Asthma In Later Life Research Articles

Does lung function in preschoolers help to predict asthma in later life?

The earliest respiratory function assessments, within or close to the neonatal period, consistently show correlations with lung function and with the development of asthma into adulthood. Measurements of lung function in infancy reflect the in utero period of lung development, and if early enough, show little influence of postnatal environmental exposures. Later in the preschool and school age periods, influences of the environment are superimposed on initial levels. Fetal exposures before birth such as maternal smoking during pregnancy, lead to reduced lung function and an increased risk of asthma in females particularly those with certain glutathione S-transferase genotypes. Lung function measurements later in the preschool period are also associated with development of asthma. Although lung function in preschoolers does help predict asthma in later life and these observations have increased our understanding of the physiology underlying asthma, the findings have not led to thewidespread use of lung function measurements being in preschoolers as clinical predictors of asthma due to the practicalities of testing in this age group.

Aeroallergen Avoidance: Updated Evidence and How to Advise Patients

Allergic rhinitis (AR) is highly prevalent in Canada, affecting approximately 20–25% of the population. Asthma is estimated to affect approximately three million Canadians, and between 12% and 25% of Canadian children. Approximately two-thirds of individuals with asthma are allergic to aeroallergens, and these allergens act as triggers for asthma exacerbations. Overall, approximately 7.7 million individuals were affected by aeroallergens in Canada in 2016. High concentrations of ambient aeroallergens, including tree pollen and fungal spores have been associated with increased risk of premature birth, myocardial infarction (MI) and asthma-related Emergency Department visits and hospitalizations in cities across Canada. This demonstrates that nation-wide aeroallergen counts are associated with severe signs and symptoms. Children exposed to various indoor allergens are placed at an increased risk of developing asthma in later life, with sensitization in these individuals being a strong predictor of disease morbidity. Common indoor exposures for infants include house dust mite, pet, cockroach, mould, and rodent allergens. Sensitization to at least one indoor allergen has been demonstrated to be present in nine of every ten children hospitalized with asthma. It has been noted that more than 90% of children worldwide breathe polluted air. While the impact of climate change on aeroallergen exposure is not fully understood, there is increasing evidence that it may have an impact on outdoor aeroallergens and, by extension, asthma control in children. Global warming has been projected to influence the duration and intensity of pollen seasons, and may lead to increased pollen production, prolonged pollen seasons, and increased pollen protein allergenicity. The changing weather patterns including rainfall and wind may cause pollen species to reach environments in which they had not previously been present, contributing to a shift in geographic pollen distributions.

Indoor aeroallergens from American cockroaches and mites initiate atopic march via cutaneous contact in a murine model.

The progression of allergic diseases from atopic dermatitis in childhood to other allergic conditions such as asthma in later life is often referred to as the atopic march. In order to study the relationship between cutaneous sensitization by aeroallergen and atopic march, we established a mouse model to test the hypothesis using American cockroaches and house dust mites as the model allergens. Mice were sensitized via skin with native cockroach extract (CraA) or recombinant Per a 2 and Der p 2 proteins without adjuvant. Each mouse was subjected to a total of three 1-week patching sensitizations with a 2-week interval in between each application. The resulting immunological variables in sera, scratching behavior, airway hyperresponsiveness (AHR), and pathology of skin lesions and nasal mucosa were evaluated. In mice, application of CraA, rPer a 2, and rDer p 2 aeroallergens through skin patching induced significantly high levels of both total IgE and specific IgEs. The epicutaneous sensitization after a subsequent allergen challenge showed a significant increase in scratch bouts, AHR, epidermal thickness, and eosinophil counts in the skin compared with the control mice. In addition, stimulation of murine splenocytes with allergens increased higher levels of Th2 cytokines, anti-inflammatory cytokines, and chemokines excretion. Our study provides evidence supporting that epicutaneous sensitization to aeroallergens also led to nasal and airway symptoms comparable to atopic march as described in humans. We hope this new allergy model will be useful in the development of new preventive and therapeutic strategies aimed at stopping the atopic march.

ITGB4 Deficiency in Airway Epithelium Aggravates RSV Infection and Increases HDM Sensitivity.

BackgroundThe heterogeneity of RSV-infected pathology phenotype in early life is strongly associate with increased susceptibility of asthma in later life. However, the inner mechanism of this heterogeneity is still obscure. ITGB4 is a down-regulated adhesion molecular in the airway epithelia of asthma patients which may participate in the regulation of RSV infection related intracellular pathways.ObjectThis study was designed to observe the involvement of ITGB4 in the process of RSV infection and the effect of ITGB4 deficiency on anti-RSV responses of airway epithelia.ResultsRSV infection caused a transient decrease of ITGB4 expression both in vitro and in vivo. Besides, ITGB4 deficiency induced not only exacerbated RSV infection, but also enhanced HDM sensitivity in later life. Moreover, IFN III (IFN-λ) was significantly suppressed during RSV infection in ITGB4 deficient airway epithelial cells. Furthermore, the suppression of IFN-λ were regulated by IRF-1 through the phosphorylation of EGFR in airway epithelial cells after RSV infection.ConclusionThese results demonstrated the involvement of ITGB4 deficiency in the development of enhance RSV infection in early life and the increased HDM sensitivity in later life by down-regulation of IFN-λ through EGFR/IRF-1 pathway in airway epithelial cells.

Association of weight change patterns across adulthood with incident asthma: a retrospective cohort study

This study aimed to investigate the relationship between weight change patterns across adulthood and the risk of incident asthma later in life using data from the National Health and Nutrition Examination Survey (NHANES) 2001–2018. In this retrospective cohort study, asthma was defined by self-report questionnaires, and age at diagnosis was used to estimate the time of asthma onset. Based on BMI at 25 years old (young adulthood) and BMI at 10 years before the survey (middle adulthood), patterns of weight change were divided into five categories including stable normal, non-obese to obese, obese to non-obese, maximum overweight and stable obese. A total of 27,359 participants (female 13,582, 49.6%) were enrolled in this study and during a mean follow-up of 9.8 years, 1035 subjects occurred asthma. After adjusting for age, gender, race, education, family income and smoking status, participants changing from non-obese to obese, stable obese had significantly higher risks of incident asthma than those with normal weight during adulthood (HR1.70, 95% CI 1.35–2.15, P < 0.0001; HR 1.66, 95% CI 1.21–2.19 P = 0.0019, respectively). The findings suggested that maintaining normal weight during adulthood may be important for preventing incident asthma in later life.

Allergen Management in Children with Type 2-High Asthma.

Children exposed to various indoor and outdoor allergens are placed at an increased risk of developing asthma in later life, with sensitization in these individuals being a strong predictor of disease morbidity. In addition, aeroallergen exposure influences asthma outcomes through an interplay with adverse determinants of health. The goal of this review is to provide an introductory overview of factors related to aeroallergen exposure in type 2-high childhood asthma. These include the relevance of exposure in asthma exacerbations and severity, and the evidence-base for avoidance and treatment for sensitization to these allergens. This review will focus on both indoor aeroallergens (house dust mite, pet, cockroach, mold, and rodent) and outdoor aeroallergens (pollens and molds). Treatment of aeroallergen sensitization in children with asthma includes avoidance and removal measures, although there is limited evidence of clinical benefit especially with single-strategy approaches. We will also address the interplay of aeroallergens and climate change, adverse social determinants, and the current COVID-19 pandemic, when we have seen a dramatic reduction in asthma exacerbations and emergency department visits among children. While there are many factors that are hypothesized to contribute to this reduction, among them is a reduced exposure to outdoor seasonal aeroallergens.

ITGB4 deficiency induces mucus hypersecretion by upregulating MUC5AC in RSV-infected airway epithelial cells.

Respiratory syncytial virus (RSV) infection is the main cause of bronchiolitis in children. Excessive mucus secretion is one of the primary symbols in RSV related lower respiratory tract infections (RSV-related LRTI), which is closely associated with the occurrence and development of asthma in later life. Integrin β4 (ITGB4) is down-regulated in the airway epithelial cells (AECs) of asthma patients which plays a critical role in the pathogenesis of asthma. However, whether ITGB4 is involved in the pathological processes of RSV infection remains unclear. In this study, we found that decreased expression of ITGB4 was negatively correlated with the level of MUC5AC in childhood AECs following RSV infection. Moreover, ITGB4 deficiency led to mucus hypersecretion and MUC5AC overexpression in the small airway of RSV-infected mice. MUC5AC expression was upregulated by ITGB4 in HBE cells through EGFR, ERK and c-Jun pathways. EGFR inhibitors treatment inhibited mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection. Together, these results demonstrated that epithelial ITGB4 deficiency induces mucus hypersecretion by upregulating the expression of MUC5AC through EGFR/ERK/c-Jun pathway, which further associated with RSV-related LRTI.

Influenza Vaccination Is Associated With Lower Incidental Asthma Risk in Patients With Atopic Dermatitis: A Nationwide Cohort Study.

BackgroundAtopic march refers to the natural history of atopic dermatitis (AD) in infancy followed by subsequent allergic rhinitis and asthma in later life. Respiratory viruses interact with allergic sensitization to promote recurrent wheezing and the development of asthma. We aimed to evaluate whether influenza vaccination reduces asthma risk in people with AD.MethodsThis cohort study was conducted retrospectively from 2000 to 2013 by the National Health Insurance Research Database (NHIRD). Patients with newly diagnosed AD (International Classification of Diseases, Ninth Revision, Clinical Modification code 691) were enrolled as the AD cohort. We matched each vaccinated patient with one non-vaccinated patient according to age and sex. We observed each participant until their first asthma event, or the end of the study on December 31, 2013, whichever came first.ResultsOur analyses included 4,414 people with a mean age of 53 years. Of these, 43.8 were male. The incidence density of asthma was 12.6 per 1,000 person-years for vaccinated patients, and 15.1 per 1000 person-years for non-vaccinated patients. The adjusted hazard ratio (aHR) of asthma in the vaccinated cohort relative to the non-vaccinated cohort was 0.69 (95% CI = 0.55–0.87). Vaccinated patients had a lower cumulative incidence of asthma than unvaccinated patients. Vaccinated participants in all age and sex groups trended toward a lower risk of asthma. People will reduce more asthma risk when taking shots every year.ConclusionInfluenza vaccination was associated with lower asthma risk in patients with AD.

Early life exposure to house dust mite allergen prevents experimental allergic asthma requiring mitochondrial H2O2.

Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H2O2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H2O2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia and increased airway hyperreactivity. WT Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naïve mice. In contrast, the lungs of MCAT Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H2O2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens.

Mechanical Abnormalities of the Airway Wall in Adult Mice After Intrauterine Growth Restriction.

Developmental abnormalities of airways may impact susceptibility to asthma in later life. We used a maternal hypoxia-induced mouse model of intrauterine growth restriction (IUGR) to examine changes in mechanical properties of the airway wall. Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11 to GD 17.5 (IUGR; term, GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A control group of pregnant mice were housed under normoxic conditions throughout pregnancy. At 8 weeks postnatal age, offspring were euthanized and a tracheasectomy performed. Tracheal segments were studied in organ baths to measure active airway smooth muscle (ASM) stress to carbachol and assess passive mechanical properties (stiffness) from stress-strain curves. In a separate group of anesthetized offspring, the forced oscillation technique was used to examine airway mechanics from relative changes in airway conductance during slow inflation and deflation between 0 and 20 cmH2O transrespiratory pressure. From predicted radius-pressure loops, storage and loss moduli and hysteresivity were calculated. IUGR offspring were lighter at birth (p < 0.05) and remained lighter at 8 weeks of age (p < 0.05) compared with Controls. Maximal stress was reduced in male IUGR offspring compared with Controls (p < 0.05), but not in females. Sensitivity to contractile agonist was not affected by IUGR or sex. Compared with the Control group, airways from IUGR animals were stiffer in vitro (p < 0.05). In vivo, airway hysteresivity (p < 0.05) was increased in the IUGR group, but there was no difference in storage or loss moduli between groups. In summary, the effects of IUGR persist to the mature airway wall, where there are clear abnormalities to ASM contractile properties and passive wall mechanics. We propose that mechanical abnormalities of the airway wall acquired through disrupted fetal growth impact susceptibility to disease.

Scalable hybrid microelectronic-microfluidic integration of highly sensitive biosensors

Abstract Point of Care devices for medical applications are becoming more and more widespread. The advantage of having test results after a very short period and without any laboratory creates is beneficial for doctors in developing countries far away from laboratory infrastructure to clinical devices disburdening in-house laboratories for example in case of an outbreak of an epidemic. Especially infectious diseases are one of the world's leading cause of morbidity and death [1]. Viral respiratory infections are a major cause of burden of disease in children. Annual human respiratory syncytial virus (RSV) related death are around 253.000, mainly in developing countries. It accounts for up to 6.7 % of mortality of children younger than 1 year. Therefore, RSV is the second most important global cause of death during infancy. Furthermore, RSV infection has been linked to an increased risk in the development of childhood wheezing and asthma in later life [2, 3]. Fast and cheap diagnostic, independent from laboratory infrastructure, will have a high impact on the healthcare system. Highly sensitive microelectronic biosensors have a superior sensitivity and accuracy compared to paper stripes. The higher miniaturization potential and production stability accompanied by a better readout simplicity makes them a cheaper alternative to optical systems. In this paper a hybrid microelectronic-microfluidic packaging strategy for a disposable for two different microelectronic biosensor platforms will be presented, targeting the diagnostic of RSV. The multiplexed detection of both, host and pathogen biomarkers in the same sample will lead to a rapid, cheap and accurate diagnosis and prognosis, providing almost real-time results. Platform 1, the BioGrFET sensor uses a graphene field effect transistor (GrFET). The liquid sample containing the biomarkers flows over the sensor's surface with probe molecules, where the target molecules (specific biomarkers) of the fluid can be immobilized. The charge of the biomarker on the surface changes the charge carrier density inside the graphene which can be detected by measuring the graphene field effect transport characteristic. Platform 2, the BioMEMS sensor is a micro electro mechanical system (MEMS) having a very thin membrane carrying the active sensor structure, offering additional challenges to device packaging. The liquid sample, containing the biomarkers, flows over the membrane's surface with detection molecules, where the specific biomarkers of the fluid can be immobilized. With the specific biomarkers on the membrane's surface changes the mass and therefore the resonance frequency of the membrane which can be read out. Specific packaging challenge for both sensors is to develop packaging technology flows that allow to add the sensor functionalization during packaging and leaves this functionalization intact until the packaging processes are finalized, which implies a process selection with reduced thermal and mechanical load on the delicate functionalized sensors. This challenge has been mastered for both sensors – yielding two dedicated packaging process flows that were used to manufacture functional sensor packages.

Increased medication costs for filaggrin-related eczema and asthma

Eczema and asthma are common chronic diseases. Eczema affects 15‐20% of schoolchildren and 2‐10% of adults while asthma affects 16‐18% of the UK population. Almost three‐quarters of children with early onset eczema, a severe and persistent form of eczema, will develop asthma in later life. The filaggrin gene helps produce a protein that creates a protective barrier on the skin against the entry of outside substances that trigger allergies. About 1 in 10 people carry a change in the filaggrin gene and this results in the production of defective protein that can no longer help maintain this skin barrier. This UK study aimed to find whether filaggrin mutations were associated with increased prescribing of medication for eczema and asthma and /or an increased number of asthma exacerbations (i.e. worsening) and whether this translated into different healthcare costs. The study shows that children with eczema and asthma carrying this gene change have substantially increased needs for both eczema and asthma medication through most of their childhood. Children with asthma carrying the gene change were also more prone to suffer asthma attacks over a nine‐year period, enhancing both hospital and human costs of the disease. It follows that a simple ‘spit’ gene test, that can be done anytime in life, including at birth or early childhood, could help predict long‐term healthcare costs and the long‐term risk of more severe disease for individuals with common chronic conditions such as eczema and asthma. Children and adults with filaggrin gene mutations may benefit from targeted treatment regimes, such as daily use of emollients from birth, which could lead to cost savings for healthcare systems and improvements in disease control and quality‐of‐life.

Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.

Respiratory syncytial virus-bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.

Should a Preschool Child with Acute Episodic Wheeze be Treated with Oral Corticosteroids? A Pro/Con Debate

Traditionally, preschool-aged children with an acute wheezing episode have been treated with oral corticosteroids (OCSs) based on the efficacy of OCSs in older children and adolescents. However, this practice has been recently challenged based on the results of recent studies. The argument supporting the use of OCSs underscores the observation that many children with recurrent preschool wheezing develop atopic disease in early life which predicts both an increased risk to develop asthma in later life and response to OCS therapy. Further, review of the literature demonstrates heterogeneity of study designs, OCS dosage, interventions, study medication adherence, and settings and overall lack of predefined preschool wheezing phenotypes. The heterogeneity of these studies does not allow a definitive recommendation discouraging OCS use. Advocates against the use of OCSs in this population argue that most of studies investigating the efficacy of OCSs in acute episodic wheeze in preschool-aged children have not demonstrated beneficial effects. Moreover, repeated OCS bursts may be associated with adverse effects. Finally, both sides can agree that there is a significant need to conduct efficacy trials evaluating OCS treatment in preschool-aged children with recurrent wheezing targeted at phenotypes that would be expected to respond to OCSs. This article presents a summary of recent literature regarding the use of OCSs for acute episodic wheezing in preschool-aged children and a "pro" and "con" debate for suchuse.

Early childhood wheezers: identifying asthma in later life.

Wheeze in young children is common, and asthma is the most common noncommunicable disease in children. Prevalence studies of recurrent asthma-like symptoms in children under the age of 5 years have reported that one third of children in the US and Europe are affected, and rates and severity appear to be higher in developing countries. Over the last few decades, significant research efforts have focused on identification of risk factors and predictors of wheeze and on tools to identify which children who wheeze will progress to develop asthma. We reviewed the phenotypes of childhood wheezing, genetic risk factors, environmental factors, testing/predictive indices, and primary prevention. While it is generally agreed that a complex interaction of environmental exposure and genetic susceptibility contributes to the development of asthma, limitations in predictive tools and tests restrict our ability to provide families with guidance as to whether their child with wheeze will ultimately develop asthma. Additional research is needed to clarify childhood wheeze phenotypes, to develop tools to determine which children will develop asthma, and to determine how and when to intervene. If these areas can be addressed, it would help reduce this large burden on children, families, and society.

Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

Respiratory syncytial virus (RSV) is the leading cause of acute respiratory tract viral infection in infants, causing bronchiolitis and pneumonia. The host antiviral response to RSV acts via retinoic acid-inducible gene I (RIG-I). We show here that RSV infection upregulates major histocompatibility complex class I (MHC-I) expression through the induction of NLRC5, a NOD-like, CARD domain-containing intracellular protein that has recently been identified as a class I MHC transactivator (CITA). RSV infection of A549 cells promotes upregulation of NLRC5 via beta interferon (IFN-β) production, since the NLRC5-inducing activity in a conditioned medium from RSV-infected A549 cells was removed by antibody to IFN-β, but not by antibody to IFN-γ. RSV infection resulted in RIG-I upregulation and induction of NLRC5 and MHC-I. Suppression of RIG-I induction significantly blocked NLRC5, as well as MHC-I, upregulation and diminished IRF3 activation. Importantly, Vero cells deficient in interferon production still upregulated MHC-I following introduction of the RSV genome by infection or transfection, further supporting a key role for RIG-I. A model is therefore proposed in which the host upregulates MHC-I expression during RSV infection directly via the induction of RIG-I and NLRC5 expression. Since elevated expression of MHC-I molecules can sensitize host cells to T lymphocyte-mediated cytotoxicity or immunopathologic damage, the results have significant implications for the modification of immunity in RSV disease. Human respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and young children worldwide. Infection early in life is linked to persistent wheezing and allergic asthma in later life, possibly related to upregulation of major histocompatibility class I (MHC-I) on the cell surface, which facilitates cytotoxic T cell activation and antiviral immunity. Here, we show that RSV infection of lung epithelial cells induces expression of RIG-I, resulting in induction of a class I MHC transactivator, NLRC5, and subsequent upregulation of MHC-I. Suppression of RIG-I induction blocked RSV-induced NLRC5 expression and MHC-I upregulation. Increased MHC-I expression may exacerbate the RSV disease condition due to immunopathologic damage, linking the innate immune response to RSV disease.

Management and complications of pneumonia

Pneumonia is estimated to be the leading cause of mortality in children under five worldwide. Death is rare in developed countries but it remains a major cause of hospital admissions and of both acute and chronic morbidities. Understanding current management and recognition of complications is important to all paediatricians. The causative organism varies with age and differentiating between viral, bacterial and other causes can be challenging. Supportive care and antibiotic treatment are the mainstays of modern management. The evidence base to support treatment policy is remarkably weak. The incidence of both uncomplicated and complicated pneumonia is increasing, particularly that of empyema and necrotic lung disease. The management of complications has changed over recent years and remains the subject of some controversy. The syndrome of inappropriate anti-diuretic hormone secretion (SIADH) has long been cited as a complication of pneumonia; but the existence of this entity is now being questioned. There is increasing evidence that pneumonia increases the risk of chronic obstructive pulmonary disease, bronchiectasis and asthma in later life.

Association between low vitamin D levels and the diagnosis of asthma in children: a systematic review of cohort studies.

BackgroundThere is conflicting evidence about the association between low vitamin D levels in children and development of asthma in later life. The objective of this study was to systematically review the evidence for an epidemiological association between low serum levels of vitamin D and the diagnosis of asthma in children.MethodsWe used the Cochrane methodology for conducting systematic reviews. The search strategy included an electronic search of MEDLINE and EMBASE in February 2013. Two reviewers completed, in duplicate and independently, study selection, data abstraction, and assessment of risk of bias.ResultsOf 1081 identified citations, three cohort studies met eligibility criteria. Two studies found that low serum vitamin D level is associated with an increased risk of developing asthma late in childhood, while the third study found no association with either vitamin D2 or vitamin D3 levels. All three studies suffer from major methodological shortcomings that limit our confidence in their results.ConclusionsAvailable epidemiological evidence suggests a potential association between low serum levels of vitamin D and the diagnosis of asthma in children. High quality studies are needed to reliably answer the question of interest.

NKT cell-dependent differential effects of OPN on functional modulation of macrophages and T lymphocytes in RSV infection (HYP6P.273)

Abstract RSV bronchiolitis is an important cause of pediatric hospitalization, which often leads to developing asthma in later life. Studies have indicated a Th2 skewed polarization of the lung environment in these children, which can be modulated by exogenous administration of osteopontin (OPN). In this study, using an NKT cell KO (CD1d-/-) mouse model, we have examined the effects of OPN on macrophages (MQ) and T lymphocytes (Tc) during RSV infection and identified the role of NKT cells in this process. Flowcytometry analysis determined that OPN treatment in RSV infection had reduced MQ and Tc recruitment in the lung parenchyma and alveolar spaces. However, OPN induced activation of the CD4 and CD8 Tcs in an NKT- dependent fashion, as the magnitude of activation was reduced to only 20% in the CD1d-/- mice as compared to the wild type (WT) mice. Also, expression of MHCII on MQs was significantly increased in the CD1d-/- mice, indicating a downregulatory effect of NKT cells. Altogether, these data suggest that OPN differentially affects MQ and Tc response and their functional modulations in an NKT cell-dependent fashion. A better understanding of these inverse effects of OPN on different immune effector cells during RSV infection may help establish OPN as a potential therapeutic for prevention of RSV-associated asthma in children.

Consequences of antibiotics and infections in infancy: bugs, drugs, and wheezing

BackgroundThe prevalence of asthma has increased alarmingly in the past 2 to 3 decades. Increased antibiotic use in infancy has been suggested to limit exposure to gastrointestinal microbes and to predispose to asthma in later life. ObjectiveTo evaluate the association between antibiotic exposure during the first year of life and the development of asthma up to the age of 7 years. MethodsA retrospective population-based study of a cohort of children enrolled in a nationwide employer-provided health insurance plan from January 1, 1999, through December 31, 2006, in the United States (n = 62,576). We evaluated the association between antibiotic exposure during the first year of life and subsequent development of 3 asthma phenotypes: transient wheezing (began and resolved before 3 years of age), late-onset asthma (began after 3 years of age), and persistent asthma (began before 3 years of age and persisted through 4-7 years of age). ResultsAntibiotic use in the first year of life was associated with the development of transient wheezing (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.9-2.2; P < .001) and persistent asthma (OR, 1.6; 95% CI, 1.5-1.7; P < .001). A dose-response effect was observed. When 5 or more antibiotic courses were received, the odds of persistent asthma doubled (OR, 1.9; 95% CI, 1.5-2.6; P < .001). There is no association between antibiotic use and late-onset asthma. ConclusionAntibiotic use in the first year life is associated with an increased risk of early-onset childhood asthma that began before 3 years of age. The apparent effect has a clear dose response. Heightened caution about avoiding unnecessary use of antibiotics in infants is warranted.