Tobacco smoke exposure and respiratory morbidity in young children.

OBJECTIVE: Secondhand smoke exposure is a potentially preventable cause of significant respiratory morbidity in young children. Our study aimed to quantify respiratory morbidity in young children exposed to secondhand smoke to identify potentially modifiable factors. MATERIALS AND METHODS: This study was embedded in a prospective birth cohort study of pregnant women and their children from fetal life onwards in Singapore (Growing Up in Singapore Towards healthy Outcomes, or GUSTO). Data on prenatal, antenatal and postnatal active and secondhand tobacco smoke exposure were obtained by an investigator-administered questionnaire for the periods before pregnancy, at 26-28 weeks' gestation and 24 months after delivery. Data on respiratory morbidity (wheezing episodes, croupy cough, nebuliser use, snoring) and other morbidity (fever, hospitalisation, ear infection) of the child was collected at week 3 and at months 3, 6, 9, 12, 15, 18 and 24 after delivery. Information on parental atopy and potential confounders such as socioeconomic status and maternal educational level were also obtained. Statistical analysis of the data was performed to quantify any significant differences in incidence of respiratory morbidity in children exposed to tobacco smoke in utero and postdelivery, compared with those in smoke-free environments. RESULTS: Women who smoked regularly prior to pregnancy comprised 12.5% (n=155) of the study population; this number fell to 2.3% (n=29) during pregnancy. Mothers exposed to secondhand smoke in the household before pregnancy comprised 35.7% of the study population (n=441) and 31.5% (n=389) were exposed during pregnancy. Postnatally, the prevalence of secondhand tobacco smoke exposure from birth to 2 years of age was 29% (n=359). Participants of Malay ethnicity (p<0.001), mothers with no or primary level education (p<0.001) and mothers with low socioeconomic status (p<0.001) had the highest exposure to tobacco smoke. Offspring secondhand smoke exposure at home by 12 months and by 24 months of age was associated with an increase in hospital admissions due to respiratory disease (RR 1.89, 95% CI 1.02 to 3.50, p=0.04 by 12 months and RR 1.64, 95% CI 1.05 to 2.55, p=0.03 by 24 months) as well as all-cause hospitalisation (RR 1.57, 95% CI 1.14 to 2.17, p=0.01 by 12 months and RR 1.49, 95% CI 1.17 to 1.90, p=0.001 by 24 months), adjusting for parental atopy and child atopic dermatitis. Participants exposed to secondhand smoke by 12 months postdelivery had a significantly increased risk of having at least one wheezing episode (RR 1.71, 95% CI 1.38 to 2.11, p<0.001). CONCLUSIONS: Secondhand smoke exposure during the prenatal and postnatal periods is associated with increased respiratory morbidity in children. Opportunistic screening and targeted smoking cessation counselling for parents at child hospital admissions and well-child outpatient visits, as well as preconception smoking cessation counselling for future pregnancies, may be beneficial to protect the child from negative health impacts.

Clinical and immunochemical profiles of food challenge proven or anaphylactic shrimp allergy in tropical Singapore.

BACKGROUND: Shellfish allergy in Singapore is highly prevalent, and shrimp allergy is the most common. OBJECTIVE: This study aims to evaluate the clinical characteristics and immunological phenotype of shellfish allergy in this population. METHODS: Patients with self-reported shellfish allergy were recruited from outpatient clinics of three large hospitals and from a population survey. Open oral food challenges (OFC) to glass prawn (Litopenaeus vannamei) and tiger prawn (Penaeus monodon) were carried out on all patients except for those who had a history of severe anaphylaxis. Skin prick tests (SPT) and specific IgE to crude and recombinant allergens were carried out to evaluate shrimp and dust mite sensitization. Immunoblots were used to assess IgE-binding proteins. RESULTS: The 104 patients recruited were categorized into shellfish allergic (SA) when OFC was positive or had a history of severe anaphylaxis (n = 39), shellfish tolerant (ST) when OFC was negative (n = 27), and house dust mite positive controls (HDM(+) ) who were ST (n = 38). Oral symptoms (87.1%) were the predominant clinical manifestation. Positive challenge doses ranged from 2 to 80 g of cooked shrimp, with 25/52 patients reacting to either one or both shrimps challenged. The presence of specific IgE to shrimp either by SPT and/or ImmunoCAP(®) assay provided diagnostic test sensitivity of 82% and specificity of 22.2%. The inclusion of specific IgE to shrimp tropomyosin and IgE immunoblots with shrimp extracts did not improve the diagnostic proficiency substantially. CONCLUSIONS AND CLINICAL RELEVANCE: This study highlights the predominance of oral symptoms in shrimp allergy in tropical Asia and that a high provocation dose may be necessary to reveal shrimp allergy. Furthermore, specific IgE diagnostic tests and immunoblots were of limited use in this population.

International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

Filaggrin mutations are associated with recurrent skin infection in Singaporean Chinese patients with atopic dermatitis.

BACKGROUND: Loss-of-function (null) mutations within the filaggrin (FLG) gene are a strong risk factor for atopic dermatitis (AD). We hypothesized that the absence or reduction of the filaggrin protein could compromise skin barrier and increase patients' susceptibility to recurrent skin infection. OBJECTIVES: To investigate the association between FLG-null mutations and the risk of recurrent skin infection among a series of patients with AD in Singapore. METHODS: This study included 228 Singaporean Chinese patients with AD with at least 1year of follow-up at the time of recruitment between January 2008 and December 2009 at the National Skin Centre in Singapore. Each patient had their medical records reviewed for history of skin infection in the preceding year and was genotyped for 22 FLG-null mutations. RESULTS: Compared with those without the FLG-null mutations, patients with AD who had FLG mutation(s) had approximately a seven times increased risk of more than four episodes of skin infection requiring antibiotics in the past year (odds ratio 6·74; 95% confidence interval 2·29-19·79). This risk was much greater in those with mild or moderate disease, and was present in both users and nonusers of oral steroids. CONCLUSION: This study highlights a novel association between FLG-null mutations and an increased susceptibility to recurrent bacterial skin infection among patients with AD.

Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations.

BACKGROUND: Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD. OBJECTIVES: To investigate further the spectrum of FLG-null mutations in Chinese patients and to compare it with that in other populations. METHODS: We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate-to-severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls. Results In total, 22 FLG-null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD [Fisher's exact test; P = 5·3 × 10⁻9; odds ratio (OR) 3·3], palmar hyperlinearity (Fisher's exact test; P = 9·0 × 10⁻¹5; OR 5·8), keratosis pilaris (Fisher's exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063). CONCLUSIONS: This study emphasizes the wider genetic landscape of FLG-null mutations in Asia that is slowly emerging.

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.

Encephalomyelitis-associated antimyelin autoreactivity induced by streptococcal exotoxins.

OBJECTIVE: After implicating Streptococcus pyogenes as causing acute disseminated encephalomyelitis (ADEM) in a child, we wanted to prove that in vivo activation of autoreactive T lymphocytes by superantigens of this Streptococcus contributed to the dramatic demyelination. BACKGROUND: ADEM is a demyelinating disorder of the CNS sharing many similarities with MS. Demyelination in MS is considered to be the result of an autoimmune process mediated by autoreactive T lymphocytes with specificity for myelin antigens. METHODS: Phenotypic analysis and proliferation assays on blood monocytes, as well as isolation of myelin basic protein (MBP)-reactive T-cell lines/clones; and TCR repertorium analysis by PCR-ELISA and cytokine production. RESULTS: 1) The blood T-cell receptor (TCR) repertoire was compatible with in vivo expansion induced by S. pyogenes exotoxins. 2) TCR expression analysis indicated clonal expansion of CD8+ MBP-reactive T cells, suggesting in vivo activation. MBP-reactive T cells showed crossreactivity to S. pyogenes supernatant and exotoxins. 3) Cytokine mRNA quantification of the mononuclear cells revealed a Th2-biased profile. CONCLUSION: In vivo exposure to S. pyogenes may have induced activation of pathogenic myelin reactive T cells, contributing to the dramatic inflammatory demyelination.

Detection of hypodense eosinophils by Percoll multilayer density gradient centrifugation in subjects with normal or slightly elevated eosinophilia. Poor reproducibility and eosinophils of density < 1.077 g/ml.

In patients with marked hypereosinophilia 'hypodense' and 'normodense' eosinophils have been found after density gradient centrifugation. Subsequently this terminology has also been used in studies of patients with milder eosinophilia. However, in these cases the differentiation between normo- and hypodense eosinophils was less clear. This might be due to the high imprecision of the test of density gradient centrifugation, as demonstrated in the first part of this study: the mean within-assay variance of the number of eosinophils in the different density layers was 35%. It was calculated that the test must be performed eight times to obtain an estimate of the true mean for the individual patient. In the second part of the study, the absolute number of 'hypodense eosinophils' in groups of patients with asthma (adults and children) and rheumatoid arthritis (adults) were compared to normal controls. Although a difference in the absolute number of hypodense eosinophils between groups of patients and controls could be demonstrated, the high imprecision of the test of density gradient centrifugation suggested that the technique used was not useful in an individual with normal or slightly elevated eosinophils in the peripheral blood.

Pharmacotherapy of childhood asthma. An inflammatory disease.

The recognition that asthma constitutes 2 kinds of physiopathological reactions, namely bronchospasms (immediate reactions) and inflammatory responses (late reactions), suggests that the treatment should be focused against these events. Furthermore, the allergen provocation model, showing the existence of immediate and late asthmatic reactions, can be used to study the effects of different antiasthmatic drugs. Recently, the importance of inflammation in the pathogenesis of asthma in adults has led to the development of therapeutic regimens in which anti-inflammatory treatments are used frequently as a first-line step in the management of asthma. Although at the moment the hard data showing inflammation in childhood asthma are scarce, it is assumed that childhood asthma constitutes the same kind of chronic inflammatory processes as in adult asthma and that its treatment should also include anti-inflammatory drugs.

Measurement of total respiratory impedance in infants by the forced oscillation technique.

The forced oscillation technique according to Làndsér et al. (J. Appl. Physiol. 41:101-106, 1976) was modified for use in infants. Adaptations, including a flexible tube to connect the infant to the measuring system and a bias flow to avoid rebreathing, did not influence impedance values. The linearity of the respiratory system was assessed and confirmed by 1) applying pseudo-random noise oscillations at three different amplitudes to 7 infants and 2) comparing in 12 infants impedance values obtained with pseudo-random noise and with sinusoidal oscillations at 12 and 32 Hz. Intersubject variability, averaged for all frequencies, was 6%. In 17 infants the relative error (+/- SD) between two series of five measurements within a time interval of 15 min was 0.5 +/- 5.7%. No statistically significant difference was found between impedance values before and after repositioning of the infant's head, whereas rotation resulted in a decrease in resistance and no effect on reactance. Our results indicate that the infant-adapted forced pseudo-random noise oscillation technique has the potential to give valuable information about ventilatory lung function in infants.

Aerosolized budesonide in asthmatic infants: a double blind study.

The efficacy of nebulized budesonide (0.5 mg b.i.d.) against placebo was evaluated in the management of asthma in 23 infants, aged 3 to 17 months, using a double blind crossover design. After an initial treatment period of 2 weeks placebo and budesonide were randomly administered during two consecutive treatment periods of 1 month. The progress of the patients was monitored using diary score cards, the number of salbutamol doses needed during the treatment periods, clinical examinations using standardized scoring cards, and registration of parents' preference period. Although there was a tendency toward fewer wheezing periods during budesonide, the results of the diary score cards were not significantly different between the budesonide period and the placebo period. The number of salbutamol doses used was also the same during both periods. Clinical examination after budesonide revealed less rhinitis and a less pathological lung auscultation, but the difference between the two periods was also not significant. Furthermore, the parents' preference could not distinguish between budesonide and placebo. We conclude that the trends in favor of nebulized budesonide are not significant and do not suggest that the suspension is effective in severe infantile asthma.

Functional residual capacity and total respiratory system impedance in wheezing infants.

Airways obstruction has been demonstrated in acutely wheezing infants. The aim of the present study was to assess functional abnormalities as detected by measurement of total respiratory system resistance (Rrs) and functional residual capacity (FRC) in infants with a history of recurrent episodes of wheezing, while not acutely ill. In 30 such infants (mean age, 10 months; range, 4-17) and in 10 healthy infants (mean age, 6 months; range, 0-14) four Rrs measurements, performed with the forced pseudo-random noise (PRN) oscillation technique, and three FRC determinations, using the closed-circuit helium dilution technique, were averaged. A lower than predicted FRC was demonstrated in 20/30 (66%) patients. At 16 Hz, Rrs was significantly above predicted in 3/30 (10%) patients. Specific Rrs (Rrs x FRC) at 16 Hz was increased in 5/30 (17%) patients. In conclusion, the PRN oscillation technique combined with FRC measurement by helium dilution detects lung function abnormalities in a minority of wheezing infants during symptom-free intervals.

Evaluation of nasal impedance using the forced oscillation technique in infants.

By applying oscillations to the respiratory system through a rigid face mask, the infant-adapted Lándsér forced oscillation technique measures impedance of the total respiratory system including the nose, at frequencies from 4 to 52 Hz. The present study was aimed at evaluating nasal impedance in infants from consecutive forced oscillation measurements through both nostrils and each nostril separately, using a simple electrical model. In 30 asthmatic infants with varying degrees of nasal obstruction, aged 1-16 months, calculated nasal resistance (Rn) at 24 Hz ranged from 1 to 16 cm H2O.L-1.s. The ratio of Rn to total respiratory system resistance varied between 1 and 48% (mean: 16%). In seven non-asthmatic infants, aged 0-12 months, Rn was between 1 and 11 cm H2O.L-1.s. Nasal patency (evaluated clinically) was correlated with the calculated Rn (P less than 0.05). Rn showed almost no frequency dependence between 24 and 48 Hz as demonstrated by a mean slope of -0.09 +/- 0.08 cm H2O.s2/L for the asthmatic and of -0.08 +/- 0.07 for the non-asthmatic infants. In seven of the asthmatic infants the differences between two Rn determinations at a 45 min interval ranged from -1.7 to 3.8 cm H2O.L-1.s-1 at 24 Hz and from -3.6 to 1.0 at 48 Hz. Changes in Rn did not correlate with changes in total respiratory system resistance (P greater than 0.05). In conclusion, nasal impedance can be approximated from three consecutive measurements through both nostrils and through each nostril separately.

Does treatment of asthmatic children with inhaled corticosteroids affect their adult height?

In this retrospective study, adult height was assessed in young adult asthmatics who were treated with inhaled corticosteroids (ICs) during childhood (n = 42; 26 boys) and compared to those obtained in asthmatic patients who were never treated with ICs during childhood (n = 43; 23 boys). Standing height of all subjects and their parents was measured. Height data were analyzed using actual length and target height in centimeters, standard deviation scores (SDS), and difference between adult height of the patients and their target height (adult height minus target height). Mean adult height was the same in subjects who took ICs during childhood as compared to those who had never received ICs (boys: 179.3cm+/-6.8 vs. 180.4 cm+/-5.6; girls: 165.8 cm+/-7.5 vs. 167.7 cm+/-7.2). SDS of adult height was also not different between the two groups: in subjects who did not take ICs it was 0.89+/-1.00, while in those who took ICs it was 0.66+/-1.10 (P = 0.31). SDS of target height was also not different between the two groups: in subjects not taking ICs it was 0.95+/-0.86, while in those who took ICs it was 0.28+/-0.76 (P = 0.30). However, subjects who took ICs during childhood showed a statistically significant lower value of adult height minus target height than those who never took ICs (whole group: -0.003+/-5.9 vs. 2.54 +/-4.8, P = 0.03 ; boys: 0.004+/-5.8 vs. 3.09+/-4.5, P = 0.04 ; girls: -0.075+/-6.3 vs. 1.91+/-5.2, P = 0.31). Patients on ICs during childhood who had ever been hospitalized for asthma showed a lower value for adult height minus target height than those who took ICs but were never hospitalized (-3.08+/-7.8 vs. 1.06+/-4.8, P = 0.046). A logistic regression analysis predicting growth impairment showed that the best-fitting model was one that used only ICs as a dependent variable (crude odds ratio, 3.3; 95% CI, 1.3-8.4). Patients who were treated with ICs in combination with intranasal corticosteroids (treatment for rhinitis) tended to have a lower value of adult height minus target height than the other children, but the difference was not statistically significant (P = 0.07). We conclude that although adult height was the same in young adults who were treated with ICs during childhood compared to those who were not treated with ICs during childhood, there was a statistically significant difference between the two groups for adult height minus target height, suggesting mild growth retardation in patients who took ICs during childhood. These findings may be explained by the use of ICs, but it seems more likely that a difference in asthma severity between both groups was responsible for it.

Aerosolized furosemide in wheezy infants: a negative report.

We investigated the effects of 10 mg aerosolized furosemide on clinical score in 28 acutely wheezing infants (Part A) and in a second group of 20 intermittently wheezing babies on airway resistance and functional residual capacity during a symptomfree period (Part B), using a double-blind, placebo-controlled design. In both parts of the study no therapeutic effects were observed during and following aerosol inhalation of 10 mg furosemide.

Lung function measures and their relationship to respiratory symptoms in 7- and 8-year-old children.

Abnormal pulmonary function in childhood is a well-known risk factor for lung function impairment in adult life. It is therefore of clinical interest to recognize lower pulmonary function in childhood. We investigated the association between asthma-like respiratory symptoms and the lung function parameters FVC, FEV1, and FEF(25-75) in a population-based sample of 402 schoolchildren, aged 7 and 8 years, using linear regression analyses. Without accounting for other respiratory symptoms, wheeze, exercise-induced wheeze, chronic cough, and history of wheezy bronchitis or lower respiratory infections in early childhood were significantly associated with reduced lung function. After stepwise elimination of symptoms from the regression models, only exercise-induced wheeze (FEV1, -15%pred, FEF(25-75), -21%pred) and a history of chronic cough (FEV1, -5%pred; FEF(25-75), -11%pred) remained significant predictors of decreased lung function. After adjustment for different variability, no significant differences were seen between the effects of symptoms on the flow measurements FEV1 and FEF(25-75). We conclude that children who report exercise-induced wheeze and/or chronic cough may have a considerable deficit in lung function at early school age.

Academy of medicine, Singapore-Ministry of Health clinical practice guidelines: management of food allergy.

The Academy of Medicine, Singapore (AMS) and the Ministry of Health (MOH) publish clinical practice guidelines to provide doctors and patients in Singapore with evidence-based guidance on managing important medical conditions. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the AMS-MOH clinical practice guidelines on the Management of Food Allergy, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Academy of Medicine website: http://www.ams.edu.sg/guidelines.asp#foodallergy. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Prevalence of drug allergy in Singaporean children.

INTRODUCTION: Adverse drug reactions (ADRs) are a common medical problem in children, affecting up to 15 percent of children, according to the literature. However, most studies on ADRs were performed in a hospital setting, and studies in the general population are limited. The current study aims to estimate the prevalence of ADRs in a large number of non-selected Singaporean children. METHODS: School children, aged 7-16 years, from 25 random schools were screened via a self-reported questionnaire on ADRs, and parents of the selected children were then followed up with a telephone interview to obtain additional information on specific manifestations, diagnosis and allergy testing. RESULTS: The prevalence of an ADR in children was 5.4 percent, with 56.7 percent of cases reporting an ADR to beta-lactam antibiotics. Dermal manifestations were reported in 60 percent of all ADRs, while multiple drug allergies accounted only for 3.8 percent. Only 6.9 percent of the children who experienced an ADR were referred to a hospital for further investigations. CONCLUSIONS: ADRs were associated with a positive history of atopy, increased income level and Chinese and Indian ethnicity, but not with gender or age. It is striking that most children suffering from a clinical ADR were not investigated further or referred for diagnostic tests. Many parents were unaware of the availability of drug allergy tests and feared compromising their children's health. This certainly could attribute to the high incidence of the over-reporting of ADRs in the general population.