Study Highlights Respiratory Tract Infection, Wheeze Risk Factors in Preterm-Born Infants

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Early life antibiotic exposure, urban environments, avoidance of breastfeeding, and delivery by Caesarean section are all risk factors for respiratory infections and wheezing among preterm-born infants, according to recent findings.¹

The review which led to these data was authored in part by Inger C. van Duuren, from the department of pediatrics’ division of respiratory medicine and allergology at Sophia Children's Hospital - Erasmus MC in The Netherlands.

Van Duuren et al. noted that respiratory infection and wheezing risk following moderate-late preterm birth can be partially blamed on exposure to several different early life risk factors. These lead to the deviation of microbiome as well as immune development.²

“This narrative review will provide an overview of the current knowledge on immune development in early life and the factors that may influence this process in preterm-born infants,” van Duuren and colleagues wrote. “This knowledge will then be used to explore the field of immune modulating therapies in early life that may prevent respiratory infections and wheezing in young children…”¹

Background and Findings

The investigators’ review highlighted that various factors early in life can substantially impact the colonization and maturation of the microbiota, which they note in turn impacts the immune system’s development. In terms of the most significant contributors to differences in preterm and term-born infants’ microbiome development, they pointed to age and environmental exposures.

The research team also reported that the gut-lung axis plays an essential part in comprehending the link between the gut microbiome and infants’ respiratory health. Gut microbiome shifts may raise infants’ risk of respiratory morbidity, in part given the gut-lung connection.

The team highlighted 1 of the most studied microbial metabolites, which is short-chain fatty acids (SCFA) like propionate, acetate, and butyrate. They are produced through anaerobic gut bacteria and the SCFAs help to protect mucosal surfaces from the invasion of pathogens by altering the local environment.

Early-in-life exposures to key elements were noted by the investigators as greatly impacting gut microbiome development as well as infants’ immune systems. As an example, they highlighted moderate to late preterm infants’ exposure to antibiotics which is known to occur more frequently than term-born infants.

Early antibiotics exposure, including ones which have been provided to mothers prior to or during birth, were shown by the research team to be linked to increased lower respiratory tract infections (LRTI) risk and asthma risk among children. This, they reported, is due to a delay in microbiome maturation which has resulted from antibiotics’ depletion of certain gut bacteria.

Additionally, the team wrote that preterm infants have a greater likelihood of being born via Cesarean section, often resulting from maternal or fetal health concerns. Cesarean section birth was noted as raising the risk of respiratory infections at the time of infancy, and the team highlighted that microbial changes after Cesarean section delivery are connected to increased rates of respiratory issues in childhood. They added that other research suggests a 20% risk of asthma increase among children delivered by Cesarean section.

In another example, the investigators reported that breastfeeding, especially when exclusive, was associated with a diminished risk of wheezing as well as LRTI within the initial year of life. Several meta-analyses indicated that breastfeeding lowers one’s odds of asthma and rhinitis by age 4 and provides protection against respiratory syncytial virus (RSV).

They also highlighted that breastfed infants also show less microbial diversity initially given the dominance of bifidobacteria, which utilize human milk oligosaccharides (HMOs), contributing to respiratory health benefits. However, the researchers also expressed that preterm infants often cannot be exclusively breastfed.

In an additional example, the investigators highlighted the fact that exposure to a traditional farming lifestyle involving contact with animals and natural environments, has been suggested to diminish childrens’ risk of hay fever, asthma, and atopic eczema. They highlighted that the gut microbiome of children raised on farms is known to be more mature by 12 months of age, containing bacteria such as Coprococcus and Roseburia, which are capable of producing SCFAs.

The research team further expressed that natural environments provide environmental biodiversity, including green spaces, which can positively impact the skin and gut microbiota and immune development among children. They added that living within a city environment with pollution is associated with poorer immune function as well as increased respiratory issues.

Preventative measures are also being evaluated, the team wrote, including immune modulation (via probiotics, prebiotics, synbiotics, bacterial lysates, postbiotics, vaccines, and monoclonal antibodies), microbiota transplantation, and antibiotic prophylaxis. This is to help lower the effects of these early life factors on infants' respiratory and immune health.

“In this review we have highlighted the role of the microbiome and the developing immune system in respiratory tract infections and wheezing in moderate-late preterm-born infants,” they concluded. “Knowledge on risk factors for these diseases and their underlying (microbial/immunological) mechanisms is insightful to understand why preterm infants are more vulnerable for RTIs and wheezing.”

References

1. ^{van Duuren IC, van Hengel ORJ, Penders J, Duijts L, Smits HH, Tramper-Stranders GA. The developing immune system in preterm born infants: From contributor to potential solution for respiratory tract infections and wheezing. Allergy. 2024; 00: 1-19. doi:10.1111/all.16342.}
2. ^{Olin A, Henckel E, Chen Y, et al. Stereotypic immune system development in newborn children. Cell. 2018; 174(5): 1277-1292.}