Prevalence of IgE-mediated cow milk, egg, and peanut allergy in young Singapore children.

Background: The rising prevalence of food allergy reported in the United States, UK, and Australia may be attributable to the rise in peanut allergy prevalence. The food allergy prevalence in other parts of the world such as Asia is, however, less well documented. Objective: This study aimed to evaluate the prevalence of cow's milk, egg, and peanut allergies in a general population of Singaporean children below 30 months of age. Methods: A total of 4,115 children from the general population who attended well-baby visits between 2011 and 2015 completed standardized questionnaires to elicit a convincing history of food allergy to estimate the population prevalence of food allergies. Results: The prevalence of a convincing history of cow's milk allergy was 0.51% (95% confidence interval [CI], 0.3-0.7), hen's egg allergy 1.43% (95% CI, 1.1-1.8), and peanut allergy 0.27% (95% CI, 0.12-0.42). Of the 15 of 59 children with a convincing history of hen's egg allergy who consented, 12 (80%) had corroborative positive skin prick tests. Conclusion: The prevalence of food allergy, in particular peanut allergy, in children below 2 years of age is lower in this South East Asian population than reported in Western cohorts. Further research should focus on deciphering differential risk factors for food allergy across different geographical locations.

An Evaluation of the Mechanisms of Galacto-Oligosaccharide (GOS)-Induced IgE Cross-Linking on Basophils in GOS Allergy.

The prebiotics, galacto-oligosaccharides (GOS), are small carbohydrate molecules with 1-7 galactose units linked to glucose and have been shown to trigger IgE-mediated anaphylaxis in some cases following ingestion. It is still an unresolved question of how GOS cross-links IgE on basophils. In this study, we examined whether human galectins, a class of lectins that bind specifically to ß-galactoside carbohydrates, are involved in GOS-induced basophil activation. Basophil activation test to GOS and control allergen, Blomia tropicalis (Blo t) extract were performed in the presence or absence of four sugar-based galectin inhibitors (lactose, thiodigalactoside [TDG], TD139, and GB1107) and one peptide-based inhibitor, G3-C12. Results showed that TD139, GB1107, and G3-C12 did not display a specific inhibitory effect on GOS-induced basophil activation as compared to control allergen. An inhibitory effect of lactose and TDG on GOS-induced basophil activation was observed and varied between subjects with up to 100% inhibition at low doses of GOS. The results of competitive ELISA suggest that the inhibitory effects of high dose lactose and TDG on the basophil activation is likely due to the cross-reactivity of GOS-specific IgE to lactose and TDG. Basophil activation is performed using purified basophils suggested that cell surface receptors on other blood cells were not required to induce basophil activation. In conclusion, our results suggest that GOS, a low molecular weight sugar, is able to cross-link IgE independently.

Methods to Improve Diagnostic Reasoning in Undergraduate Medical Education in the Clinical Setting: a Systematic Review.

BACKGROUND: In recent years, there have been numerous studies exploring different teaching methods for improving diagnostic reasoning in undergraduate medical students. This systematic review examines and summarizes the evidence for the effectiveness of these teaching methods during clinical training. METHODS: PubMed, Embase, Scopus, and ERIC were searched. The inclusion criteria for the review consist of articles describing (1) methods to enhance diagnostic reasoning, (2) in a clinical setting (3) on medical students. Articles describing original research using qualitative, quantitative, or mixed study designs and published within the last 10 years (1 April 2009-2019) were included. Results were screened and evaluated for eligibility. Relevant data were then extracted from the studies that met the inclusion criteria. RESULTS: Sixty-seven full-text articles were first identified. Seventeen articles were included in this review. There were 13 randomized controlled studies and four quasi-experimental studies. Of the randomized controlled studies, six discussed structured reflection, four self-explanation, and three prompts for generating differential diagnoses. Of the remaining four studies, two employed the SNAPPS1 technique for case presentation. Two other studies explored schema-based instruction and using illness scripts. Twelve out of 17 studies reported improvement in clinical reasoning after the intervention. All studies ranked level two on the New World Kirkpatrick model. DISCUSSION: The authors posit a framework to teach diagnostic reasoning in the clinical setting. The framework targets specific deficiencies in the students' reasoning process. There remains a lack of studies comparing the effectiveness of different methods. More comparative studies with standardized assessment and evaluation of long-term effectiveness of these methods are recommended.

Implementation of Universal Newborn Screening for Severe Combined Immunodeficiency in Singapore While Continuing Routine Bacille-Calmette-Guerin Vaccination Given at Birth.

Introduction: Severe Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth. However, delaying BCG vaccination can be detrimental to the population in tuberculosis-endemic regions. Early diagnosis of SCID through newborn screening followed by pre-emptive treatment with anti-mycobacterial therapy may be an alternative strategy to delaying routine BCG vaccination. We report the results of the first year of newborn SCID screening in Singapore while continuing routine BCG vaccination at birth. Method: Newborn screening using a T-cell receptor excision circle (TREC) assay was performed in dried blood spots received between 10 October 2019 to 9 October 2020 using the Enlite Neonatal TREC kit. Patients with low TREC had lymphocyte subset analysis and full blood count performed to determine the severity of lymphopenia and likelihood of SCID to guide further management. Results: Of the 35888 newborns screened in 1 year, no SCID cases were detected, while 13 cases of non-SCID T-cell lymphopenia (TCL) were picked up. Using a threshold for normal TREC to be >18 copies/µL, the retest rate was 0.1% and referral rate to immunologist was 0.04%. Initial low TREC correlated with low absolute lymphocyte counts (ALC), and subsequent normal ALC corresponded with increases in TREC, thus patients with normal first CD3+ T cell counts were considered to have transient idiopathic TCL instead of false positive results. 7/13 (54%) had secondary TCL (from sepsis, Trisomy 21 with hydrops and stoma losses or chylothorax, extreme prematurity, or partial DiGeorge Syndrome) and 6/13 (46%) had idiopathic TCL. No cases of SCID were diagnosed clinically in Singapore during this period and for 10 months after, indicating that no cases were missed by the screening program. 8/9 (89%) of term infants with abnormal TREC results received BCG vaccination within the first 6 days of life when TREC and ALC were low. No patients developed BCG complications after a median follow-up of 17 months. Conclusion: Newborn screening for SCID can be implemented while continuing routine BCG vaccination at birth. Patients with transient TCL and no underlying primary immunodeficiency are able to tolerate BCG vaccination.

Efficacy and safety of oral immunotherapy for peanut allergy: a pilot study in Singaporean children.

BACKGROUND: Peanut allergy is an increasing problem in Singapore and strict avoidance is difficult as peanut is ubiquitous in Asian cuisine. OBJECTIVE: We aimed to assess the efficacy and safety of peanut oral immunotherapy (OIT) in children with obvious peanut allergy in Singapore. METHODS: This was an open-label study of peanut OIT in children living in Singapore, with 2 weekly dose escalation until final maintenance dose of 3,000 mg of peanut protein and a maintenance phase of 12 months. An oral food challenge was performed at 6 months to assess for desensitisation and at 4 weeks after discontinuation of OIT having completed 12 months of maintenance therapy to assess for possible sustained unresponsiveness. The adverse events were monitored using the symptom diaries. RESULTS: Nine subjects were started on OIT, with 7 managing to complete maintenance phase of therapy. Of these 7, all were able to tolerate at least 3,000 mg of peanut protein by 6 months of maintenance therapy, showing that the OIT was effective. Of these 7, 3 patients complied with the 4-week abstinence period after completion of OIT before another peanut challenge; 2 of the 3 subjects showed a significant decrease from the initial ability to tolerate 3,000 mg of peanut protein. Side effects were mainly gastrointestinal in nature and were more common during the updosing phase than the maintenance phase. No episodes of anaphylaxis were observed in this study. CONCLUSION: Peanut OIT seemed to be effective and safe in our cohort of Singaporean children.

Novel strategies in immunotherapy for allergic diseases.

Conventional immunotherapy (IT) for optimal control of respiratory and food allergies has been fraught with concerns of efficacy, safety, and tolerability. The development of adjuvants to conventional IT has potentially increased the effectiveness and safety of allergen IT, which may translate into improved clinical outcomes and sustained unresponsiveness even after cessation of therapy. Novel strategies incorporating the successful use of adjuvants such as allergoids, immunostimulatory DNA sequences, monoclonal antibodies, carriers, recombinant proteins, and probiotics have now been described in clinical and murine studies. Future approaches may include fungal compounds, parasitic molecules, vitamin D, and traditional Chinese herbs. More robust comparative clinical trials are needed to evaluate the safety, clinical efficacy, and cost effectiveness of various adjuvants in order to determine ideal candidates in disease-specific and allergen-specific models. Other suggested approaches to further optimize outcomes of IT include early introduction of IT during an optimal window period. Alternative routes of administration of IT to optimize delivery and yet minimize potential side effects require further evaluation for safety and efficacy before they can be recommended.

Establishment of the nasal microbiota in the first 18 months of life: Correlation with early-onset rhinitis and wheezing.

BACKGROUND: Dynamic establishment of the nasal microbiota in early life influences local mucosal immune responses and susceptibility to childhood respiratory disorders. OBJECTIVE: The aim of this case-control study was to monitor, evaluate, and compare development of the nasal microbiota of infants with rhinitis and wheeze in the first 18 months of life with those of healthy control subjects. METHODS: Anterior nasal swabs of 122 subjects belonging to the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort were collected longitudinally over 7 time points in the first 18 months of life. Nasal microbiota signatures were analyzed by using 16S rRNA multiplexed pair-end sequencing from 3 clinical groups: (1) patients with rhinitis alone (n = 28), (2) patients with rhinitis with concomitant wheeze (n = 34), and (3) healthy control subjects (n = 60). RESULTS: Maturation of the nasal microbiome followed distinctive patterns in infants from both rhinitis groups compared with control subjects. Bacterial diversity increased over the period of 18 months of life in control infants, whereas infants with rhinitis showed a decreasing trend (P < .05). An increase in abundance of the Oxalobacteraceae family (Proteobacteria phylum) and Aerococcaceae family (Firmicutes phylum) was associated with rhinitis and concomitant wheeze (adjusted P < .01), whereas the Corynebacteriaceae family (Actinobacteria phylum) and early colonization with the Staphylococcaceae family (Firmicutes phylum; 3 weeks until 9 months) were associated with control subjects (adjusted P < .05). The only difference between the rhinitis and control groups was a reduced abundance of the Corynebacteriaceae family (adjusted P < .05). Determinants of nasal microbiota succession included sex, mode of delivery, presence of siblings, and infant care attendance. CONCLUSION: Our results support the hypothesis that the nasal microbiome is involved in development of early-onset rhinitis and wheeze in infants.

Cause and Clinical Presentation of Anaphylaxis in Singapore: From Infancy to Old Age.

BACKGROUND: The study objective was to compare age-related differences in the cause and clinical presentation of anaphylaxis. METHODS: We conducted a prospective study of patients visiting the emergency department for anaphylaxis. Data were collected from 3 emergency departments from 1 April 2014 to 31 December 2015. Patient electronic records with the diagnoses of allergy, angioedema, urticaria, and anaphylaxis (ICD-9 codes 9953, 9951, 7080, 9950, 7089) were screened and cases fulfilling World Allergy Organisation criteria for anaphylaxis were included. RESULTS: A total of 426 cases of anaphylaxis were identified with a median age of 23 years (range 3 months to 88 years and 9 months). The causes of anaphylaxis were food (n = 236, 55%), drugs (n = 85, 20%), idiopathic (n = 64, 15%), and insect bites or stings (n = 28, 7%). The most common food was shellfish (n = 58, 14%) and the most common drugs were non-steroidal anti-inflammatory drugs (n = 26, 6%). There were more cases of food anaphylaxis in children than in adults (72 vs. 42%, p < 0.001) and more cases of drug anaphylaxis in adults than in children (28 vs. 10%, p < 0.001). Compared to patients of other ages, infants and young children had more gastrointestinal symptoms (adjusted odds ratio [aOR] 2.1, 95% CI 1.1-3.9), while schoolchildren and adolescents had more respiratory symptoms (aOR 2.7, 95% CI 1.4-5.2). Adults had more cardiovascular symptoms (aOR 2.9, 95% CI 1.8-4.6) and hypotension (aOR 3.7, 95% CI 2.1-6.8) compared to children. However, 42% of the infants lacked blood pressure measurements. CONCLUSIONS: Knowledge of age-related variation in the cause and clinical presentation of anaphylaxis aids in diagnosis and acute management.

Corrigendum: Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

[This corrects the article on p. 798 in vol. 8, PMID: 28769923.].

Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

The use of inhaled corticosteroids in pediatric asthma: update.

Despite the availability of several formulations of inhaled corticosteroids (ICS) and delivery devices for treatment of childhood asthma and despite the development of evidence-based guidelines, childhood asthma control remains suboptimal. Improving uptake of asthma management plans, both by families and practitioners, is needed. Adherence to daily ICS therapy is a key determinant of asthma control and this mandates that asthma education follow a repetitive pattern and involve literal explanation and physical demonstration of the optimal use of inhaler devices. The potential adverse effects of ICS need to be weighed against the benefit of these drugs to control persistent asthma especially that its safety profile is markedly better than oral glucocorticoids. This article reviews the key mechanisms of inhaled corticosteroid action; recommendations on dosage and therapeutic regimens; potential optimization of effectiveness by addressing inhaler technique and adherence to therapy; and updated knowledge on the real magnitude of adverse events.

Particularities of allergy in the Tropics.

Allergic diseases are distributed worldwide and their risk factors and triggers vary according to geographical and socioeconomic conditions. Allergies are frequent in the Tropics but aspects of their prevalence, natural history, risk factors, sensitizers and triggers are not well defined and some are expected to be different from those in temperate zone countries. The aim of this review is to investigate if allergic diseases in the Tropics have particularities that deserve special attention for research and clinical practice. Such information will help to form a better understanding of the pathogenesis, diagnosis and management of allergic diseases in the Tropics. As expected, we found particularities in the Tropics that merit further study because they strongly affect the natural history of common allergic diseases; most of them related to climate conditions that favor permanent exposure to mite allergens, helminth infections and stinging insects. In addition, we detected several unmet needs in important areas which should be investigated and solved by collaborative efforts led by the emergent research groups on allergy from tropical countries.

Carbohydrates as food allergens.

The literature supports the notion that carbohydrate epitopes, on their own, do not contribute significantly to the induction of allergic reactions. They bind weakly to IgE antibodies and have been termed as cross reactive carbohydrate determinants. These epitopes cause confusion in in vitro IgE testing through nonspecific cross-reactivity. Coincident with the rising trends in food allergy prevalence, there has recently been reports of anaphylaxis induced by carbohydrate epitopes. There are two distinct groups, each with unique characteristics and geographical distribution. Anaphylaxis and acute allergic reactions related to the carbohydrate galactose-α-1,3-galactose (α-Gal) epitope that are present in the monoclonal antibody, cetuximab and red meat have been described in the United States and Europe populations where tick bites have been found to be the primary sensitizer. Another carbohydrate inducing anaphylaxis is galacto-oligosaccharides in commercial milk formula which has been described in the several Asian populations including Singapore. The latter is unique in that the allergen is a pure carbohydrate. We summarize the current literature on carbohydrate-induced food allergy, and evaluate the two new groups of carbohydrate allergy that have defied previous findings on carbohydrates and their role.

Rhinitis in the first 18 months of life: exploring the role of respiratory viruses.

BACKGROUND: Rhinitis is common in early childhood, but allergic rhinitis is considered a later manifestation of the atopic march. This study aimed to evaluate rhinitis (allergic and non-allergic) in the first 18 months of life, its link with other atopic manifestations and the role of respiratory viruses. METHODS: Subjects (n = 1237) of the Singapore GUSTO birth cohort were followed up quarterly until 18 months of age with questionnaires to screen for rhinitis symptoms lasting at least 2 wk and with monthly calls to positive subjects to detect prolonged/recurrent rhinitis symptoms (total duration ≥ 4 wk). Anterior nasal swabbing for molecular-based virus detection was conducted during these visits and near (within a month) rhinitis episodes. Skin prick testing to common environmental and food allergens was conducted at the 18 month visit. RESULTS: Prolonged/recurrent rhinitis was significantly associated with history of parental atopy (mother: aOR = 2.17; father: aOR = 1.82) and atopic comorbidities of eczema (aOR = 2.53) and wheeze (aOR = 4.63) (p < 0.05), though not with allergen sensitization. Although the frequency of nasal respiratory virus detection during scheduled quarterly visits did not differ between prolonged/recurrent rhinitis and matched controls (p > 0.05), virus detection was higher in swabs obtained within a month following rhinitis episodes in prolonged/recurrent rhinitis subjects compared with scheduled visits (adjusted p = 0.04). CONCLUSIONS: Based on the duration of rhinitis symptoms, this study defined a subset of early childhood rhinitis which was associated with atopic predisposition and comorbidities. Persistent respiratory viral shedding may contribute to the symptomatology. Whether this entity is a precursor of subsequent childhood allergic rhinitis will require longer follow-up.

Wheat-dependent exercise-induced anaphylaxis: a retrospective case review from a tertiary hospital.

BACKGROUND: Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy caused by the combination of wheat ingestion and physical exercise and has been reported in other parts of Asia. At present, there are no published reports of WDEIA in Singapore. The objective of this study is to characterise the common local clinical and laboratory manifestations of WDEIA. METHODS: This was a retrospective descriptive study of all WDEIA who presented to a tertiary Singaporean Hospital over a 5-year-period from 1 January 2009 to 30 June 2013. RESULTS: Eight patients aged 9-41 years old were characterised. Six were males and the majority (5) was of Chinese ethnicity. An atopic history was found in four patients. The symptoms of anaphylaxis included cutaneous manifestations such as urticaria (n=7), angioedema (n=6), respiratory symptoms of dyspnoea and wheezing (n=5) and hypotension (n=5). The symptoms occurred 20-75 min after consumption of wheat-based products, often upon cessation of exercise [running (n=3), walking (n=4) and swimming (n=1)]. The WDEIA was recurrent in seven patients. The skin prick tests were positive to wheat in seven patients, and ω-5 gliadin test to wheat was positive in five patients. CONCLUSIONS: With the emergence of wheat allergy in East Asian countries, WDEIA has become an important condition for physicians and Singapore is no exception. Under-recognition combined with life-threatening symptoms warrants better public awareness measures. In addition, further studies are necessary to identify possible unique genetic and environmental exposures that could explain the inter-regional differences of WDEIA.

Ten-year prescription trends of asthma medications in the management of childhood wheeze.

Asthma is the most common chronic disorder of childhood. The aim of this study was to assess prescription trends of asthma medications to provide a measure to evaluate treatment practices and compliance with established international practice guidelines. A retrospective study of data obtained from outpatient prescription databases (2001-2010) of the University Children's Medical Institute for children aged 0-18 years was performed. The following drugs were included: short-acting beta-agonists (SABAs), long-acting beta-agonists in combination with inhaled corticosteroids (LABA-ICSs), ICS, and leukotriene receptor antagonists. Statistical analysis of prescription trends was performed with linear regression to determine the trends in prescription of controller medications. From 2001 to 2010, the number of patients who were prescribed SABA increased significantly by 72% (p = 0.016). The increases in ICS patient numbers and ICS/SABA drug unit ratios were significant only in the school-going (>5 years) age group. There was a trend away from the use of nebulized SABA and ICS, although this was statistically insignificant. LABA-ICS patient numbers decreased significantly by 32.4% (p = 0.003), especially in preschoolers (1-5 years). There was a corresponding rise in montelukast patient numbers by 194.6% (p = 0.009) and montelukast/SABA ratio by 345.3% (p = 0.032) in preschoolers (aged 1-5 years). Montelukast patient numbers, but not the montelukast/SABA ratio, increased in school-going children. The move away from LABA-ICS combination especially in younger children and a tendency toward more montelukast usage is a reflection of practice preferences in accordance with current international guidelines in young children.