Another challenge to reported risks of long-acting β2-agonists

The FDA’s position on long-acting β2-agonists has taken another hit, this time in an article reporting results from analysis of a massive database: the UK’s General Practice Research Database.

De Vries et al. (Eur Resp J 2010, published online, doi:10.1183/09031936.00124209) look at SABAs and LABAs prescribed for adults with asthma and associated clinical outcomes of death, asthma death, and hospitalization for status asthmaticus. The authors use a new pattern analysis method to determine absolute hazard rates rather than relative risk, which has the advantage of detecting differential effects independent of changes in exposure to treatment.

Starting with the British Thoracic Society’s guidelines for asthma management, exposure outcomes follow the 5 treatment steps that go from minimal intervention with SABAs to routine use of oral corticosteroids in addition to LABAs and ICS. Hazard rates were highest for the first-step and last-step interventions. These populations are recent starters and heavy, long-term treatment users, respectively. Heterogeneity of asthma medication exposure resulted in substantial variability of risk, but overall, no significant risk increases in all-cause and asthma deaths are associated with LABAs, irrespective of other concomitant therapies.

The finding associated with long-term exposure isn’t entirely surprising, but the high risk for new users is unexpected. De Vries et al. speculate that this effect could derive from excessive use of SABAs when no other treatment is prescribed or treatment of misdiagnosed cardiovascular dyspnoea.

Tell us what you think. Please feel free to post your own comments and/or predictions below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.

Long-acting β2-agonists effective for acute asthma exacerbations

The FDA has just issued an alert not to use long-acting β2 agonists (LABAs) as single control agents for asthma or for the treatment of acute severe asthma. Yet, a few studies show that LABAs, formoterol in particular, may be used in place of short-acting β2 agonists (SABAs) for acute attacks. This is consistent with discussion in the Global Initiative for Asthma guidelines about the possibility that inhaled formoterol might be just as effective as salbutamol for acute intervention. Formoterol has a rapid effect (within 3 minutes) and, unlike SABAs, has 12-hour duration.

In a recent article published in the Annals of Allergy, Asthma, and Immunology (2010; 104:247-252), Rodrigo et al. report the results of meta-analysis on a literature search for treatment interventions for acute asthma attacks that presented to emergency departments. They report that the number of studies was small, but comprised over 500 subjects. The authors found no difference in spirometric measures between formoterol and SABAs across all time points. Importantly, this shared efficacy was independent of dose ratios, age, severity, sponsorship and analysis method. On the other hand, there was no clear physiologic advantage to formoterol, as both formoterol and SABAs had the same effect on serum potassium, heart rate, QT interval and hospitalization.

The authors suggest, in conclusion, that formoterol is equally effective as SABAs for the treatment of acute asthma. They caution that their findings do not extend to life-threatening asthma since none of the studies analyzed included the very severe population.

These findings appear to challenge the recent FDA recommendation.

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Allergy healthcare costs could rise as climate change causes longer pollen seasons

Greenhouse gases, like CO2, have been linked to warming trends across the globe. With increased durations of warmer weather, plants not only have longer growing seasons (and therefore pollen seasons), but agricultural growing zones will be slowly climbing north, allowing trees and plants to move into the zones they don’t currently inhabit, but that have become too warm for growing food crops.

According to an April 14 news item from Reuters, citing a joint Asthma and Allergy Foundation and National Wildlife Federation report, the impact of continued global warming may include higher allergen levels for longer periods in the eastern part of the US. Currently, the costs in the US associated with allergies and allergic asthma are at $32 billion, which includes direct medical care, lost workdays, and lower work productivity.

Plants that are already highly allergenic, such as ragweed, would not only grow and pollinate for longer, but could produce more allergenic pollen proteins as a result. A researcher comments in the news item that there is evidence that ragweed actually grows faster in higher concentrations of atmospheric CO2 and that poison ivy produces a different, more allergenic form of its allergen, urushiol.

(For more on this topic, see the open-access review article by Shea et al. from our September 2008 issue.)

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FDA pulls CFC-propelled metered dose inhalers from production

In the late 1980s, a variety of legislation was passed to reduce the production and use of chlorofluorocarbons (CFCs) around the world. The concern is that CFCs are damaging to the Earth's ozone layer.

Beginning June 14, 2010, the FDA has mandated a phase-out of 7 metered dose inhalers (MDIs) that use chlorofluorocarbons (CFCs) as propellants. The products, which include Asmacort, Maxair, and Combivent, are prescribed for the treatment of asthma and COPD. Final phase-out will be December 2013.

The FDA has also posted a Consumer Health Information sheet to help clinicians and their patients prepare for the transition to other medications such as MDIs that use hydrofluoroalkanes as propellants.

The FDA news release explains the action as concordant with US obligations under the Montreal Protocol, which initiated the ban on CFCs in all marketed products, and the Clean Air Act. MDIs were excepted from these obligations, pending development of alternative delivery products.

What do you think? Please feel free to post your own comments and/or predictions below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.

Vitamin D levels tied to lung function and steroid sensitivity

Is it sunscreen? Or video games? Can we blame it on the weather or overeating? There is mounting evidence that vitamin D deficiency/insufficiency may be a critical factor in healthy lung function and far more common than we know.

Vitamin D and lung function in patients with asthma are the topics of articles by Sutherland et al. (Am J Respir Crit Care Med 2010, 181:699-704) and Freishtat et al. (J Pediatr 2010, doi:10.1016/j.jpeds.2009.12.033).

Sutherland and colleagues look at vitamin D2 and D3 levels, FEV1, and PC20 FEV1 in a small sample comprised of ICS-treated and –untreated asthmatic subjects. They report a significant finding of 22 ml mean increase in FEV1 for each ng/ml increase in vitamin D levels. This effect was most prominent in the ICS-untreated subjects. And there's more. Deficient/insufficient vitamin D levels were correlated to greater airway hyperreactivity and obesity. The authors also show that vitamin D improved in vitro glucocorticoid responses across both groups and suggest that serum vitamin D levels be assessed in adult patients with asthma that have poor response to ICS therapy.

Freishtat et al. present results from a cross-sectional study of African American (AA) youth with and without asthma from inner-city Washington, DC. Confirming previous research that AA individuals are more likely to be vitamin D deficient than other races, they report that vitamin D levels were significantly lower in the subjects with asthma as compared to the subjects without asthma, and prevalence of vitamin D insufficiency was significantly greater. Freishtat and colleagues point out that their AA cohort has lower levels of vitamin D than that reported recently for a Costa Rican cohort. They suggest that many factors could contribute to this, such as dark skin, obesity, high rates of poverty and northern latitude.

Tell us what you think. Please feel free to post your own comments and/or predictions below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.

Keeping children with allergic diseases safe at school

Allergic diseases often occur early in life and many children present severe symptoms while at school. It is important that parents inform schoolteachers and nurses of the possible occurrence of severe allergic reactions (to foods in particular) or severe asthma, and that teachers and staff can act quickly if a reaction occurs.

A task force representing the EAACI and GA2LEN has published a position paper in Allergy that presents the case for adoption of school-based programs that identify allergic children and take responsibility for training staff and implementing appropriate interventions for their well-being (Muraro et al. 25 March 2010, online ahead of print).

The task force consensus presents an allergic child’s bill of rights and outlines the structure of school-based responsibility, physician/parent/teacher roles, and a ground plan for anaphylaxis management.

The platform includes descriptions of asthma, eczema, food allergy and anaphylaxis in the context of school presentation, allergic triggers, challenges facing schools, and suggested intervention actions that schools might enforce. Anaphylaxis management has additional guidance that includes acute management and recommended standing medications for school health clinics.

The task force concludes with a brief discussion of a few nationalized efforts to establish uniform approaches to school-based care of allergic children in the US, UK, and Australia, with attendant identification of liability for school personnel.

[For more on this topic, please see the August 2009 JACI issue, which featured reviews on managing food allergies in schools, indoor allergens in schools and day cares, and school-based asthma programs.

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