Effects of Vertical Transmission of Respiratory Viruses to the Offspring.

Overt and subclinical maternal infections in pregnancy can have multiple and significant pathological consequences for the developing fetus, leading to acute perinatal complications and/or chronic disease throughout postnatal life. In this context, the current concept of pregnancy as a state of systemic immunosuppression seems oversimplified and outdated. Undoubtedly, in pregnancy the maternal immune system undergoes complex changes to establish and maintain tolerance to the fetus while still protecting from pathogens. In addition to downregulated maternal immunity, hormonal changes, and mechanical adaptation (e.g., restricted lung expansion) make the pregnant woman more susceptible to respiratory pathogens, such as influenza virus, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Depending on the infectious agent and timing of the infection during gestation, fetal pathology can range from mild to severe, and even fatal. Influenza is associated with a higher risk of morbidity and mortality in pregnant women than in the general population, and, especially during the third trimester of pregnancy, mothers are at increased risk of hospitalization for acute cardiopulmonary illness, while their babies show higher risk of complications such as prematurity, respiratory and neurological illness, congenital anomalies, and admission to neonatal intensive care. RSV exposure in utero is associated with selective immune deficit, remodeling of cholinergic innervation in the developing respiratory tract, and abnormal airway smooth muscle contractility, which may predispose to postnatal airway inflammation and hyperreactivity, as well as development of chronic airway dysfunction in childhood. Although there is still limited evidence supporting the occurrence of vertical transmission of SARS-CoV-2, the high prevalence of prematurity among pregnant women infected by SARS-CoV-2 suggests this virus may alter immune responses at the maternal-fetal interface, affecting both the mother and her fetus. This review aims at summarizing the current evidence about the short- and long-term consequences of intrauterine exposure to influenza, RSV, and SARS-CoV-2 in terms of neonatal and pediatric outcomes.

Respiratory syncytial virus seropositivity at birth is associated with adverse neonatal respiratory outcomes.

BACKGROUND: More than 60 years since the discovery of the respiratory syncytial virus (RSV), the effects of prenatal exposure to this virus remain largely unknown. In this investigation, we sought to find evidence of RSV seroconversion in cord blood and explore its clinical implications for the newborn. METHODS: Offspring from 22 pregnant women with a history of viral respiratory infection during the third trimester of pregnancy (respiratory viral illness [RVI] group) and 40 controls were enrolled in this study between 1 September 2016 and 31 March 2019. Cord blood sera were tested for anti-RSV antibodies by indirect fluorescent antibody assay. RSV seropositivity was defined as the presence of anti-RSV immunoglobulin M (IgM) or immunoglobulin A (IgA), in addition to IgG in cord blood serum at ≥1:20 dilution. RESULTS: Anti-RSV IgG was present in all cord blood serum samples from infants born to RVI mothers (95% confidence interval [CI] = 82%-100%), with 16 samples also having elevated titers for either anti-RSV IgA or IgM (73%; 95% CI = 52%-87%). No controls had evidence of anti-RSV antibodies. Eight (50%) seropositive newborns developed at least one respiratory tract finding, including respiratory distress syndrome (N = 8), respiratory failure (N = 3), and pneumonia (N = 1). RSV seropositive newborns also required more days on oxygen, had leukocytosis and elevated C-reactive protein (P = .025, P = .047, and P < .001, respectively). CONCLUSION: This study provides evidence of acute seropositivity against RSV in cord blood of newborns delivered from mothers with a history of upper respiratory tract illness in the third trimester. Cord blood seropositivity for anti-RSV IgA or IgM was associated with adverse clinical and laboratory outcomes in newborns.

Serum neurotrophins at birth correlate with respiratory and neurodevelopmental outcomes of premature infants.

OBJECTIVE: Preterm birth is a significant cause of infant morbidity and mortality, which are primarily the result of respiratory and neurodevelopmental complications. However, no objective biomarker is currently available to predict at birth the risk and severity of such complications. Thus, we sought to determine whether serum neurotrophins concentrations measured at birth correlate with risk for later development of bronchopulmonary dysplasia (BPD) and long-term neurodevelopmental outcomes. METHODS: This study prospectively included 223 newborns admitted to neonatal intensive care units (NICU) and divided into three groups: (i) preterm infants who developed BPD; (ii) preterm infants who did not develop BPD; (iii) term infants. An exploratory cohort was enrolled in West Virginia, followed by a validation cohort recruited in four NICUs in Ohio. Specimens for serum and tracheal neurotrophins concentrations were collected within 48 h of admission. Infants requiring a fraction of inspired oxygen >0.21 for at least 28 days were diagnosed with BPD. Neurodevelopmental outcomes were extrapolated from Bayley Scales of Infant Development-Third Edition (BSID-III) administered at the 24-month follow-up visit. RESULTS: Serum brain-derived neurotrophic factor (BDNF) concentration at birth had significant negative correlation with later diagnosis of BPD (P = 0.011) and with duration of invasive ventilation and oxygen supplementation (P = 0.009 and 0.015, respectively). Serum nerve growth factor (NGF) concentration at birth had significant positive correlation with BSID-III cognitive and language composite scores at 24 months (P < 0.001 and 0.010, respectively). CONCLUSIONS: These data suggest that serum neurotrophins concentrations measured at birth provide prognostic information on subsequent respiratory and neurodevelopmental outcomes.

Detection of respiratory syncytial virus (RSV) at birth in a newborn with respiratory distress.

Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children. From the nasopharyngeal or conjunctival mucosa of infected individuals, RSV spreads to the lower respiratory tract causing acute bronchiolitis and pneumonia after an incubation period of 4-6 days. In addition to its well-documented tropism for the airway epithelium, it has been shown previously that RSV can also spread hematogenously and efficiently infect extrapulmonary tissues of human hosts. Furthermore, it has been shown in animal models that RSV can spread transplacentally from the respiratory tract of a pregnant mother to the lungs of the fetus. This report describes a documented case of neonatal RSV infection strongly suggestive of prenatal transmission of this infection in humans from an infected mother to her offspring.

Nanoparticles increase human bronchial epithelial cell susceptibility to respiratory syncytial virus infection via nerve growth factor-induced autophagy.

Cytotoxic and neuroinflammatory effects of TiO2 nanoparticles (TiO2-NP) in human airways are mediated by nerve growth factor (NGF), which is also implicated in the pathophysiology of respiratory syncytial virus (RSV) infection. We tested the hypothesis that exposure to TiO2-NP results in increased susceptibility to RSV infection and exacerbation of airway inflammation via NGF-mediated induction of autophagy in lower respiratory tract cells. Human primary bronchial epithelial cells were exposed to TiO2-NP for 24 h prior to infection with recombinant red RSV (rrRSV). Expression of NGF and its TrkA and p75NTR receptors was measured by real-time PCR and fluorescence-activated cell sorting (FACS). Autophagy was assessed by beclin-1 expression analysis. Cell death was studied by FACS after annexin V/propidium iodide staining. rrRSV infection efficiency more than doubled in human bronchial cells pre-exposed to TiO2-NP compared to controls. NGF and its TrkA receptor were upregulated in RSV-infected bronchial cells pre-exposed to TiO2-NP compared to controls exposed to either rrRSV or TiO2-NP alone. Silencing NGF gene expression with siRNA significantly inhibited rrRSV infection. rrRSV-infected cells pre-exposed to TiO2-NP also showed increase in necrotic cell death and reduction in apoptosis, together with 4.3-fold increase in expression of the early autophagosomal gene beclin-1. Pharmacological inhibition of beclin-1 by wortmannin resulted in increased apoptotic rate along with lower viral load. This study shows that TiO2-NP exposure enhances the infectivity of RSV in human bronchial epithelial cells by upregulating the NGF/TrkA axis. The mechanism of this interaction involves induction of autophagy promoting viral replication and necrotic cell death.

Nanoparticles-induced apoptosis of human airway epithelium is mediated by proNGF/p75NTR signaling.

Environmental and occupational exposures to respirable ultrafine fractions of particulate matter (PM) have been implicated in the initiation and exacerbation of lung diseases. However, the precise mechanisms underlying production of cell damage and death attributed to nanoparticles (NP) on human airway epithelium are not fully understood. This study examined the role of neurotrophic pathways in NP-induced airway toxicity. Size and agglomeration of TiO2 nanoparticles (TiO2-NP) and fine (TiO2-FP) particles were measured by dynamic light scattering. Expression and signaling of key neurotrophic factors and receptors were assessed by real-time polymerase chain reaction, flow cytometry, immunostaining, and Western blot in various respiratory epithelial cells after exposure to TiO2-NP or TiO2-FP. Particle-induced cell death was measured by flow cytometry after annexin V/propidium iodide staining. The role of neurotrophin-dependent apoptotic pathways was analyzed with specific blocking antibodies or siRNAs. Exposure of human epithelial cells to TiO2-NP enhanced interleukin (IL)-1α synthesis, as well as nerve growth factor (NGF) gene expression and protein levels, specifically the precursor form (proNGF). TiO2-NP exposure also increased expression of p75NRF receptor genes. These neurotropic factor and receptor responses were stimulated by IL-1α and abolished by its specific receptor antagonist (IL-1-ra). TiO2-NP also increased JNK phosphorylation and apoptosis, which was prevented by anti-p75NRF or NGFsiRNA. Data demonstrated that TiO2-NP exerted adverse effects in the respiratory tract by inducing unbalanced overexpression of immature neurotrophins, which led to apoptotic death of epithelial cells signaled through the death receptor p75NTR. This may result in airway inflammation and hyperreactivity after exposure to TiO2-NP.

Detection of airborne respiratory syncytial virus in a pediatric acute care clinic.

OBJECTIVE: Respiratory syncytial virus (RSV) is the most common cause of respiratory illness in infants and young children, but this virus is also capable of re-infecting adults throughout life. Universal precautions to prevent its transmission consist of gown and glove use, but masks and goggles are not routinely required because it is believed that RSV is unlikely to be transmitted by the airborne route. Our hypothesis was that RSV is present in respirable-size particles aerosolized by patients seen in a pediatric acute care setting. STUDY DESIGN: RSV-laden particles were captured using stationary 2-stage bioaerosol cyclone samplers. Aerosol particles were separated into three size fractions (<1, 1-4.1, and ≥4.1 µm) and were tested for the presence of RSV RNA by real-time PCR. Samplers were set 152 cm ("upper") and 102 cm ("lower") above the floor in each of two examination rooms. RESULTS: Of the total, 554 samples collected over 48 days, only 13 (or 2.3%) were positive for RSV. More than 90% of the RSV-laden aerosol particles were in the ≥4.1 µm size range, which typically settle to the ground within minutes, whereas only one sample (or 8%) was positive for particles in the 1-4.1 µm respirable size range. CONCLUSIONS: Our data indicate that airborne RSV-laden particles can be detected in pediatric outpatient clinics during the epidemic peak. However, RSV airborne transmission is highly inefficient. Thus, the logistical and financial implications of mandating the use of masks and goggles to prevent RSV spread seem unwarranted in this setting. Pediatr Pulmonol. 2017;52:684-688. © 2016 Wiley Periodicals, Inc.

Maternal high-fat hypercaloric diet during pregnancy results in persistent metabolic and respiratory abnormalities in offspring.

BACKGROUND: We have shown in a previous population-based study significant correlation between childhood asthma and early abnormalities of lipid and glucose metabolism. This study's specific aim was to determine whether maternal nutrition in pregnancy affects postnatal metabolic and respiratory outcomes in the offspring. METHODS: On gestation day 1, dams were switched from standard chow to either high-fat hypercaloric diet or control diet. Terminal experiments were performed on newborn and weanling offspring of dams fed the study diet during gestation and lactation, and on adult offspring maintained on the same diet as their mother. RESULTS: Pups born from high-fat hypercaloric diet (HFD) dams developed metabolic abnormalities persistent throughout development. Cytokine expression analysis of lung tissues from newborns born to HFD dams revealed a strong proinflammatory pattern. Gene expression of neurotrophic factors and receptors was upregulated in lungs of weanlings born to HFD dams, and this was associated to higher respiratory system resistance and lower compliance at baseline, as well as hyperreactivity to aerosolized methacholine. Furthermore, HFD dams delivered pups prone to develop more severe disease after respiratory syncytial virus (RSV) infection. CONCLUSION: Maternal nutrition in pregnancy is a critical determinant of airway inflammation and hyperreactivity in offspring and also increases risk for bronchiolitis independent from prepregnancy nutrition.

Metabolic asthma: is there a link between obesity, diabetes, and asthma?

Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. However, the relationship between asthma, obesity, and abnormal metabolism is not well understood nor has it been adequately explored in children. This article discusses the concept of metabolic asthma and the recent hypothesis that early derangement in lipid and glucose metabolism is independently associated with increased risk for asthma.

Alternative mechanisms for respiratory syncytial virus (RSV) infection and persistence: could RSV be transmitted through the placenta and persist into developing fetal lungs?

PURPOSE OF REVIEW: Respiratory syncytial virus (RSV) represents the most common respiratory pathogen observed worldwide in infants and young children and may play a role in the inception of recurrent wheezing and asthma in childhood. We discuss herein the recent hypothesis that RSV vertically transmitted from the mother to the fetus in utero causes persistent structural and functional changes in the developing lungs of the offspring, thereby predisposing to postnatal airway obstruction. RECENT FINDINGS: A number of observations in humans support the notion that extrapulmonary tissues may be infected hematogenously by RSV and harbor this virus allowing the persistence of latent infection. More recent data from animal models suggest that RSV can be transmitted across the placenta from the respiratory tract of the mother to that of the fetus, and persist in the lungs both during development, as well as during adulthood. Vertical RSV infection is associated with dysregulation of crucial neurotrophic pathways during ontogenesis, leading to aberrant parasympathetic innervation and airway hyperreactivity after postnatal reinfection. SUMMARY: These new data challenge the current paradigm that acquisition of RSV infection occurs only after birth and shift attention to the prenatal effects of the virus, with the potential to result in more severe and lasting consequences by interfering with crucial developmental processes. The most immediate implication is that prophylactic strategies targeted to the mother-fetus dyad may reduce the incidence of postviral sequelae like childhood wheezing and asthma.

Metabolic abnormalities in children with asthma.

RATIONALE: Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. Yet, the relationship between asthma, obesity, and abnormal lipid and glucose metabolism is not well understood, nor has it been adequately explored in children. OBJECTIVES: To analyze the relationship between asthma diagnosis and body mass in children across the entire range of weight percentile categories, and to test the hypothesis that early derangement in lipid and glucose metabolism is independently associated with increased risk for asthma. METHODS: Cross-sectional analysis of a representative sample of public school children from a statewide community-based screening program, including a total of 17,994 children, 4 to 12 years old, living in predominantly rural West Virginia, and enrolled in kindergarten, second, or fifth grade classrooms. MEASUREMENTS AND MAIN RESULTS: We analyzed demographics; family history; smoke exposure; parent-reported asthma diagnosis; body mass index; evidence of acanthosis nigricans as a marker for developing insulin resistance; and fasting serum lipid profile including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Regardless of their body mass index percentile, children diagnosed with asthma were more likely than children without asthma to have higher triglyceride levels and acanthosis nigricans after controlling for sex differences and smoke exposure. CONCLUSIONS: This study provides the first set of community-based data linking asthma, body mass, and metabolic variables in children. In particular, these findings uniquely describe a statistically significant association between asthma and abnormal lipid and glucose metabolism beyond body mass index associations.

Less air pollution leads to rapid reduction of airway inflammation and improved airway function in asthmatic children.

OBJECTIVE: Air pollution can promote airway inflammation, posing significant health risks for children with chronic respiratory problems. However, it is unknown whether this process is reversible, so that limiting pollution will benefit these children. We measured the short-term response of allergic asthmatic children exposed to a real-life reduction in outdoor air pollution by using noninvasive biomarkers of airway inflammation and function. PATIENTS AND METHODS: Thirty-seven untreated allergic children with mild persistent asthma were recruited from a highly polluted urban environment and relocated to a less polluted rural environment. Air pollution, pollen counts, and meteorological conditions were carefully monitored at both sites. Nasal eosinophils, fractional exhaled nitric oxide, peak expiratory flow, and urinary leukotriene E(4) were measured first in the urban environment and then again 7 days after relocation to the rural environment. RESULTS: One week after relocation to the rural environment, we measured, on average, a fourfold decrease in nasal eosinophils and significant decrease in fractional exhaled nitric oxide. We also noted an improvement in lower airway function, reflected by highly significant increase in peak expiratory flow. In contrast, mean urinary leukotriene E(4) concentration remained unchanged after 1 week of exposure to the rural environment. CONCLUSIONS: Better air quality is associated with a rapid reduction of airway inflammation in allergic asthmatic children. Nasal eosinophils and fractional exhaled nitric oxide are sensitive indicators of this effect, and their rapid decline is paralleled by improved airway function measured by peak expiratory flow. Leukotriene synthesis has a more variable response to environmental modifications.

Role of early-life environmental influences in the development of asthma. How painful is it when you catch a bad cold too early?

A number of studies have implicated lower respiratory tract viral infections early in life as a risk factor for the subsequent development of asthma. Despite extensive research, the precise molecular mechanisms and pathways by which virus infection causes airway inflammation and affects long-term control of airway function subsequent to the initial insult remain unclear. Compromised epithelial integrity, the elaboration of local pro-inflammatory mediators, and dysfunction of neural pathways may all influence airway responses to environmental stimuli. Our research has provided evidence that combined neuroimmune interactions primed by the virus can initiate and propagate a cascade of events leading to recurrent cycles of airway inflammation and obstruction. Nerve growth factor, or NGF, represents an ideal link between virus-infected respiratory epithelium and the dense subepithelial network of sensory fibers. Studies show that RSV infection promotes a large increase in the expression of NGF and its receptors in the respiratory tract of rodents and humans. Changes in neurotrophin expression in the respiratory tract may coordinate a variety of interactions between sensory afferent nerves and multiple components of the immune system and inflammatory pathways, thus generating a pathophysiological link between early-life viral infections and childhood asthma. Such pathways may provide new avenues for the prevention and treatment of asthma and allergy in the near future.