Merci Kusel

Role of respiratory viruses in acute upper and lower respiratory tract illness in the first year of life : A birth cohort study

Introduction: Although acute respiratory illnesses (ARI) are major causes of morbidity and mortality in early childhood worldwide, little progress has been made in their control and prophylaxis. Most studies have focused on hospitalized children or children from closed populations. It is essential that the viral etiology of these clinical diseases be accurately defined in the development of antiviral drugs. Objective: To investigate the role of all common respiratory viruses as upper and lower respiratory tract pathogens in the first year of life. Study Design: This community-based birth cohort study prospectively collected detailed information on all ARI contracted by 263 infants from birth until 1 year of age. Nasopharyngeal aspirates were collected for each ARI episode, and all common respiratory viruses were detected by polymerase chain reaction. Episodes were classified as upper respiratory illnesses or lower respiratory illnesses (LRI), with or without wheeze. Results: The majority reported 2–5 episodes of ARI in the first year (range, 0–11 episodes; mean, 4.1). One-third were LRI, and 29% of these were associated with wheeze. Viruses were detected in 69% of ARI; most common were rhinoviruses (48.5%) and respiratory syncytial virus (RSV) (10.9%). Compared with RSV, >10 times the number of upper respiratory illnesses and >3 times the number of both LRI and wheezing LRI were attributed to rhinoviruses. Conclusion: Rhinoviruses are the major upper and lower respiratory pathogens in the first year of life. Although RSV is strongly associated with severe LRI requiring hospitalization, the role of rhinoviruses as the major lower respiratory pathogens in infants has not previously been recognized.

The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.

Summary The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.

Maternal Serum Vitamin D Levels During Pregnancy and Offspring Neurocognitive Development

OBJECTIVES: To determine the association between maternal serum 25(OH)-vitamin D concentrations during a critical window of fetal neurodevelopment and behavioral, emotional, and language outcomes of offspring. METHODS: Serum 25(OH)-vitamin D concentrations of 743 Caucasian women in Perth, Western Australia (32°S) were measured at 18 weeks pregnancy and grouped into quartiles. Offspring behavior was measured with the Child Behavior Checklist at 2, 5, 8, 10, 14, and 17 years of age (n range = 412–652). Receptive language was assessed with the Peabody Picture Vocabulary Test—Revised at ages 5 (n = 534) and 10 (n = 474) years. Raw scores were converted to standardized scores, incorporating cutoffs for clinically significant levels of difficulty. RESULTS: χ2 analyses revealed no significant associations between maternal 25(OH)-vitamin D serum quartiles and offspring behavioral/emotional problems at any age. In contrast, there were significant linear trends between quartiles of maternal vitamin D levels and language impairment at 5 and 10 years of age. Multivariate regression analyses, incorporating a range of confounding variables, found that the risk of women with vitamin D insufficiency (≤46 nmol/L) during pregnancy having a child with clinically significant language difficulties was increased close to twofold compared with women with vitamin D levels >70 nmol/L. CONCLUSIONS: Maternal vitamin D insufficiency during pregnancy is significantly associated with offspring language impairment. Maternal vitamin D supplementation during pregnancy may reduce the risk of developmental language difficulties among their children.

Toward improved prediction of risk for atopy and asthma among preschoolers: A prospective cohort study

BACKGROUND Atopy and asthma are commonly initiated during early life, and there is increasing interest in the development of preventive treatments for at-risk children. However, effective methods for assessing the level of risk in individual children are lacking. OBJECTIVE We sought to identify clinical and laboratory biomarkers in 2-year-olds that are predictive of the risk for persistent atopy and wheeze at age 5 years. METHODS We prospectively studied 198 atopic family history-positive children to age 5 years. Clinical and laboratory assessments related to asthma history and atopy status were undertaken annually; episodes of acute respiratory illness were assessed and classified throughout and graded by severity. RESULTS Aeroallergen-specific IgE titers cycled continuously within the low range in nonatopic subjects. Atopic subjects displayed similar cycling in infancy but eventually locked into a stable pattern of upwardly trending antibody production and T(H)2-polarized cellular immunity. The latter was associated with stable expression of IL-4 receptor in allergen-specific T(H)2 memory responses, which was absent from responses during infancy. Risk for persistent wheeze was strongly linked to early sensitization and in turn to early infection. Integration of these data by means of logistic regression revealed that attaining mite-specific IgE titers of greater than 0.20 kU/L by age 2 years was associated with a 12.7% risk of persistent wheeze, increasing progressively to an 87.2% risk with increasing numbers of severe lower respiratory tract illnesses experienced. CONCLUSION The risk for development of persistent wheeze in children can be quantified by means of integration of measures related to early sensitization and early infections. Follow-up studies along similar lines in larger unselected populations to refine this approach are warranted.

Do early-life viral infections cause asthma?

Epidemiologic associations between viral lower respiratory infections (LRIs) and asthma in later childhood are well known. However, the question of whether such infections cause asthma or unmask asthma in a susceptible host has still not been settled. Most early evidence centered on the role of the respiratory syncytial virus; however, recent studies highlight a potential role for human rhinovirus as a risk factor for asthma. The links between early-life viral LRI and subsequent asthma are generally via wheeze; however, the presence of wheeze does not give any information about why the child is wheezing. Wheeze in early life is, at best, a fuzzy phenotype and not specific for subsequent asthma. The risk of asthma after viral LRI is increased in the presence of allergic sensitization in early life and if the infection is more severe. Atopy-associated mechanisms also appear to be involved in viral-induced acute exacerbations of asthma, especially in prolonging symptomatology after the virus has been cleared from the lungs. Breaking the nexus between viral respiratory infections and asthma may be possible with interventions designed to inhibit atopy-related effectors mechanisms from participating in the host response to respiratory viral infections.

CpG methylation patterns in the IFN promoter in naive T cells: Variations during Th1 and Th2 differentiation and between atopics and non-atopics

Interferon‐γ (IFNγ) gene expression is tightly regulated in early life, and exaggerated negative control of IFNγ production in CD4+ T cells has been associated with risk for subsequent development of atopy. Recent studies have demonstrated hypermethylation of CpG sites in the IFNγ promoter in neonates, a mechanism which in mice leads to strong suppression of IFNγ gene transcription. In the present study, the methylation status of six CpG sites in the proximal promoter of the human IFNγ gene was determined by bisulphite sequencing. Cell populations studied were Th1 or Th2 polarized cell lines derived from neonatal and adult CD4+/CD45RA+ T cells, CD4+ and CD8+ naive T cells from cord blood of children followed to outcome age 2 for assessment of atopy status, and CD4+ and CD8+ naive T cells from 6 yr old and adult atopics and controls. We demonstrate that in vitro differentiation of CD4+ T cells down the Th1 pathway (but not the Th2 pathway) is accompanied by progressive demethylation of CpG sites in the IFNγ promoter, which is most marked in neonatal cells. Atopy development by age 2 was not associated with variations in methylation patterns in cord blood T cells. However, IFNγ promoter methylation was reduced in CD8+ T cells from atopic children in the age range in which hyperproduction of IFNγ as recently been identified as a common feature of the atopic phenotype. The findings demonstrate the potency of IFNγ promoter methylation as a mechanism for control of human IFNγ gene expression, particularly during early life. Differential regulation of IFNγ promoter methylation in T cells may be an important contributory factor in atopy development in childhood, and this possibility warrants further detailed investigation.

Assessment of bronchodilator responsiveness in preschool children using forced oscillations

Background: The forced oscillation technique (FOT) requires minimal patient cooperation and is feasible in preschool children. Few data exist on respiratory function changes measured using FOT following inhaled bronchodilators (BD) in healthy young children, limiting the clinical applications of BD testing in this age group. A study was undertaken to determine the most appropriate method of quantifying BD responses using FOT in healthy young children and those with common respiratory conditions including cystic fibrosis, neonatal chronic lung disease and asthma and/or current wheeze. Methods: A pseudorandom FOT signal (4–48 Hz) was used to examine respiratory resistance and reactance at 6, 8 and 10 Hz; 3–5 acceptable measurements were made before and 15 min after the administration of salbutamol. The post-BD response was expressed in absolute and relative (percentage of baseline) terms. Results: Significant BD responses were seen in all groups. Absolute changes in BD responses were related to baseline lung function within each group. Relative changes in BD responses were less dependent on baseline lung function and were independent of height in healthy children. Those with neonatal chronic lung disease showed a strong baseline dependence in their responses. The BD response in children with cystic fibrosis, asthma or wheeze (based on both group mean data and number of responders) was not greater than in healthy children. Conclusions: The BD response assessed by the FOT in preschool children should be expressed as a relative change to account for the effect of baseline lung function. The limits for a positive BD response of −40% and 65% for respiratory resistance and reactance, respectively, are recommended.

Dendritic cell immaturity during infancy restricts the capacity to express vaccine-specific T-cell memory

ABSTRACT The capacity of the immune system in infants to develop stable T-cell memory in response to vaccination is attenuated, and the mechanism(s) underlying this developmental deficiency in humans is poorly understood. The present study focuses on the capacity for expression of in vitro recall responses to tetanus and diphtheria antigens in lymphocytes from 12-month-old infants vaccinated during the first 6 months of life. We demonstrate that supplementation of infant lymphocytes with “matured” dendritic cells (DC) cultured from autologous CD14+ precursors unmasks previously covert cellular immunity in the form of Th2-skewed cytokine production. Supplementation of adult lymphocytes with comparable prematured autologous DC also boosted vaccine-specific T-cell memory expression, but in contrast to the case for the infants, these cytokine responses were heavily Th1 skewed. Compared to adults, infants had significantly fewer circulating myeloid DC (P < 0.0001) and plasmacytoid DC (P < 0.0001) as a proportion of peripheral blood mononuclear cells. These findings suggest that deficiencies in the numbers of antigen-presenting cells and their functional competence at 12 months of age limit the capacity to express effector memory responses and are potentially a key factor in reduced vaccine responsiveness in infants.

Maternal vitamin D status during pregnancy and bone mass in offspring at 20 years of age: a prospective cohort study.

It is uncertain whether the vitamin D status of pregnant women influences bone mass of their children. Cohort studies have yielded conflicting results; none have examined offspring at skeletal maturity. This longitudinal, prospective study investigated the association between maternal vitamin D status and peak bone mass of offspring in 341 mother and offspring pairs in the Western Australian Pregnancy Cohort (Raine) Study. Maternal serum samples collected at 18 weeks gestation were assayed for 25‐hydroxyvitamin D (25OHD). Outcomes were total body bone mineral content (BMC) and bone mineral density (BMD) measured by dual‐energy X‐ray absorptiometry in offspring at 20 years of age. The mean (± SD) maternal serum 25OHD concentration was 57.2 ± 19.2 nmol/L; 132 women (38.7%) were vitamin D‐deficient (25OHD <50 nmol/L). After adjustment for season of sample collection, maternal factors, and offspring factors (sex, birth weight, and age, height, lean mass, and fat mass at 20 years), maternal 25OHD concentration was positively associated with total body BMC and BMD in offspring, with a mean difference of 19.2 (95% confidence interval [CI], 5.6–32.7) g for BMC and 4.6 (95% CI, 0.1–9.1) mg/cm2 for BMD per 10.0 nmol/L of maternal 25OHD. Maternal vitamin D deficiency was associated with 2.7% lower total body BMC (mean ± SE) (2846 ± 20 versus 2924 ± 16 g, p = 0.004) and 1.7% lower total body BMD (1053 ± 7 versus 1071 ± 5 mg/cm2, p = 0.043) in the offspring. We conclude that vitamin D deficiency in pregnant women is associated with lower peak bone mass in their children. This may increase fracture risk in the offspring in later life.

RESPIRATORY FUNCTION IN HEALTHY YOUNG CHILDREN USING FORCED OSCILLATIONS

Background: Monitoring of respiratory function is important in the diagnosis and management of respiratory disease. The forced oscillation technique requires minimal patient cooperation and is ideal for the determination of respiratory function in young children. This study aimed to develop reference ranges and to document the repeatability in healthy young children using commercially available forced oscillation equipment. Methods: The forced oscillation technique, which uses a pseudo-random noise forcing signal between 4 and 48 Hz, was used to measure respiratory function in healthy young children. Repeatability over a 15 min period was also assessed. Regression equations and standardised Z scores were determined for respiratory resistance (Rrs) and reactance (Xrs) at 6, 8 and 10 Hz. Results: Respiratory function was obtained in 158 healthy children aged two to seven years and between 92 and 127 cm in height. Oscillatory respiratory mechanics exhibited linear relationships with height. Within-test variability for resistance ranged between 6% and 9% and between 17% and 20% for reactance. Resistance and reactance did not change significantly over a 15 min period. Conclusions: Reference ranges for respiratory impedance variables in healthy children aged two to seven years are presented. The short-term repeatability of forced oscillatory variables in this age group is reported, allowing appropriate cut-off values for therapeutic interventions to be defined.