Childhood Sensitization Plus Respiratory Infections Impair Lung Function by 25

A recent study supported the “two-hit” hypothesis, used to describe the interplay of allergic sensitization and respiratory infections during asthma development in childhood.1 The research showed that the interplay can impair lung function up to age 25 years.

“This is the first study to investigate and demonstrate the presence of an interactive relationship between early-life allergic sensitization at age 2 years and respiratory infections up to 2 years of age on lung function outcomes at 18 years and at 25 years,” wrote investigators, led by Vikas Wadhwa, PhD, from the Allergy and Lung Health Unit at the University of Melbourne, Melbourne, Victoria, Australia.

Evidence supports that lung function trajectory may be established in early childhood, impacted by factors of prematurity, early-life exposure to tobacco smoke, environmental air pollution, allergic sensitization, and respiratory infections.2,3,4,5,6 However, no studies have evaluated the two-hit hypothesis on adult lung function.

Investigators evaluated the interactions between allergic sensitizations and respiratory infections with lung function outcomes into adulthood. They used a birth cohort from the prospective Melbourne Atopy Cohort study that recruited 620 infants who were born between 1990 – 1994 and were at high risk for allergic diseases, having ≥ 1 parent or sibling with self-reported allergic diseases. Among the 620 infants, lung function data were available for 58.9% of participants at age 12 years, 66.1% at 18 years, and 39.4% at 25 years.

The team assessed allergic sensitization in children aged 24 months via skin prick testing to aero and food allergens, including cow’s milk, egg white, peanut, rye grass, cat dander, and dust mite. A wheal reaction of ≥ 2 mm was considered positive. The study defined a respiratory infection as cough, rattle, or wheeze lasting ≥ 3 days within the previous months, measured through frequent questionnaires.

Parents had telephone interviews every 4 weeks from 1 month after the child was born, until the age of 15 months, 18 months, and 2 years. Afterward, questionnaires were completed annually until the age of 6 – 7 years, and participants were followed up at ages 12, 18, and 25 years. Regression models were used to identify interactions between these exposures with lung function at ages 12, 18, and 25 years.

The study found that had age 2 years, 330 participants were sensitized. The mean number of respiratory infections was 5.56 months in those sensitized and 5.15 months in those not sensitized.

At 25 years old, those who had been sensitized at 2 years old (n = 118) demonstrated reductions in pre-bronchodilator FEV1 of 0.06 (95% confidence interval [CI], - 0.12; P = .055) for each additional month of respiratory infections. Participants not sensitized at 2 years had increases in pre-bronchodilator FEV1 of 0.07 (95% CI, 0.02 – 0.13; P = .012) for each additional month of respiratory infection.

“Our results show this association to have two distinct patterns. Early-life respiratory infections in children who were sensitized were associated with worsening of lung function,” investigators wrote. “Conversely, in those who were not sensitized, respiratory infections appeared protective against lower lung function in adulthood.”

The team referred to the latter finding as an unclear “apparent paradox.” They suggested it is possible that, in the group who were not sensitized, early-life respiratory infections could have been milder and prevented the initiation of airway remodeling. The infections could have had beneficial effects on immune maturation.

Investigators observed similar findings for the FEV1/FVC ratio (P = .011), FEF25–75 (P = .007), and absolute change in pre- and post-bronchodilator lung function. They also saw similar findings when participants were 18 years old. Less evidence existed for the interactions at 12 years old.

“These study findings are of both major clinical and public health significance,” investigators wrote. “In children who have allergic sensitization, close monitoring and efforts to prevent recurrent respiratory infections may help minimize disease progression and lung function impairment, thereby enabling the achievement of optimal functional outcomes into adulthood.”

References

1. Wadhwa V, Dharmage SC, Wurzel D, et al. Early-life allergic sensitization and respiratory infection-Two hits on lung function?. Pediatr Allergy Immunol. 2025;36(6):e70115. doi:10.1111/pai.70115

2. Grad R, Morgan WJ. Long-term outcomes of early-onset wheeze and asthma. J Allergy Clin Immunol. 2012;130(2):299-307. doi:10.1016/j.jaci.2012.05.022

3. Grant T, Brigham EP, McCormack MC. Childhood Origins of Adult Lung Disease as Opportunities for Prevention. J Allergy Clin Immunol Pract. 2020;8(3):849-858. doi:10.1016/j.jaip.2020.01.015

4. Bont L, Aalderen WM, Kimpen JL. Long-term consequences of respiratory syncytial virus (RSV) bronchiolitis. Paediatr Respir Rev. 2000;1(3):221-227. doi:10.1053/prrv.2000.0052

5. Kirkeleit J, Riise T, Wielscher M, et al. Early life exposures contributing to accelerated lung function decline in adulthood - a follow-up study of 11,000 adults from the general population. EClinicalMedicine. 2023;66:102339. Published 2023 Dec 8. doi:10.1016/j.eclinm.2023.102339

6. Kotaniemi-Syrjänen A, Reijonen TM, Korhonen K, Waris M, Vainionpää R, Korppi M. Wheezing due to rhinovirus infection in infancy: Bronchial hyperresponsiveness at school age. Pediatr Int. 2008;50(4):506-510. doi:10.1111/j.1442-200X.2008.02620.x