Association between allergen component sensitisation and clinical allergic disease in children.

BACKGROUND: Allergen component sensitisation testing is becoming increasingly important in the diagnosis of peanut allergy. The aim of the present study was to evaluate the relationship between sensitisation and symptoms of allergic disease in children by testing a large panel of inhalants, food allergens, and allergen components. METHODS: For 287 children visiting our laboratory for allergy testing, symptoms of allergic disease were recorded by standardised validated questionnaires. Specific IgE to 11 whole allergens was assessed by ImmunoCAP, and to 112 allergen components by ISAC ImmunoCAP assay. We used latent class analysis (LCA) to distinguish clinical phenotypes. RESULTS: Inhalant and food allergen sensitisation was common, irrespective of the children's allergic symptom type. Less than 10% of the variance in symptom scores was explained by variations in the number of allergens (components) that the child was sensitised to. In LCA, 135 children (50.2%) had mild allergy, with few symptoms and sensitisation to no or few allergens, 74 children (27.5%) had more symptoms and sensitisation to inhalant allergens (respiratory allergy) and 60 children (22.3%) showed polysensitisation to a median of six allergens and had more severe symptoms of different organ systems. Adding allergen component test results to LCA failed to result in identifiable classes of allergic disease in children. CONCLUSIONS: In this group of children with allergic symptoms, referred for allergy testing by their physician, broad screening for allergen component sensitisation did not contribute to distinguishing phenotypes of allergic disease.

Association between allergen component sensitisation and clinical allergic disease in children

Background Allergen component sensitisation testing is becoming increasingly important in the diagnosis of peanut allergy. The aim of the present study was to evaluate the relationship between sensitisation and symptoms of allergic disease in children by testing a large panel of inhalants, food allergens, and allergen components.Methods For 287 children visiting our laboratory for allergy testing, symptoms of allergic disease were recorded by standardised validated questionnaires. Specific IgE to 11 whole allergens was assessed by ImmunoCAP, and to 112 allergen components by ISAC ImmunoCAP assay. We used latent class analysis (LCA) to distinguish clinical phenotypes.Results Inhalant and food allergen sensitisation was common, irrespective of the children’s allergic symptom type. Less than 10% of the variance in symptom scores was explained by variations in the number of allergens (components) that the child was sensitised to. In LCA, 135 children (50.2%) had mild allergy, with few symptoms and sensitisation to no or few allergens, 74 children (27.5%) had more symptoms and sensitisation to inhalant allergens (respiratory allergy) and 60 children (22.3%) showed polysensitisation to a median of six allergens and had more severe symptoms of different organ systems. Adding allergen component test results to LCA failed to result in identifiable classes of allergic disease in children.Conclusions In this group of children with allergic symptoms, referred for allergy testing by their physician, broad screening for allergen component sensitisation did not contribute to distinguishing phenotypes of allergic disease (AU)

The validity of Dutch health claims data for identifying patients with chronic kidney disease: a hospital-based study in the Netherlands.

BACKGROUND: Health claims data may be an efficient and easily accessible source to study chronic kidney disease (CKD) prevalence in a nationwide population. Our aim was to study Dutch claims data for their ability to identify CKD patients in different subgroups. METHODS: From a laboratory database, we selected 24 895 adults with at least one creatinine measurement in 2014 ordered at an outpatient clinic. Of these, 15 805 had ≥2 creatinine measurements at least 3 months apart and could be assessed for the chronicity criterion. We estimated the validity of a claim-based diagnosis of CKD and advanced CKD. The estimated glomerular filtration rate (eGFR)-based definitions for CKD (eGFR < 60 mL/min/1.73 m2) and advanced CKD (eGFR < 30 mL/min/1.73 m2) satisfying and not satisfying the chronicity criterion served as reference group. Analyses were stratified by age and sex. RESULTS: In general, sensitivity of claims data was highest in the population with the chronicity criterion as reference group. Sensitivity was higher in advanced CKD patients than in CKD patients {51% [95% confidence interval (CI) 47-56%] versus 27% [95% CI 25-28%]}. Furthermore, sensitivity was higher in young versus elderly patients. In patients with advanced CKD, sensitivity was 72% (95% CI 62-83%) for patients aged 20-59 years and 43% (95% CI 38-49%) in patients ≥75 years. The specificity of CKD and advanced CKD was ≥99%. Positive predictive values ranged from 72% to 99% and negative predictive values ranged from 40% to 100%. CONCLUSION: When using health claims data for the estimation of CKD prevalence, it is important to take into account the characteristics of the population at hand. The younger the subjects and the more advanced the stage of CKD the higher the sensitivity of such data. Understanding which patients are selected using health claims data is crucial for a correct interpretation of study results.

Interpretation of Folate Results in Hemolytic Plasma Samples: A Practical Approach.

Folate analysis in plasma is affected by hemolysis, which can lead to biased results. However, the degree of hemolysis that is considered acceptable is unclear. We explored the relationship between folate concentration and degree of hemolysis. Heparin plasma samples (N=77, hemolysis index ≤10 µmol/L) were spiked with increasing amounts of corresponding patient-specific hemolysate. Subsequently, the folate concentration and hemolysis index were measured using two Roche Cobas platforms, and their incremental relationship was investigated. The folate concentration ranged from 2.9 to 30.9 nmol/L with a median (interquartile range) of 11.4 (8.6-19.1) nmol/L. The linear relationship between the increments in folate concentration and hemolysis index was approximated by the function y=1.86x+1.56 (R2=0.996), where x represents the laboratory-specific critical difference in folate concentration, which can be calculated from the analytical variation of the employed folate assay(s), and y represents the hemolysis threshold. The hemolysis threshold did not significantly differ between the tertiles of plasma folate concentration (P=0.10). In conclusion, we have provided an evidence-based approach that can be used to reliably interpret folate concentrations in hemolytic samples, independent of the patient's folate status.

Folate reference interval estimation in the Dutch general population.

BACKGROUND: Folate functions as an enzyme co-factor within the one-carbon metabolic pathway, providing key metabolites required for DNA synthesis and methylation. Hence, insufficient intake of folate can negatively affect health. As correct interpretation of folate status is dependent on a well-established reference interval, we set out to perform a new estimation following the restandardization of the Roche folate assay against the international folate standard. MATERIALS AND METHODS: The folate reference interval was estimated using samples obtained from the Dutch population-based Lifelines cohort. The reference interval was estimated using two methods: a nonparametric estimation combined with bootstrap resampling and by fitting the data to a gamma distribution. The lower reference limit was verified in a patient cohort by combined measurement of folate and homocysteine. RESULTS: Dependent on the method used for estimation and in- or exclusion of individuals younger than 21 years of age, the lower reference limit ranged from 6.8 to 7.3 nmol/L and the upper reference limit ranged from 26 to 38.5 nmol/L. Applying a lower reference limit of 7.3 nmol/L resulted in the following percentage of folate deficiencies over a period of 12 months: general practitioner 15.5% (IQR 4.0%), general hospital 12.8% (IQR 5.3%), academic hospital 9.6% (IQR 4.3%). CONCLUSIONS: We estimated the folate reference interval in the Dutch general population which is not affected by a folic acid fortification program and verified the obtained lower reference limit by homocysteine measurements. Based on our results, we propose a folate reference interval independent of age of 7.3-38.5 nmol/L.

A multi-site coronary sampling study on CRP in non-STEMI: Novel insights into the inflammatory process in acute coronary syndromes.

BACKGROUND AND AIMS: Inflammation has become a key element in cardiovascular disease, and recently, new anti-inflammatory interventions have shown promising results. In this context, CRP levels have been thoroughly studied in vitro and in animals, but studies in humans are scarce and insights into its release, site(s) of production and uptake are not uniform. METHODS: We performed a biomarker study with multi-site sampling in the coronary circulation, in non-ST elevation MI (NSTEMI) patients with coronary angiography and right-sided catheterisation. Trans-lesional gradients were obtained by sampling distal to the culprit lesion, in patients with a suitable anatomy. To asses trans-cardiac gradients, blood was sampled from the systemic circulation, coronary sinus (CS) and great cardiac vein. Concentrations of CRP were measured with a high-sensitivity assay. RESULTS: In 42 patients, a median systemic venous CRP concentration of 4.97 mg/L was observed. There was no evidence of a trans-lesional gradient (4.59 mg/L versus 4.56 mg/L, p = 0.278; n = 14). A significant decrease in CRP concentration was observed between systemic arterial and CS samples (4.88 mg/L versus 4.44 mg/L; p < 0.001; n = 42). This trans-cardiac gradient was irrespective of time of presentation, infarct size and culprit lesion location. The gradient was not only driven by blood that ran through the injured myocardium, but also by lower CRP concentrations in the coronary veins that drain non-infarcted myocardium. CONCLUSIONS: In the context of NSTEMI, we observed a trans-cardiac decrease in CRP, which may indicate the first human in vivo proof of a net CRP uptake by the myocardium, with a role for CRP both in the injured and adjacent myocardium.

Predictive value of specific IgE for clinical peanut allergy in children: relationship with eczema, asthma, and setting (primary or secondary care).

The usefulness of peanut specific IgE levels for diagnosing peanut allergy has not been studied in primary and secondary care where most cases of suspected peanut allergy are being evaluated. We aimed to determine the relationship between peanut-specific IgE levels and clinical peanut allergy in peanut-sensitized children and how this was influenced by eczema, asthma and clinical setting (primary or secondary care). We enrolled 280 children (0-18 years) who tested positive for peanut-specific IgE (> 0.35 kU/L) requested by primary and secondary physicians. We used predefined criteria to classify participants into three groups: peanut allergy, no peanut allergy, or possible peanut allergy, based on responses to a validated questionnaire, a detailed food history, and results of oral food challenges.Fifty-two participants (18.6%) were classified as peanut allergy, 190 (67.9%) as no peanut allergy, and 38 (13.6%) as possible peanut allergy. The association between peanut-specific IgE levels and peanut allergy was significant but weak (OR 1.46 for a 10.0 kU/L increase in peanut-specific IgE, 95% CI 1.28-1.67). Eczema was the strongest risk factor for peanut allergy (aOR 3.33, 95% CI 1.07-10.35), adjusted for demographic and clinical characteristics. Asthma was not significantly related to peanut allergy (aOR 1.93, 95% CI 0.90-4.13). Peanut allergy was less likely in primary than in secondary care participants (OR 0.46, 95% CI 0.25-0.86), at all levels of peanut-specific IgE.The relationship between peanut-specific IgE and peanut allergy in children is weak, is strongly dependent on eczema, and is weaker in primary compared to secondary care. This limits the usefulness of peanut-specific IgE levels in the diagnosis of peanut allergy in children.

Sensitization patterns to food and inhalant allergens in childhood: a comparison of non-sensitized, monosensitized, and polysensitized children.

The clinical interpretation of children sensitized to numerous allergens is challenging. We examined differences between children sensitized to zero, one, or more allergens. This was a retrospective analysis of all specific IgE tests in children 0-18 yrs of age sent to our laboratory by general practitioners and hospital-based specialists for allergy testing between 1990 and 2003. Of all 9044 children tested, 5439 (60.1%) were not sensitized to any of the aeroallergens or food allergens tested. Three thousand six hundred and five children (39.9%) had one or more positive specific IgE tests, 1120 of which (31.1%) were monosensitized (73% to aeroallergens and 27% to food allergens), 1709 (47.4%) were sensitized to two to four allergens, and 776 (21.5%) to five or more allergens (polysensitization). Polysensitization was more common in children 4-11 yrs of age (24.8%) than in younger (18.7%) or older children (18.3%, p < 0.001), and more common in boys (9.8%) than in girls (7.3%, p < 0.001). Median total IgE values increased with increasing number of positive specific IgE tests (p < 0.001). House dust mite more commonly showed monosensitization (22.2%) than other aeroallergens (grass pollen 10.5%, tree pollen 3.6%, cat 2.9%, and dog 1.5%); cow's milk (27.6%) more commonly than other food allergens (hen's egg 9.7%, peanut 4.6%, wheat 0.8%, soy 0.7%). Between 55.7% (cow's milk) and 87.9% (soy) of children sensitized to food were cosensitized to aeroallergens, while only 25.4% (house dust mite) to 39.5% (dog) of children sensitized to aeroallergens were cosensitized to food. Polysensitization is common in children, in particular in boys. It is most common in school-aged children. The strong association with total serum IgE values and the striking cosensitization between biologically unrelated allergens suggest that polysensitization is the expression of a distinct clinical, more severe, atopic phenotype, and not of biologic cross-reactivity to similar allergens.

Genetic loci influencing kidney function and chronic kidney disease.

Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.

High prevalence of sensitization to aeroallergens in children 4 yrs of age or younger with symptoms of allergic disease.

The assumption that sensitization to aeroallergens is rare in preschool children is based on population studies in which most subjects have little or no symptoms of atopic disease. We assessed the prevalence of atopic sensitization in children 0 to 4 yr of age presenting with symptoms of allergic disease by reviewing results of all specific immunoglobulin (IgE) tests performed in our hospital laboratory in children 4 yr of age or younger between 1985 and 2003. Tests were ordered by general practitioners or hospital-based pediatricians in children presenting with symptoms of allergic disease. Specific IgE tests to a panel of common food and inhalant allergens were performed in 2946 children; a specific IgE concentration >0.35 kU/l was considered positive. Overall, 505 (17%) tests were positive to aeroallergens: 346 (12%) for house dust mite, 257 (9%) for dog dander, 240 (8%) for cat dander, and 197 (7%) for grass pollen. Positive tests were more common in boys (19.2%) than in girls (14.2%, p < 0.01), irrespective of age. Although sensitization to food allergens was more common in 0-<3 yr olds, aeroallergen and food allergen showed comparable prevalence rates in 3-<5 yr olds. Sensitization to aeroallergens is common in preschool children with symptoms of allergic disease, and more common in boys than in girls. Screening tests for allergy in infants and toddlers should include inhalant allergens.

The predictive value of cumulative lactate dehydrogenase release within the first 72 h of acute myocardial infarction in patients treated with primary angioplasty.

BACKGROUND: In patients with acute myocardial infarction, estimation of infarct size by cumulative lactate dehydrogenase release at 72 h (LDHQ(72)) is a simple and widely used method. Our objective was to study the value of estimating infarct size, by the cumulative release of LDH over 72, 60, 48 and 36 h in predicting left ventricular ejection fraction (LV(ef)) and cardiac death at 1 year. METHODS: In the Zwolle Infarction Study infarct size estimated as LDHQ was calculated in 1224 patients treated with primary percutaneous coronary intervention for acute myocardial infarction between December 1993 and June 2001. Patients were categorized as having small (LDHQ(72)<800 U/L), medium (LDHQ(72) 800-2500 U/L) or large (LDHQ(72)>2500 U/L) myocardial infarction. RESULTS: LDHQ(72) was closely correlated with LDHQ(60), LDHQ(48) and LDHQ(36) (r = 0.998, 0.993 and 0.987, respectively, P <0.0001). The relations between LDHQ infarct size classification and mean LV(ef) (51% vs 45% vs 35%, P <0.001) or cardiac death at 1 year (0-0.3% vs 0.7-1% vs 6-8%) showed a similar pattern, irrespective of whether LDH was measured up to 36, 48, 60 or 72 h. CONCLUSION: Infarct size classification based on LDHQ(36) is an objective and widely available method for early risk stratification in patients treated with primary angioplasty for acute ST-segment elevation myocardial infarction.

Sex-related hearing impairment in Wolfram syndrome patients identified by inactivating WFS1 mutations.

This study examined the audiovestibular profile of 11 Wolfram syndrome patients (4 males, 7 females) from 7 families, with identified WFS1 mutations, and the audiometric profile of 17 related heterozygous carriers of WFS1 mutations. Patients with Wolfram syndrome showed a downsloping audiogram and progressive hearing impairment. None of the carriers had sensorineural hearing loss. Two patients with missense (non-inactivating) mutations in WFS1 had normal hearing and mild symptoms of Wolfram syndrome and were excluded from the analyses. Of the identified patients with inactivating WFS1 mutations, 5 female patients were significantly more hearing impaired than four male patients (p < 0.05). Female patients showed hearing impairment progressing by 1.5-2.0 dB HL per year for the low frequencies and 4.0-4.5 dB HL per year for the mid and high frequencies. The age of onset (90% phoneme recognition score) was 21 years and the onset level 78 dB HL. The deterioration rate was 4.0% per year and the deterioration gradient 1.4% per dB HL. One of the 6 examined patients had vestibular areflexia.

Molecular characterization of WFS1 in patients with Wolfram syndrome.

Wolfram (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is a rare autosomal-recessive neurodegenerative disorder that is characterized by juvenile-onset diabetes mellitus, optic atrophy, diabetes insipidus, and sensorineural hearing impairment. A gene responsible for Wolfram syndrome (WFS1) has been identified on the short arm of chromosome 4 and subsequently mutations in WFS1 have been described. We have screened 12 patients with Wolfram syndrome from nine Dutch families for mutations in the WFS1-coding region by single-strand conformation polymorphism analysis and direct sequencing. Furthermore, we analyzed the mitochondrial genome for gross abnormalities and the A3243G point mutation in the leucyl-tRNA gene, because Wolfram syndrome shows phenotypic similarities with mitochondrial disease. Seven mutations in WFS1 were identified in six of nine families: two missense mutations, one frameshift mutation, one splice donor site mutation, and three deletions. In addition, a splice variant near the 5'UTR of WFS1 was identified, present in patient as well as control RNA samples in various percentages, alternating the translation initiation consensus sequence. Whether this WFS1 splice variant displays impaired translation efficiency remains to be determined. No MtDNA lesions were identified in any of the Wolfram patients. Our results demonstrate the usefulness of molecular analysis of WFS1 in the refinement of clinical diagnostic criteria for Wolfram syndrome that helps to dissect the clinically overlapping syndromes sharing diabetes mellitus and optic atrophy.