From neonatal lung function to lung function and respiratory morbidity at 6-year follow-up.

BACKGROUND: Lung function is traceable from infancy to adulthood. Only a few studies have examined lung function from birth to childhood longitudinally in children born moderate to late preterm. We aimed to investigate how prematurity and lung function in the neonatal period are related to lung function and respiratory morbidity at age 6 in former moderate to late preterm children compared with children born at term. METHODS: Lung function was measured in a cohort of moderately to late preterm (n = 48) and term-born (n = 53) infants in the neonatal period by FeNO, and tidal breathing flow-volume loops (TBFVL) and at age 6 (n = 52) by spirometry, whole-body plethysmograph and impulse oscillation combined with a respiratory symptom questionnaire. RESULTS: Moderate to late preterm children had a higher TPEF /TE ratio neonatally (42.6% vs. 33.7%, p = 0.02) and a lower % predicted orced expiratory volume in the first second at age 6 (94.4% vs. 101.9%, p = 0.01) compared to term-born children. We found a significant association between the variability of neonatal tidal volume and effective airway resistance at age 6 (ß = -0.34, p = 0.03). No association between neonatal FeNO or TBFVL and respiratory morbidity at 6-year follow-up was shown. CONCLUSION: Children born moderate to late preterm had lower lung function at age 6 than term-born children. We did not find evidence for the use of neonatal tidal breathing parameters as a predictor for subsequent respiratory morbidity or lung function, however sample size was small.

Cohort profile: the vitamin A and D and nitric oxide (AD-ON) observational cohort on lung development and symptoms in premature and mature children in North Zealand, Denmark.

PURPOSE: The risk of developing asthma-like symptoms and asthma in childhood is influenced by genetics, environmental exposures, prenatal and early postnatal events, and their interactions. The cohort name refers to vitamins A and D, and nitric oxide (NO) spelt backwards and this cohort profile paper aims to present the data collection and aim of the cohort.The overall aim when establishing this cohort was to investigate if childhood lung function can be traced back to early neonatal lung function and fractional exhaled NO (FeNO) and investigate prenatal and postnatal risk factors including maternal and neonatal vitamin A and D levels in preterm and term born children. PARTICIPANTS: One thousand five hundred women and their babies born at Nordsjaellands Hospital in Denmark from 2013 to 2014 were included in the AD-ON research biobank prior to birth.Neonates from the AD-ON research biobank, admitted to the Neonatal Intensive Care Unit at Nordsjaellands Hospital, were included in the AD-ON neonatal cohort. The neonatal cohort consisted of 149 neonates hereof 63 preterm and 86 term born. The children in the cohort have been invited to follow-up visits at age 1 and 6 years. FINDINGS TO DATE: Published data from this cohort includes a validated and clinically applicable method to measure FeNO in neonates. We found an age-specific pattern of association between respiratory symptoms at age 1 and neonatal FeNO in preterm children. Moreover, we found that the respiratory symptoms risk was associated with postnatal factors (Respiratory Syncytial Virus infection and parental smoking) in preterm infants and prenatal factors (parental asthma and maternal infection during pregnancy) in term born infants. FUTURE PLANS: In the future, the children will be examined continuously with 3-year to 5-year intervals until the age of 18. Lung function, allergy tests, environmental exposure measurements and questionnaires will be collected at each follow-up visit.

National multi-centre study found a low prevalence of severely impaired lung function in children and adolescents.

AIM: As no data to our knowledge exist, the aim of the study was to describe the national prevalence and characteristics of Danish children and adolescents with severely impaired lung function. METHODS: We performed a descriptive, cross-sectional Danish multi-centre study. Children and adolescents between 6 and 18 years old demonstrating severely impaired lung function from 2015 to 2018, defined by forced expiratory volume in 1 second (FEV1 ) <60% or who had lung transplantation, were eligible for inclusion. RESULTS: This study included 113 children with a mean age (standard deviation) of 12.9 years (3.5 years). The prevalence of severely impaired lung function was approximately 13 in 100,000. The mean (standard deviation) FEV1 was 46.1% (10.1%) of predicted, and z-score was -4.5 (0.8). The most frequent diagnosis was cystic fibrosis (20.4%), followed by asthma (19.5%) and bronchiolitis obliterans (16.8%), while almost 25% had different elements of airway malformations or non-pulmonary conditions. Two adolescents with cystic fibrosis underwent lung transplantation. CONCLUSION: The estimated prevalence of severely impaired lung function in Danish children and adolescents was low, and extremely, few children underwent lung transplantation. The most frequent diagnosis was cystic fibrosis, while almost 25% had different elements of airway malformations or non-pulmonary conditions, which may require clinical attention.

Association of serum surfactant protein D and SFTPD gene variants with asthma in Danish children, adolescents, and young adults.

BACKGROUND: Surfactant Protein D (SP-D) is a pattern recognition molecule belonging to the family of collectins expressed in multiple human organ systems, including the lungs. Previous studies have shown that SP-D levels in bronchoalveolar lavage samples decrease and serum levels increase in patients suffering from asthma, possibly due to a combination of induced SP-D synthesis and decreased air-blood barrier integrity. The aims of this study were to investigate whether serum levels of SP-D and common variants in the SP-D gene were associated with asthma in adolescents and young adults. METHODS: Prospective observational study including 449 adolescents and young adults (age 11-27 years) previously diagnosed with asthma during a 2-year period from 2003 to 2005 (0-16 years). At follow-up from 2016 to 2017, 314 healthy controls with no history of asthma were recruited. Serum SP-D was analyzed on samples obtained at baseline as well as samples obtained at follow-up. SP-D genotyping was performed for rs721917, rs2243639, and rs3088308. RESULTS: No differences were found in mean levels of sSP-D and SFTPD genotype among subjects with current asthma, no current asthma, and controls. Serum SP-D and SFTPD genotype were not associated with any clinical parameters of asthma. Furthermore, baseline sSP-D was not associated with asthma at follow-up. CONCLUSION: Serum surfactant protein D and common SP-D gene variants were not associated with asthma in Danish adolescents and young adults with mild to moderate asthma. Serum surfactant protein D did not demonstrate any value as a clinical biomarker of asthma.

Neonatal FeNO, risk factors, and respiratory morbidity in infants: A cohort study.

BACKGROUND: Respiratory symptoms in infancy are more common in premature infants. Nitric oxide (NO) is involved in prenatal and neonatal lung development. Measurement of exhaled NO is easy and well-tolerated by neonates. We investigated whether neonatal exhaled NO can be used to predict subsequent respiratory symptoms. Furthermore, we sought to determine prenatal and postnatal factors associated with increased respiratory symptom risk during the first year of life in premature and mature infants. METHODS: Tidal fractional exhaled NO (FeNO) was measured in a birth cohort (n = 135) of premature and mature infants, up to six times during the first month of life. Primary outcomes were troublesome respiratory symptoms (TRS) and doctor-diagnosed asthmatic bronchitis (AB) at 1 year of age. FINDINGS: The correlation between FeNO and TRS changed significantly in an age-dependent pattern in moderately premature infants (p = .02). Moderately premature infants with a low FeNO of 2 ppb on postnatal Day 3 had a 48% (95% confidence interval [CI]: 17%-80%) probability of TRS, compared with a probability of 12% (95% CI: 1%-64%) for otherwise similar infants with a FeNO of 11 ppb. Respiratory syncytial virus infection and parental smoking significantly increased the TRS risk in premature infants. Parental asthma and maternal antibiotic use during pregnancy significantly increased the TRS risk in mature infants. INTERPRETATION: An age-specific association between neonatal FeNO and respiratory symptoms was seen in moderately premature infants. TRS risk was associated with postnatal factors in premature and prenatal factors in mature infants.

Exhaled nitric oxide in premature and mature infants during the first months of life.

AIM: In this review, we aim to describe how exhaled Nitric Oxide(NO) changes during the first months of life in premature and mature infants. METHOD: Review of the literature up to August 2020, on online, tidal breathing NO measurements in unsedated infants. The association between Fractional exhaled NO(FeNO) values, postnatal age, and prematurity was analysed using linear mixed modeling and Spearman's rank correlation. RESULTS: Median FeNO during the first months of life was 5.9 and 8.5 ppb in premature and mature infants, respectively. The linear mixed model analysis showed a significant effect of postnatal age on FeNO (p = 0.007). CONCLUSION: Our study suggests that FeNO is higher in mature infants than premature infants, and FeNO increased with postnatal age at approximately the same pace in both groups.

Late-onset group B streptococcus infections and severe bronchopulmonary dysplasia in an extremely preterm born infant.

This case report is about a boy born extremely preterm at gestational age of 24 weeks, with extremely low birth weight, developing severe bronchopulmonary dysplasia and in need of mechanical ventilation for 155 days. He also had five recurrent infections with group B streptococcus (GBS) within 4 months from birth, and his respiratory condition clearly deteriorated with every GBS infection. It was difficult to wean him from mechanical ventilation. Finally he was extubated when he was 7 months old and kept out of mechanical ventilation after receiving high-dose methylprednisolone, given according to international recommendations. After GBS was cultured for the fifth time, he received oral rifampicin along with intravenous penicillin and after this treatment, GBS did not occur again. At the age of 22 months, the boy no longer needed any respiratory support and he was about 6 months late in his neurological development.

Microfibrillar-associated protein 4 in serum is associated with asthma in Danish adolescents and young adults.

BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen-related protein superfamily, which plays multifaceted roles in innate immunity and normal endothelial function. It has been proposed that MFAP4 promotes the development of asthma in vivo and proasthmatic pathways of bronchial smooth muscle cells in vitro. The aim of this study was to investigate the significance of serum MFAP4 in adolescents and young adolescents with persistent asthma. METHODS: Prospective, observational study including adolescents and young adults (age 11-27 years) previously diagnosed with asthma during childhood 2003 to 2005 (0-15 years) at the four pediatric outpatient clinics in the Region of Southern Denmark (n = 449). Healthy controls were recruited at follow-up (n = 314). Detection of serum MFAP4 was performed by AlphaLISA technique. RESULTS: Current asthma was associated to a 14% higher mean level of serum MFAP4 compared with controls (expß 1.14, 95% confidence intervals [CI], 1.05-1.23) and a 6% higher mean level compared with subjects with no current asthma (expß 1.06, 95% CI, 0.99-1.13). No association was found at follow-up between serum MFAP4 and self-reported atopic symptoms (other than asthma), Asthma Control Test-score, fractional exhaled nitric oxide (FeNO), nor to flow rate at 1 second, forced vital capacity, and forced expiratory flow 25% to 75%, response to short-acting beta 2 agonist or mannitol. CONCLUSIONS: We found a significantly higher mean level of serum MFAP4 in adolescent and young adults with mild to moderate asthma compared with healthy controls but no association to FeNO and lung function nor to the response to short-acting beta 2 agonist or mannitol. The result supports the hypothesis that MFAP4 plays a role in the pathogenesis of asthma although the marker did not demonstrate any obvious potential as an asthma biomarker in adolescents and young adults with asthma. To understand the possible proasthmatic functions of MFAP4, further investigation in specific asthma phenotypes and the underlying molecular mechanisms is warranted.

Improved lung function at age 6 in children born very preterm and fed extra protein post-discharge.

BACKGROUND: In very preterm-born children, alveolar maturation is challenged and lung function is often compromised during childhood. So far, very few studies have focused on type of early nutrition and lung function in children born preterm. METHODS: This study is a 6 years follow-up of 281 very preterm-born infants (VPI) with a gestational age (GA) <32 + 0 weeks. Infants breastfed at discharge from hospital were randomized to unfortified (UHM) or fortified (FHM) mother's (human) milk, whereas those not breastfed received a preterm formula (PF). The intervention lasted until 4 months corrected age. At 6 years of age fractional exhaled nitric oxide (FeNO), airway resistance and occlusion measurements with reversibility were performed. Data on predisposition to asthma and allergy as well as possible allergic symptoms of the child were obtained with questionnaires. RESULTS: Outcome data was fully or partially available on 160 (66.9%) of 239 children. This included 49 (30.6%) children fed UHM, 58 (36.3%) fed FHM and 53 (33.1%) fed PF. Successful FeNO measurements were obtained in 119 (74.4%) children and airway resistance measurements in 160. FeNO results were not significantly different between feeding groups. Children fed a protein-enriched diet (FMH/PF) had the lowest, for example, best, airway resistance; FHM-fed had lower values than UHM-fed (P = 0.042) before, and PF-fed had significantly lower values than UHM-fed after beta-2-agonist inhalation (P = 0.050). The tendency of lower airway resistance when protein enriched were the same in gender-specific analyses. In SGA children, the same tendency was found between PF- and UHM-fed (P = 0.007 before and P = 0.046 after beta-2-agonist inhalation). All values were within reference limits. CONCLUSIONS: Lung function in very preterm-born children may improve when fed a protein-enriched nutrition post-discharge.

Catch-Up Growth, Rapid Weight Growth, and Continuous Growth from Birth to 6 Years of Age in Very-Preterm-Born Children.

BACKGROUND: Breastfeeding promotes healthy growth in very-preterm-born infants (VPI), but extra nutritional supply is needed to ensure catch-up growth and brain development. OBJECTIVES: To investigate how different types of post-discharge nutrition affect growth until 6 years of age in children born VPI. METHODS: This was a 6-year follow-up study of 281 VPI. Median gestational age (GA) was 30 + 0 weeks (range 24-32 weeks). When breastfed at discharge, they were randomized to unfortified human milk (UHM) or fortified human milk (FHM). If not breastfed at discharge, they received a preterm formula (PF). The intervention lasted until 4 months of corrected age (CA). At 6 years CA, their height and weight were measured. RESULTS: A total of 239 children participated in the follow-up. UHM-feeding compared to both PF- and FHM-feeding resulted in a slower but continuous catch-up growth until 6 years of age. Participants born small-for-GA compared to appropriate-for-GA more often demonstrated continuous catch-up growth until 6 years of age (p = 0.018). Rapid weight growth (a change in z score > 1 SD during a short time period) was found to be most pronounced from 34 weeks post-menstrual age to 2 months CA, and especially among those fed PF (p = 0.002 vs. UHM, p = 0.07 vs. FHM). CONCLUSIONS: Catch-up growth occurred mainly before discharge, regardless of the feeding group. UHM-fed infants demonstrated catch-up growth that was slower, but extended until 6 years of age. Rapid weight growth was most pronounced shortly after discharge and especially if PF-fed.

Pediatric Expression of Mast Cell Activation Disorders.

Mast cell activation disorders is a term proposed to cover diseases and conditions related to activation of mast cells and effects of mast cell mediators. In its broadest sense, the term encompasses a wide range of diseases from allergic asthma to rhinoconjunctivitis, urticaria, food allergy, anaphylaxis, mastocytosis, and other conditions where MC activation is contributing to the pathogenesis. This article focuses on clinical presentations, challenges, and controversies in pediatric mastocytosis and gives an overview of current knowledge and areas in need of further research.

Early nutrition and signs of metabolic syndrome at 6 y of age in children born very preterm.

Background: In term-born infants, the risk of developing metabolic syndrome (MetS) has been shown to be associated with formula feeding and early rapid growth. Breastfeeding, however, seems to be associated with a lower risk of MetS among term-born infants. Objective: The possible association between type of early nutrition, early growth, and possible influence on different metabolic outcomes at 6 y of age was investigated in very-preterm-born children. Design: This study is a 6-y follow-up of 281 very-preterm-born infants with a gestational age of ≤32 wk. Infants breastfed at discharge from the hospital were randomly assigned to receive unfortified or fortified mother's milk, whereas those who were not breastfed received a preterm formula. The intervention lasted until 4 mo of corrected age. At 6 y of age, height, weight, and body mass index were measured and a dual-energy X-ray absorptiometry scan and blood sampling were performed. Results: In total, 239 children participated in the follow-up. No differences were found between the 2 breastfed groups. Formula-fed children were more often predisposed to obesity and from families with a lower social status than were children who were breastfed only. Early rapid growth (crossing of weight percentiles with >1 SD in either direction) was seen in 53% of the children from 34 wk of postmenstrual age and until 2 mo of corrected age and was significantly correlated with several metabolic outcomes at 6 y of age. Conclusions: Children fed a preterm formula postdischarge more often showed early rapid growth than did breastfed children, and early rapid growth was correlated with early signs of MetS at 6 y of age. However, all of the values were within normal ranges. This trial was registered at as NCT02078687.

Long-term pulmonary function in esophageal atresia-A case-control study.

BACKGROUND: Esophageal atresia (EA) is a congenital anomaly associated with substantial pulmonary morbidity throughout childhood. AIM: The aim of this study was to evaluate pulmonary complications among 59 five to 15-year-old children and adolescents with surgically corrected congenital EA. METHODS: Participants underwent a structured interview, spirometry, body plethysmography, mannitol challenge test, skin prick test, as well as measurements of the diffusion capacity, airway resistance, fraction of exhaled NO, and specific immunoglobulin E in serum. A control group consisted of 25 children being evaluated for gastroesophageal reflux disease. RESULTS: Among the EA patients 33 (55.9%) had respiratory symptoms, 31 (53.4%) had a history of at least three pneumonias, and 32 (54.2%) reported more frequent cough episodes than peers. The Forced Vital Capacity (FVC) was 84.9% ± 13.2% of predicted, forced expiratory volume 1 sec (FEV1) was 78.2% ± 12.4% of predicted, and forced expiratory fraction 25-75% (FEF25-75%) was 71.5 ± 17.8% of predicted in EA patients, lower than disease controls (P < 0.0001 for all). In addition, the total lung capacity (TLC) was lower in patients with EA than in the controls (P < 0.0001). Fifteen patients (28.8%) with EA had obstructive ventilatory impairment, compared to nine patients (17.3%) with restrictive ventilatory impairment, while one had a combination. CONCLUSIONS: The present study demonstrated significantly decreased pulmonary characteristics in EA patients. Restrictive ventilatory impairment occurring in EA is probably due to poor lung growth after thoracotomy. No single factor predicted ventilatory impairment in children and adolescents with EA. Pediatr Pulmonol. 2017;52:98-106. © 2016 Wiley Periodicals, Inc.

The Danish National Database for Asthma.

AIM OF THE DATABASE: Asthma is the most prevalent chronic disease in children, adolescents, and young adults. In Denmark (with a population of 5.6 million citizens), >400,000 persons are prescribed antiasthmatic medication annually. However, undiagnosed cases, dubious diagnoses, and poor asthma management are probably common. The Danish National Database for Asthma (DNDA) was established in 2015. The aim of the DNDA was to collect the data on all patients treated for asthma in Denmark and to monitor asthma occurrence, the quality of diagnosis, and management. STUDY POPULATION: Persons above the age of 6 years, with a specific focus on 6-44 years, are included. The DNDA links three existing nationwide registries of administrative records in the Danish health care system: the National Patient Register, the National Health Insurance Services Register, and the National Prescription Registry. For each year, the inclusion criteria are a second purchase of asthma prescription medicine within a 2-year period (National Prescription Registry) or a diagnosis of asthma (National Patient Register). Patients with chronic obstructive pulmonary disease are excluded, but smokers are not excluded. DESCRIPTIVE DATA: A total of 366,471 prevalent patients with asthma have been identified (year 2014 - as a preliminary test search). This number is in agreement with the estimates of ~400,000 inhabitants that are available for patients with possible asthma in Denmark. Data encompass the following quality indicators: annual asthma control visits and pharmacological therapy. MAIN VARIABLES: The variables included are spirometry, as well as tools for diagnosis (including allergy testing), smoking status, height, weight, and acute hospital admissions and unscheduled visits. CONCLUSION: DNDA is available from January 1, 2016.

The Danish National Database for Asthma: establishing clinical quality indicators.

Asthma is one of the most common chronic diseases worldwide affecting more than 300 million people. Symptoms are often non-specific and include coughing, wheezing, chest tightness, and shortness of breath. Asthma may be highly variable within the same individual over time. Although asthma results in death only in extreme cases, the disease is associated with significant morbidity, reduced quality of life, increased absenteeism, and large costs for society. Asthma can be diagnosed based on report of characteristic symptoms and/or the use of several different diagnostic tests. However, there is currently no gold standard for making a diagnosis, and some degree of misclassification and inter-observer variation can be expected. This may lead to local and regional differences in the treatment, monitoring, and follow-up of the patients. The Danish National Database for Asthma (DNDA) is slated to be established with the overall aim of collecting data on all patients treated for asthma in Denmark and systematically monitoring the treatment quality and disease management in both primary and secondary care facilities across the country. The DNDA links information from population-based disease registers in Denmark, including the National Patient Register, the National Prescription Registry, and the National Health Insurance Services register, and potentially includes all asthma patients in Denmark. The following quality indicators have been selected to monitor trends: first, conduction of annual asthma control visits, appropriate pharmacological treatment, measurement of lung function, and asthma challenge testing; second, tools used for diagnosis in new cases; and third, annual assessment of smoking status, height, and weight measurements, and the proportion of patients with acute hospital treatment. The DNDA will be launched in 2016 and will initially include patients treated in secondary care facilities in Denmark. In the nearby future, the database aims to include asthma diagnosis codes and clinical data registered by general practitioners and specialised practitioners as well.

A child with mastocytosis and lymphomatoid papulosis.

A change in clinical behavior of a disease should prompt search for differential diagnoses. Here, the appearance of ulcerated skin nodules in a preexisting cutaneous mastocytosis revealed a concurrent lymphomatoid papulosis - a CD30+ lymphoproliferative skin disease with histological features of a malignant lymphoma, but with a benign self-healing course.

[Mastocytosis]. / Mastocytose.

Mastocytosis is a heterogeneous disease with an increased number and activation of mast cells. Subtypes range from benign to rare aggressive forms, and the disease may affect people of all ages. The pathogenesis involves mutations in the KIT gene in both children and adult patients. Estimated prevalence is one per 10,000, but the disease is very likely underdiagnosed. The diagnosis may be challenging and patients may present to several medical specialties. This article presents an overview of clinical signs and symptoms as well as a diagnostic algorithm and treatment options of mastocytosis.

Multidisciplinary Management of Mastocytosis: Nordic Expert Group Consensus.

Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.

Five-grass pollen 300IR SLIT tablets: efficacy and safety in children and adolescents.

The efficacy and safety of five-grass pollen 300IR sublingual immunotherapy (SLIT) tablets (Stallergènes SA, France) have previously been demonstrated in paediatric patients. This report presents additional data concerning efficacy at pollen peak, efficacy and safety according to age, nasal and ocular symptoms, use of rescue medication, satisfaction with treatment and compliance. Children (5-11 yr) and adolescents (12-17 yr) with grass pollen-allergic rhinoconjunctivitis were included in a multinational, randomized, double-blind, placebo-controlled study and received either a 300IR five-grass pollen tablet or placebo daily in a pre- (4 months) and co-seasonal protocol. The severity of six symptoms (sneezing, rhinorrhoea, nasal congestion, nasal and ocular pruritis, and tearing) was scored, and rescue medication use was recorded daily during the pollen season. Patient satisfaction was recorded at the season end. A total of 161 children and 117 adolescents were evaluated (n = 267). 300IR SLIT was effective over the whole season (p = 0.0010) and at the pollen peak (p = 0.0009). The adjusted mean difference between 300IR and placebo groups was significant for both nasal (p = 0.0183) and ocular (p < 0.0001) symptoms. Rescue medication use was statistically lower in the SLIT group during the pollen season and at the pollen peak (both p < 0.05). More patients in the SLIT group were satisfied with their treatment compared to placebo (83.2% vs. 68.1%, p = 0.0030), and compliance was high (SLIT 93.9% of patients were compliant, placebo 94.8% of patients were compliant). SLIT was well tolerated by children and adolescents. 300IR five-grass pollen tablets are effective and safe during the pollen season and at the pollen peak in children and adolescents with grass pollen rhinoconjunctivitis.