Early‐life respiratory infection: How do we react to this red flag?

A recent manuscript highlighted that early childhood lower respiratory tract infection (LRTI) is associated with a nearly twofold increased risk of premature adult death.1 Whether infection is causal of later mortality, or a marker of high risk is unclear. Nonetheless, very early LRTI is a clear indication of future risk. However, this is not recognized in guidelines on the management of community-acquired pneumonia or bronchiolitis. The purpose of this letter is to propose initial responses to early LRTI, specifically nutritional interventions of low risk and potential benefit, pending research to delineate pathways and therapeutic opportunities. These interventions might (a) prevent recurrent early LRTI and (b) possibly favorably modulate later risk. A reduced ability to manage oxidative stress is an important and potentially modifiable aspect in the pathogenesis of RSV bronchiolitis.2 There are known high-risk groups, such as survivors of prematurity, in whom it may be feasible to measure antioxidant levels and supplement if deficient. Obviously, most infants with bronchiolitis come from the general population, and this strategy is unlikely to be practical in all low-risk infants. It should, however, be noted that although immunization against RSV in pregnant women and the widespread use of Nirsevimab offer hope of dramatically reducing RSV infections in infancy, there is no strategy to prevent infection with rhinovirus and metapneumovirus, also common causes of bronchiolitis. Furthermore, it may be that Nirsevimab may be unaffordable in low-income settings. Acute RSV infection induces significant downregulation of the airway antioxidant system in vivo, resulting in airway oxidative damage.2 Infants with bronchiolitis have reduced blood levels of oxidized glutathione (GSSG) correlating with disease severity.3 A nested case-control study showed that unconjugated bilirubin (UCB), a naturally occurring antioxidant, was lower in children with at least one wheeze episode, with a dose-response effect compared with those who never wheezed.4 Infants with bronchiolitis also have higher levels of malondialdehyde (a marker of lipid peroxidation) and lower levels of selenium (Se), an antioxidant element, both during the their hospital stay and 2 months after discharge.5 The effects of Se deficiency may be aggravated by lower levels of zinc (Zn), which is also frequently deficient in children with recurrent lower respiratory tract infection.6 Magnesium (Mg) deficiency may also be important.7 Moreover, the fact that infants who developed life-threatening RSV disease had significantly lower vitamin D levels suggest vitamin D supplementation may be another potential preventive strategy.8 Micronutrient deficiencies do not occur in isolation9 and an approach optimizing multiple micronutrients may have significant short- and even long-term benefits10 (Table 1).11 Supplementation with antioxidants after discharge from hospitalization for LRTI might represent an opportunity for the prevention not only of recurrent wheezing but possibly of asthma since development of allergic diseases can be favored by oxidative stress12 and promoted by Zn deficiency while there is a preventive effect of diets rich in vegetables and fruits on the development of asthma and allergic diseases.13 In terms of longer-term risk, the elevation of unconjugated bilirubin in Gilbert's syndrome may be the reason for the lower incidence of cardiovascular diseases, arterial hypertension, diabetes, obesity, metabolic syndrome, certain cancers, immune, and neurodegenerative diseases.14 Hypothetically, correcting any impaired antioxidant capacity after bronchiolitis could reduce the risk of later mortality from noncommunicable diseases. Measure micronutrient status in all babies at high risk (e.g., preterm delivery) and supplement those who are deficient. We accept that this will fail to pick up the low-risk, term babies who form the bulk of those admitted with severe RSV disease. Measure micronutrient status and supplement as above in all babies and infants admitted to hospital with bronchiolitis. In addition to supplementing those deficient in micronutrients, offer a general health assessment to the families focusing not merely on the bronchiolitic child, but also health improvement for future unborn children, including dietary advice, nicotine avoidance, and breastfeeding. There needs to be a campaign to increase the public awareness of the vulnerability of the fetus and young child, and the long-term consequences of early life adverse influences, and especially that LRTI is not a transient inconvenience, but a marker of adverse long-term outcomes which should be addressed. None of the above should be seen as in competition with other evidence-based strategies such as immunization in pregnancy and the deployment of monoclonals, but rather as cheap general health measures which could contribute to better outcomes for infants. There is a huge need for research to understand in detail the mechanistic links between early LRTI and premature death. Above all, there needs to be recognition in International guidelines that LRTI in infancy is not a transient inconvenience, but a serious red flag event with serious long-term implications, which should provoke an energetic response. Andrew Bush: Conceptualization; writing—review and editing; writing—original draft. Danilo Buonsenso: Writing—review and editing; conceptualization. Diego Peroni: Conceptualization; writing—review and editing. Michele Piazza: Conceptualization; writing—review and editing. Giorgio Piacentini: Conceptualization; writing—review and editing. Attilio L. Boner: Conceptualization; writing—original draft; writing—review and editing. The authors declare no conflict of interest.