Diagnostic test accuracy of procalcitonin and C-reactive protein for predicting invasive and serious bacterial infections in young febrile infants: a systematic review and meta-analysis.

BACKGROUND: Febrile infants presenting in the first 90 days of life are at higher risk of invasive and serious bacterial infections than older children. Modern clinical practice guidelines, mostly using procalcitonin as a diagnostic biomarker, can identify infants who are at low risk and therefore suitable for tailored management. C-reactive protein, by comparison, is widely available, but whether C-reactive protein and procalcitonin have similar diagnostic accuracy is unclear. We aimed to compare the test accuracy of procalcitonin and C-reactive protein in the prediction of invasive or serious bacterial infections in febrile infants. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Web of Science, and The Cochrane Library for diagnostic test accuracy studies up to June 19, 2023, using MeSH terms "procalcitonin", and "bacterial infection" or "fever" and keywords "invasive bacterial infection*" and "serious bacterial infection*", without language or date restrictions. Studies were selected by independent authors against eligibility criteria. Eligible studies included participants aged 90 days or younger presenting to hospital with a fever (≥38°C) or history of fever within the preceding 48 h. The primary index test was procalcitonin, and the secondary index test was C-reactive protein. Test kits had to be commercially available, and test samples had to be collected upon presentation to hospital. Invasive bacterial infection was defined as the presence of a bacterial pathogen in blood or cerebrospinal fluid, as detected by culture or quantitative PCR; authors' definitions of serious bacterial infection were used. Data were extracted from selected studies, and the detection of invasive or serious bacterial infections was analysed with two models for each biomarker. Diagnostic accuracy was determined against internationally recognised cutoff values (0·5 ng/mL for procalcitonin, 20 mg/L for C-reactive protein) and pooled to calculate partial area under the curve (pAUC) values for each biomarker. Optimum cutoff values were identified for each biomarker. This study is registered with PROSPERO, CRD42022293284. FINDINGS: Of 734 studies derived from the literature search, 14 studies (n=7755) were included in the meta-analysis. For the detection of invasive bacterial infections, pAUC values were greater for procalcitonin (0·72, 95% CI 0·56-0·79) than C-reactive protein (0·28, 0·17-0·61; p=0·016). Optimal cutoffs for detecting invasive bacterial infections were 0·49 ng/mL for procalcitonin and 13·12 mg/L for C-reactive protein. For the detection of serious bacterial infections, procalcitonin and C-reactive protein had similar pAUC values (0·55, 0·44-0·69 vs 0·54, 0·40-0·61; p=0·92). For serious bacterial infections, the optimal cutoffs for procalcitonin and C-reactive protein were 0·17 ng/mL and 16·18 mg/L, respectively. Heterogeneity was low for studies investigating the test accuracy of procalcitonin in detecting invasive bacterial infection (I2=23·5%), high for studies investigating procalcitonin for serious bacterial infection (I2=75·5%), and moderate for studies investigating C-reactive protein for invasive bacterial infection (I2=49·5%) and serious bacterial infection (I2=28·3%). The absence of a single definition of serious bacterial infection across studies was the greatest source of interstudy variability and potential bias. INTERPRETATION: Within a large cohort of febrile infants, a procalcitonin cutoff of 0·5 ng/mL had a superior pAUC value to a C-reactive protein cutoff of 20 mg/L for identifying invasive bacterial infections. In settings without access to procalcitonin, C-reactive protein should therefore be used cautiously for the identification of invasive bacterial infections, and a cutoff value below 20 mg/L should be considered. C-reactive protein and procalcitonin showed similar test accuracy for the identification of serious bacterial infection with internationally recognised cutoff values. This might reflect the challenges involved in confirming serious bacterial infection and the absence of a universally accepted definition of serious bacterial infection. FUNDING: None.

The impact of the newly developed school-based 'Digital Health Contact'-Evaluating a health and wellbeing screening tool for adolescents in England.

INTRODUCTION: Supporting adolescents with their health and wellbeing is an international public health priority. Schools are well placed to universally detect unmet health needs and support pupils. This study aimed to evaluate the effectiveness of a digital health and wellbeing screening tool, called the 'Digital Health Contact' (DHC) implemented in schools in the East Midlands of England. The DHC, delivered by Public Health Nurses (School Nurses) (PHN(SN)), aims to identify pupils with unmet health needs (via a 'red flag' system) and provide appropriate support. MATERIALS AND METHODS: Using data from 22 schools which took part in the DHC and 14 schools which did not take part, across three academic years (2018-2020), we conducted a controlled interrupted timeseries analysis with negative binomial regression to explore the effect of the DHC on the number of annual referrals to PHN(SN). Using DHC data from 164 pupils, we further conducted a Difference-in-Difference analysis to explore the impact of 'red flag' and referral via the DHC in Year 9 (age 13-14) on the number of red flags in Year 11 (age 15-16). RESULTS: Across all schools, the mean annual number of referrals increased over the three year follow-up period. In the adjusted model, the number of referrals was comparable between schools taking part in the DHC and non-participating schools (0.15 referrals [95% CI -0.21, 0.50]). Red flag score was not significantly different among Year 11 pupils, after being referred via the DHC in Year 9 (-0.36 red flags [95% CI -0.97, 0.24]). DISCUSSION: The DHC, and similar screening tools, have the potential to raise awareness of the health and wellbeing support in schools and provide an additional pathway of referral to this support for pupils with unmet health needs, without replacing the traditional pathway where pupils refer themselves or are referred by teachers.

Role of diagnostic tests for sepsis in children: a review.

Paediatric sepsis has a significant global impact and highly heterogeneous clinical presentation. The clinical pathway encompasses recognition, escalation and de-escalation. In each aspect, diagnostics have a fundamental influence over outcomes in children. Biomarkers can aid in creating a larger low-risk group of children from those in the clinical grey area who would otherwise receive antibiotics 'just in case'. Current biomarkers include C reactive protein and procalcitonin, which are limited in their clinical use to guide appropriate and rapid treatment. Biomarker discovery has focused on single biomarkers, which, so far, have not outperformed current biomarkers, as they fail to recognise the complexity of sepsis. The identification of multiple host biomarkers that may form a panel in a clinical test has the potential to recognise the complexity of sepsis and provide improved diagnostic performance. In this review, we discuss novel biomarkers and novel ways of using existing biomarkers in the assessment and management of sepsis along with the significant challenges in biomarker discovery at present. Validation of biomarkers is made less meaningful due to methodological heterogeneity, including variations in sepsis diagnosis, biomarker cut-off values and patient populations. Therefore, the utilisation of platform studies is necessary to improve the efficiency of biomarkers in clinical practice.

Applying clinical decision aids for the assessment and management of febrile infants presenting to emergency care in the UK and Ireland: Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study protocol.

INTRODUCTION: Febrile infants 90 days and younger are at risk of invasive bacterial infections (bacteraemia and meningitis) and urinary tract infections. Together this is previously termed serious bacterial infection with an incidence of approximately 10-20%. The National Institute for Health and Care Excellence guidance advocates a cautious approach with most infants requiring septic screening, parenteral broad-spectrum antibiotics and hospital admission. Internationally, variations exist in the approach to febrile infants, with European and North American guidance advocating a tailored approach based on clinical features and biomarker testing. None of the available international clinical decision aids (CDAs) has been validated in the UK and Irish cohorts. The aim of the Febrile Infant Diagnostic Assessment and Outcome (FIDO) Study is to prospectively validate a range of CDAs in a UK and Irish population including CDAs that use procalcitonin testing. METHODS AND ANALYSIS: The FIDO Study is a prospective multicentre mixed-methods cohort study conducted in UK and Irish hospitals. All infants aged 90 days and younger presenting with fever or history of fever (≥38°C) are eligible for inclusion. Infants will receive standard emergency clinical care without delay. Clinical data and blood samples will be collected, and consent will be obtained at the earliest appropriate opportunity using research without prior consent methodology. The performance and cost-effectiveness of CDAs will be assessed. An embedded qualitative study will explore clinician and caregiver views on different approaches to care and perceptions of risk. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Office for Research Ethics Committees Northern Ireland-Health and Social Care Research Ethics Committee B, Public Benefit and Privacy Panel for Health and Social Care Scotland, and Children's Health Ireland Research and Ethics Committee Ireland. The results of this study will be presented at academic conferences and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05259683.

Progenitor cell-derived basophils: A novel barcoded passive degranulation assay in allergic diseases.

BACKGROUND: Effector cells assays provide an overall measure of responsiveness to allergen, but the lack of reliable and high-throughput assays limits the clinical utility. We aimed to develop a high-throughput basophil activation test based on human progenitor cell-derived basophils (PCB) and investigate the role of PCB activation test (PCBAT) in allergic diseases. METHODS: Progenitor cell-derived basophils were differentiated from CD34+ progenitor cells and sensitized with sera from subjects sensitized to cat, peanut or atopic controls. Sensitized PCBs were stimulated with increasing concentrations of the corresponding allergens in vitro. Degranulation was assessed by measuring CD63 expression using flow cytometry. The correlations between PCBAT and clinical allergy were assessed. RESULTS: Following passive sensitization of the mature PCBs with serum and allergen stimulation, an allergen specific dose-dependent increase in CD63 expression was observed. Sera from subjects sensitized to cat (n = 35, of which 17 subjects had clinical reactivity quantified using inhaled allergen challenge), peanut allergic (n = 30, of which 15 subjects had clinical reactivity validated using double blind, placebo controlled food challenges [DBPCFC]), peanut-sensitized but tolerant subjects (n = 5) were used to sensitize PCBs. PCBAT area under the curve (AUC) correlated with sIgE (r2  = .49, p = .001) in subjects sensitized to cat (sIgE ≥ 0.35KU/L). The provocation concentration of inhaled cat allergen (PC20 ) correlated with PCBAT AUC (r2  = .33, p = .016). In subjects sensitized to peanut, PCBAT AUC was highly correlated with sIgE to Ara h 2 (r2  = .59, p < .0001). Peanut threshold cumulative dose during DBPCFC was negatively correlated with PCBAT AUC (r2  = .57, p = .001) and IgE to Ara h1 (r2  = .55, p = .007), but not with sIgE to whole peanut or Ara h2. All peanut-sensitized but tolerant subjects showed no reaction to peanut on PCBAT. CONCLUSION: Progenitor cell-derived basophils activation test is a high-throughput assay, which correlates with clinical allergy and may confer a powerful alternative tool in allergy testing.

Managing food allergy: GA2LEN guideline 2022.

Food allergy affects approximately 2-4% of children and adults. This guideline provides recommendations for managing food allergy from the Global Allergy and Asthma European Network (GA2LEN). A multidisciplinary international Task Force developed the guideline using the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We reviewed the latest available evidence as of April 2021 (161 studies) and created recommendations by balancing benefits, harms, feasibility, and patient and clinician experiences. We suggest that people diagnosed with food allergy avoid triggering allergens (low certainty evidence). We suggest that infants with cow's milk allergy who need a breastmilk alternative use either hypoallergenic extensively hydrolyzed cow's milk formula or an amino acid-based formula (moderate certainty). For selected children with peanut allergy, we recommend oral immunotherapy (high certainty), though epicutaneous immunotherapy might be considered depending on individual preferences and availability (moderate certainty). We suggest considering oral immunotherapy for children with persistent severe hen's egg or cow's milk allergy (moderate certainty). There are significant gaps in evidence about safety and effectiveness of the various strategies. Research is needed to determine the best approaches to education, how to predict the risk of severe reactions, whether immunotherapy is cost-effective and whether biological therapies are effective alone or combined with allergen immunotherapy.

Multiplex Lateral Flow Assay and the Sample Preparation Method for the Simultaneous Detection of Three Marine Toxins.

A multiplex lateral flow immunoassay (LFA) has been developed to detect the primary marine biotoxin groups: amnesic shellfish poisoning toxins, paralytic shellfish poisoning toxins, and diarrhetic shellfish poisoning toxins. The performance characteristics of the multiplex LFA were evaluated for its suitability as a screening method for the detection of toxins in shellfish. The marine toxin-specific antibodies were class-specific, and there was no cross-reactivity between the three toxin groups. The test is capable of detecting all three marine toxin groups, with working ranges of 0.2-1.5, 2.5-65.0, and 8.2-140.3 ng/mL for okadaic acid, saxitoxin, and domoic acid, respectively. This allows the multiplex LFA to detect all three toxin groups at the EU regulatory limits, with a single sample extraction method and dilution volume. No matrix effects were observed on the performance of the LFA with mussel samples spiked with toxins. The developed LFA uses a simple and pocket-sized, portable Cube Reader to provide an accurate result. We also evaluated the use of this Cube Reader with commercially available monoplex lateral flow assays for marine toxins.

Systematic review and meta-analysis assessing the diagnostic test accuracy of procalcitonin in the diagnosis of invasive bacterial infections in febrile infants: a study protocol.

INTRODUCTION: Young febrile infants are at higher risk of invasive bacterial infections (IBIs) compared with older children. The clinical features of IBI are subtle in this cohort mandating that clinicians take a cautious approach to their initial assessment and management. This includes the measurement of blood biomarkers of infection such as C reactive protein (CRP) and procalcitonin (PCT). In the UK, PCT is not widely available and not recommended for routine use in hospital. This is in contrast to Europe and the USA where PCT is regularly used to assist clinical decision-making. The objective of this review and meta-analysis is to report the diagnostic test accuracy of PCT in detecting IBI in febrile infants less than 91 days old, compare its accuracy with CRP and define optimal PCT cut-off values in this cohort. METHODS AND ANALYSIS: A search strategy will include MEDLINE, EMBASE, Web of Science, The Cochrane Library and grey literature. There will be no language or date limitations. Diagnostic accuracy studies compliant with STARD criteria will be considered against eligibility criteria. Abstracts, then full texts, of potentially eligible studies will be independently screened for selection. Data extraction and quality assessment, using the QUADAS-2 tool, will be completed by two independent authors and a third author used for any inconsistencies. True positives, false positives, true negatives and false negatives will be pooled to collate specificity and sensitivity with 95% CIs. Results will be portrayed in forest plots, alongside their quality assessments. ETHICS AND DISSEMINATION: This review does not require ethical clearance. This review will be published in peer-reviewed journals and key messages will be disseminated through presentations at local and international conferences related to this field. The authors aim for this review to be completed and published in 2023.

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease.

Inflammation and fibrosis are important components of diseases that contribute to the malfunction of epithelia and endothelia. The Rho guanine nucleotide exchange factor (GEF) GEF-H1/ARHGEF-2 is induced in disease and stimulates inflammatory and fibrotic processes, cell migration, and metastasis. Here, we have generated peptide inhibitors to block the function of GEF-H1. Inhibitors were designed using a structural in silico approach or by isolating an inhibitory sequence from the autoregulatory C-terminal domain. Candidate inhibitors were tested for their ability to block RhoA/GEF-H1 binding in vitro, and their potency and specificity in cell-based assays. Successful inhibitors were then evaluated in models of TGFß-induced fibrosis, LPS-stimulated endothelial cell-cell junction disruption, and cell migration. Finally, the most potent inhibitor was successfully tested in an experimental retinal disease mouse model, in which it inhibited blood vessel leakage and ameliorated retinal inflammation when treatment was initiated after disease diagnosis. Thus, an antagonist that blocks GEF-H1 signaling effectively inhibits disease features in in vitro and in vivo disease models, demonstrating that GEF-H1 is an effective therapeutic target and establishing a new therapeutic approach.

Effects of Exercise and Sleep Deprivation on Reaction Severity During Oral Peanut Challenge: A Randomized Controlled Trial.

BACKGROUND: The severity of allergic reactions to foods can vary markedly. Little is known of variations in reaction severity within or between individuals or the effects of cofactors. OBJECTIVE: We examined the effects of sleep deprivation and exercise and repeat challenges on the severity and patterns of allergic reactions to peanut. METHODS: In a randomized crossover study, adults with peanut allergy underwent 3 open peanut challenges in random order: with exercise after each dose, with sleep deprivation preceding challenge, and with no intervention. The primary outcome was eliciting dose, reported elsewhere. Reaction severity was a secondary outcome, evaluated using a weighted log-transformed numerical severity score. Analyses estimated the difference in severity between nonintervention challenge and challenges with exercise or sleep deprivation, adjusting for challenge order and using the highest dose tolerated by each individual across all their challenges. Symptom pattern reproducibility was assessed by comparing symptom sequences using pairwise sequence alignment to obtain a percentage match in symptom pattern. RESULTS: Eighty-one participants (mean age 25 y) completed at least 1 postbaseline challenge. Sleep deprivation, but not exercise, significantly increased severity score by 48% (95% CI 12%-84%; P = .009) compared with no intervention. A 38% increase in severity was observed between the first and the last postbaseline challenge (95% CI 1%-75%; P = .044). The average pairwise match of symptoms within individuals was 82.4% and across individuals was 78.3%. CONCLUSIONS: A novel severity score demonstrates that sleep deprivation and repeated challenges increase reaction severity. Understanding factors affecting severity is essential for effective risk management. We also show that symptom patterns in repeat peanut challenges are similar within and between individuals.

Exploring the Potential of a School-Based Online Health and Wellbeing Screening Tool: Young People's Perspectives.

Despite high levels of need, many young people who experience health issues do not seek, access or receive support. Between May and November 2021, using semi-structured interviews, we explored the perspectives of 51 young people (aged 13-14) from two schools who had taken part in a novel online health and wellbeing screening programme, the Digital Health Contact (DHC). One school delivered the DHC during home-learning due to COVID-19 restrictions, whilst the other delivered it in school when restrictions were lifted. The DHC was seen as a useful approach for identifying health need and providing support, and had high levels of acceptability. Young people appreciated the online format of the DHC screening questionnaire and thought this facilitated more honest responses than a face-to-face approach might generate. Completion at home, compared to school-based completion, was perceived as more private and less time-pressured, which young people thought facilitated more honest and detailed responses. Young people's understanding of the screening process (including professional service involvement and confidentiality) influenced engagement and responses. Overall, our findings afford important insights around young people's perspectives of participating in screening programmes, and highlight key considerations for the development and delivery of health screening approaches in (and out of) school.

A new chapter for anti-idiotypes in low molecular weight compound immunoassays.

There is an increasing demand for rapid, affordable, in-field screening methods for low molecular weight (LMW) compound detection. Anti-idiotypes (Ab2s) are biologically derived surrogates that can replace LMW compounds and their protein conjugates in immunoassays. Substitution with anti-idiotypes can improve assay standardisation, reduce cost, and contribute to environmental safety. Their application has been limited by difficult generation processes and varied effects on assay performance. This review examines a recent resurgence in the use of Ab2s within LMW compound detection, driven by the application of phage display and nanobodies. The methods used for Ab2 production are critically discussed and their potential role in improving LMW compound immunoassays is highlighted. Finally, forward-looking ideas for the production of anti-idiotypes are provided, along with barriers to their generation.

Effect of sprouting on the proteome of chickpea flour and on its digestibility by ex vivo gastro-duodenal digestion complemented with jejunal brush border membrane enzymes.

The demand for sustainably produced proteins is increasing with the world population and is prompting a dietary shift toward plant sourced proteins. Vegetable proteins have lower digestibility and biological value compared to animal derived counterparts. We explored sprouting of chickpea seeds as a strategy for improving digestibility. Protein evolution associated with by the sprouting process was assessed by proteomics. The sprouting induced breakdown of seed storage proteins and doubled the release of free alpha-amino nitrogen in sprouted chickpea flour. During sprouting, several enzymes involved in plant development were newly expressed. An ex vivo model of gastroduodenal and jejunal digestion was applied to assess the bioaccessibility of the protein digests. Proteins from chickpea sprouts showed a greater susceptibility to digestion with a 10% increase in alpha amino nitrogen. Peptides with potential immunoreactivity or bioactivity were catalogued in both digested chickpea sprouts and seeds using an in-silico approach. Peptides belonging to the non-specific transfer proteins, which are allergens in pulses, and peptides belonging to an IgE-binding hemagglutinin protein could only be identified in the digested chickpea sprouts. The observation collected paved the way to immune-based evaluations to assess the effect of germination on the allergenic potential.

Exploring the potential of a school-based online health and wellbeing screening tool: professional stakeholders' perspectives and experiences.

BACKGROUND: Supporting children and young people's (CYP) mental and physical health is a global policy priority but detecting need and facilitating access to health services and support is challenging. This paper explores professional stakeholders' perspectives of the acceptability, utility and effectiveness of a school-based online health and wellbeing screening tool, the Digital Health Contact (DHC). The DHC, delivered by Public Health School Nurses (PHSN), aims to identify, and put in place strategies to support, unmet health needs among CYP. METHODS: We employed a qualitative study design, using semi-structured interviews. Fourteen key stakeholders involved in the design and implementation of the DHC (commissioners, providers, PHSN and healthcare staff, school leaders) were purposively sampled. Data were analysed thematically. RESULTS: Our analysis generated two key themes: the perceived benefits of the DHC; and challenges in delivering the DHC. Stakeholders perceived the universal application of the DHC with linked follow-up intervention as an effective means of identifying and supporting CYP with unmet needs, and an efficient way to target limited service resources. There were barriers around enabling school engagement in the DHC, typically in terms of logistics, school infrastructure, and perspectives of fit with schools. These barriers were seen as being negated through developing effective working relationships between schools and PHSN. Effective relationships could highlight the potential benefits of participation. Overall, the DHC was seen as a valuable and effective use of resources, with a low burden on school staff. CONCLUSIONS: The DHC, as a universal school-based health and wellbeing screening tool with linked follow-up intervention, has great potential in identifying and supporting unmet health needs among CYP. The perspectives and experiences of those involved in delivering the DHC highlight important considerations which may enable effective implementation and delivery of school screening programmes across other areas.

Wheat ATIs: Characteristics and Role in Human Disease.

Amylase/trypsin-inhibitors (ATIs) comprise about 2-4% of the total wheat grain proteins and may contribute to natural defense against pests and pathogens. However, they are currently among the most widely studied wheat components because of their proposed role in adverse reactions to wheat consumption in humans. ATIs have long been known to contribute to IgE-mediated allergy (notably Bakers' asthma), but interest has increased since 2012 when they were shown to be able to trigger the innate immune system, with attention focused on their role in coeliac disease which affects about 1% of the population and, more recently, in non-coeliac wheat sensitivity which may affect up to 10% of the population. This has led to studies of their structure, inhibitory properties, genetics, control of expression, behavior during processing, effects on human adverse reactions to wheat and, most recently, strategies to modify their expression in the plant using gene editing. We therefore present an integrated account of this range of research, identifying inconsistencies, and gaps in our knowledge and identifying future research needs. Note  This paper is the outcome of an invited international ATI expert meeting held in Amsterdam, February 3-5 2020.

Prevalence and early-life risk factors of school-age allergic multimorbidity: The EuroPrevall-iFAAM birth cohort.

BACKGROUND: Coexistence of childhood asthma, eczema and allergic rhinitis is higher than can be expected by chance, suggesting a common mechanism. Data on allergic multimorbidity from a pan-European, population-based birth cohort study have been lacking. This study compares the prevalence and early-life risk factors of these diseases in European primary school children. METHODS: In the prospective multicentre observational EuroPrevall-iFAAM birth cohort study, we used standardized questionnaires on sociodemographics, medical history, parental allergies and lifestyle, and environmental exposures at birth, 12 and 24 months. At primary school age, parents answered ISAAC-based questions on current asthma, rhinitis and eczema. Allergic multimorbidity was defined as the coexistence of at least two of these. RESULTS: From 10,563 children recruited at birth in 8 study centres, we included data from 5,572 children (mean age 8.2 years; 51.8% boys). Prevalence estimates were as follows: asthma, 8.1%; allergic rhinitis, 13.3%; and eczema, 12.0%. Allergic multimorbidity was seen in 7.0% of the whole cohort, ranging from 1.2% (Athens, Greece) to 10.9% (Madrid, Spain). Risk factors for allergic multimorbidity, identified with AICc, included family-allergy-score, odds ratio (OR) 1.50 (95% CI 1.32-1.70) per standard deviation; early-life allergy symptoms, OR 2.72 (2.34-3.16) for each symptom; and caesarean birth, OR 1.35 (1.04-1.76). Female gender, OR 0.72 (0.58-0.90); older siblings, OR 0.79 (0.63-0.99); and day care, OR 0.81 (0.63-1.06) were protective factors. CONCLUSION: Allergic multimorbidity should be regarded as an important chronic childhood disease in Europe. Some of the associated early-life factors are modifiable and may be considered for prevention strategies.

Single-dose oral challenges to validate eliciting doses in children with cow's milk allergy.

BACKGROUND: There is increasing interest in the use of eliciting doses (EDs) to inform allergen risk management. The ED can be estimated from the distribution of threshold doses for allergic subjects undergoing food challenges within a specified population. Estimated ED05 values for cow's milk (the dose expected to cause objective allergic symptoms in 5% of the milk-allergic population) range from 0.5 mg to 13.9 mg cow's milk protein. We undertook a single-dose challenge study to validate a predicted ED05 for cow's milk of 0.5 mg protein. METHODS: Participants were recruited from 4 clinical centres. Predetermined criteria were used to identify patients reacting to 0.5 mg cow's milk protein (approximately 0.015 mL of fresh cow's milk). Children over 1 year underwent formal challenge to cow's milk to confirm clinical reactivity. RESULTS: 172 children (median age 6.0 (IQR 0.7-11) years, 57% male) were included in this analysis. Twelve (7.0%, 95% CI 3.7%-11.9%) children experienced objective symptoms that met the predetermined criteria. One participant had mild anaphylaxis that responded to a single dose of adrenaline, the remainder experienced only mild symptoms with no treatment required. We did not identify any baseline predictors of sensitization that were associated with objective reactivity to the single-dose challenge using 0.5 mg cow's milk protein. CONCLUSIONS: These data support an estimated ED05 for cow's milk of 0.5 mg protein. Values for ED05 above 0.5 mg for cow's milk protein proposed for allergen risk management need to be reviewed.

Predicting food allergy: The value of patient history reinforced.

BACKGROUND: EAACI guidelines emphasize the importance of patient history in diagnosing food allergy (FA) and the need for studies investigating its value using standardized allergy-focused questionnaires. OBJECTIVE: To determine the contribution of reaction characteristics, allergic comorbidities and demographics to prediction of FA in individuals experiencing food-related adverse reactions. METHODS: Adult and school-age participants in the standardized EuroPrevall population surveys, with self-reported FA, were included. Penalized multivariable regression was used to assess the association of patient history determinants with "probable" FA, defined as a food-specific case history supported by relevant IgE sensitization. RESULTS: In adults (N = 844), reproducibility of reaction (OR 1.35 [95% CI 1.29-1.41]), oral allergy symptoms (OAS) (4.46 [4.19-4.75]), allergic rhinitis (AR) comorbidity (2.82 [2.68-2.95]), asthma comorbidity (1.38 [1.30-1.46]) and male sex (1.50 [1.41-1.59]) were positively associated with probable FA. Gastrointestinal symptoms (0.88 [0.85-0.91]) made probable FA less likely. The AUC of a model combining all selected predictors was 0.85 after cross-validation. In children (N = 670), OAS (2.26 [2.09-2.44]) and AR comorbidity (1.47 [CI 1.39-1.55]) contributed most to prediction of probable FA, with a combined cross-validation-based AUC of 0.73. When focusing on plant foods, the dominant source of FA in adults, the pediatric model also included gastrointestinal symptoms (inverse association), and the AUC increased to 0.81. CONCLUSIONS: In both adults and school-age children from the general population, reporting of OAS and of AR comorbidity appear to be the strongest predictors of probable FA. Patient history particularly allows for good discrimination between presence and absence of probable plant FA.