ACAAI 2011: Immunopathology and Asthma Development, Part I

Andrew Bush, MD, FRCP, FRCPCH of the Imperial College & Royal Brompton Hospital presented a lecture “Immunopathologic Events in the Development of Childhood Asthma” at the Annual Meeting of the American College of Allergy, Asthma and Immunology in Boston. He asked his colleagues to consider the possibility that very early airway hyperresponsiveness, not inflammation, initiates asthma.

Dr. Bush stated that whatever initiates asthma is different from what maintains it. Established asthma is characterized by airway eosinophilia, and Dr. Bush showed a typical biopsy slide with thickened basement membranes and eosinophils. Dr. Bush next showed a biopsy slide of an infant with very bad wheezing and was very symptomatic; however, the histology appeared normal, without any eosinophils. Patients with established asthma also generally respond well to low dose inhaled corticosteroids (ICS).However, intermittent and continuous ICS are equally bad at disease modification. Paradoxically, ICS are effective in treating school-age asthma, but not for treating preschool asthma.

Dr. Bush stated, “Clearly there are structural errors occurring in the airway and lungs before birth” in children with asthma. Antenatal factors, especially smoking, should be considered regarding childhood asthma development. Mothers who smoke during pregnancy have children with structural effects as collagen deposition and increased mucus deposition. SIDS victims of mothers who smoked in pregnancy had increased airway smooth muscle (ASM) and wall thickness. Maternal exposure to pollutants is another possible agent that could have harmful effects on the developing respiratory system.

There appears to be a trans-generational risk from smoking. If your grandmother smoked, the odds ratio (OR) for maternal asthma unsurprisingly increases. However, even if your mother did not smoke, the OR for grandchild asthma also increases. Lastly, if your mother and grandmother smoked, the OR for grandchild asthma increases.

“The model we were all brought up on—inflammation causes airway hyperresponsiveness (AHR) and remodeling—is just plain wrong! It’s too simple, and the data do not support it.”

Dr. Bush explained that there is a poor relationship between inflammation and AHR. In fact, the relationship between change in Inflammation and change in AHR is also poor. Thus, the conventional model does not seem viable. He offered the following alternatives:

• Probable model: Airway inflammation and remodelling are parallel processes driven by an unknown “Factor X.”
• EMTU (Epithelial-Mesenchymal Trophic Unit) model: Structural changes are first, and drive inflammation.
• Friend or Foe model: Are some changes protective? Perhaps thickening the basement membranes helps protect against proteolytic damage?
• Multi-paced, multi-component model: Changes may go at different rates and serve different purposes.
• Maverick model: It all begins with AHR!

To read our article on the rest of Dr. Bush’s lecture, click here.