Early Environment and Exposures Related to the Development of Asthma in Young Children

During a session at the 2018 AAAAI Annual Meeting, several speakers discussed how early events and exposures—even in the womb—can be predictive of asthma in young children.

Augusto A. Litonjua, MD, MPH, of the University of Rochester Medical Center in New York, began by discussing in utero events in asthma. In the mid-1980s, Dr. David Barker first popularized the concept of fetal origins of adult disease, in which events during early development have a profound impact on the risk for development of future adult disease. “Lung development occurs very early in life,” Dr. Litonjua said, noting that most research hypothesizes that lung budding begins around four to seven weeks after conception, continuing through pregnancy and postnatally.

Early exposures are very important, as the fetal immune system is already functioning early in life. Maternal factors include maternal age, asthma and allergy, nutrition, smoking, obesity, infections, stress, and microbiome. Perinatal factors include the mode of delivery, infections, and birth weight. However, he noted that there are caveats in studying diet related to asthma. Most studies focus on individual nutrients (such as vitamins C, D, and E), rather than the diet as a whole, and there are no randomized clinical trials in this space. In addition, the “dramatic” changes in food production and distribution in recent decades makes comparing older versus newer data difficult.

“A topic that I think doesn’t get enough attention is antibiotics leeching into our water and food supply,” said Dr. Litonjua. He highlighted a 2014 study published by Kostich et al in Environmental Pollution, which measured concentrations of 56 active pharmaceutical ingredients in samples from 50 large wastewater treatment plants across the United States. The researchers found hydrochlorothiazide in every sample, while metoprolol, atenolol, and carbamazepine were found in more than 90% of the samples. Valsartan had the highest concentration (5300 ng/L) and the highest average concentration (1600 ng/L) across the samples. Dr. Litonjua said these chronic low levels of chemicals appear to be tolerable in adults, but it is unclear what the impact is on a fetus.

James E. Gern, MD, FAAAAI, of the University of Wisconsin Health, then discussed early allergen sensitization and the consequences. Many studies have demonstrated that early sensitization to aeroallergens indicates high risk of asthma. The German Multicentre Allergy Study linked early perennial sensitization and exposure to wheezing, asthma, and airway obstruction, while the Tucson Children’s Respiratory Study linked early allergic sensitization and wheezing to asthma.

He then discussed a 2017 study published by Rubner et al in the Journal of Allergy and Clinical Immunology, which included 217 children who were followed prospectively from birth to 13 years. They assessed the etiology and timing of viral wheezing illnesses during the first three years of life, as well as patterns of allergen sensitization. Wheezing with rhinovirus was associated with asthma at 13 years (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.5-7.1) but respiratory syncytial virus was not (OR, 1.0; 95% CI, 0.4-2.3). They also found that age of aeroallergen sensitization influenced asthma risk: 65% of children sensitized by 1 year had asthma at 13 years compared with 40% of children who were not sensitized at 1 year but were by 5 years, and 17% among children not sensitized by 5 years. “Sensitization in first 3 years really affected the course of wheezing in childhood,” he concluded.

Tina V. Hartert, MD, MPH, of Vanderbilt Pulmonary Medicine‎ in Nashville, Tennessee, discussed early viral infection and asthma, with a focus on respiratory syncytial virus (RSV) and human rhinovirus (HRV). Lower respiratory tract infections (LRTI) are strongly associated with these two viruses and subsequent asthma development. First, she discussed differences between the two viruses:

• RSV peaks in infancy and decreases with age, while HRV is uncommon in early infancy and increases with age
• A prior history of wheeze does not affect RSV, but it does affect HRV
• RSV is not responsive to asthma medications, while HRV is
• RSV is not related to aeroallergen sensitization, while LRTI with HRV is more likely with prior aeroallergen sensitization
• A family history of asthma does not impact RSV, but this can increase the risk for HRV
• RSV causes more severe disease and is one of the most significant causes of worldwide infant morbidity and mortality, while HRV severity is more significant in those with family history of asthma

Both RSV and HRV are associated with an increased asthma risk, with a large and consistent effect demonstrated across various studies.

Because RSV is not a ubiquitous infection in the first year of life, researchers can study impacts and compare outcomes with infants who never had RSV, Dr. Hartert said. In a study, researchers demonstrated that RSV infection increases the risk of wheeze compared with those without RSV.

The risk of asthma is associated with birth timing in relationship to RSV seasonality: Infants who are, on average, four months of age at peak RSV season have the highest risk of asthma, with up to a 30% increased risk of asthma development depending on when the baby is born with regard to RSV course of action.

Both RSV and HRV impact the microbiome, airway epithelium, and immune system, and the viruses are associated with distinct upper airway microbiome signatures. A study found that RSV immunoprophylaxis leads to a decrease in asthma risk compared with those who were not immunized.

Dr. Hartert noted that there is a public health impact of these viruses, as they contribute to a substantial amount of disease. Infant RSV and LRTI and HRV at less than 3 years have significant population attributable fraction. She discussed how vaccines are in development targeting both infants and pregnant mothers, although none have reached the market. “There needs to be acceptable interventions,” she concluded.

Christine Cole Johnson, PhD, MPH, FAAAAI, of the Henry Ford Health System in Detroit, Michigan, noted that early patterns of gut microbial communities are likely associated with risk of allergic sensitization and asthma, and maternal factors likely play a strong role in the development of the child’s gut microbial community. The home environment also affects gut microbiota. She gave some examples: If a dog is in the home prenatally, the trajectory of asthma is decreased. In addition, a study found that children born of a C-section with no pet in the home had the highest trajectory of total immunoglobulin E, which is associated with markers of allergic disease. Children of mothers with current atopic asthma had higher bacterial diversity in the first six months of life and a lower diversity in the second half of the first year.

Peter Le Souef, MBBS, MD, MRCP, FRACP, of the University of Western Australia, concluded the session with an overview of lung function in infants with early wheezing. Airway function and structure determines the outcome of various airway illnesses, including asthma. From birth through six years, various factors should be examined, including:

• Airway structure forced expiratory flows at functional residual capacity, which is important for bronchiolitis, early wheeze, and asthma
• Lung size, which is impacted by in utero smoke exposure
• Airway responsiveness, which is important in preschool children
• Atopy and immune maturation, which are closely associated with outcomes from birth
• Genetics, for which the importance is still unclear

Presentation 1203: AH: NIAID: Early Events in the Development of Asthma