ACAAI 2011: Immunopathology and Asthma Development, Part II

Virtually all asthma starts as episodic viral wheeze (EVW). Dr. Bush presented results from the Colt-Ashford Study, a community based, all-comers study of 642 babies born. Annual wheeze data was followed to 5.5 years, then at 8 and 14 years. Over the 14 years, the proportion of EVW gradually decreased, whereas multiple trigger wheeze (MTW) persisted.

Dr. Bush noted the role of viruses in asthma development. The COAST study found that children who developed asthma by age 6 had far more infections in the first 3 years of life, especially rhinoviruses. However, one cannot differentiate whether frequency or severityis most important factor. Dr. Bush then discussed the Tucson study, which examined the relationship between RSV and asthma, with a 13-year follow up. RSV-positive children showed improvements in symptoms and lung function over time.

Recalling his days in medical school, Dr. Bush was taught that the gut is full of bacteria, which can be modulated by diet, antibiotics, etc., and that the airway is sterile under normal circumstances. However, we inhale > 7,500 L of (unpurified) gas/day, and only 1% of bacteria can be cultured in the laboratory. Surely we’re kidding ourselves about its sterility. Studies using 16S rRNA have demonstrated a rich, diverse flora from the nose, oropharynx, and left upper lobe. Studies in farm children show that the more bacterial diversity in your environment, the less likely you’ll develop asthma; the same effect was observed for fungal diversity. However, bacterial exposure is not always beneficial, as shown in the COPSAC Study of 321 infants with hypopharyngeal cultures at one month. Twenty-one percent were colonized with one or more types of bacteria, and their wheeze outcomes had worsened.

Two epidemiologic studies stressed the importance of AHRin early age asthma development. In the first study, AHR + SPTs of 95 children were measured at one month of age and then again at age 6. AHR at one month was an independent predictor of spirometry, asthma symptoms, and physician-diagnosed asthma at age 6. Thus, AHR in newborns may define a physiologic status that may be associated with asthma manifestation by age 6. The second study had an initial component and a 10 year follow up. At the follow up, neonatal BHR still predicted FEV1 (p=0.03), and was associated with wheeze < 4 years only.

Dr. Bush revisited his hypothetical model, pleased that at least airway wall changes did indeed occur in utero. Also, structural changes were shown to lead to early AHR, which is very important epidemiologically. Biopsies from the Helsinki study (age 1 with very severe wheeze), showed no difference in smooth muscle area between infants with reversible airflow obstruction and those with normal lung function.

In conclusion, Dr. Bush outlined his hypothetical model. In brief, in utero structural changes lead to early AHR. Also, in utero immunological effects (including smoke exposure) and in utero structural changes increase susceptibility toviral, and perhaps other types of, infections, leading to epithelial injury and augmented airway constriction. This constriction influences mediator and growth factor release, which then, and only then, leads to inflammation, structural airway wall changes, and asthma.

Dr. Bushcalled his last slide his most important one. It was his young grandson enjoying an ice cream cone under the words, “Remember: Early life rocks!”