Long-term changes in milk component immunoglobulins reflect milk oral immunotherapy outcomes in Finnish children.

BACKGROUND: Milk oral immunotherapy (OIT) may increase the amount of milk protein that can be ingested without triggering an allergic reaction. It is important to understand why some patients benefit from the treatment while others do not. OBJECTIVE: The aim was to define the differences in the milk allergen component-specific (casein, α-lactalbumin, ß-lactoglobulin) immunoglobulin (sIg [sIgE, sIgG4, and sIgA]) levels relative to the long-term outcomes of milk OIT. METHODS: In this long-term, open-label follow-up study, 286 children started milk OIT between 2005 and 2015. Follow-up data were collected at two points: the post-buildup phase and long term (range 1-11 years, median 6 years). Comparisons of sIg levels were made among three outcome groups of self-reported long-term milk consumption (high-milk dose, low-milk dose, and avoidance). RESULTS: A total of 168 (59%) of the 286 patients on OIT participated. Most patients (57%) were in the high-dose group; here, 80% of these patients had a baseline casein sIgE value less than 28 kUA/L, they had the lowest casein sIgE levels at all time (p < .001), their casein sIgG4/IgE levels increased, and long-term casein sIgA was highest compared with the low-dose and avoidance groups (p = .02). Low-milk dose group had the highest casein sIgG4/IgE levels in long term (p = .002). CONCLUSION: The baseline Ig profiles and responses to milk OIT differed depending on long-term milk consumption. Lower casein sIgE levels were associated with better outcome. Milk casein sIgA differed in the long term among high-milk consumers.

Immunogenicity and safety of an investigational quadrivalent meningococcal conjugate vaccine administered as a booster dose in children vaccinated against meningococcal disease 3 years earlier as toddlers: A Phase III, open-label, multi-center study.

Booster doses of meningococcal conjugate vaccines induce long-term protection against invasive meningococcal disease. We evaluated the immunogenicity and safety of a booster dose of MenACYW-TT in pre-school children who were primed 3 years earlier with MenACYW-TT or MCV4-TT (Nimenrix®). In this Phase III, open-label, multi-center study (NCT03476135), children (4-5 years old), who received a primary dose of MenACYW-TT or MCV4-TT as toddlers in a previous study, received a booster dose of MenACYW-TT. Titers of antibody against meningococcal serogroups A, C, W and Y were measured by serum bactericidal assay using human (hSBA) and baby rabbit (rSBA) complement in samples collected before (D0) and 30 days after (D30) booster vaccination. Safety was assessed over the 30-day study period. Ninety-one participants received the booster dose. In both study groups, hSBA titers increased from D0 to D30; serogroup C titers [95% confidence interval] were higher in the MenACYW-TT-primed vs MCV4-TT-primed group at D0 (106 [73.2, 153] vs 11.7 [7.03, 19.4], respectively) and D30 (5894 [4325, 8031] vs 1592 [1165, 2174], respectively); rSBA results were similar. Nearly all participants achieved ≥1:8 hSBA and rSBA titers at D30, which were higher or comparable to those observed post-primary dose, suggesting rapid booster responses. At D0, all hSBA and rSBA titers were higher than those observed pre-primary dose, suggesting persistence of immunogenicity. The MenACYW-TT booster dose was well-tolerated and had similar safety outcomes across study groups. These findings suggest that MenACYW-TT elicits robust booster responses in children primed 3 years earlier with MenACYW-TT or MCV4-TT.

Immunogenicity and safety of different schedules of the meningococcal ABCWY vaccine, with assessment of long-term antibody persistence and booster responses - results from two phase 2b randomized trials in adolescents.

The meningococcal serogroup B (MenB) protein vaccine, 4CMenB, combined with MenA, MenC, MenW and MenY polysaccharide-protein conjugates for a pentavalent MenABCWY vaccine, can potentially protect against most causative agents of invasive meningococcal disease worldwide. Two phase 2b, randomized, multicenter studies were conducted (NCT02212457, NCT02946385) to assess the immunogenicity and safety of the MenABCWY vaccine as well as antibody persistence and response to a booster dose 2 years after the last vaccination, compared to 4CMenB vaccination. Participants (10 - 18 years), randomized (3:3:2:2:2:2), received the 4-component 4CMenB vaccine according to a 0-2 month (M) schedule or MenABCWY according to a 0-2, 0-6, 0-2-6, 0-1, or 0-11 M schedule. All participants received 5 injections (at M0, M1, M2, M6 and M12) with either the study vaccines or placebo/hepatitis A vaccine. Follow-on participants (4CMenB-0-2, MenABCWY-0-2, MenABCWY-0-6 and MenABCWY-0-2-6 groups) received one dose of either 4CMenB (4CMenB-0-2 group) or MenABCWY and newly enrolled, age-matched, meningococcal vaccine-naïve adolescents (randomized 1:1) received 2 doses (0-2 M) of either 4CMenB or MenABCWY. MenABCWY vaccination was immunogenic against MenB test strains. Non-inferiority for all 4 components of the 4CMenB vaccine could not be demonstrated for the 0-2 M schedule. Antibodies persisted up to 2 years post-MenABCWY vaccination and a booster dose induced an anamnestic response as higher titers were observed in follow-on participants compared to the first-dose response in vaccine-naïve participants. MenABCWY had a clinically-acceptable safety profile, not different from that of 4CMenB.

Reduced expiratory variability index (EVI) is associated with controller medication withdrawal and symptoms in wheezy children aged 1-5 years.

BACKGROUND: Lung function testing is an essential part of diagnostic workup and monitoring of asthma, but young children are lacking easy, routine testing methods. However, recent discoveries show reduced tidal breathing variability measured using impedance pneumography (IP) at home during sleep as a sign of airway obstruction. In this study, we assessed (a) the discriminative capacity of expiratory variability index (EVI) between healthy controls and young children with recurrent wheeze on-and-off controller medication, (b) association between EVI and parentally perceived obstructive symptoms (need for bronchodilator) and (c) measurement success rate. METHODS: We included 68 patients (aged 1.0-5.6) and 40 healthy controls (aged 1.0-5.9 years). The patients were prescribed a three-month inhaled corticosteroid (ICS) treatment due to recurrent obstructive bronchitis. We measured EVI using IP at home at the end of the treatment (0W) and 2 (2W) and 4 (4W) weeks after ICS withdrawal. RESULTS: EVI was higher in controls than in patients, and significant within-patient reduction occurred at 4W as compared to 2W or 0W. Area under curve of the ROC curve (controls vs all patients) at 4W was 0.78 (95% CI 0.70-0.85). Children who were administered bronchodilator by parental decision had lower EVI than those without bronchodilator need at 4W, but not at 0W or 2W. Patients with parent-reported airway infection, but no bronchodilator need, had normal EVI. Measurement success rate was 94%. CONCLUSION: EVI was lower in patients than in controls and it reduced further after controller medication withdrawal, especially in the presence of parentally perceived wheeze symptoms. This technique shows a significant potential for routine lung function testing of wheezy young children.

Noninvasive Cardiorespiratory Signals Analysis for Asthma Evolution Monitoring in Preschool Children.

OBJECTIVE: Despite its increasing prevalence, diagnosis of asthma in children remains problematic due to their difficulties in producing repeatable spirometric maneuvers. Moreover, low adherence to inhaled corticosteroids (ICS) treatment could result in permanent airway remodeling. The growing interest in a noninvasive and objective way for monitoring asthma, together with the apparent role of autonomic nervous system (ANS) in its pathogenesis, have attracted interest towards heart rate variability (HRV) and cardiorespiratory coupling (CRC) analyses. METHODS: HRV and CRC were analyzed in 68 children who were prescribed ICS treatment due to recurrent obstructive bronchitis. They underwent three different electrocardiogram and respiratory signals recordings, during and after treatment period. After treatment completion, they were followed up during 6 months and classified attending to their current asthma status. RESULTS: Vagal activity, as measured from HRV, and CRC, were reduced after treatment in those children at lower risk of asthma, whereas it kept unchanged in those with a worse prognosis. CONCLUSION: Results suggest that HRV analysis could be useful for the continuous monitoring of ANS anomalies present in asthma, thus contributing to evaluate the evolution of the disease, which is especially challenging in young children. SIGNIFICANCE: Noninvasive ANS assessment using HRV analysis could be useful in the continuous monitoring of asthma in children.

Tidal breathing flow profiles during sleep in wheezing children measured by impedance pneumography.

For the first time, impedance pneumography (IP) enables a continuous analysis of the tidal breathing flow volume (TBFV), overnight. We studied how corticosteroid inhalation treatments, sleep stage, and time from sleep onset modify the nocturnal TBFV profiles of children. Seventy children, 1-5 years old and with recurrent wheezing, underwent three, full-night TBFVs recordings at home, using IP. The first recorded one week before ending a 3-months inhaled corticosteroids treatment, and remaining two, 2 and 4 weeks after treatment. TBFV profiles were grouped by hour from sleep onset and estimated sleep stage. Compared with on-medication, the off-medication profiles showed lower volume at exhalation peak flow, earlier interruption of expiration, and less convex middle expiration. The differences in the first two features were significant during non-rapid eye movement (NREM), and the differences in the third were more prominent during REM after 4 h of sleep. These combinations of TBFV features, sleep phase, and sleep time potentially indicate airflow limitation in young children.

Exposure to sewage water and the development of allergic manifestations in Finnish children.

BACKGROUND: The hygiene hypothesis suggests that a decreased microbial load contributes to an increased risk of allergies. In the Finnish municipality of Nokia, sewage water was accidentally mixed with drinking water for 2 days. We studied the association between exposure and the emergence of allergies in children. METHODS: Children aged 2-5 years living in the accident area and an age-matched cohort from the control municipality were recruited. Based on the questionnaires, we identified 139 children exposed to the contaminated water and selected age- and sex-matched controls for them (mean age 16.59 months at the time of the accident). Allergic symptoms and diseases were recorded by ISAAC questionnaires and skin prick tests (SPTs) performed 2 and 5 years after the accident. RESULTS: SPT positivity at 5 years of follow-up was decreased in the children exposed to the sewage water below 1 year of age (OR 0.311, 95% CI 0.118-0.820; P = 0.019), particularly in children who did not develop gastroenteritis at exposure. In contrast, the children over 1 year of age at the exposure tended more likely to be SPT-positive at 5 years of follow-up (OR 1.997, 95% CI 0.963-4.143; P = 0.070). CONCLUSIONS: Sewage water exposure during the first year of life, but not later, decreased the risk of IgE sensitization emphasizing the importance of age as a modulator. The modulation of IgE sensitization by the presence of clinical gastroenteritis at the exposure suggests that the nature of microbial load may have importance or alternatively shared host defense mechanisms protect from infection and atopic sensitization.

Airway obstruction is associated with reduced variability in specific parts of the tidal breathing flow-volume curve in young children.

Impedance pneumography recordings during sleep at night show reduced variability in specific parts of the expiratory flow-volume curve in children with recurrent wheeze http://bit.ly/2Wkfap0.

Outcome of oral immunotherapy for persistent cow's milk allergy from 11 years of experience in Finland.

BACKGROUND: The safety and efficacy of long-term milk oral immunotherapy (OIT) in Finnish children with persistent cow's milk allergy (CMA) were evaluated in an open-label, non-randomized study. METHODS: During the 11-year study, 296 children aged 5 years or older with immunoglobulin E (IgE)-mediated CMA started milk OIT. Follow-up data were collected at three time points: the post-buildup phase, 1 year thereafter, and at the cross-sectional long-term follow-up between January 2016 and December 2017. Patients were divided according to baseline milk-specific IgE (sIgE) level and by the amount of milk consumption at the long-term follow-up. The high-dose group consumed ≥2 dL of milk daily, while the failure group consumed <2 dL of milk or were on a milk-avoidance diet. RESULTS: Out of the initial study group, 244/296 (83%) patients participated in the long-term follow-up. Among these patients, 136/244 (56%) consumed ≥2 dL of milk daily. The median follow-up time was 6.5 years. Of the recorded markers and clinical factors, the baseline milk sIgE level was most associated with maintaining milk OIT (P < 0.001). Respiratory symptoms in the post-buildup phase increased the risk of treatment failure (OR 3.5, 95% CI: 1.5-8.1, P = 0.003) and anaphylaxis (OR 14.3, 95% CI: 1.8-114, P = 0.01). CONCLUSION: More than half of the patients were able to maintain the targeted milk dose in their daily diet. Baseline milk sIgE level and reactivity during the early treatment stage strongly predicted the long-term outcome and safety of milk OIT.

Asthma and atopic dermatitis after early-, late-, and post-term birth.

OBJECTIVE: To assess the incidence and risk factors of asthma and atopic dermatitis by seven years of age after early-term (ET) (37+0 -38+6 weeks), full-term (FT) (39+0 -40+6 weeks), late-term (LT) (41+0 -41+6 weeks), and especially post-term (PT) (≥42 weeks) birth. METHODS: Altogether, 965 203 infants born between 1991 and 2008 in Finland were investigated in ET, FT, LT, and PT groups. Data on asthma medication reimbursement and hospital visits for atopic dermatitis were retrieved from national health databases. RESULTS: The frequencies of asthma medication reimbursement in the ET, FT, LT, and PT groups were 4.5%, 3.7%, 3.3%, and 3.2%, respectively. Hospital visits due to atopic dermatitis were most common after PT birth. Compared with FT births, ET births were associated with an increased risk of asthma (adjusted odds ratio (aOR), 95% confidence interval (CI) 1.20, 1.17-1.23), while LT (aOR, 95%CI 0.91, 0.89-0.93) births and PT (aOR, 95%CI 0.87, 0.83-0.92) births decreased this risk. PT birth (aOR, 95%CI 1.06, 1.01-1.10) predicted atopic dermatitis. From a population point of view, the most relevant risk factors for asthma were male sex, ET birth, smoking during pregnancy and birth by elective cesarean section, and for atopic dermatitis male sex, first delivery, birth in a level II hospital and birth by cesarean section. CONCLUSIONS: Early-term birth was a predictor of asthma, and PT birth was associated with atopic dermatitis. Counseling against smoking and following strict indications for planned ET deliveries and cesarean sections may be means to reduce the risk of later asthma.

Wheat oral immunotherapy was moderately successful but was associated with very frequent adverse events in children aged 6-18 years.

AIM: This study investigated oral immunotherapy (OIT) for children aged 6-18 years with wheat allergies. METHODS: Well-cooked wheat spaghetti was given to 100 children with wheat allergies every day for 17 weeks, increasing from 0.3 to 2000 mg of wheat protein, followed by three- and nine-month maintenance phases. Blood samples were taken before therapy and at follow-up visits. The study was carried out in 2009-2015 in four Finnish paediatric allergology units. RESULTS: The children (67% male) had a mean age of 11.6 years (range 6.1-18.6), and 57 were using wheat daily 16 months after the initiation of therapy. Allergic symptoms occurred in 94/100 children: mild in 34, moderate in 36 and severe in 24. Specific immunoglobulin E (IgE) for ω-5-gliadin was significantly higher in patients who did not reach the target dose and were related to the intensity of reactions. CONCLUSION: The majority (57%) of children with wheat allergies could use wheat in their daily diet 16 months after the initiation of OIT, but 94/100 had adverse reactions and 60 were moderate or severe. Specific IgE to ω-5-gliadin may provide a biomarker for how much wheat can be tolerated and the intensity of the reactions to immunotherapy.

Elevated serum adipsin may predict unsuccessful treatment for cows' milk allergy but other biomarkers do not.

AIM: This study evaluated whether 15 allergy, immunology or inflammatory markers predicted the long-term use of cows' milk or milk products seven years after the start of oral immunotherapy (OIT) for cows' milk allergy in children. METHODS: The following laboratory parameters were measured before the OIT at Tampere University Hospital, Finland, and after the six-month escalation phase: serum total immunoglobulin (Ig) E, milk-specific IgG and IgG4, eosinophil cationic protein, eosinophil-derived neurotoxin, interleukins 4, 5, 6, 10 and 12p70 and serum adipokines adiponectin, adipsin, leptin and resistin. Follow-up data from a seven-year phone questionnaire in 2015 were available for 24 children: 14 successful and 10 unsuccessful milk users. RESULTS: There were no significant differences in any of the 15 markers measured at the start of the study between the subjects who later formed the successful and unsuccessful groups. At the end of the six-month escalation phase of OIT, serum adipsin was higher in the group who were unsuccessful milk users at the seven-year follow-up study. CONCLUSION: None of the 15 allergy, immunology or inflammatory markers were useful in predicting the outcome of OIT. Preliminary evidence was found that high serum adipsin after the six-month escalation phase of OIT might predict unsuccessful outcome.

Changes in biomarkers during a six-month oral immunotherapy intervention for cow's milk allergy.

AIM: Oral immunotherapy (OIT) is a promising but still experimental method to treat children with cow's milk (CM) allergy (CMA). We evaluated changes in allergic, immunological and inflammatory parameters, which happened during the six-month OIT for CMA. METHODS: We treated 28 school-aged children with CMA using OIT with a double-blind placebo-controlled design. After the controlled study finished, the placebo group was treated with the same but open-label OIT protocol. Sixteen immune variables were tested before and after the six-month OIT. RESULTS: Before OIT, the median serum CM-specific immunoglobulin (Ig) E was 18.0kIU/L in the intervention group and 9.4kIU/L in the placebo group (p = 0.46). At six months, interleukin (IL)-6 and IL-10 were significantly higher in the intervention group. When the changes during the blinded and open OIT were analysed together for both groups, blood eosinophils and serum total IgE decreased and milk-specific IgG and IgG4, serum IL-4 and IL-6, and serum leptin and resistin increased significantly. CONCLUSION: Preliminary evidence was found that markers of allergy such as blood eosinophils and serum IgE decreased and milk-specific IgG and IgG4 increased during OIT. Adipokines, leptin and resistin, which functionally are cytokines linked to Th1-type response, increased during OIT.

Following up infant bronchiolitis patients provided new evidence for and against the united airway disease hypothesis.

AIM: The united airway disease (UAD) hypothesis suggests that allergic rhinitis and asthma develop together. We evaluated the evidence for and against the UAD hypothesis at five to seven years of age after hospitalisation for bronchiolitis at less than six months. METHODS: This study used prospective follow-up data for 102 children hospitalised for bronchiolitis under the age of six months. We included the presence of previous and current asthma, prolonged rhinitis and skin prick tests (SPT) to common inhaled allergens and lung function by impulse oscillometry (IOS) at five to seven years of age. Bronchial hyper-reactivity (BHR) was assessed using the exercise challenge test and bronchodilation test. RESULTS: Current asthma, but not previous transient asthma, was associated with prolonged rhinitis and a positive SPT. BHR, which reflected reactive airways, but not lung function, was associated with respiratory allergy, namely the combination of current asthma, prolonged rhinitis and a positive SPT. CONCLUSION: This post-bronchiolitis follow-up study suggested an association between respiratory allergy and reactive airways at five to seven years of age, which supported the UAD hypothesis. However, previous transient asthma and a reduction in lung function reduction did not support the hypothesis.

Asthma and atopic dermatitis in children born moderately and late preterm.

UNLABELLED: This national register study aimed to evaluate the need of asthma medication reimbursement and hospitalization due to asthma and atopic dermatitis up to 7 years of age in moderately preterm (MP) (32-33 weeks) and late preterm (LP) (34-36 weeks) children compared to very preterm (VP) (<32 weeks) and term (≥37 weeks) children. Altogether, 1,018,302 children born in Finland between 1991 and 2008 were assessed. The MP and LP groups received asthma medication reimbursement more frequently than term controls (8.0 and 5.7 vs. 3.8 %), but less frequently than VP children (15.4 %). Hospitalization due to asthma was more common among MP (10.6 %) and LP (7.3 %) children than term children (4.8 %) but less common than in VP children (20.1 %). Hospitalization due to atopic dermatitis was more frequent among term (5.2 %) compared to MP (4.2 %) and LP (4.7 %) children. Male sex, maternal smoking, maternal diabetes, and ventilator therapy predicted asthma medication in the MP and/or LP children. CONCLUSION: MP and LP children seem to need medication and hospitalization for asthma more often than term controls but less frequently than VP children followed by 7 years of age. Hospitalization due to atopic dermatitis becomes more common with increasing gestational age. WHAT IS KNOWN: • MP and LP infants have an increased risk for early respiratory morbidity and to asthma. • Less is known on the occurrence of atopic dermatitis in this patient group. What is New: • Medication and hospital care due to asthma were more frequent in school-aged MP and LP than in term infants. Male sex, maternal smoking, maternal diabetes and ventilator therapy predicted asthma. • Hospitalization due to atopic dermatitis became more common with increasing gestational age.

Children who were treated with oral immunotherapy for cows' milk allergy showed long-term desensitisation seven years later.

AIM: This was a follow-up of 28 schoolchildren with cows' milk allergy (CMA) who attended a randomised double-blind placebo-controlled oral immunotherapy (OIT) study. In the original study, 26 (92.9%) completed the six-month escalation phase, and 25 (89.3%) used milk daily at 12 months and 24 (85.7%) at 36 months. This study evaluated the outcome seven years later, with special attention paid to milk consumption and symptoms. METHODS: Outcome data were collected through a postal questionnaire completed three, four and five years after enrolment and by a phone questionnaire after seven years. We asked about the daily dose of milk products, any adverse reactions, any medication needed and possible discontinuation of daily milk consumption. RESULTS: Data were available at the seven-year point for 24 children and 14 (58.3%) of these continued to use milk (≥200 mL) or milk products (protein ≥6400 mg) daily for seven years. However, three (21.4%) of these still reported symptoms associated with milk consumption. Of the 10 remaining children, two children used milk products daily but consumed less due to symptoms and eight (33.3%) had discontinued milk consumption. CONCLUSION: Oral immunotherapy was an effective and safe way of desensitising schoolchildren with persistent CMA.

Half of the children who received oral immunotherapy for a cows' milk allergy consumed milk freely after 2.5 years.

AIM: Strict milk protein avoidance has been the standard therapy of cows' milk allergy (CMA) in children, but oral immunotherapy (OIT) seems to provide an alternative treatment. The aim of this study was to evaluate the impact of OIT on milk consumption during the first 2.5 years after a start of OIT. METHODS: This open-label, noncontrolled, real-life OIT study was conducted in 74 children with CMA, who were aged 5-15. It included a 6-month induction phase and a 2-year maintenance phase. Data on the complete 2.5-year trial were available for 57 children. RESULTS: Most of the children (82%) completed the 6-month induction phase and were able to consume at least 200 mL of milk or 6400 mg of milk protein a day. After the 2-year maintenance phase, half were consuming milk daily. Risk factors for OIT failure during the induction phase were asthma and high milk-specific immunoglobulin E, but a history of anaphylaxis before OIT was not. Allergies to eggs or wheat decreased the risk of immediate OIT failure. CONCLUSION: This study confirmed the efficacy of milk OIT in real life, including the whole spectrum of persistent CMA at school age, and revealed certain risk factors associated with OIT failure.

Obesity and bronchial obstruction in impulse oscillometry at age 5-7 years in a prospective post-bronchiolitis cohort.

BACKGROUND AND AIMS: Obesity has been linked with asthma symptoms, need for asthma treatment and reduced lung function but not with increased bronchial reactivity in children. The aim of this study was to evaluate the association between previous or current weight status and current lung function and bronchial reactivity to exercise at early school age. METHODS: Ninety-nine children hospitalized for bronchiolitis at the age of less than 6 months were studied with impulse oscillometry (IOS) at the mean age of 6.3 years. Data on birth weight and weight gain in infancy before hospitalization were collected during hospitalization. Current weight and height data were transformed into age- and sex-specific height-related body mass index z scores (zBMI) using the Finnish national population-based weight and height data as reference. RESULTS: Some significant though only low or modest correlations were found between current zBMI and baseline, post-exercise and post-bronchodilator IOS values in adjusted linear regression analysis. Seven obese children by zBMI had higher post-bronchodilator airway impedance (Zrs) and resistance (Rrs) at 5 Hz and lower post-bronchodilator frequency dependency of resistance (dRrs/df) than normal weight children. There were no significant differences in responses to exercise or to bronchodilators between currently obese or overweight children and normal weight children. Birth weight less than 3,000 g was associated with larger exercise-induced changes in Zrs and Rrs at 5 Hz, and in reactance (Xrs) at 5 Hz, than those with birth weight more than 3,000 g. CONCLUSIONS: Preliminary evidence was found that obesity may be associated with airway obstruction, but not with bronchial hyper-reactivity.