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.

FDA report on safety and efficacy of allergen extracts

This month, Slater et al. report the conclusions from the FDA’s internal review of literature supporting the efficacy of nonstandardized allergen extracts (J Allergy Clin Immunol 2012; 129:1014-1019). The FDA commenced this review in 2003, recognizing that 20 years had passed since the last advisory panel had made recommendations. Additionally, the group used additional resources, such as a greater publication base, in order to expand the search for reliable publications, and the review included consultation of the FDA Adverse Events Reporting System (AERS).

Slater et al. present the interesting historical context for their re-evaluation, beginning with the shift of regulatory responsibility for non-standardized allergenic extracts from the NIH to the FDA in 1972. They note that the FDA convened two separate advisory panels – the first from1974 through 1979 and the second from 1982 through1983 – to recommend classifications for non-standardized allergenic extracts.. The second panel was convened to amend certain previous classification recommendations, as required by a change in the regulations framing the classification process.

The authors discuss extensively the findings of the literature review as well as the review of the current nomenclature. The FDA’s internal committee presented the following results from their review of 1269 allergen extracts:

· 480 extracts used in the diagnosis and treatment of allergic disease were addressed in the literature;

· 207 extracts for diagnostic use only were addressed in the literature;

· 565 extracts had minimal or no supportive literature; and

· 17 extracts were associated with potential safety concerns.

The authors report that almost half of the allergen extracts have little or no data that support their use as a diagnostic and/or therapeutic agent. There is, however, no evidence of product-class safety-specific issues. The committee did identify seventeen extracts as having possible safety concerns.

Acetominophen sensitivity in children with asthma linked to decreased glutathione levels

Stephenson et al. present results of their investigation into mechanisms of acetaminophen sensitivity risk in children with moderate to severe asthma in a Letter to the Editor in this issue (J Allergy Clin Immunol 2012;129:863-865.e2). Based on their previous findings of (nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor-associated glutathione deficiency in children with severe asthma, the authors report decreased expression of the aryl hydrocarbon receptor (AHR) and AHR nuclear translocator heterodimer genes (ARNT), which regulates toxin metabolism, after ex vivo acetaminophen exposure. Phase II toxin metabolism enzymes, such as dehydrogenases, hydrolases, and kinases were decreased in children with asthma compared to controls. Extracellular glutathione release was unaltered in children with asthma, whereas glutathione was elevated in controls after acetaminophen exposure. Stephenson et al. note that AHR/ARNT regulates Nrf2 signaling, which is consistent with their previous research results.

Preliminary evidence of bed bug allergy

An interesting Letter to the Editor in this month’s issue reports findings from a small study by Price et al (J Allergy Clin Immunol 2012;129:863-865.e2) on IgE levels in individuals that have been bitten by bed bugs. The authors developed an assay to detect specific IgE against whole bed bug (Cimex lectularius) extract as well as against a bed bug salivary protein, nitrophorin (cNP). Out of 30 subjects enrolled, greater than 50% had specific IgE to whole extract and 30% had specific IgE to both whole extract and cNP. Subjects with whole extract IgE only also had dust mite and cockroach specific IgE, which was partially cross-reactive in their assay.

Consensus guidelines for managing women with HAE C1 inhibitor deficiency

This month’s issue features an important contribution by the Budapest HAE-C1-INH Study Group and the European C1-INH Deficiency Working Group (PREHAEAT) on the gynecological and obstetric management of females with hereditary angioedema due to C1-INHIBITOR deficiency (HAE-C1-INH). Caballero et al. (J Allergy Clin Immunol 2012;129:308-320) report consensus guidelines based on empirical clinical expertise and review of the literature covering treatment reports and gynecological and obstetric event reports in females with HAE-C1-INH (pp#).

The authors divide the recommendations into HAE-C1-INH treatment, prenatal/natal/newborn diagnosis, pregnancy management, lactation management, contraception, menstruation, menopause, cancer management, and infertility. Discussion focuses on treatment approaches for prophylaxis and side-effect minimization, particularly during pregnancy, labor, and delivery. Along with the standard therapies, such as attenuated androgens, plasma-derived human C1-INH concentrate (pdhC1-INH) and tranexamic acid (TA), the authors cover the newer drug therapies icatibant, ecallantide, and recombinant human C1-INH (rhC1-INH).

The following highlights but a few of the recommendations proposed by Caballero et al.

• Estrogens and estrogen combination products should be avoided for contraception. Barrier methods and progestins can be used; also, females with HAE-C1-INH tolerate intrauterine devices, with minor edematous events from the mechanical trauma incurred during placement.


• Plasma-derived human C1-INH is the treatment of choice during pregnancy for acute, short-term and long-term intervention. Where pdhC1-INH is unavailable, TA or fresh frozen plasma can be substituted.


• Maternal and fetal safety has not been determined for icatibant, ecallantide, and rhC1-INH, though there are no reports of adverse outcomes in pregnant women on those therapies.
  Interestingly, complications during vaginal delivery are rare and prophylactic treatment prior to labor may not be necessary; however acute treatment should be readily available.


• Lactation can produce acute episodes because of the high levels of prolactin and mechanical aspects of breastfeeding. pdhC1-INH prophylaxis is recommended for the duration of breastfeeding.
  
  

We asked Dr. Caballero to tell us more about the significance of these guidelines:

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare disease that has been the object of research interest in the last decade. The regulations on the development of new drugs for rare diseases around the world have favored the interest of pharmaceutical companies in the so called “orphan drugs”. Patients with HAE-C1-INH have benefited from this new market and have seen how new drugs were marketed in different countries. Some of these drugs are completely new, as ecallantide, a kallikrein inhibitor, or icatibant acetate, a specific B2 receptor blocker; other drugs, such as C1 inhibitor concentrate, were already in the market, but it is now when clinical trials have been fulfilled or changes in the purification process have been implemented and they have been approved in wider markets and wider indications (acute treatment, short term prophylaxis and long term prophylaxis).

The creation in 1999 of the European Group for the Study of HAE-C1-INH during the first HAE Workshop held in Budapest has been an important basis for this improvement in the management of patients with HAE-C1-INH. Hungarian HAE Group continued hosting these Workshops every two years facilitating the exchange of experiences among physicians dealing with the disease, basic researches, pharmaceutical companies interested in this disease and last, but not least, patients. These workshops were extended to participants not only from European countries but also from all around the world.

There is no doubt that management of HAE-C1-INH has improved a lot, but there remains a need for improvement. One of the main needs is to have cheaper and easier to use effective and safe medications not only for acute treatment, but also for maintenance treatment, as well as short term prophylaxis, available. Female patients with HAE-C1-INH have specific characteristics in the expression of the disease and in the management of specific issues related to the sex, such as a more severe expression of the disease, more important side effects with traditional long term prophylaxis with attenuated androgens and restriction of available treatments during pregnancy and lactation among others. These specific issues related to HAE-C1-INH in female patients had not been fully addressed in the different published guidelines or in the different clinical trials and was a common demand from individual patients to physicians. The European Working Group on HAE-C1-INH coordinated by Professor Marco Cicardi addressed this issue as part of the PREHAEAT study granted by the European Union. This work package was coordinated by Professor Laurance Bouillet and a very useful manuscript was published (Bouillet L, et al. Am J Obstet Gynecol. 2008). However, this manuscript could not address all the specific female issues and the PREHAEAT group decided to review specific literature on HAE-C1-INH in search of details on management of female patients, to put in common their management of specific issues and to come to a consensus and practical guidelines during 2009 HAE Budapest Workshop. Advice from other specialists, such as gynecologists, and geneticists was also given. I had the honor of coordinating all this work together with Professor Laurence Bouillet and Professor Henriette Farkas.

These practical guidelines are intended to improve the management of female patients with HAE-C1-INH in order to avoid unnecessary side effects and unnecessary burden due to the fear of treating patients during their pregnancy. We also tried to highlight the lack of scientific evidence to support adequate treatment during pregnancy and encourage physicians to address these issues in prospective studies. Moreover, the development of new medical techniques, such as in vitro fertilization or prenatal diagnosis, has brought important challenges in the management of these patients. We expect that these practical guidelines [will] serve as an important aid in the management of female patients with HAE-C1-INH.