Publications by authors named "Mika J Mäkelä"

103 Publications

A Randomized, Open-Label Trial of Hen's Egg Oral Immunotherapy: Efficacy and Humoral Immune Responses in 50 Children.

J Allergy Clin Immunol Pract 2021 Jan 30. Epub 2021 Jan 30.

Skin and Allergy Hospital, Helsinki University Hospital, Meilahdentie 2, Helsinki, Finland; University of Helsinki, Helsinki, Finland.

Background: Egg allergy is the second most common food allergy in children. Persistent food allergy increases the risk of anaphylaxis and reduces the quality of life.

Objective: To determine the efficacy of oral immunotherapy (OIT) with raw egg white powder and study its effects on humoral responses in children with persistent egg allergy.

Methods: Fifty children aged 6 to 17 years with egg allergy, diagnosed by double-blind, placebo-controlled food challenge, were randomized 3:2 to 8 months of OIT with a maintenance dose of 1 g of egg white protein or 6 months of avoidance after which the avoidance group crossed over to OIT. We examined changes in IgE, IgG, and IgA concentrations to Gal d 1-4 during OIT compared with avoidance and assessed clinical reactivity at 8 and 18 months.

Results: After 8 months, 22 of 50 children (44%) on OIT and 1 of 21 (4.8%) on egg avoidance were desensitized to the target dose, 23 of 50 (46%) were partially desensitized (dose <1 g), and 5 of 50 (10%) discontinued. IgG concentrations to Gal d 1-4 and IgA to Gal d 1-2 increased significantly, whereas IgE to Gal d 2 decreased. A heatmap analysis of the IgE patterns revealed 3 distinct clusters linked with the clinical outcome. High baseline egg white-specific IgE and polysensitization to Gal d 1-4 related with failure to achieve the maintenance dose at 8 months. After 18 months of treatment, 36 of 50 patients (72%) were desensitized and 8 of 50 (16%) partially desensitized.

Conclusions: OIT with raw egg enables liberation of egg products into the daily diet in most patients. Subjects with high egg white-specific IgE concentrations and sensitization to multiple egg allergen components at baseline benefit from prolonged treatment.
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http://dx.doi.org/10.1016/j.jaip.2021.01.020DOI Listing
January 2021

Are Infants and Toddlers with Moderate-to-severe Atopic Dermatitis Undertreated? Experiences of a Finnish Tertiary Care Hospital.

Acta Derm Venereol 2021 Jan 5;101(1):adv00368. Epub 2021 Jan 5.

Department of Dermatology and Allergology, Helsinki University Hospital, FIN-00250 Helsinki, Finland.

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http://dx.doi.org/10.2340/00015555-3739DOI Listing
January 2021

Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways.

medRxiv 2020 Sep 2. Epub 2020 Sep 2.

The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.
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http://dx.doi.org/10.1101/2020.08.31.20169946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480059PMC
September 2020

Immune-microbiota interaction in Finnish and Russian Karelia young people with high and low allergy prevalence.

Clin Exp Allergy 2020 10 18;50(10):1148-1158. Epub 2020 Sep 18.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: After the Second World War, the population living in the Karelian region was strictly divided by the "iron curtain" between Finland and Russia. This resulted in different lifestyle, standard of living, and exposure to the environment. Allergic manifestations and sensitization to common allergens have been much more common on the Finnish compared to the Russian side.

Objective: The remarkable allergy disparity in the Finnish and Russian Karelia calls for immunological explanations.

Methods: Young people, aged 15-20 years, in the Finnish (n = 69) and Russian (n = 75) Karelia were studied. The impact of genetic variation on the phenotype was studied by a genome-wide association analysis. Differences in gene expression (transcriptome) were explored from the blood mononuclear cells (PBMC) and related to skin and nasal epithelium microbiota and sensitization.

Results: The genotype differences between the Finnish and Russian populations did not explain the allergy gap. The network of gene expression and skin and nasal microbiota was richer and more diverse in the Russian subjects. When the function of 261 differentially expressed genes was explored, innate immunity pathways were suppressed among Russians compared to Finns. Differences in the gene expression paralleled the microbiota disparity. High Acinetobacter abundance in Russians correlated with suppression of innate immune response. High-total IgE was associated with enhanced anti-viral response in the Finnish but not in the Russian subjects.

Conclusions And Clinical Relevance: Young populations living in the Finnish and Russian Karelia show marked differences in genome-wide gene expression and host contrasting skin and nasal epithelium microbiota. The rich gene-microbe network in Russians seems to result in a better-balanced innate immunity and associates with low allergy prevalence.
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http://dx.doi.org/10.1111/cea.13728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589450PMC
October 2020

Impact of COVID-19 on Pediatric Asthma: Practice Adjustments and Disease Burden.

J Allergy Clin Immunol Pract 2020 09 17;8(8):2592-2599.e3. Epub 2020 Jun 17.

Department of Pediatrics & Child Health, MRC Unit on Child & Adolescent Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa.

Background: It is unclear whether asthma may affect susceptibility or severity of coronavirus disease 2019 (COVID-19) in children and how pediatric asthma services worldwide have responded to the pandemic.

Objective: To describe the impact of the COVID-19 pandemic on pediatric asthma services and on disease burden in their patients.

Methods: An online survey was sent to members of the Pediatric Asthma in Real Life think tank and the World Allergy Organization Pediatric Asthma Committee. It included questions on service provision, disease burden, and the clinical course of confirmed cases of COVID-19 infection among children with asthma.

Results: Ninety-one respondents, caring for an estimated population of more than 133,000 children with asthma, completed the survey. COVID-19 significantly impacted pediatric asthma services: 39% ceased physical appointments, 47% stopped accepting new patients, and 75% limited patients' visits. Consultations were almost halved to a median of 20 (interquartile range, 10-25) patients per week. Virtual clinics and helplines were launched in most centers. Better than expected disease control was reported in 20% (10%-40%) of patients, whereas control was negatively affected in only 10% (7.5%-12.5%). Adherence also appeared to increase. Only 15 confirmed cases of COVID-19 were reported among the population; the estimated incidence is not apparently different from the reports of general pediatric cohorts.

Conclusions: Children with asthma do not appear to be disproportionately affected by COVID-19. Outcomes may even have improved, possibly through increased adherence and/or reduced exposures. Clinical services have rapidly responded to the pandemic by limiting and replacing physical appointments with virtual encounters.
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http://dx.doi.org/10.1016/j.jaip.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297686PMC
September 2020

For hazelnut allergy, component testing of Cor a 9 and Cor a 14 is relevant also in birch-endemic areas.

Allergy 2020 11 26;75(11):2977-2980. Epub 2020 Jul 26.

Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1111/all.14430DOI Listing
November 2020

Cut-off values to evaluate exercise-induced asthma in eucapnic voluntary hyperventilation test for children.

Clin Physiol Funct Imaging 2020 Sep 26;40(5):343-350. Epub 2020 Jun 26.

Department of Pediatrics and Adolescent Medicine, Turku University Hospital and University of Turku, Turku, Finland.

Background And Aim: The eucapnic voluntary hyperventilation (EVH) testing is a diagnostic tool for diagnostics of exercise-induced bronchoconstriction; while the testing has become more common among children, data on the test's feasibility among children remain limited. Our aim was to investigate EVH testing feasibility among children, diagnostic testing cut-off values, and which factors affect testing outcomes.

Methods: We recruited 134 patients aged 10-16 years with a history of exercise-induced dyspnoea and 100 healthy control children to undergo 6-min EVH testing. Testing feasibility was assessed by the children's ability to achieve ≥70% of the target minute ventilation of 30 times forced expiratory volume in 1 s (FEV1). Bronchoconstriction was assessed as a minimum of 8%, 10%, 12%, 15% or 20% fall in FEV1. Patient characteristics were correlated with EVH outcomes.

Results: Overall, 98% of the children reached ≥70%, 88% reached ≥80%, 79% reached ≥90% and 62% reached ≥100% of target ventilation in EVH testing; of children with a history of exercise-induced dyspnoea, the decline percentages were as follows: 24% (≥8% fall), 17% (≥10% fall), 10% (≥12% fall), 6% (≥15% fall) and 5% (≥20% fall) in FEV1, compared to 11%, 4%, 3%, 1% and 0% among the healthy controls, respectively. Healthy controls and boys performed testing at higher ventilation rates (p < .05).

Conclusion: Eucapnic voluntary hyperventilation testing is feasible among children aged 10-16 years and has diagnostic value in evaluating exercise-induced dyspnoea among children. A minimum 10% fall in FEV1 is a good diagnostic cut-off value. Disease status appears to be important covariates.
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http://dx.doi.org/10.1111/cpf.12647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496314PMC
September 2020

Airway hyperresponsiveness, remodeling and inflammation in infants with wheeze.

Clin Exp Allergy 2020 05 23;50(5):558-566. Epub 2020 Mar 23.

Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: The relationship of airway hyperresponsiveness to airway remodeling and inflammation in infants with wheeze is unclear.

Objective: To investigate airway hyperresponsiveness, remodeling and inflammation in infants with wheeze and troublesome breathing.

Methods: Inclusion criteria were as follows: full-term, 3-23 months of age; doctor -diagnosed wheeze and persistent recurrent troublesome breathing; without obvious structural defect, suspicion of ciliary dyskinesia, cystic fibrosis, immune deficiency or specified use of corticosteroids. Airway hyperresponsiveness (AHR) was evaluated by performing a methacholine bronchial challenge test combined with whole body plethysmography and rapid thoracoabdominal compression. Endobronchial biopsies were analysed for remodeling (thickness of reticular basement membrane and amount of airway smooth muscle) and for inflammation (numbers of inflammatory cells). Correlation analyses were performed.

Results: Forty-nine infants fulfilled the inclusion criteria for the present study. Median age was 1.06 years (IQR 0.6; 1.5). Lung function was impaired in 39/49 (80%) children, at the median age of 1.1 years. Methacholine challenge was successfully performed in 38/49 children. Impaired baseline lung function was correlated with AHR (P = .047, Spearman). In children with the most sensitive quartile of AHR, the percentage of median bronchial airway smooth muscle % and the number of bronchial mast cells in airway smooth muscle were not significantly higher compared to others (P = .057 and 0.056, respectively). No association was found between AHR and thickness of reticular basement membrane or inflammatory cells. Only a small group of children with both atopy and AHR (the most reactive quartile) had thicker airway smooth muscle area than non-atopics with AHR (P = .031).

Conclusions And Clinical Relevance: These findings do not support the concept that AHR in very young children with wheeze is determined by eosinophilic inflammation or clear-cut remodeling although it is associated with impaired baseline lung function. The possible association of increased airway smooth muscle area among atopic children with AHR remains to be confirmed.
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http://dx.doi.org/10.1111/cea.13598DOI Listing
May 2020

Research Priorities in Pediatric Asthma: Results of a Global Survey of Multiple Stakeholder Groups by the Pediatric Asthma in Real Life (PeARL) Think Tank.

J Allergy Clin Immunol Pract 2020 06 4;8(6):1953-1960.e9. Epub 2020 Mar 4.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom; Allergy Department, 2nd Paediatric Clinic, National and Kapodistrian University of Athens, Athens, Greece. Electronic address:

Background: Pediatric asthma remains a public health challenge with enormous impact worldwide.

Objective: The aim of this study was to identify and prioritize unmet clinical needs in pediatric asthma, which could be used to guide future research and policy activities.

Methods: We first identified unmet needs through an open-question survey administered to international experts in pediatric asthma who were members of the Pediatric Asthma in Real Life Think Tank. Prioritization of topics was then achieved through a second, extensive survey with global reach, of multiple stakeholders (leading experts, researchers, clinicians, patients, policy makers, and the pharmaceutical industry). Differences across responder groups were compared.

Results: A total of 57 unmet clinical need topics identified by international experts were prioritized by 412 participants from 5 continents and 60 countries. Prevention of disease progression and prediction of future risk, including persistence into adulthood, emerged as the most urgent research questions. Stratified care, based on biomarkers, clinical phenotypes, the children's age, and demographics were also highly rated. The identification of minimum diagnostic criteria in different age groups, cultural perceptions of asthma, and best treatment by age group were priorities for responders from low-middle-income countries. There was good agreement across different stakeholder groups in all domains with some notable exceptions that highlight the importance of involving the whole range of stakeholders in formulation of recommendations.

Conclusions: Different stakeholders agree in the majority of research and strategic (eg, prevention, personalized approach) priorities for pediatric asthma. Stakeholder diversity is crucial for highlighting divergent issues that future guidelines should consider.
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http://dx.doi.org/10.1016/j.jaip.2020.01.059DOI Listing
June 2020

Early bronchial inflammation and remodeling and airway hyperresponsiveness at school age.

Allergy 2020 07 11;75(7):1765-1768. Epub 2020 Feb 11.

Department of Allergy, Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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http://dx.doi.org/10.1111/all.14198DOI Listing
July 2020

Serum chitinase-like protein YKL-40 is linked to small airway function in children with asthmatic symptoms.

Pediatr Allergy Immunol 2019 12 2;30(8):803-809. Epub 2019 Oct 2.

Department of Allergology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Lung function impairment among asthmatic children begins in early life, and biomarkers for identifying this impairment are needed. The chitinase-like protein YKL-40 has been associated with asthma and lung function in adults, but studies in children have yielded conflicting results. We evaluated the potential of YKL-40 and other systemic biomarkers for identifying lung function deficits in children with asthmatic symptoms.

Methods: We determined the levels of serum YKL-40, periostin, and high-sensitivity C-reactive protein (hs-CRP) from the blood samples of 49 children with asthmatic symptoms. Lung function was assessed with impulse oscillometry (IOS) and spirometry, combined with an exercise challenge and a bronchodilator test. Fractional exhaled nitric oxide was measured at multiple flow rates.

Results: Serum levels of YKL-40 showed significant correlations with most IOS indices at baseline (P = .008-.039), but there was no association between YKL-40 and spirometry parameters. Neither periostin nor hs-CRP were associated with baseline lung function. Children with a significant response in either the exercise challenge or the bronchodilator test had increased serum levels of YKL-40 (P = .003) and periostin (P = .035). YKL-40 correlated significantly with the blood neutrophil count (r  = .397, P = .005) but was not associated with biomarkers of eosinophilic inflammation.

Conclusion: Serum YKL-40 is a potential biomarker for lung function deficits in children with asthmatic symptoms. These deficits appear to be focused on small airways and may remain undetected with spirometry.
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http://dx.doi.org/10.1111/pai.13119DOI Listing
December 2019

Young children with moderate-to-severe atopic dermatitis can be treated safely and effectively with either topical tacrolimus or mild corticosteroids.

Acta Paediatr 2020 03 7;109(3):550-556. Epub 2019 Oct 7.

University of Helsinki and Helsinki University Hospital, Skin and Allergy Hospital, Helsinki, Finland.

Aim: We collected evidence and safety data for topical tacrolimus in small children with atopic dermatitis (AD) and compared the usage with topical corticosteroid.

Methods: This was an interim analysis of 75 patients (55% female) at 1 year of an ongoing 3-year randomised open-label comparative follow-up study of topical tacrolimus vs corticosteroid treatment. One- to three-year-old children with moderate-to-severe eczema referred to the Skin and Allergy Hospital in Helsinki, Finland, were enrolled.

Results: Efficacy parameters, the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), transepidermal water loss (TEWL), eczema area, serum total immunoglobulin E (IgE) and the blood eosinophil count, showed improvement in both groups during the study. However, patients with signs of early sensitisation at baseline (elevated serum total IgE, elevated eosinophil count, positive prick tests or specific IgEs to aero or food allergens) had statistically significantly lower TEWL at the eczema site and a smaller eczema area at 12 months in the tacrolimus group. No severe adverse effects were seen during the treatment.

Conclusion: Children with AD and signs of early sensitisation appeared to benefit more from early tacrolimus than corticosteroid treatment. Small children may need stronger but nevertheless safe ointment options when treating moderate-to-severe AD.
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http://dx.doi.org/10.1111/apa.15001DOI Listing
March 2020

Children with wheat allergy usually tolerate oats.

Pediatr Allergy Immunol 2019 12 8;30(8):855-857. Epub 2019 Sep 8.

Skin and Allergy Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1111/pai.13112DOI Listing
December 2019

Genetic and environmental susceptibility to food allergy in a registry of twins.

J Allergy Clin Immunol Pract 2019 Nov - Dec;7(8):2916-2918. Epub 2019 May 24.

Division of Allergy and Clinical Immunology, Department of Pediatrics, McGill University, Montreal, QC, Canada.

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http://dx.doi.org/10.1016/j.jaip.2019.05.016DOI Listing
October 2020

Eliciting allergens and treatment of anaphylaxis: Report of the finnish national anaphylaxis registry.

Allergy 2019 10 9;74(10):2010-2013. Epub 2019 May 9.

Department of Dermatology, Allergology and Venereology, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1111/all.13858DOI Listing
October 2019

High-Dose Vitamin D Supplementation Does Not Prevent Allergic Sensitization of Infants.

J Pediatr 2019 06 20;209:139-145.e1. Epub 2019 Mar 20.

Helsinki University Hospital, Helsinki, Finland; Department of Allergy, University of Helsinki, Helsinki, Finland.

Objective: To investigate the effect of vitamin D supplementation dose on allergic sensitization and allergic diseases in infants, and to evaluate whether vitamin D status in pregnancy and at birth are associated with infant allergy outcomes.

Study Design: Altogether, 975 infants participated in a randomized, controlled trial of daily vitamin D supplementation of 10 μg (400 IU) or 30 μg (1200 IU) from the age of 2 weeks. At 12 months of age, food and aeroallergen IgE antibodies were measured, and the occurrence of allergic diseases and wheezing were evaluated.

Results: We found no differences between the vitamin D supplementation groups in food (OR, 0.98; 95% CI, 0.66-1.46) or aeroallergen sensitization at 12 months (OR, 0.76; 95% CI,0.34-1.71). Allergic diseases or wheezing did not differ between groups, except for milk allergy which occurred more often in infants administered 30 μg vitamin D compared with the 10 μg dose (OR, 2.23; 95% CI, 1.00-4.96). Infants with high cord blood 25-hydroxyvitamin D (≥100 nmol/L) had a higher risk of food allergen sensitization compared with those with lower 25(OH)D concentration (75-99.9 nmol/L; OR, 2.00; 95% CI, 1.19-3.39).

Conclusions: High-dose vitamin D supplementation did not prevent allergic sensitization, allergic diseases, or wheezing during the first year of life. In contrast, we observed an increased risk of milk allergy in infants randomized to higher vitamin D supplementation, and an increased risk of allergic sensitization in infants with high cord blood vitamin D status, indicating a possible adverse effect of high concentrations of vitamin D.
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http://dx.doi.org/10.1016/j.jpeds.2019.02.021DOI Listing
June 2019

Airway hyperresponsiveness in young children with respiratory symptoms: A five-year follow-up.

Ann Allergy Asthma Immunol 2019 May 2;122(5):492-497. Epub 2019 Mar 2.

Helsinki University Hospital, Skin and Allergy Hospital, Helsinki, Finland.

Background: Recurrent wheezing in early life is transient in most children. The significance of airway hyperresponsiveness (AHR) in persistence of respiratory symptoms from infancy to early childhood is controversial.

Objective: We evaluated whether AHR in wheezy infants predicts doctor-diagnosed asthma (DDA) or AHR at the age of 6 years.

Methods: Sixty-one wheezy infants (age 6-24 months) were followed up to the median age of 6 years. Lung function and AHR with methacholine challenge test were assessed at infancy and 6 years. The exercise challenge test was performed at the age of 6 years. Atopy was assessed with skin prick tests.

Results: At 6 years, 21 (34%) of the children had DDA. Children with DDA had higher logarithmic transformed dose-response slope (LOGDRS) to methacholine in infancy than children without DDA (0.047 vs 0.025; P = .033). Furthermore, AHR to methacholine in infancy and at 6 years were associated with each other (r = 0.324, P = .011). Children with exercise-induced bronchoconstriction (EIB) at 6 years were more reactive to methacholine in infancy than those without EIB (P = .019).

Conclusion: Increased AHR in symptomatic infants was associated with increased AHR, DDA, and EIB at median the age of 6 years, suggesting early establishment of AHR.
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http://dx.doi.org/10.1016/j.anai.2019.02.025DOI Listing
May 2019

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

Pediatr Allergy Immunol 2019 05 18;30(3):356-362. Epub 2019 Feb 18.

Helsinki University Hospital, Skin and Allergy Hospital, Helsinki, 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.
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http://dx.doi.org/10.1111/pai.13025DOI Listing
May 2019

Environmental Tobacco Smoke Affects Lung Function of Preschoolers with Asthma Even after a Decade.

Am J Respir Crit Care Med 2019 02;199(4):534-536

3 Helsinki University Hospital Helsinki, Finland.

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http://dx.doi.org/10.1164/rccm.201809-1729LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376620PMC
February 2019

Small airway function in children with mild to moderate asthmatic symptoms.

Ann Allergy Asthma Immunol 2018 10 27;121(4):451-457. Epub 2018 Jul 27.

Pediatric Unit, Department of Allergy, Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: Clinical significance of small airway obstruction in mild pediatric asthma is unclear.

Objective: To evaluate small airway properties in children with mild to moderate asthmatic symptoms and the association of small airway function with asthma control and exercise-induced bronchoconstriction (EIB).

Methods: Children (5-10 years old) with recurrent wheezing (n = 42) or persistent troublesome cough (n = 16) and healthy controls (n = 19) performed impulse oscillometry (IOS), spirometry, and a multiple-breath nitrogen washout (MBNW) test. Exhaled nitric oxide (NO) was measured at multiple flow rates to determine alveolar NO concentration (Calv). Asthma control was evaluated with the Childhood Asthma Control Test (C-ACT), short-acting β-agonist (SABA) use within the past month, and asthma exacerbations within the past year.

Results: IOS, spirometry, and exhaled NO indexes that are related to small airway function differed between children with recurrent wheezing and healthy controls, whereas only forced expiratory flow at 25% to 75% of the forced vital capacity was associated with persistent cough. The MBNW indexes showed no difference between the groups. Among symptomatic children, conducting airway ventilation inhomogeneity and Calv were associated with asthma exacerbations (P = .03 and P = .002, respectively), and lung clearance index and Calv were associated with EIB (P = .04 and P = .004, respectively). None of the proposed small airway indexes was associated with the C-ACT score or SABA use.

Conclusion: Subtle changes were observed in the proposed small airway indexes of IOS, spirometry, and exhaled NO among children with mild to moderate recurrent wheezing. Small airway dysfunction, expressed as ventilation inhomogeneity indexes and Calv, was also associated with asthma exacerbations and EIB.
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http://dx.doi.org/10.1016/j.anai.2018.07.026DOI Listing
October 2018

Nocturnal Heart Rate Variability Spectrum Characterization in Preschool Children With Asthmatic Symptoms.

IEEE J Biomed Health Inform 2018 09 17;22(5):1332-1340. Epub 2017 Nov 17.

Asthma is a chronic lung disease that usually develops during childhood. Despite that symptoms can almost be controlled with medication, early diagnosis is desirable in order to reduce permanent airway obstruction risk. It has been suggested that abnormal parasympathetic nervous system (PSNS) activity might be closely related with the pathogenesis of asthma, and that this PSNS activity could be reflected in cardiac vagal control. In this work, an index to characterize the spectral distribution of the high frequency (HF) component of heart rate variability (HRV), named peakness ($\wp$), is proposed. Three different implementations of $\wp$, based on electrocardiogram (ECG) recordings, impedance pneumography (IP) recordings and a combination of both, were employed in the characterization of a group of preschool children classified attending to their risk of developing asthma. Peakier components were observed in the HF band of those children classified as high-risk ( $p < 0.005$), who also presented reduced sympathvoagal balance. Results suggest that high-risk of developing asthma might be related with a lack of adaptability of PSNS.
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http://dx.doi.org/10.1109/JBHI.2017.2775059DOI Listing
September 2018

Health care resource utilization and characteristics of patients with eosinophilic asthma in secondary health care in Finland.

Eur Clin Respir J 2018 15;5(1):1458560. Epub 2018 Apr 15.

Medaffcon Oy, Espoo, Finland.

: Eosinophilic airway inflammation is common in asthma patients and appears to be associated with severe exacerbations and loss of asthma control. : To describe the resource utilization and clinical characteristics of patients with eosinophilic asthma. : Asthma patients ≥18 years with ≥1 blood eosinophil count in secondary care (South West Finland) during 2003‒2013 were included. Clinical characteristics (age, lung function, body mass index, and comorbidities) and asthma-related resource utilization (hospital admissions, outpatient visits, and emergency room [ER] visits) were retrieved. Resource utilization rates were compared for patients with blood eosinophil ≤ or >300 cells/μL, using adjusted negative binomial regression models. : Overall, 4,357 eligible patients were identified (mean age 60 years, females 68%), of which 1,927 (44%) had >300 eosinophil cells/μL blood. Patients with ≤300 and >300 eosinophil counts, exhibited similar clinical characteristics, including advanced age, poor lung function, and overweight. Comorbidities such as pneumonia, sinusitis, and nasal polyps, were more frequent among those with >300 eosinophil cells/μL blood compared with patients with lower counts. Eosinophil counts >300 cells/μL were associated with greater hospital admissions (rate ratio [RR] [95% confidence interval CI]: 1.13 [1.02;1.24]) and outpatient visits (RR [95% CI]: 1.11 [1.03;1.20]) compared with patients with lower eosinophil counts. Rates of ER visits were similar between the patient groups (RR [95% CI]: 0.99 [0.87;1.12]). : Hospital admissions and outpatient visits occurred more often for patients with eosinophil counts >300 cells/µL, than for patients with lower eosinophil counts. Routine blood eosinophil screening might be useful to identify patients with an eosinophilic phenotype eligible for more targeted treatments.
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http://dx.doi.org/10.1080/20018525.2018.1458560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912706PMC
April 2018

Immunotherapy With the SQ Tree SLIT-tablet in Adults and Adolescents With Allergic Rhinoconjunctivitis.

Clin Ther 2018 04 16;40(4):574-586.e4. Epub 2018 Mar 16.

Department of Dermato-Allergology, Copenhagen University Hospital, Copenhagen, Denmark.

Purpose: The SQ tree sublingual immunotherapy (SLIT)-tablet containing allergen extracts with the major allergen Bet v 1 from birch pollen is currently being developed for the treatment of tree pollen-induced allergic rhinitis/conjunctivitis with or without asthma. The aim of this Phase II trial was to investigate the dose-related efficacy and safety of the SQ tree SLIT-tablet.

Methods: This study was a randomized, parallel-group, double-blind, placebo-controlled, multi-national trial conducted in Europe. A total of 637 participants were randomized equally to receive placebo or treatment with the SQ tree SLIT-tablet in doses of 0.5, 1, 2, 4, 7, or 12 development units (DU). Treatment was initiated ~16 weeks before onset of the 2013 birch pollen season (BPS) and was continued throughout the BPS with a total duration of at least 6 months. During the BPS and tree pollen season (TPS), subjects assessed rhinoconjunctivitis symptoms and medication use on a daily basis in an electronic diary; weekly assessments of rhinoconjunctivitis quality of life were also made.

Findings: Analysis of the average daily symptom score during the BPS and the TPS showed that the difference between active treatment and placebo was statistically significant for the 7 DU group (BPS, P = 0.02; TPS, P = 0.03), with no clear dose-response relationship. All doses of the SQ tree SLIT-tablet induced changes from baseline in birch-specific IgE and IgG that were statistically significant compared with placebo at all time points assessed (P < 0.0001) with a clear dose-response relationship for birch specific IgG. In general, the SQ tree SLIT-tablet was well tolerated, with the majority of treatment-related adverse events (≥95%) being mild or moderate in severity. The most frequently reported treatment-related adverse events were generally related to the sublingual administration of the tablet (ie, they occurred in the oral cavity).

Implications: The results from this trial suggest that the SQ tree SLIT-tablet in doses up to 12 DU has a tolerability profile suitable for at-home administration. The immunomodulatory changes indicate a dose-response relationship, but clinical efficacy parameters were inconclusive, probably due to low pollen counts, emphasizing the importance of pollen exposure for the outcome of a pollen allergy immunotherapy trial. EudraCT no: 2012-000031-59.
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http://dx.doi.org/10.1016/j.clinthera.2018.02.012DOI Listing
April 2018

Abnormal lung function at preschool age asthma in adolescence?

Ann Allergy Asthma Immunol 2018 05 6;120(5):520-526. Epub 2018 Mar 6.

Department of Allergology, Skin and Allergy Hospital, University of Helsinki, and Helsinki University Hospital, Helsinki, Finland.

Background: Asthma often begins early in childhood. However, the risk for persistence is challenging to evaluate.

Objective: This longitudinal study relates lung function assessed with impulse oscillometry (IOS) in preschool children to asthma in adolescence.

Methods: Lung function was measured with IOS in 255 children with asthma-like symptoms aged 4-7 years. Baseline measurements were followed by exercise challenge and bronchodilation tests. At age 12-16 years, 121 children participated in the follow-up visit, when lung function was assessed with spirometry, followed by a bronchodilation test. Asthma symptoms and medication were recorded by a questionnaire and atopy defined by skin prick tests.

Results: Abnormal baseline values in preschool IOS were significantly associated with low lung function, the need for asthma medication, and asthma symptoms in adolescence. Preschool abnormal R5 at baseline (z-score ≥1.645 SD) showed 9.2 odds ratio (95%CI 2.7;31.7) for abnormal FEV1/FVC, use of asthma medication in adolescence, and 9.9 odds ratio (95%CI 2.9;34.4) for asthma symptoms. Positive exercise challenge and modified asthma-predictive index at preschool age predicted asthma symptoms and the need for asthma medication, but not abnormal lung function at teenage.

Conclusion: Abnormal preschool IOS is associated with asthma and poor lung function in adolescence and might be utilised for identification of asthma persistence.
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http://dx.doi.org/10.1016/j.anai.2018.03.002DOI Listing
May 2018

Standardizing dose in dosimetric bronchial challenge tests.

Clin Physiol Funct Imaging 2018 Sep 17;38(5):903-906. Epub 2018 Jan 17.

Department of Allergy, Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland.

Recent technical recommendations on bronchial challenge testing aim at standardized assessment of provocative dose of causing 20% decrease in FEV1 (PD20). The aim of this study was to investigate the effect of mode of nebulization on the output of a computerized dosimeter (APS) and to compare PD20 obtained by two different dosimetric systems in vivo. The output of the APS system was tested during continuous nebulization, and using simulated breaths, for intermittent actuations with four different durations. Using output data, a modified methacholine challenge protocol was applied for APS and compared with a standard set-up using Spira dosimeter in 14 asthmatic patients attending duplicate methacholine challenges using both systems, within median (range) 3 (1-6) days apart. The calculated output (mg min ) with all the intermittent mode settings was significantly higher (P<0·001) than in the continuous mode, and in the intermittent mode, the output was dependent of the pulse duration. The PD20 values assessed with the APS and Spira systems were significantly correlated (r = 0·69; P<0·007), without systematic difference in the geometric means (P = 0·10). A moderate to good agreement was found for assessment of significant hyperresponsiveness. The results suggest that in dosimetric systems for bronchial challenge tests, the output of the nebulizer is dependent on the mode of nebulization, and this should be considered when standardizing the dose between devices and protocols. As long as the delivered dose is determined for the specified nebulization mode of the protocol, it may be possible to obtain comparable results between different devices.
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http://dx.doi.org/10.1111/cpf.12498DOI Listing
September 2018

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

Acta Paediatr 2018 05 6;107(5):861-870. Epub 2018 Feb 6.

Department of Allergy, Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland.

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.
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http://dx.doi.org/10.1111/apa.14226DOI Listing
May 2018

Small airway oscillometry indices: Repeatability and bronchodilator responsiveness in young children.

Pediatr Pulmonol 2017 10 18;52(10):1260-1267. Epub 2017 Aug 18.

Pediatric Unit of the Department of Allergy, Skin and Allergy Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Introduction: The impulse oscillometry (IOS) indices absolute and relative difference between respiratory resistance at 5 and 20 Hz (R5-20 and R5-20%, respectively) and the area under the reactance curve (AX) are postulated to reflect small airway function. Data on their cutoff values to evaluate bronchodilator responsiveness (BDR) or between-visit changes after interventions are limited in young children.

Methods: We evaluated the BDR of 103 healthy children aged 2-7 years, who received either salbutamol (n = 84) or placebo (n = 19) in order to determine cutoff values for BDR of R5-20, R5-20%, and AX. We then determined the repeatability within and between two IOS measurements 7-14 days apart in young children aged 4-8 years with asthmatic symptoms (n = 43), including cutoff values for significant between-visit changes.

Results: The investigated IOS parameters showed marked BDR (fifth percentile cutoff of 75-110% of the baseline value) in healthy children, whereas no significant changes were seen after inhalation of placebo. The agreement within the triplicate IOS measurement was excellent (ICC > 0.80), and the agreement of results between visits was good (ICC > 0.60). A change in R5-20, R5-20%, and AX of 0.65, 1.08, and 0.84 z-scores, respectively, would exceed 95% confidence intervals for between-visit variability.

Conclusion: We introduce cutoff values for BDR of R5-20, R5-20%, and AX, and their repeatability indices and cutoff limits for significant between-visit changes. These IOS parameters may show greater variability than the conventional IOS indices during follow-up, but the between-visit agreement remains good, providing potentially useful endpoints for monitoring lung function in young children.
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http://dx.doi.org/10.1002/ppul.23794DOI Listing
October 2017

Vitamin D, high-sensitivity C-reactive protein, and airway hyperresponsiveness in infants with recurrent respiratory symptoms.

Ann Allergy Asthma Immunol 2017 09 28;119(3):227-231. Epub 2017 Jul 28.

Skin and Allergy Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Background: Vitamin D insufficiency might be associated with biased T-cell responses resulting in inflammatory conditions such as atopy and asthma. Little is known about the role of vitamin D in low-grade systemic inflammation and airway hyperresponsiveness (AHR) in young children.

Objective: To evaluate whether vitamin D insufficiency and increased serum high-sensitivity C-reactive protein (hs-CRP) are linked to AHR in symptomatic infants.

Methods: Seventy-nine infants with recurrent or persistent lower respiratory tract symptoms underwent comprehensive lung function testing and a bronchial methacholine challenge test. In addition, skin prick tests were performed and serum 25-hydroxyvitamin D (S-25-OHD), hs-CRP, total immunoglobulin E, and blood eosinophil levels were determined.

Results: S-25-OHD was lowest in infants with blood eosinophilia and AHR (n = 10) compared with those with eosinophilia only (n = 6) or AHR only (n = 50) or those with neither (n = 13; P = .035). Moreover, vitamin D insufficiency (S-25-OHD <50 nmol/L) was most common in infants with blood eosinophilia and AHR (P = .041). Serum hs-CRP was lower in infants with recurrent physician-diagnosed wheezing (P = .048) and in those with blood eosinophilia (P = .015) than in infants without these characteristics and was not associated with S-25-OHD or AHR. S-25-OHD levels were significantly lower (median 54 nmol/L) during the autumn-winter season than in the spring-summer season (median 63 nmol/L; P = .026).

Conclusion: Vitamin D insufficiency could underlie eosinophilia and AHR in infants with troublesome lung symptoms, whereas hs-CRP-mediated low-grade systemic inflammation is rare in early childhood wheezing.
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http://dx.doi.org/10.1016/j.anai.2017.06.014DOI Listing
September 2017

A History of Cow's Milk Allergy Is Associated with Lower Vitamin D Status in Schoolchildren.

Horm Res Paediatr 2017 14;88(3-4):244-250. Epub 2017 Jul 14.

Division of Nutrition, Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland.

Background/aims: Vitamin D insufficiency is common in children. We aimed to evaluate the main determinants of vitamin D status in Finnish school-aged children, including the history of allergic diseases.

Methods: We conducted a cross-sectional study on 171 ten-year-olds where serum 25-hydroxyvitamin D (25[OH]D) levels were measured, and data on food consumption and use of vitamin D supplements were collected. The history of allergic diseases was evaluated with a validated questionnaire.

Results: Vitamin D insufficiency (<50 nmol/L) was observed in 16% of the children. In children with a history of cow's milk allergy, the mean 25(OH)D levels were lower than in children without allergy (60.5 ± 12.6 nmol/L vs. 75.5 ± 22.3 nmol/L, p = 0.004). Lack of vitamin D supplementation, female gender, non-Caucasian ethnicity, and a history of milk allergy were associated with lower vitamin D status.

Conclusion: The vitamin D status in our study sample of Finnish schoolchildren was sufficient, which suggests that health policy strategies - such as the recommendation of vitamin D supplementation and the fortification of food products with vitamin D - have been successful in improving vitamin D status in children. Special concern should be given to children with a history of milk allergy to ensure their vitamin D sufficiency.
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http://dx.doi.org/10.1159/000478779DOI Listing
June 2018