Asthma development is associated with low mucosal IL-10 during viral infections in early life.

BACKGROUND: Viral infection is a common trigger of severe respiratory illnesses in early life and a risk factor for later asthma development. The mechanism leading to asthma could involve an aberrant airway immune response to viral infections, but this has rarely been studied in a human setting. OBJECTIVES: To investigate in situ virus-specific differences in upper airway immune mediator levels during viral episodes of respiratory illnesses and the association with later asthma. METHODS: We included 493 episodes of acute respiratory illnesses in 277 children aged 0-3 years from the COPSAC2010 mother-child cohort. Levels of 18 different immune mediators were assessed in nasal epithelial lining fluid using high-sensitivity MesoScale Discovery kits and compared between children with and without viral PCR-identification in nasopharyngeal samples. Finally, we investigated whether the virus-specific immune response was associated with asthma by age 6 years. RESULTS: Viral detection were associated with upregulation of several Type 1 and regulatory immune mediators, including IFN-É£, TNF-α, CCL4, CXCL10 and IL-10 and downregulation of Type 2 and Type 17 immune mediators, including CCL13, and CXCL8 (FDR <0.05). Children developing asthma had decreased levels of IL-10 (FDR <0.05) during viral episodes compared to children not developing asthma. CONCLUSION: We described the airway immune mediator profile during viral respiratory illnesses in early life and showed that children developing asthma by age 6 years have a reduced regulatory (IL-10) immune mediator level. This provides insight into the interplay between early-life viral infections, airway immunity and asthma development.

Genetic predisposition to high BMI increases risk of early life respiratory infections and episodes of severe wheeze and asthma.

BACKGROUND: High body mass index (BMI) is an established risk factor for asthma, but the underlying mechanisms remain unclear. OBJECTIVE: To increase understanding of the BMI-asthma relationship by studying the association between genetic predisposition to higher BMI and asthma, infections and other asthma traits during childhood. METHODS: Data were obtained from the two ongoing Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) mother-child cohorts. Polygenic risk scores for adult BMI were calculated for each child. Replication was done in the large-scale register-based Integrative Psychiatric Research (iPSYCH) cohort using data on hospitalisation for asthma and infections. RESULTS: In the COPSAC cohorts (n=974), the adult BMI polygenic risk score was significantly associated with lower respiratory tract infections (incidence rate ratio (IRR) 1.20, 95% CI 1.08-1.33, false discovery rate p-value (pFDR)=0.005) at age 0-3 years and episodes of severe wheeze (IRR 1.30, 95% CI 1.06-1.60, pFDR=0.04) at age 0-6 years. Lower respiratory tract infections partly mediated the association between the adult BMI polygenic risk score and severe wheeze (proportion mediated: 0.59, 95% CI 0.28-2.24, p-value associated with the average causal mediation effect (pACME)=2e-16). In contrast, these associations were not mediated through the child's current BMI and the polygenic risk score was not associated with an asthma diagnosis or reduced lung function up to age 18 years. The associations were replicated in iPSYCH (n=114 283), where the adult BMI polygenic risk score significantly increased the risk of hospitalisations for lower respiratory tract infections and wheeze or asthma throughout childhood to age 18 years. CONCLUSION: Children with genetic predisposition to higher BMI had increased risk of lower respiratory tract infections and severe wheeze, independent of the child's current BMI. These results shed further light on the complex relationship between body mass BMI and asthma.

Limited clinical role of blood eosinophil levels in early life atopic disease: A mother-child cohort study.

BACKGROUND: Blood eosinophil count is a well-established biomarker of atopic diseases in older children and adults. However, its predictive role for atopic diseases in preschool children is not well established. OBJECTIVE: To investigate the association between blood eosinophil count in children and development of atopic diseases up to age 6 years. METHODS: We investigated blood eosinophil count at age 18 months and 6 years in relation to recurrent wheeze/asthma, atopic dermatitis, allergic rhinitis, and allergic sensitization during the first 6 years of life in the two Copenhagen Prospective Studies on Asthma in Childhood cohorts (n = 1111). Blood eosinophil count was investigated in association with remission of existing atopic disease, current atopic disease, and later development of atopic disease. RESULTS: Blood eosinophil count at 18 months was not associated with current wheezing/asthma or atopic dermatitis, while blood eosinophil count at age 6 years was associated with increased occurrence of current wheezing/asthma (OR = 1.1; 1.04-1.16, p = .0005), atopic dermatitis (OR = 1.06; 1.01-1.1, p = .02), and allergic rhinitis (OR = 1.11; 1.05-1.18, p = .0002). Blood eosinophil count at 18 months did not predict persistence or development of recurrent wheeze/asthma or atopic dermatitis at age 6 years. CONCLUSION: Blood eosinophil count at 18 months was not associated with current wheezing/asthma or atopic dermatitis and did not predict persistence or development of disease. This implies a limited clinical role of blood eosinophil levels in early-life atopic disease and questions the clinical value of blood eosinophil counts measured in toddlers as a predictive biomarker for subsequent atopic disease in early childhood.

Risk Factors and Age-Related Patterns of Asthma-Like Symptoms in Early Childhood.

BACKGROUND: Episodes of asthma-like symptoms in young children are common, but little is known about risk factors and their patterns for the daily symptom burden. OBJECTIVE: We investigated a variety of possible risk factors and their age-related impact on the number of asthma-like episodes during age 0 to 3 years. METHODS: The study population included 700 children from the Copenhagen Prospective Studies on Asthma in Childhood2010 mother-child cohort followed prospectively from birth. Asthma-like symptoms were recorded until age 3 by daily diaries. Risk factors were analyzed by quasi-Poisson regressions, and interaction with age was explored. RESULTS: Diary data were available in 662 children. Male sex, maternal asthma, low birth weight, maternal antibiotic use, high asthma exacerbation polygenic risk score, and high airway immune score were associated with a higher number of episodes in a multivariable analysis. Maternal asthma, preterm birth, caesarean section, and low birth weight showed an increasing impact with age, whereas sibling(s) at birth showed a decreased association with age. The remaining risk factors had a stable pattern during age 0 to 3 years. For every additional clinical risk factor (male sex, low birth weight, and maternal asthma) a child had, we found 34% more episodes (incidence rate ratio: 1.34, 95% confidence interval: 1.21-1.48; P < .001). CONCLUSION: Using unique day-to-day diary recordings, we identified risk factors for the burden of asthma-like symptoms in the first 3 years of life and described their unique age-related patterns. This provides novel insight into the origin of asthma-like symptoms in early childhood that potentially pave a path for personalized prognostics and treatment.

Determinants of Bacille Calmette-Guérin scarification in Danish children.

BACKGROUND: Studies in low-income countries have shown that among Bacille Calmette-Guérin (BCG) vaccinated children, those who develop a BCG-scar have significantly better survival than those who do not develop a scar. In a Danish multicenter randomized clinical trial we assessed determinants for developing a BCG-scar and for BCG scar size following neonatal BCG vaccination. METHODS: At three Danish hospitals, newborns were randomized 1:1 to BCG vaccination or no BCG vaccination. The infants were invited for a clinical examination at the ages of 3 and 13 months. At 13 months, the scar site was inspected and scar size measured. We investigated three groups of determinants; external, parental, and individual-level determinants on relative scar prevalence and differences in median scar sizes. RESULTS: Among 2118 BCG vaccinated infants, 2039 (96 %) were examined at 13 months; 1857 of these (91 %) had developed a BCG-scar. Compared with Copenhagen University Hospital, Hvidovre (85 %), Copenhagen University Hospital, Rigshospitalet had a scar prevalence of 95 % (adjusted Prevalence ratio (aPR) = 1.24 [CI 95 %: 1.18 to 1.30]); it was 93 % at Kolding Hospital (aPR 1.27 [CI 95 %: 1.19 to 1.35]). Increasing vaccine experience was positively associated with developing a scar and with scar size. CONCLUSION: Across multiple potential determinants of BCG scaring and size, logistical factors dominated. The results support that injection technique is an important determinant of developing a scar. Given the strong link between having a BCG scar and subsequent health, improved BCG vaccination technique could play a major role for child health.

Bacille Calmette-Guérin vaccination at birth and differential white blood cell count in infancy. A randomised clinical trial.

BACKGROUND: The Bacille Calmette-Guérin (BCG) vaccine against tuberculosis (TB) may have beneficial non-specific effects (NSEs) beyond the protection against TB. This may be related to modifications of the innate immune system. We investigated the effect of BCG at birth on differential white blood cell (WBC) count in healthy, Danish infants. METHOD: The Danish Calmette Study randomised newborns to BCG at birth (Danish strain 1331, Statens Serum Institut) or no intervention. A sub-group of infants had blood samples collected 4 days after randomisation (n = 161), and at age 3 months (n = 152) and 13 months (n = 300). We evaluated the effect of BCG on WBC differential count (total leucocytes, lymphocytes, monocytes, eosinophil, neutrophil and basophil granulocytes (109 cells/L)) measured in peripheral blood. RESULTS: Overall, we found no effect of BCG on differential WBC counts at any time point. CONCLUSION: BCG at birth did not affect WBC count in our cohort of healthy, Danish infants.

The association between Bacillus Calmette-Guérin vaccination (1331 SSI) skin reaction and subsequent scar development in infants.

BACKGROUND: The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis is administered intradermally, and vaccination is often followed by a scar at the injection site. Among BCG-vaccinated individuals, having a scar has been associated with lower mortality. We aimed to examine the impact of vaccination technique for scarring in a high income setting, by assessing the associations between the post injection reaction, the wheal size, and the probability of developing a scar, and scar size. METHODS: This study was nested within a clinical multicenter study randomizing 4262 infants to either BCG vaccination (BCG 1331 SSI) or no intervention. In this substudy, including 492 vaccinated infants, the immediate post BCG vaccination reaction was registered as either wheal (a raised, blanched papule at the injection site), bulge (a palpable element at the injection site), or no reaction. The presence or absence of a BCG scar and the size the scar was measured at 13 months of age. RESULTS: Of 492 infants included, 87% had a wheal after vaccination, 11% had a bulge, and 2% had no reaction. The mean wheal size was 3.8 mm (95% confidence interval 3.7-3.9). Overall, 95% (442/466, 26 lost to follow-up) of BCG-vaccinated infants had a scar at 13 months of age. In infants with a wheal, the probability of developing a scar was 96%, declining to 87% in the case of a bulge, and to 56% in the case of no reaction (p for same probability = 0.03). Wheal size was positively correlated with the probability of getting a scar and scar size. CONCLUSION: Scarring after BCG vaccination has been associated with lower infant mortality. In a high-income setting, we found that correct injection technique is highly important for the development of a BCG scar and that registration of the category of BCG skin reaction (as wheal, bulge, or no reaction) may be used to identify infants at risk of scar failure. Finally, the wheal size was positively associated with both the probability of getting a scar and scar size. TRIAL REGISTRATION: The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108 .