Exhaled NO levels and blood eosinophil counts independently associate with wheeze and asthma events

Eosinophils and exhaled Nitric Oxide (NO) levels are prominent features of asthma.  It is known that both exhaled NO and blood eosinophil counts (B-Eos) are markers of local and systemic eosinophil inflammation respectively, and are elevated in patients with the disease. However, little is known about the association of these markers with wheeze and asthma events.  Malinovschi et al [J Allergy Clin Immunol 2013; 132(4):821-827] examined subjects from National Health and Nutrition Examination Survey 2007-2008 and 2009-2010 to determine individual and independent B-Eos and Fraction of Exhaled Nitric Oxide (FENO) levels in relation to wheeze, asthma diagnosis, and asthma events.

From the cross sectional study, 12,408 subjects ranging from 6-80 years old were selected who had FENO measurements and blood differential counts.  The authors report that the prevalence of current asthma and wheeze increased progressively with FENO values and B-Eos values.  Furthermore, there was an increase in asthma attacks and asthma related ED visits which associated with an increase in both FENO and B-Eos respectively. While intermediate or high FENO and B-Eos levels were independently associated with having asthma, wheeze, and asthma attacks, only the B-Eos values were independently associated with asthma-related ED visits. 

Malinovschi explains that these 2 markers cannot be used interchangeably but rather in combination due to the finding that the correlation between the markers is weak. This indicates that they represent 2 different inflammatory pathways with separate trigger mechanisms, contrary to previous thought.  The B-Eos levels associated with asthma-related ED visits, which is in-line with recent findings that eosinophilic asthma patients receiving anti-IL-5 treatment have a reduction in severe asthma symptoms. Whereas FENO values appear to precede moderate but not severe asthma exacerbations and signal local IL-4/IL-13 mediated mechanisms in bronchial mucosa that are triggered by aeroallergen exposure. 

The authors conclude that both local and systemic Th2 cytokine-driven mechanisms, partly with different triggers, are involved in eosinophilic asthma, suggesting a double-hit mechanism for the development of respiratory symptoms and asthma.   The clinical significance of assessing both of these components for individualizing treatment warrants further study.

A major allergen of public health relevance in the inner city of Baltimore

The prevalence of asthma is ubiquitous across the United States, but the major allergens of public health relevance that contribute to the disease vary across geographical regions.  Within inner cities, the 2 most common allergens are mouse and cockroach. Ahluwalia et al [J Allergy Clin Immunol 2013; 132(4):830-835] sought to determine the relevant antigen(s) most highly associated with inner city asthma morbidity within Baltimore city. The motivation of their study was not only to aid in the management of asthma within the community but to assist in the reduction of levels of these antigens community wide. 

The authors selected 144 children between 7 and 10 years old that had been clinically identified with asthma at least one year before the start of the study.  At the start of the study, they underwent skin prick tests and had clinical data collected at baseline and again at 3, 6, 9, and 12 months.  At the same time points, settled house dust samples were collected to quantify indoor allergens.  The participants were grouped based on sensitization and exposure status of common allergens from the dust samples. 

Results indicated that mouse was the most relevant allergen with regard to asthma outcomes.  Both mouse and cockroach sensitization and exposure was significantly associated with an increased prevalence of heath care use for asthma, but only mouse sensitization and exposure was associated with higher levels of pulmonary inflammation.  Furthermore, the authors report that mouse IgE levels were also associated with poor asthma health whereas cockroach-specific IgE levels were not.   The authors went on to determine that the relationships between asthma outcomes and mouse antigen were independent of cockroach antigen. 

Ahluwalia points out that although cockroach antigen is prevalent and has some effect on outcomes, mouse antigen appears to be the strong driver of asthma morbidity among Baltimore City children.  Their data show that mouse allergen is strongly associated with a range of outcomes, including acute asthma visits, pulmonary inflammation, and lung function.  There is a profound clinical implication of these data by allowing for specific treatments for the patients and reduction of the mouse antigen at the community level.

Question for the authors: If individual urban communities used this type of study to determine the primary antigen(s) that cause community wide allergy and asthma exacerbation, what type of outcomes do you anticipate both clinically and financially both within the community and across the country? 

This question is terrific and gets to the heart of whether community-wide environmental interventions would be expected to have a broad public health benefit - by, for example, reducing asthma ED visits or hospitalizations - and what the associated costs would be.  The best means we have of estimating the potential public health impact is to calculate the proportion of asthma-related hospitalizations, for example, that can be attributed to sensitization and exposure to a particular allergen in a community.  We have done this using another Baltimore City population and estimated that between 20 and 25% of hospitalizations for asthma among Baltimore City children may be attributed to mouse allergen sensitization and exposure. In terms of costs, one multifaceted environmental intervention cost about $1500 per child [Morgan W et al NEJM 2004], which is currently the best estimate we have for the cost of an effective environmental intervention.  Whether the reduction in hospitalizations expected with, for example a mouse-targeted public health intervention in Baltimore, would be worth the cost remains to be seen.  However, a year's supply of controller medication typically costs more than $1500, so that if a mouse-targeted environmental intervention was at least as effective as controller medication, a strong case could be made to allocate more public health resources to target mouse infestation and for insurance to cover such an intervention.  Thus, the data accumulated to date suggest that a public health approach to environmental control has the potential to make a meaningful dent in asthma morbidity and asthma-related costs, not just in Baltimore City, but also in other communities with high asthma prevalence and morbidity.