Eosinophil-derived neurotoxin levels in early childhood and association with preschool asthma – A prospective observational study

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Reference values of serum total IgE in Uppsala – comparison over four decades

Background: Total immunoglobulin E (IgE) analysis is a common tool in allergy diagnosis. Suggested reference values for IgE are divergent and sometimes based on outdated assay methods. We aimed to validate the published reference values (geometric mean [GM]: 13.2 kU/L, upper limit of normal [ULN], 114 kU/L) shown in an Uppsala cohort from 1974 using Phadebas IgE PRIST, and the suggested clinical threshold of 100 kU/L (Zetterström and Johansson 1981). Methods: Immunoglobulin E was measured in two Uppsala cohorts from 1997 (Blood bank) and 2011 to 2013 (the European community respiratory health survey part III [ECRHS III]) using ImmunoCAP™ Total IgE. For the reference value calculations, exclusion criteria were atopy (both cohorts), doctor’s diagnosis of asthma and self-reported allergy (hay fever, rhinitis, rash) (only ECRHS III). Upper limit of normal was defined as mean + 2 standard deviations (SD) calculated using log-transformed values and back-transformation of the ULN prior to presentation. Common imputation methods for results below the assay range were evaluated. Results: The average GM was 14.2 kU/L (Blood bank, n = 63; imputation method range: 16.9–17.4 kU/L; ECRHS III, n = 113: 10.7–11.6 kU/L) and the overall mean ULN was 118 kU/L (Blood bank: 113–130 kU/L; ECRHS III: 104–128 kU/L). The clinical sensitivity and specificity of the 100 kU/L IgE threshold were 37.8 and 94.3% for atopy, 34.9 and 89.5% for doctor’s diagnosis of asthma, and 24.5 and 97.3% for any self-reported allergy (ECRHS III). Conclusion: The calculated ULN values were similar between the cohorts. We conclude that the total IgE reference values shown for Uppsala subjects from 1974 are still valid and suitable also for the ImmunoCAP Total IgE assay. The 100 kU/L threshold for total IgE had a low sensitivity but high specificity for atopy, asthma, and allergy

Measurement of Serum IgG Anti-Integrin alpha v beta 6 Autoantibodies Is a Promising Tool in the Diagnosis of Ulcerative Colitis

IgG anti-integrin alpha v beta 6 autoantibodies (IgG anti-alpha v beta 6) have been described as highly sensitive and specific markers of ulcerative colitis (UC) in the sera of Japanese inflammatory bowel disease (IBD) patients. We aimed to evaluate the diagnostic performance of IgG anti-alpha v beta 6 as a biomarker in Swedish patients with IBD or irritable bowel syndrome (IBS). The study included adult UC (n = 59), Crohn's disease (CD, n = 38), and IBS patients (n = 100). Partial Mayo score and Harvey-Bradshaw index were used to assess disease severity for UC and CD, respectively. Serum levels of IgG anti-alpha v beta 6, reported as absorbance units (AU), were measured using an in-house ELISA where the 95th percentile of 76 healthy controls defined positivity. Faecal calprotectin (fCP) was measured using a commercial assay. The majority of the IBD patients were on medical treatment, and many were in remission (UC: 40.7%; CD: 47.4%). Seventy-one percent of the UC patients, 74.2% of CD patients, and 23.1% of the IBS patients had fCP test results >50 mg/kg. The UC group had significantly higher IgG anti-alpha v beta 6 levels (median: 1.76 AU) than the CD and IBS groups (0.34 and 0.31 AU, both p < 0.0001). The diagnostic sensitivity of IgG anti-alpha v beta 6 in UC was 76.3%, and the specificities were 79.0% (vs. CD) and 96.0% (vs. IBS). The IgG anti-alpha v beta 6 levels related to disease severity of the UC patients (p < 0.01-0.05). Our study shows that IgG anti-alpha v beta 6 is associated with UC in Swedish IBD patients and that the levels of the autoantibodies reflect disease severity. IgG anti-alpha v beta 6 could be an attractive complement to fCP in the diagnostic work up of IBD patients

Importance of type and degree of IgE sensitisation for defining fractional exhaled nitric oxide reference values

Background Fractional exhaled nitric oxide (FENO) is a marker of type 2 airway inflammation used in clinical practice in asthma. However, reference values are needed to broaden the clinical use of FENO and this is within the scope of a newly started Global Lung Function Initiative task force. We aim to study FENO levels with special emphasis on the upper limit of normal (ULN) in relation to the type and degree of IgE sensitisation. Methods FENO was measured in 1855 non-smoking, respiratory healthy subjects from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Atopic subjects (n = 424), defined as being IgE-sensitised to aeroallergens (ImmunoCAP Phadiatop™, ≥0.35 PAU/l) were compared to non-atopic subjects (<0.35 PAU/l, n = 1431). Atopic subjects were further characterised according to their grade of IgE sensitisation (IgE antibody tertiles: (T1<1.16, T2 1.16–3.72 and T3 >3.72 PAU/l) and sensitisation to perennial (cat or mite) or seasonal (birch) allergens. Results Subjects IgE-sensitised to cat or mite had higher FENO compared to non-atopic subjects (FENO (ppb): median 20.0 vs. 15.0, and ULN 50.4 vs. 33.0, p < 0.001). This was seen to a lesser extent for subjects IgE-sensitised to birch only (median 18.0 vs. 15.0, and ULN 38.0 vs. 33.0, p = 0.048). Atopic subjects with a high degree of IgE sensitisation (Phadiatop: >3.72 PAU/l) had the highest FENO compared to non-atopic subjects (median 20.0 vs. 15.0, and ULN 56.0 vs. 33.0, p < 0.001). Conclusions The type and degree of IgE sensitisation should be considered in generating FENO reference values

The usefulness of casein-specific IgE and IgG4 antibodies in cow's milk allergic children

Abstract Background Cow's milk allergy is one of the most common food allergies among younger children. We investigated IgE antibodies to milk, and IgE and IgG4 antibodies to casein, α-lactalbumin and β-lactoglobulin in cow's milk allergic (CMA) and non-allergic (non-CMA) children in order to study their clinical usefulness. Methods Eighty-three children with suspected milk allergy (median age: 3.5 years, range: 0.8-15.8 years) were diagnosed as CMA (n = 61) or non-CMA (n = 22) based on an open milk challenge or convincing clinical history. Their serum concentrations of allergen-specific (s) IgE and IgG4 antibodies were measured using ImmunoCAP®. For the sIgG4 analysis, 28 atopic and 31 non-atopic control children were additionally included (all non-milk sensitized). Results The CMA group had significantly higher levels of milk-, casein- and β-lactoglobulin-sIgE antibodies as compared to the non-CMA group. The casein test showed the best discriminating performance with a clinical decision point of 6.6 kUA/L corresponding to 100% specificity. All but one of the CMA children aged > 5 years had casein-sIgE levels > 6.6 kUA/L. The non-CMA group had significantly higher sIgG4 levels against all three milk allergens compared to the CMA group. This was most pronounced for casein-sIgG4 in non-CMA children without history of previous milk allergy. These children had significantly higher casein-sIgG4 levels compared to any other group, including the non-milk sensitized control children. Conclusions High levels of casein-sIgE antibodies are strongly associated with milk allergy in children and might be associated with prolonged allergy. Elevated casein-sIgG4 levels in milk-sensitized individuals on normal diet indicate a modified Th2 response. However, the protective role of IgG4 antibodies in milk allergy is unclear.</p

Tryptase reference values in a Swedish middle-aged general population and association with diabetes mellitus

International audienc

Allergic sensitisation and type-2 inflammation is associated with new-onset and persistent allergic disease

Background: Allergic disease is common. The aim of this study was to look at the change in asthma and rhinitis over time and to characterise factors contributing to remission and persistence of disease. Methods: This cohort study included 255 individuals with or without asthma and or rhinitis that participated in a population survey and a follow-up 10 years later. The participants were tested for allergic sensitisation, total IgE, multiplex allergen component analysis and type-2 inflammatory markers: exhaled nitric oxide (FENO), eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN). Results: Of the 132 healthy individuals, 112 remained healthy, 16 developed rhinitis, 4 asthma and rhinitis over the 10 years. Out of 82 subjects with rhinitis, 26 went into remission, 53 remained unchanged and 3 developed asthma in addition to rhinitis. None of the 41 participants with asthma and rhinitis went into remission. Subjects with persistent rhinitis and asthma had higher levels of total IgE (odds ratio [OR] 95% confidence interval [CI]: 6.16 [3.05-12.5]) at baseline and after 10 years, and FENO and ECP at baseline (OR per log unit increase, 95% CI 5.21 [1.20-22.7] and 6.32 [1.52-26.4], respectively), compared with those that remained healthy. Subjects with persistent rhinitis were more likely to be sensitised to grass pollen and had higher total IgE levels than those that went into remission. Individuals with persistent asthma were more likely to be sensitised to tree pollen and furry animals than those with only persistent rhinitis (OR 95% CI: 3.50 [1.29-9.49] and 6.73 [2.00-22.6], respectively). Conclusion: IgE sensitisation and total IgE levels are associated with the persistence of rhinitis and asthma. Participants with persistent allergic disease had higher levels of allergen sensitisation and type 2 inflammation markers at baseline than those who remained healthy

Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

Abstract WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures