Severe respiratory syncytial virus disease in preterm infants: a case of innate immaturity

Anderson, Jeremy; Ha, Lien Anh; Wurzel, Danielle; Toh, Zheng Quan; Mulholland, Kim; Pellicci, Daniel G.; Licciardi, Paul V.

doi:10.1136/thoraxjnl-2020-216291

Cited by 20 publications

(26 citation statements)

References 113 publications

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“…with the later development of asthma [8,[35][36][37][38]. In a study of American Indian children living in the Great Plain geographic area of rural South Dakota, we observed many similarities in the clinical characteristics of children with asthma as with prior studies, including increased BMI [39,40], increased hospitalizations or a diagnosis of RSV [41], higher levels of total serum IgE [42,43], and higher % eosinophils [44,45].…”

Section: Discussionsupporting

confidence: 57%

Respiratory syncytial virus-specific immunoglobulin G (IgG) concentrations associate with environmental and genetic factors: the Factors Influencing Pediatric Asthma Study

Erdei

Torgerson

O'Leary

et al. 2021

Preprint

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Exposure to respiratory syncytial virus (RSV) during childhood is nearly ubiquitous by age two, and infants who develop severe RSV bronchiolitis are more likely to develop asthma later in life. In the Factors Influencing Pediatric Asthma (FIPA) study including 319 children from a Northern Plains American Indian community, we found 73% of children to have high concentrations of RSV-specific IgG (>40 IU/mL). High concentration of RSV-specific IgG was associated with increased exposure to second-hand tobacco smoke (p=7.5x10-4), larger household size (p=4.0x10-3), and lower levels of total serum IgE (p=5.1x10-3). Parents of children with asthma more often reported an RSV diagnosis and/or hospitalization due to RSV, and children with asthma had lower concentrations of RSV IgG as compared to those without asthma among RSV-exposed individuals (mean 117 IU/mL vs. 154, p=7.1x10-4). However, lower RSV IgG was surprisingly exclusive to children with asthma recruited during the winter months when RSV is thought to circulate more broadly. Multivariate regression indicated the strongest predictors of RSV-specific IgG concentration included asthma status (p=0.040), per cent eosinophils (p=0.035), and an asthma x RSV season interaction (p=3.7x10-3). Among candidate genes, we identified a genetic association between an intronic variant in IFNL4 and RSV-specific IgG concentration whereby the minor allele (A) was associated with higher concentration (rs12979860, p=4.3x10-3). Overall our findings suggest there are seasonal differences in immunological response to RSV infection in asthma cases vs. controls, and identify both environmental and genetic contributions that warrant further investigation.

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Section: Discussionsupporting

confidence: 57%

Respiratory syncytial virus-specific immunoglobulin G (IgG) concentrations associate with environmental and genetic factors: the Factors Influencing Pediatric Asthma Study

Erdei

Torgerson

O'Leary

et al. 2021

Preprint

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“…In particular, identification of immune biomarkers and therapeutic targets within immunological pathways enhancing the Th1 immune response may be of benefit. 16 The potential causal relationship between severe RSV infection and asthma is supported by long-term follow-up studies of children who received RSV monoclonal antibody prophylaxis. 12 A randomised controlled trial (MAKI trial) of palivizumab versus placebo in 429 healthy preterm infants born at 33-35 weeks resulted in a nearly 50% reduction in recurrent wheeze (11% vs. 21%, P = 0.01) in the first year of life.…”

Section: Causality and Pathophysiology Of The Rsv-asthma Relationshipmentioning

confidence: 99%

Respiratory syncytial virus, recurrent wheeze and asthma: A narrative review of pathophysiology, prevention and future directions

Binns

Tuckerman

Licciardi

et al. 2022

J Paediatrics Child Health

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Globally, respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in young children, and the association between severe RSV disease and later recurrent wheeze and asthma is well established. Whilst a causal link between RSV and wheeze/asthma is not yet proven, immunological evidence suggests skewing towards a Th2‐type response, and dampening of IFN‐γ antiviral immunity during RSV infection underpins airway hyper‐reactivity in a subset of susceptible children after RSV infection. Age at primary RSV infection, viral co‐infection and genetic influences may act as effect‐modifiers. Despite the significant morbidity and mortality burden of RSV disease in children, there is currently no licensed vaccine. Recent advancements in RSV preventatives, including long‐acting monoclonal antibodies and maternal vaccinations, show significant promise and we are on the cusp of a new era in RSV prevention. However, the potential impact of RSV preventatives on subsequent wheeze and asthma remains unclear. The ongoing COVID‐19 pandemic and associated public health measures have disrupted the usual seasonality of RSV. Whilst this has posed challenges for health‐care services it has also enhanced our understanding of RSV transmission. The near absence of RSV cases during the first year of the pandemic in the context of strict public health measures has provided a rare opportunity to study the impact of delayed age of primary RSV infection on asthma prevalence. In this review, we summarise current understanding of the association between RSV, recurrent wheeze and asthma with a focus on pathophysiology, preventative strategies and future research priorities.

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“…It is worth noting that there is significant heterogeneity of RSV infection and this variation in RSV-infected disease phenotype is strongly associate with subsequent morbidity of airway diseases. Although spontaneous resolution is the outcome for most RSV-infected individuals, part of RSV-infected patients cannot be controlled and continue to aggravate, which always have high-risk of asthma in later life (5)(6)(7)(8)(9). However, the mechanism regulating the discrepancy of underlying pathology processes after RSV infection is still obscure.…”

Section: Introductionmentioning

confidence: 99%

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

Lin

Yao

et al. 2022

Front. Immunol.

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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.

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Severe respiratory syncytial virus disease in preterm infants: a case of innate immaturity

Cited by 20 publications

References 113 publications

Respiratory syncytial virus-specific immunoglobulin G (IgG) concentrations associate with environmental and genetic factors: the Factors Influencing Pediatric Asthma Study

Respiratory syncytial virus-specific immunoglobulin G (IgG) concentrations associate with environmental and genetic factors: the Factors Influencing Pediatric Asthma Study

Respiratory syncytial virus, recurrent wheeze and asthma: A narrative review of pathophysiology, prevention and future directions

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

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