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Over the past decade, there have been substantial advances in our understanding about how viral infections regulate asthma. Important lessons have been learned from birth cohort studies examining viral infections and subsequent asthma and from understanding the relationships between host genetics and viral infections, the contributions of respiratory viral infections to patterns of immune development, the impact of environmental exposure on the severity of viral infections, and how the viral genome influences host immune responses to viral infections. Further, there has been major progress in our knowledge about how bacteria regulate host immune responses in asthma pathogenesis. In this article, we also examine the dynamics of bacterial colonization of the respiratory tract during viral upper respiratory tract infection, in addition to the relationship of the gut and respiratory microbiomes with respiratory viral infections. Finally, we focus on potential interventions that could decrease virus-induced wheezing and asthma. There are emerging therapeutic options to decrease the severity of wheezing exacerbations caused by respiratory viral infections. Primary prevention is a major goal, and a strategy toward this end is considered., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: In infants, distinct nasopharyngeal bacterial microbiotas differentially associate with the incidence and severity of acute respiratory tract infection and childhood asthma development., Objective: We hypothesized that distinct nasal airway microbiota structures also exist in children with asthma and relate to clinical outcomes., Methods: Nasal secretion samples (n = 3122) collected after randomization during the fall season from children with asthma (6-17 years, n = 413) enrolled in a trial of omalizumab (anti-IgE) underwent 16S rRNA profiling. Statistical analyses with exacerbation as the primary outcome and rhinovirus infection and respiratory illnesses as secondary outcomes were performed. Using A549 epithelial cells, we assessed nasal isolates of Moraxella, Staphylococcus, and Corynebacterium species for their capacity to induce epithelial damage and inflammatory responses., Results: Six nasal airway microbiota assemblages, each dominated by Moraxella, Staphylococcus, Corynebacterium, Streptococcus, Alloiococcus, or Haemophilus species, were observed. Moraxella and Staphylococcus species-dominated microbiotas were most frequently detected and exhibited temporal stability. Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species-dominated microbiotas were associated with reduced respiratory illness and exacerbation events, whereas Streptococcus species-dominated assemblages increased the risk of rhinovirus infection. Nasal microbiota composition remained relatively stable despite viral infection or exacerbation; only a few taxa belonging to the dominant genera exhibited relative abundance fluctuations during these events. In vitro, Moraxella catarrhalis induced significantly greater epithelial damage and inflammatory cytokine expression (IL-33 and IL-8) compared with other dominant nasal bacterial isolates tested., Conclusion: Distinct nasal airway microbiotas of children with asthma relate to the likelihood of exacerbation, rhinovirus infection, and respiratory illnesses during the fall season., (Copyright © 2019. Published by Elsevier Inc.)

Background: Mycoplasma pneumoniae, an atypical human pathogen, has been associated with asthma initiation and exacerbation. Asthmatic patients have been reported to have higher carriage rates of M pneumoniae compared with nonasthmatic subjects and are at greater risk for invasive respiratory infections., Objective: We sought to study whether prior allergen sensitization affects the host response to chronic bacterial infection., Methods: BALB/cJ and IL-4 receptor α -/- mice were sensitized with ovalbumin (OVA) and then infected with M pneumoniae or Streptococcus pneumoniae. Immune parameters were analyzed at 30 days postinfection and included cellular profiles in bronchoalveolar lavage fluid (BALF) and serum IgG and IgE antibody levels to whole bacterial lysate, recombinant P1 adhesin, and OVA. Total lung RNA was examined for transcript levels, and BALF was examined for cytokine protein profiles., Results: Anti-M pneumoniae antibody responses were decreased in allergen-sensitized, M pneumoniae-infected animals compared with control animals, but OVA-specific IgG responses were unaffected. Similar decreases in anti-S pneumoniae antibody levels were found in OVA-sensitized animals. However, M pneumoniae, but not S pneumoniae, infection augmented anti-OVA IgE antibody responses. Loss of IL-4 receptor signaling partially restored anti-M pneumoniae antibody responses in IgG 2a and IgG 2b subclasses. Inflammatory cytokine levels in BALF from OVA-sensitized, M pneumoniae-infected or S pneumoniae-infected animals were reduced compared with those in uninfected OVA-sensitized control animals. Unexpectedly, airway hyperreactivity to methacholine was essentially ablated in M pneumoniae-infected, OVA-sensitized animals., Conclusions: An established type 2-biased host immune response impairs the host immune response to respiratory bacterial infection in a largely pathogen-independent manner. Some pathogens, such as M pneumoniae, can augment ongoing allergic responses and inhibit pulmonary type 2 cytokine responses and allergic airway hyperreactivity., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Virus-associated febrile lower respiratory tract infections (fLRIs) during infancy have been identified as risk factors for persistent wheeze development. We hypothesized that variations in innate immune defense capacity during this period, as exemplified by production of type 1 and 3 interferons (T1/3IFNs), might be an underlying determinant of risk., Objective: We sought to investigate relationships between postnatal development of innate interferon response capacity and susceptibility to early infections and persistent wheeze., Methods: We studied a subset of subjects from a birth cohort at high risk for asthma/allergy and determined the capacity of cord blood cells (n = 151) to produce any of a panel of 17 T1/3IFNs in response to the viral mimic polyinosinic-polycytidylic acid using a sensitive PCR assay. We investigated relationships between neonatal interferon responses and lower respiratory tract infection history during infancy, wheezing history to 5 age years, and ensuing maturation of innate immune capacity by age 4 years (n = 160) and 10 years (n = 125)., Results: Although cohort subjects produced an average of 2.6 ± 0.3 of the 17 innate interferons tested at birth, 24% showed no T1/3IFN production. This nonproducer subgroup showed increased risk for infant fLRIs (odds ratio, 2.62; 95% CI, 1.14-6.06; P = .024) and persistent wheeze (odds ratio, 4.24; 95% CI, 1.60-11.24; P = .004) at age 5 years relative to those producing 1 or more T1/3IFNs, whereas risk for infant wheezy lower respiratory tract infections or "transient early wheeze" was unaffected. Moreover, infants who experienced fLRIs subsequently demonstrated accelerated development of T1/3IFN response capacity between 1 and 4 years of age., Conclusions: T1/3IFN response capacity appears strongly developmentally constrained at birth. Infants in whom this negative regulation is strongest manifest increased risk for severe respiratory tract infections during infancy and subsequent persistent wheeze., (Copyright © 2018. Published by Elsevier Inc.)

Background: Viral respiratory tract infections increase the risk of development and exacerbation of atopic disease. Previously, we demonstrated the requirement for a neutrophil (PMN) subset expressing CD49d to drive development of postviral atopic airway disease in mice., Objective: We sought to determine whether human CD49d + PMNs are present in the nasal mucosa during acute viral respiratory tract infections and further characterize this PMN subset in human subjects and mice., Methods: Sixty subjects (5-50 years old) were enrolled within 4 days of acute onset of upper respiratory symptoms. Nasal lavage for flow cytometry and nasal swabs for viral PCR were performed at enrollment and during convalescence. The Sendai virus mouse model was used to investigate the phenotype and functional relevance of CD49d + PMNs., Results: CD49d + PMN frequency was significantly higher in nasal lavage fluid during acute respiratory symptoms in all subjects (2.9% vs 1.0%, n = 42, P < .001). In mice CD49d + PMNs represented a "proatopic" neutrophil subset that expressed cysteinyl leukotriene receptor 1 (CysLTR1) and produced TNF, CCL2, and CCL5. Inhibition of CysLTR1 signaling in the first days of a viral respiratory tract infection was sufficient to reduce accumulation of CD49d + PMNs in the lungs and development of postviral atopic airway disease. Similar to the mouse, human CD49d + PMNs isolated from nasal lavage fluid during a viral respiratory tract infection expressed CysLTR1., Conclusion: CD49d and CysLTR1-coexpressing PMNs are present during symptoms of an acute viral respiratory tract infection in human subjects. Further study is needed to examine selective targeting of proatopic neutrophils as a potential therapeutic strategy to prevent development of postviral atopic airway disease., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Viral respiratory tract infections are associated with asthma inception in early life and asthma exacerbations in older children and adults. Although how viruses influence asthma inception is poorly understood, much research has focused on the host response to respiratory viruses and how viruses can promote; or how the host response is affected by subsequent allergen sensitization and exposure. This review focuses on the innate interferon-mediated host response to respiratory viruses and discusses and summarizes the available evidence that this response is impaired or suboptimal. In addition, the ability of respiratory viruses to act in a synergistic or additive manner with T H 2 pathways will be discussed. In this review we argue that these 2 outcomes are likely linked and discuss the available evidence that shows reciprocal negative regulation between innate interferons and T H 2 mediators. With the renewed interest in anti-T H 2 biologics, we propose a rationale for why they are particularly successful in controlling asthma exacerbations and suggest ways in which future clinical studies could be used to find direct evidence for this hypothesis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Severe steroid-insensitive asthma is a substantial clinical problem. Effective treatments are urgently required, however, their development is hampered by a lack of understanding of the mechanisms of disease pathogenesis. Steroid-insensitive asthma is associated with respiratory tract infections and noneosinophilic endotypes, including neutrophilic forms of disease. However, steroid-insensitive patients with eosinophil-enriched inflammation have also been described. The mechanisms that underpin infection-induced, severe steroid-insensitive asthma can be elucidated by using mouse models of disease., Objective: We sought to develop representative mouse models of severe, steroid-insensitive asthma and to use them to identify pathogenic mechanisms and investigate new treatment approaches., Methods: Novel mouse models of Chlamydia, Haemophilus influenzae, influenza, and respiratory syncytial virus respiratory tract infections and ovalbumin-induced, severe, steroid-insensitive allergic airway disease (SSIAAD) in BALB/c mice were developed and interrogated., Results: Infection induced increases in the levels of microRNA (miRNA)-21 (miR-21) expression in the lung during SSIAAD, whereas expression of the miR-21 target phosphatase and tensin homolog was reduced. This was associated with an increase in levels of phosphorylated Akt, an indicator of phosphoinositide 3-kinase (PI3K) activity, and decreased nuclear histone deacetylase (HDAC)2 levels. Treatment with an miR-21-specific antagomir (Ant-21) increased phosphatase and tensin homolog levels. Treatment with Ant-21, or the pan-PI3K inhibitor LY294002, reduced PI3K activity and restored HDAC2 levels. This led to suppression of airway hyperresponsiveness and restored steroid sensitivity to allergic airway disease. These observations were replicated with SSIAAD associated with 4 different pathogens., Conclusion: We identify a previously unrecognized role for an miR-21/PI3K/HDAC2 axis in SSIAAD. Our data highlight miR-21 as a novel therapeutic target for the treatment of this form of asthma., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Most patients with MHC class I (MHC-I) deficiency carry genetic defects in transporter associated with antigen processing 1 (TAP1) or TAP2. The clinical presentation can vary, and about half of the patients have severe skin disease. Previously, one report described β2-microglobulin (β2m) deficiency as another monogenetic cause of MHC-I deficiency, but no further immunologic evaluation was performed., Objective: We sought to describe the molecular and immunologic features of β2m deficiency in 2 Turkish siblings with new diagnoses., Methods: Based on clinical and serologic findings, the genetic defect was detected by means of candidate gene analysis. The immunologic characterization comprises flow cytometry, ELISA, functional assays, and immunohistochemistry., Results: Here we provide the first extensive clinical and immunologic description of β2m deficiency in 2 siblings. The sister had recurrent respiratory tract infections and severe skin disease, whereas the brother was fairly asymptomatic but had bronchiectasis. Not only polymorphic MHC-I but also the related CD1a, CD1b, CD1c, and neonatal Fc receptor molecules were absent from the surfaces of β2m-deficient cells. Absent neonatal Fc receptor surface expression led to low serum IgG and albumin levels in both siblings, whereas the heterozygous parents had normal results for all tested parameters except β2m mRNA (B2M) expression. Similar to TAP deficiency in the absence of a regular CD8 T-cell compartment, CD8(+) γδ T cells were strongly expanded. Natural killer cells were normal in number but not "licensed to kill.", Conclusion: The clinical presentation of patients with β2m deficiency resembles that of patients with other forms of MHC-I deficiency, but because of the missing stabilizing effect of β2m on other members of the MHC-I family, the immunologic defect is more extensive than in patients with TAP deficiency., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent., Objective: We sought to study the association between specific infections in early life and development of asthma later in childhood., Methods: Three hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years., Results: In unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma., Conclusion: The number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory tract infections in general rather than on the specific triggering agent., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Asthma is a highly prevalent chronic lung disease that commonly originates in early childhood. Colonization of neonatal airways with the pathogenic bacterial strains Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae is associated with increased risk of later childhood asthma. We hypothesized that children with asthma have an abnormal immune response to pathogenic bacteria in infancy., Objective: We aimed to assess the bacterial immune response in asymptomatic infants and the association with later development of asthma by age 7 years., Methods: The Copenhagen Prospective Studies on Asthma in Childhood birth cohort was followed prospectively, and asthma was diagnosed at age 7 years. The immune response to H influenzae, M catarrhalis, and S pneumoniae was analyzed in 292 infants using PBMCs isolated and stored since the age of 6 months. The immune response was assessed based on the pattern of cytokines produced and T-cell activation., Results: The immune response to pathogenic bacteria was different in infants with asthma by 7 years of age (P = .0007). In particular, prospective asthmatic subjects had aberrant production of IL-5 (P = .008), IL-13 (P = .057), IL-17 (P = .001), and IL-10 (P = .028), whereas there were no differences in T-cell activation or peripheral T-cell composition., Conclusions: Children with asthma by school age exhibited an aberrant immune response to pathogenic bacteria in infancy. We propose that an abnormal immune response to pathogenic bacteria colonizing the airways in early life might lead to chronic airway inflammation and childhood asthma., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Evidence from longitudinal cohort studies demonstrates that wheezing that begins in early life and continues into the school years generally persists into adulthood. This persistent wheezing is associated with lung function deficits and airways hyperresponsiveness that appear to be established in the first few years of life. Allergic sensitization early in life, early-life infection with rhinovirus, or colonization with any of a number of bacteria have been associated with increased risk of persistent wheeze. Early life, whether in utero or in the first few years of life, presents a window of vulnerability during which airway injury results in persistent airways dysfunction. Available data further suggest that a second such window of vulnerability might be present in the preadolescent and adolescent years. Lung function growth patterns established by age 6 years generally continue into early adulthood to middle adulthood, typically leaving groups of subjects with wheezing that persists into or relapses during adulthood with a mean FEV(1) of about 10% of predicted value less than their peers who do not wheeze. Subgroups of patients with persistent asthma, however, can have progressive decreases in lung function and enter adulthood with even lower lung function. The concern exists that these deficits in lung function apparent in early adulthood might put subjects at risk for the later development of chronic obstructive pulmonary disease., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Associations between respiratory tract infections and asthma inception and exacerbations are well established. Infant respiratory syncytial virus and rhinovirus infections are known to be associated with an increased risk of asthma development, and among children with prevalent asthma, 85% of asthma exacerbations are associated with viral infections. However, the exact nature of this relationship remains unclear. Is the increase in severity of infections an epiphenomenon, meaning respiratory tract infections just appear to be more severe in patients with underlying respiratory disease, or instead a reflection of altered host susceptibility among persons with asthma and atopic disease? The main focus of this review is to summarize the available levels of evidence supporting or refuting the notion that patients with asthma or atopic disease have an altered susceptibility to selected pathogens, as well as discussing the biological mechanism or mechanisms that might explain such associations. Finally, we will outline areas in need of further research because understanding the relationships between infections and asthma has important implications for asthma prevention and treatment, including potential new pathways that might target the host immune response to select pathogens., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Viral respiratory tract infections are the leading cause of acute illness during infancy and are closely linked to chronic inflammatory airway diseases later in life. However, the determinants of susceptibility to acute respiratory tract infections still need to be defined., Objective: We investigated whether the individual variation in antiviral response at birth determines the risk for acute respiratory tract illness in the first year of life., Methods: We studied 82 children who were enrolled in a birth cohort study of inner-city children with at least 1 parent with allergy or asthma. We cultured cord blood monocytes and assessed IFNG and CCL5 mRNA production at 24 hours after inoculation with respiratory syncytial virus. We also monitored the frequency of acute respiratory tract illness at 3-month intervals and analyzed nasal lavage samples for respiratory tract viruses at the time of illness during the first year., Results: Respiratory tract infection was reported for 88% of subjects, and respiratory tract viruses were recovered in 74% of symptomatic children. We observed a wide range of antiviral responses in cord blood monocytes across the population. Furthermore, a decrease in production of IFNG (but not CCL5) mRNA in response to respiratory syncytial virus infection of monocytes was associated with a significant increase in the frequency of upper respiratory tract infections (r = -0.42, P < .001) and the prevalence of ear and sinus infections, pneumonias, and respiratory-related hospitalizations., Conclusion: Individual variations in the innate immune response to respiratory tract viruses are detectable even at birth, and these differences predict the susceptibility to acute respiratory tract illness during the first year of life., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Interactions between exposure to ambient air pollutants and respiratory pathogens have been shown to modify respiratory immune responses. Emerging data suggest key roles for Toll-like receptor (TLR) and nucleotide-binding oligomerization domain-like receptor (NLR) signaling in pathogen-induced immune responses. Similarly, immune responses elicited by exposure to air pollutants are mediated by specific TLR- and NLR-dependent mechanisms. This review article will summarize current knowledge about how air pollutants modify TLR- and NLR-dependent signaling and host defense responses in the lung., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children in the Western world. Despite advances in asthma management, acute exacerbations continue to occur and impose considerable morbidity on patients and constitute a major burden on health care resources. Respiratory tract viruses have emerged as the most frequent triggers for exacerbations in both children and adults; however, the mechanisms underlying these remain poorly understood. More recently, it has become increasingly clear that interactions might exist between viruses and other triggers, increasing the likelihood of an exacerbation. In this article we begin with an overview of the health, economic, and social burden that exacerbations of asthma carry with them. This is followed by a review of the pathogenesis of asthma exacerbations, highlighting the various triggers responsible and multiple interactions that exist between them. The final section first addresses what preventative measures are currently available for asthma exacerbations and subsequently examines which of the new treatments in development might lessen the burden of exacerbations in the future., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Disruption of the epithelial barrier might be a risk factor for allergen sensitization and asthma. Viral respiratory tract infections are strongly associated with asthma exacerbation, but the effects of respiratory viruses on airway epithelial barrier function are not well understood. Many viruses generate double-stranded RNA, which can lead to airway inflammation and initiate an antiviral immune response., Objectives: We investigated the effects of the synthetic double-stranded RNA polyinosinic:polycytidylic acid (polyI:C) on the structure and function of the airway epithelial barrier in vitro., Methods: 16HBE14o- human bronchial epithelial cells and primary airway epithelial cells at an air-liquid interface were grown to confluence on Transwell inserts and exposed to polyI:C. We studied epithelial barrier function by measuring transepithelial electrical resistance and paracellular flux of fluorescent markers and structure of epithelial apical junctions by means of immunofluorescence microscopy., Results: PolyI:C induced a profound decrease in transepithelial electrical resistance and increase in paracellular permeability. Immunofluorescence microscopy revealed markedly reduced junctional localization of zonula occludens-1, occludin, E-cadherin, β-catenin, and disorganization of junction-associated actin filaments. PolyI:C induced protein kinase D (PKD) phosphorylation, and a PKD antagonist attenuated polyI:C-induced disassembly of apical junctions and barrier dysfunction., Conclusions: PolyI:C has a powerful and previously unsuspected disruptive effect on the airway epithelial barrier. PolyI:C-dependent barrier disruption is mediated by disassembly of epithelial apical junctions, which is dependent on PKD signaling. These findings suggest a new mechanism potentially underlying the associations between viral respiratory tract infections, airway inflammation, and allergen sensitization., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Recent studies of the natural history of asthma have shifted attention toward viral respiratory tract illness in early life as a major risk factor associated with the development of the most persistent forms of the disease. Although early aeroallergen sensitization is strongly associated with chronic asthma, several trials in which single-aeroallergen exposure in pregnancy and early childhood was successfully accomplished and compared with sham avoidance have failed to show any decrease in asthma incidence. New evidence suggests that complex interactions occur between viral infection and aeroallergen sensitization in genetically susceptible subjects that trigger the immune responses and airway changes that are characteristic of persistent asthma. The finding that exposure to bacterial products among children raised on farms is associated with diminished asthma prevalence during the school years has now been replicated, and experimental studies have suggested that these effects are mediated by the activation of regulatory T cells in the airway. It is thus plausible to hypothesize that primary prevention of asthma could be attained through surrogate therapeutic interventions that activate similar mechanisms in young children at high risk for asthma., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Inquiries into the relationships between viral respiratory tract illnesses and the inception and exacerbation of asthma are being facilitated by recent advances in research approaches and technology. In this article we identify important knowledge gaps and future research questions, and we discuss how new investigational tools, including improved respiratory tract virus detection techniques, will permit current and future researchers to define these relationships and the host, virus, developmental, and environmental mechanisms that regulate them. A better understanding of these processes should facilitate the development of improved strategies for the prevention and treatment of virus-induced wheezing illnesses and asthma exacerbations and, possibly, the ultimate goal of discovering effective approaches for the primary prevention of asthma., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Viral respiratory infections are the most common cause of an acute asthma exacerbation in both children and adults and represent a significant global health burden. An increasing body of evidence supports the hypothesis that these infections cause a greater degree of morbidity in asthmatic subjects than in the healthy population, emphasizing a discrepancy in the antiviral response of asthmatics. In this review we discuss why such a discrepancy might exist, examining the role of the bronchial epithelium as well as the main inflammatory cells, mediators, and molecular pathways that are involved in the immune response. In addition, the potential impact of virus-induced asthma exacerbations on airway remodelling is reviewed and we explore which therapeutic options might be of benefit in preventing the deterioration of asthma control seen following viral infection., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

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.

Background: It has been proposed that immune dysfunction during early childhood plays an important role in asthma pathogenesis. However, it is not known specifically whether changes in dendritic cells (DCs) during infancy antedate the development of respiratory tract infections, asthma, and related clinical phenotypes., Objectives: We sought to assess the association between the level of blood DCs during the first year and the subsequent development of respiratory tract infections, wheezing, and allergic sensitization., Methods: A community-based cohort of children with a family history of atopy was followed to age 5 years. Children were monitored intensively for respiratory tract infections. History of wheeze and asthma was collected annually, atopy was documented at 5 years, and flow cytometry was used to identify DC subsets in blood samples collected when children were well., Results: Levels of plasmacytoid DCs (pDCs) during infancy were inversely correlated with symptoms of lower respiratory tract infections, parent-reported wheezing, and the cumulative rate of physician-diagnosed asthma up to age 5 years. These relationships were independent of atopy, as determined by allergy skin test results and total and specific IgE levels. In contrast, levels of myeloid DCs were not associated with respiratory tract infections, asthma, or wheezing but were associated with total IgE levels at age 5 years., Conclusion: In children with a family history of atopy, relative deficiency of circulating pDCs during infancy appears to be a risk factor for more frequent and more severe respiratory tract infections, wheezing, and a diagnosis of asthma. Infants with higher numbers of pDCs are protected against these outcomes.

Viral respiratory infections can have a profound effect on many aspects of asthma including its inception, exacerbations, and, possibly, severity. Of the many viral respiratory infections that influence asthma, the common cold virus, rhinovirus, has emerged as the most frequent illness associated with exacerbations and other aspects of asthma. The mechanisms by which rhinovirus influences asthma are not fully established, but current evidence indicates that the immune response to this virus is critical in this process. Many airway cell types are involved in the immune response to rhinovirus, but most important are respiratory epithelial cells and possibly macrophages. Infection of epithelial cells generates a variety of proinflammatory mediators to attract inflammatory cells to the airway with a subsequent worsening of underlying disease. Furthermore, there is evidence that the epithelial airway antiviral response to rhinovirus may be defective in asthma. Therefore, understanding the immune response to rhinovirus is a key step in defining mechanisms of asthma, exacerbations, and, perhaps most importantly, improved treatment.

Background: The original hygiene hypothesis predicts that infections should protect against asthma but does not account for increasing evidence that certain infections might also promote asthma development. A mechanistic reconciliation of these findings has not yet emerged. In particular, the role of innate immunity in this context is unclear., Objective: We sought to test whether bacterial respiratory tract infection causes airway sensitization toward an antigen encountered in parallel and to elucidate the contribution of innate immune responses., Methods: Mice were infected with different doses of Chlamydia pneumoniae, followed by exposure to human serum albumin (HSA) and challenge with HSA 2 weeks later. Airway inflammation, immunoglobulins, and lymph node cytokines were assessed. Furthermore, adoptive transfer of dendritic cells (DCs) and depletion of regulatory T (Treg) cells was performed., Results: C pneumoniae-induced lung inflammation triggered sensitization toward HSA, resulting in eosinophilic airway inflammation after HSA challenge. Airway sensitization depended on the severity and timing of infection: low-dose infection and antigen exposure within 5 days of infection induced allergic sensitization, whereas high-dose infection or antigen exposure 10 days after infection did not. Temporal and dose-related effects reflected DC activation and could be reproduced by means of adoptive transfer of HSA-pulsed lung DCs from infected mice. MyD88 deficiency in DCs abolished antigen sensitization, and depletion of Treg cells prolonged the time window in which sensitization could occur., Conclusions: We conclude that moderate, but not severe, pulmonary bacterial infection can induce allergic sensitization to inert inhaled antigens through a mechanism that requires MyD88-dependent DC activation and is controlled by Treg cells.

Background: Lower respiratory tract infection is a differentiating feature of children with poorly controlled asthma., Objective: Given the role of alveolar macrophages (AMs) in innate immunity, we hypothesized that AM phagocytosis might be impaired in poorly controlled asthma., Methods: Bronchoalveolar lavage fluid AMs were isolated from 28 asthmatic children (moderate asthma, n = 12; severe asthma, n = 16), 10 nonasthmatic children with chronic cough treated with inhaled corticosteroids, and 10 healthy adult control subjects. AMs were stimulated with LPS and exposed to fluorescein isothiocyanate-conjugated Staphylococcus aureus for 2 hours. Phagocytosis was quantified by using a phagocytic index (PI) calculated from the percentage of phagocytic cells multiplied by the relative fluorescence (RFU) units of S. aureus per cell. Apoptosis was determined from the percentage of cells positive for poly (adenosine diphosphate-ribose) polymerase., Results: Phagocytosis as measured by using the unstimulated PI was decreased in subjects with poorly controlled asthma (healthy control subjects, 9330 +/- 3992 RFU; chronic cough, 9042 +/- 5976 RFU; moderate asthma, 4361 +/- 2536 RFU; severe asthma, 3153 +/- 1886 RFU; P < .001) and remained unchanged with LPS stimulation. Children with severe asthma also had increased AM apoptosis, both the unstimulated and LPS-simulated states (P < .001), which correlated with the PI., Conclusions: AM function is compromised in children with poorly controlled asthma and is characterized by decreased phagocytosis and increased apoptosis.

A number of investigations have linked respiratory viral infections and the intensity and subsequent exacerbation of asthma through host response mechanisms. For example, it is likely that the immune-inflammatory response to respiratory syncytial virus can cause a predisposition toward an intense inflammatory reaction associated with asthma, and adenovirus might cause exacerbation of the immune response associated with chronic obstructive pulmonary disease. In each of these situations, the host's immune response plays a critical mechanistic role through the production of certain cytokines and chemokines. Specific aspects of these augmented immune responses are determined by the biology of the virus, the genetic variability of the host, and the cytokine-chemokine phenotype of the involved tissue. For instance, the type 1/type 2 cytokine ratio in the airways during infection with rhinovirus determines how long the viral infection endures. By this same theory, it has been demonstrated that chemokine levels produced during respiratory syncytial virus infection determine host responses to later immune stimuli in the lung, with the potential to augment the asthmatic response. Further research in this area will clarify cytokines, chemokines, or cell targets, which will provide the basis for next-generation therapies.

Background: Respiratory syncytial virus (RSV) infections during infancy are considered to be a risk factor for developing asthma and possibly allergic sensitization., Objective: The aim of this study was to investigate the cytokines, chemokines, and eosinophil cationic protein in the nasopharyngeal secretions of infants < or = 7 months of age with RSV infections or other respiratory viral infections and healthy infants as controls. Groups were also analyzed according to age, < or = 3 months and >3 months, and the levels were compared within and between groups., Results: Thirty-nine infants with RSV, 9 with influenza or parainfluenza virus infections and 50 controls with no history of infections, were enrolled in the study. The RSV-infected infants had significantly higher levels of IL-4; macrophage inflammatory protein 1beta, a chemoattractant for T cells; and eosinophil cationic protein in nasopharyngeal secretions compared with the control group. The levels of the TH2 cytokine IL-4 were significantly higher in RSV-infected infants < or = months of age compared with RSV-infected infants >3 months of age. In infants < or = 3 months of age, infections with influenza or parainfluenza virus caused TH2-like responses similar to those produced by RSV., Conclusion: Infections with RSV as well as with influenza and parainfluenza virus during early infancy preferentially promote a TH2-like response in the nose with local production of IL-4, IL-5, and macrophage inflammatory protein 1beta and infiltration and activation of eosinophils.

Background: An imbalance of production of T-helper lymphocyte cytokines, favoring overproduction of IL-4, is believed to be important in the pathogenesis of allergic asthma. However, less is known about the cytokine response in virus-induced wheezing, which is a major cause of morbidity in asthma., Objective: We undertook this study to determine the magnitude of IFN-gamma, IL-4 and IL-10, and leukotriene (LT) responses in infants and children with virus-induced wheezing., Methods: We measured the concentrations of IFN-gamma, IL-4 and IL-10, and cysteinyl LTs in respiratory secretions of 82 infants and young children during acute episodes of virus-induced wheezing. Control subjects were 47 infants and children with uncomplicated upper respiratory infections and 18 normal healthy infants., Results: Ratios of IFN-gamma to IL-4 were higher (due to increased quantities of IFN-gamma) in subjects with wheezing than in those with upper respiratory infection alone (P =. 003). Quantities of LTs were also increased in wheezing subjects in comparison with those with upper respiratory infections (P =.009). There was a significant correlation between measured concentrations of IFN-gamma and LTs (correlation coefficient =.451, P =.007). Quantities of IL-4 were slightly suppressed in the wheezing groups., Conclusions: An imbalance favoring overproduction of IFN-gamma appears to be associated temporarily with virus-induced wheezing. A possible mechanism is the enhanced release of LTs from eosinophils or mast cells after sensitization by IFN-gamma.

Background: The common cold is a potent trigger for asthma symptoms. Although the mechanisms are not completely understood, inflammatory events may play an important role., Objective: We tested the hypothesis that changes in steroid responsiveness are implicated in the relationship between asthma and the common cold., Methods: We investigated the steroid sensitivity of T cells from 10 patients with asthma (not taking steroids) and 10 control subjects, during upper respiratory infection and at recovery (6 weeks later). We stimulated peripheral blood mononuclear cells with phytohemagglutinin to measure T-cell proliferation, sensitivity to the inhibitory effects of steroids, and cytokine production., Results: During infection compared with recovery, the asthma group exhibited lower responsiveness to dexamethasone at 10(-10) and 10(-9)mol/L and to 10(-10)mol/L hydrocortisone (P <.05) and both groups had decreased T-cell proliferation (P <.05). During recovery, patients with asthma had greater T-cell proliferation than control subjects (P <.02); the values expressed as uptake of [3H]-thymidine were 60119+/-3944 cpm (asthma) and 39078+/-6459 cpm (control subjects). The asthma group had higher TNF-alpha and IFN-gamma production during infection (P <.05); changes in IL-8 and IL-10 levels were not significant, and IL-4 was not detected., Conclusion: During infection, asthmatic subjects exhibit decreased T-cell responsiveness to steroids. The T-cell proliferative response to phytohemagglutinin, higher in asthma, is decreased with a common cold. These findings are associated with changes in the cytokine profile. Thus viral-induced upper respiratory infections can produce an inflammatory milieu with altered steroid function and selective increases in cytokines.

Shwachman-Diamond syndrome is a rare congenital disorder of unknown etiology. Characteristic abnormalities of this disease include pancreatic insufficiency, skeletal anomalies, growth retardation, recurrent infections, and hematologic abnormalities. Significant morbidity and mortality in these patients result from respiratory infections, which are not well explained on the basis of neutrophil defects. We have had the opportunity to perform an in-depth clinical immunologic and endocrinologic evaluation of a patient with this syndrome with recurrent respiratory tract infections. She was found to have profound humoral immunologic defects, and serum thymulin was absent. In addition, endocrinologic evaluation for growth retardation revealed growth hormone deficiency. The patient responded to treatment with supplemental growth hormone and intravenous gammaglobulin with accelerated growth and cessation of infections. This case is unique in that it links growth hormone deficiency and hypogammaglobulinemia in a non-X-linked manner and may provide the basis for treatment of other patients with this rare syndrome.

Background: Recurrent pyogenic infections are known to occur in patients with an impaired response to polysaccharide antigens. We investigated the occurrence of deficient responses to pneumococcal capsular polysaccharides in patients with recurrent respiratory tract and recurrent systemic infections., Methods: Forty-five patients, 1.7 to 17.1 years of age, were immunized with 23-valent pneumococcal polysaccharide vaccine. Antibody levels to seven pneumococcal serotypes (3, 4, 6A, 9N, 14, 19F, 23F) were determined by ELISA before and after immunization. In addition, patients received a booster immunization with diphtheria toxoid, tetanus toxoid, and poliomyelitis virus vaccine., Results: Thirty-five patients had normal serum immunoglobulin levels. Five of these patients (14%) had low antipneumococcal preimmunization antibody levels and failed to respond to pneumococcal vaccination, whereas the response to booster immunization with protein antigens was appropriate. Three patients were younger than 3 years old, and one had a family history of IgG2 deficiency. Low IgG developed in a fifth patient during follow-up. Ten patients had a humoral immunodeficiency. Seven of these patients failed to respond to pneumococcal vaccination., Conclusions: We conclude that a defective immune response to polysaccharide antigens in patients requires long-term follow-up to distinguish transient maturational delay from a persistent selective impaired response to polysaccharide antigens, which on occasion may precede the development of humoral immunodeficiency disease.

To determine the immunologic and clinical status of individuals from a general population with subnormal levels of IgG2, we prospectively studied 37 of 312 blood donors with low IgG2 levels identified among 8015 donors. We examined (1) G2m(23) allotypes, (2) levels of other IgG subclasses and immunoglobulin classes, (3) composition of peripheral leukocyte populations, (4) responses to two carbohydrate antigen vaccines, (5) in vitro secretion of IgG subclasses by isolated lymphocytes after mitogen stimulation, and (6) clinical histories. We found that most (90%) individuals with subnormal IgG2 levels had G2m(23)- allotypes, whereas only 30% of the unselected donors had G2m(23)-. When individuals were separated according to their G2m(23) allotype, we found that IgG2 "normal" range for individuals with G2m(23)- allotype is 35% lower than for individuals with G2m(23)+ allotype. Individuals who had G2m(23)- allotype and had IgG2 levels greater than or equal to 0.8 but less than 1.3 gm/L had no other immunologic abnormalities. In contrast, the individuals with G2m(23)+ allotype and with IgG2 levels less than 1.3 gm/L and the individuals with G2m(23)- allotype and with IgG2 levels less than 0.8 gm/L often had additional immunologic abnormalities, including IgA and/or IgG4 deficiency and decreased in vitro expression of IgG2 subclass. None of these individuals had a clinical history remarkable for recurrent infections. Thus, subnormal IgG2 levels interpreted with G2m(23) corrected normal ranges may be a marker of other immunologic abnormalities but taken alone probably have little clinical significance in a general healthy population.

Of 247 patients referred to the Pediatric Immunology Clinic, University of Connecticut Health Center, Farmington, Conn., for recurrent infections, 13 patients were found to have an abnormal delay in the onset of IgG synthesis and prolongation of the physiologic hypogammaglobulinemia of infancy. At first observation, their mean age was 10.6 months. All patients had abnormally low serum IgG levels (less than or equal to 2 SD for their age). The mean serum IgG level for our patient population was 270 +/- 81 mg/dl; the mean serum IgG level of the control group was 749 +/- 440 mg/dl. Clinically, these patients were first observed with recurrent otitis media, respiratory infections, bronchitis and/or asthma, and formula intolerance. Despite recurrent respiratory tract infections, specific antibodies to the respiratory viruses were absent in nine of 11 patients tested who were observed before 17 months of age. On follow-up, two of the 13 patients never developed specific antibodies to viral agents, although their serum IgG levels normalized; one patient became serology positive at the same time that the serum IgG normalized. In two patients, the serum IgG levels returned to within the normal range for age before the appearance of specific viral antibodies. In eight patients, the appearance of specific viral antibodies was detected before the serum IgG levels returned to normal. Five of these eight patients were treated for short periods (9 months) with replacement immune serum globulin (intramuscular) therapy and did clinically well. These observations suggest that replacement immune serum globulin for short periods of time does not appear to suppress the production of specific, naturally occurring antibodies and the resolution of the hypogammaglobulinemia.

One hundred and three patients (90 nonatopics and 13 atopics) with respiratory infections to various viral agents were studied retrospectively with respect to IgE immunoglobulin levels during acute (1 to 7 days) and convalescent (8 to 30 days) phases of infection. It was found that 59% of patients had a decrease of 20% or more in IgE level, 27% remained the same, and only 14% showed a rise 20% or more from the acute to the convalescent phases of infection. IgE levels decreased up to 3 to 4 wk after symptoms and the degree of decrease was more apparent for the nonatopics who had higher IgE levels in their acute phase of infection. Less dramatic decrease in IgE was observed for the 13 atopics studied. The changes in IgE levels during the viral infectious period are discussed in terms of possible cellular mechanisms that may control IgE immunoglobulin.