Paediatrics (RCH) - Theses
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ItemClinical and immunological features of severe RSV disease in preterm and term infants( 2022)Respiratory syncytial virus (RSV) is the leading viral pathogen causing acute lower respiratory tract infections in children under 5 years of age. Despite advancements in medical technology and in-hospital care, there is still no vaccine available for RSV, and the burden from RSV remains substantial, particularly in low- and middle-income countries (LMIC). Severe (hospitalised) RSV disease is also associated with the development of chronic respiratory conditions such as recurrent wheeze. One of the highest risk groups for severe RSV disease are preterm infants. While there are a number of complications associated with premature birth that may predispose preterm infants to severe RSV disease (e.g. bronchopulmonary dysplasia), their relatively immature immune system is thought to play a key role. The extent to which this immature immune system contributes to disease susceptibility remains an important question to be answered. Two cohorts were investigated in this thesis. The first cohort was used for results chapter 1 and the second cohort for results chapters 2 and 3. The first was a cohort of 970 children under the age of 2 years that were admitted to the Royal Children’s Hospital with RSV disease from 2017-2019 (RCH cohort). The aim of this cohort was to identify risk factors associated with severe disease by comparing demographic, clinical and laboratory data between moderate and severe groups defined using established criteria. The second cohort was based on cord blood mononuclear cell (CBMC) samples from 25 infants born preterm (30.4-34.1 weeks gestational age (wGA)) and 25 infants born term (37-40 wGA) from Tu Du Hospital, Ho Chi Minh City, Vietnam (Vietnam cohort). The aim was to explore differences in the immune response to RSV in preterm and term infants by comparing neutralising antibodies, immune profiles, cytokine response and immune gene signatures following ex vivo RSV stimulation. For the first results chapter, we analysed clinical data from hospitalised children with moderate versus severe RSV infection, as determined by the level of respiratory support received during their admission. In this chapter, we identified that young age (<2 months), parainfluenza virus type 3 (PIV3) co-detection and premature birth were significantly associated with severe RSV disease on multivariable analysis. The PIV3 co-detection as a predictor of severe disease is a unique finding that requires further investigation in the future. Additionally, we identified a reduced number of neutrophils in the peripheral blood of children with severe compared to those with moderate RSV disease, suggesting this may be associated with disease severity. In results chapter 2, we performed high-dimensional immune profiling on CBMCs to examine baseline differences between preterm and term infants. We identified reduced frequencies in classical monocytes, myeloid dendritic cells, gamma-delta T-cells and an increased frequency of regulatory T-cells (Treg) and transitional B-cells in preterm infants. Additionally, pro-inflammatory cytokines (IL-1b, IL-6 and IL-17A) and chemokines (IL-8, eotaxin, MIP-1a and MIP-1b) were reduced in the plasma of preterm infants. This suggested a reduced pro-inflammatory profile in preterm infants compared with term infants. In results chapter 3, we stimulated CBMBs with RSVA and RSVB to identify how their innate immune response differs. Stimulation of CBMCs with RSV resulted in similar cytokine and cellular profiles between preterm and term infants. The level of maternally derived RSV neutralising antibodies was also similar. However, key differences in their transcriptome were observed. Genes involved in pro-inflammation, immune regulation and cytotoxicity were expressed at higher levels in term infants compared to preterm infants (CSF2, IL-1b, IL-10, GZMB, SOCS1, SOCS3). Additionally, weighted gene co-expression network analysis (WGCNA) identified a unique module related to the pro-inflammatory response and immune regulation in term infants but not preterm infants. These results suggest that preterm infants may be less able to regulate the inflammatory response to RSV, thereby increasing their risk of severe RSV disease. In summary, this thesis found that premature birth was significantly associated with severe RSV infections which supports previous observations. This thesis conducted an in-depth look at severe RSV disease, immune differences in preterm and term infants and further explores these differences in cord blood in an RSV specific manner. Specifically, it was found that preterm infants have a reduced capacity to produce pro-inflammatory responses and for immune regulation in response to RSV. These results are crucial in our understanding of preterm susceptibility to severe RSV disease and will aid the development of strategies to reduce the burden of disease in this highly vulnerable group.