The iatrogenic effect of successful ICS therapy on the progress of asthma research

This month’s issue features an editorial by Jeffrey Drazen, MD (J Allergy Clin Immunol 2012;129:1200-1201). Dr. Drazen presents the intriguing argument that our success in treating asthma with inhaled corticosteroids (ICS) has hampered significantly our ability to discern the complex, heterogeneous pathophysiology of the disease.

He briefly reviews for the reader the lengthy history of medicine’s attempts to understand and classify asthma, with reference to the JACI's 2011-2012 Asthma: Current Status and Future Directions series, which featured contributions from leaders in the field of asthma on topics such as asthma’s natural history and clinical presentation, gaps in diagnosis and treatment response, and new targets for therapy based on asthma genotypes. Dr. Drazen commends the efforts that have been made over the years, but notes that for all the research that’s been done, little true progress in early detection and prevention has resulted.

His argument is predicated on the observation that ICS efficacy for treating the inflammatory component of asthma is not specific to a single pathway and, thus, doesn’t inform the mechanisms of asthma biology. Notable work on anti-cytokine therapies for asthma is discussed, with the observation that its success has been less than expected. Drazen comments that these trials have demonstrated sensitive subgroups, but there are limited diagnostics available to identify them.

With a nod to a point raised in Stephen Holgate’s article in the JACI series (J Allergy Clin Immunol 2011;128:495-505), Dr. Drazen supports the idea that the immune dysfunction theory of asthma may need to be discarded in favor of focus on structural abnormality fundamental to the epithelium.

Drazen concludes by deflecting the idea that ICS therapy is the perfect treatment precisely because asthma is so heterogenous. He insists that understanding the specifics of asthma pathology and targeting those elements directly is the patient-centered mandate.

Three injections and counting...

Senti et al. have “injected” new hope into allergy immunotherapy (IT) with this month's report of the results of their research into intralymphatic administration of cat dander allergen for treatment of cat allergy (J Allergy Clin Immunol 2012;129:1290-1296). 

Conventional IT has a low appeal for most allergy sufferers because of the lengthy time requirement to achieve desensitization/tolerance. This is true for subcutaneous as well as sublingual IT. Although this treatment duration can be shortened by higher doses of allergen per treatment, the authors point out that this significantly increases risk of systemic reaction.

Senti et al. generated a unique delivery platform for the cat allergen, Fel d 1, using an HIV-derived translocation peptide combined with part of a human invariant chain that permitted targeting of the vaccine to the MHC class II pathway, avoiding phagocytosis and subsequent degradation. They report that the modular vehicle, MAT-Fel d 1, induced less in vitro degranulation of basophils and of mast cells in skin tests, suggesting that the vaccine may be safer than administration of unmodified allergen.

Subjects in the study received three inguinal intralymphatic injections of sequentially increased doses of MAT-Fel d 1 or placebo under ultrasound guidance. Subjects received injections once every 4 weeks. At 5 weeks after the 3^rd injection, subjects in the treatment group had 5-fold increased levels of IgG₄ compared to controls. This was positively correlated to increased titers of IL-10. The authors report nasal tolerance increased in the treatment group by a factor of 74 compared to the control group. Senti et al. also report increased tolerance of skin prick testing and intradermal testing.  At day 300 follow up, the treatment group reported continued nasal and ocular tolerance.

In conclusion, Senti et al. emphasize the rapid achievement of increased tolerance with a greater safety profile of their modular vaccine, MAT-Fel d 1. They note the need for larger studies permitting increased statistical power as well as efficacy assessment by symptom and medication reduction. 

[Update 5/2/12] We asked Dr. Senti and senior author Thomas Kündig to comment on the next steps in their research. They note, "[We] are currently planning a dose escalation and phase IIb study for further clinical development. Also, MAT molecules containing major bee venom allergen Api m 1, and dust mite allergens and birch allergens have been generated and work well in mice."

Protective effect shown in infants at risk for atopy treated with bacterial lysate

Lau et al. (J Allergy Clin Immunol 2012;129:1040-1047) report their findings from a controlled trial of heat-inactivated bacterial lysate treatment in infants with inherited risk of atopy in this month’s issue. Citing proof-of-concept research and epidemiological reports on lowered atopy incidence in rural populations, the authors hypothesize that intentional exposure to heat-inactivated bacteria might confer protection from atopy. Their study included infants with one or both parents with a history of atopic disease (allergic rhinitis, eczema, asthma or combination).

Infants were treated orally with heat-killed Echerichia coli and Enterococcus faecalis lysate for 7 months, then followed until age 3 years. The primary outcome was the presence or absence of atopic dermatitis (AD) at the end of treatment. At 31 weeks, only 10% of treated infants with single parent risk developed AD compared to 19% of infants treated with placebo. The effect was even greater in infants with paternal atopy only. Treatment effect was strongest in infants with a single parent with allergic rhinitis. No effect was observed for infants with allergic asthma, AD, or combination.

Though Lau et al. measured gut flora during the treatment period, there was no measurable alteration in flora that could be attributed to treatment. Additionally, total serum IgE levels did not differ between the two groups. The authors conclude that their study shows a possible differential atopy risk associated with paternal heredity.