine were reported in 221 participants. 62 participants (8.1%, 95% CI for population 6.3% to 10.3%) experienced lower respiratory tract symptoms within 72 hours, including 29 with parent reported wheeze. No participants were admitted to hospital. No increase in lower respiratory tract symptoms occurred in the four weeks after vaccination (assessed with asthma control test). The study cohort may represent young people with more severe allergy requiring specialist input, since they were recruited from secondary and tertiary allergy centres. WHAT THIS STUDY ADDS: LAIV is associated with a low risk of systemic allergic reactions in young people with egg allergy. The vaccine seems to be well tolerated in those with well controlled asthma or recurrent wheeze. FUNDING, COMPETING INTERESTS, DATA SHARING: This report is independent research commissioned and funded by a Department of Health policy research programme grant to the National Vaccine Evaluation Consortium. Additional funding was provided by the NIHR Clinical Research Networks, Health Protection Scotland (Edinburgh site), and Health & Social Care Services in Northern Ireland (Belfast site). PJT and MEL had support from the Department of Health for the submitted work; PJT has received research grants from the Medical Research Council and NIHR. No additional data available.Study registration ClinicalTrials.gov (NCT02111512) and the EU Clinical Trials Register EudraCT (2014-001537-92).

Anaphylaxis as an adverse event following immunisation in the UK and Ireland.

UNLABELLED: Anaphylaxis is a rare adverse event following immunisation (AEFI) and unlikely to be detected in prelicensure vaccine trials. Previous retrospective studies have been hampered by the paucity of information available to passive reporting schemes. The aim of the present study was to estimate the incidence and clinical presentation of anaphylaxis as an AEFI using prospective active surveillance. METHODS: Children under 16 in the UK and Ireland with suspected anaphylaxis as an AEFI were reported through the British Paediatric Surveillance Unit (BPSU) between September 2008 and October 2009. Paediatricians completed questionnaires on presentation, diagnosis, management and outcome. RESULTS: A total of 7 out of 15 reports met criteria for anaphylaxis following immunisation. Four of the seven children reacted more than 30 min after administration of the vaccine. Six children required treatment with intramuscular adrenaline and intravenous fluids, but all made a full recovery. Denominators were not available for all vaccines so an overall incidence was not calculated, however the estimated incidence was 12.0 per 100,000 dose for single component measles vaccine and 1.4 cases per million doses for the bivalent human papilloma virus vaccine (Cervarix, GSK). CONCLUSIONS: Anaphylaxis remains a rare adverse event following immunisation. No cases were related to vaccines given as part of the 'routine' infant and preschool immunisation programme, despite over 5.5 million vaccines being delivered in this time period. Some children had delayed onset of symptoms and this should be considered when vaccinating those at higher risk of anaphylaxis.

What factors affect the carriage of epinephrine auto-injectors by teenagers?

BACKGROUND: Teenagers with allergies are at particular risk of severe and fatal reactions, but epinephrine auto-injectors are not always carried as prescribed. We investigated barriers to carriage. METHODS: Patients aged 12-18 years old under a specialist allergy clinic, who had previously been prescribed an auto-injector were invited to participate. Semi-structured interviews explored the factors that positively or negatively impacted on carriage. RESULTS: Twenty teenagers with food or venom allergies were interviewed. Only two patients had used their auto-injector in the community, although several had been treated for severe reactions in hospital. Most teenagers made complex risk assessments to determine whether to carry the auto-injector. Most but not all decisions were rational and were at least partially informed by knowledge. Factors affecting carriage included location, who else would be present, the attitudes of others and physical features of the auto-injector. Teenagers made frequent risk assessments when deciding whether to carry their auto-injectors, and generally wanted to remain safe. Their decisions were complex, multi-faceted and highly individualised. CONCLUSIONS: Rather than aiming for 100% carriage of auto-injectors, which remains an ambitious ideal, personalised education packages should aim to empower teenagers to make and act upon informed risk assessments.

Diagnostic utility of two case definitions for anaphylaxis: a comparison using a retrospective case notes analysis in the UK.

Anaphylaxis is a clinical diagnosis with no gold-standard test. Recent case definitions have attempted to provide objective criteria for diagnosis. The aim of this study was to compare the diagnostic concordance of the Brighton Collaboration case definition (the 'Brighton' case definition) to the consensus case definition from the Second Symposium on the Definition and Management of Anaphylaxis (the 'Symposium' definition). The study setting was a hospital-based emergency department in the UK. We identified cases of anaphylaxis by physicians' discharge diagnoses over a 2-year period from 2005 to 2006, and used randomly selected cases of allergic reaction, asthma and urticaria as a control group. Data was extracted by clinicians (who were unaware of the content of either case definition), and the two case definitions were applied by Boolean operators in a Microsoft Excel spreadsheet. Concordance between the case definitions was measured using Cohen's kappa (kappa) statistic. We reviewed 128 sets of notes, with 47 cases of anaphylaxis. Brighton and Symposium definitions had sensitivities of 0.681 and 0.671, respectively, and specificities of 0.790 and 0.704, respectively. A discordant result was found in 36/128 cases (28.1%; kappa = 0.414 [95% CI 0.253, 0.574]), which represents a moderate level of agreement between case definitions. The Brighton case definition has a similar diagnostic concordance to the Symposium case definition. It does not seem to over- or underestimate cases and is sufficiently unique that the identification of an allergic trigger does not have to form part of the case definition. This will be important in the recognition of anaphylaxis resulting from the administration of drug and vaccines, where causality should be examined separately from case ascertainment.

Bronchoalveolar lavage MMP-9 and TIMP-1 in preschool wheezers and their relationship to persistent wheeze.

Atopic preschool children are more likely to develop persistent wheezing, which could be a consequence of early airway remodeling. Protease-antiprotease balance between MMP-9 and its cognate inhibitor TIMP-1 may be involved in this process. Our hypothesis was that atopic wheezing preschool children would have an imbalance of MMP-9 to TIMP-1 in bronchoalveolar lavage (BAL). BAL from 52 preschool wheezers was compared with 14 controls without wheeze. A subgroup completed an International Study of Asthma and Allergy in Childhood symptom questionnaire 2 y later. Molar ratios of MMP-9/TIMP-1 were higher in wheezy children (p < 0.001; median 4.0%, range 0-8.7) than controls (0.6%, 0-1.8), and showed an excess of TIMP-1 in the airway. BAL TIMP-1 was raised in children with persistent wheezing (p = 0.028; 34.4 ng/mL, 9.1-93.1 compared with 10.6 ng/mL 6.1-18.6), as was serum levels of intercellular adhesion molecule-1 (p = 0.027). The absolute concentration of TIMP-1 in the airway, rather than its molar ratio with MMP-9, was associated with persistent wheezing. The processes involved with airway remodeling are complex but excess TIMP-1 may impede matrix protein turnover and thereby contribute to persistent changes in airway structure and wheezing.