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.

An overview of allergic lower respiratory illnesses associated with fungi

Allergy to molds is known to be correlated with the development and severity of asthma, with Aspergillus fumigatus, in particular, associated with persistent, severe asthma in adults. A. fumigatus is the cause of allergic bronchopulmonary aspergillosis (ABPA), an asthma co-morbidity that results in exacerbations, recurrent transient chest infiltrates, peripheral and pulmonary eosinophilia, thick mucus expectorates, elevated IgE, and persistent colonization of the lower lung.

Knutsen and colleagues from the AAAAI’s Fungi and Lower Respiratory Disease Task Force present a comprehensive discourse on fungi implicated in allergic lower lung diseases in this month’s issue (J Allergy Clin Immunol 2012;129:208-291). The authors begin briefly discussing mold sensitivity and asthma, prevalence of fungal sensitivity, and relative risk of fungal sensitization and negative respiratory outcomes. They discuss the environmental ecology and biology of airborne fungi, common indoor and outdoor fungi, and fungal allergens recognized in the most common pathogenic fungi, Aspergillus fumigatus, Penicillium spp., Alternaria alternata, and Cladosporium herbarum.

The authors point out the ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM), though Candida and Penicillium are also causal fungi in ABPM. In the absence of ABPM, fungal colonization in severe asthma is common and occurs with and without sensitization. Knutsen et al. note that fungal sensitization is associated with adverse clinical presentations. Diagnostic work up of fungal sensitization in asthma includes skin prick testing and serum specific IgE and the authors discuss congruence between skin testing and specific IgE results.

Knutsen et al. extensively cover the pathophysiology of allergic fungal airway diseases, including the role of dectin receptors, proteases and protease-activated receptors, chitinases, and mycotoxins. Genetic polymorphisms identified in genes coding HLA class II, IL4 receptor, IL-13, and TLRs in patients with ABPA are briefly reviewed.

The authors conclude with a discussion of treatment approaches for ABPA and severe asthma with fungal sensitization (SAFS). Oral corticosteroids dosed for 3-6 weeks are indicated for ABPA exacerbations. Greater than half of ABPA patients respond to itraconazole therapy, for which a minimum of 6 months of therapy is recommended. Knutsen et al. note that itraconazole therapy can be extended safely for years in patients that tolerate it.

We asked Dr. Knutsen to tell us about research gaps identified by the committee. He sent us the following list of research questions that have been identified as requiring further discussion:

· Clarifying the contributions of environmental (in home, local) and microbial triggers on activity and severity of fungal asthma and allergic bronchopulmonary mycosis

· Determining the effects of climate change on disease severity and exacerbations of fungal asthma

· Improving the understanding the role of genetic, epigenetic and innate and adaptive immunity in protection from and susceptibility to Aspergilli in atopic patients, patients with fungal asthma and patients with allergic bronchopulmonary mycosis

· Learning the role of the microbiome and monitoring changes in association with treatment and exacerbations

· Determining the utility and validity of diagnostic tests for skin testing and in vitro detection of IgE antibodies

· Developing epidemiology, diagnosis and treatment consortia to create registries and respositories to reach agreement on uniform, essential criteria for diagnosis of allergic bronchopulmonary mycosis and severe asthma with fungal sensitization and its treatment

· Exploring the contributions of co-morbidities including chronic rhinosinusitis or allergic fungal rhinosinusitis in patients with fungal asthma, severe asthma with fungal sensitization and in allergic bronchopulmonary mycosis

· Identifying pharmacogenetic pathways and therapeutic heterogeneity in fungal diseases of the lower airways

· Exploring whether severe asthma with fungal sensitization meets criteria as an endotype of asthma with distinctive pathogenesis and response to treatment

· Discovering novel therapies and treatment regimens to prevent bronchiectasis in allergic bronchopulmonary mycosis

· Determining factors associated with remission of allergic bronchopulmonary mycosis and reduction in severity of fungal asthma

· Clarifying uses of bio markers and patterns of inflammation that identify stages of allergic bronchopulmonary mycosis or mild versus severe persistent asthma with fungal sensitization

· Demonstrating whether advanced recovery methodology for fungi in sputum is associated with disease activity and responses to treatment

· Elucidating the susceptibility of women to allergic bronchopulmonary mycosis and fungal asthma

· Utilizing improvements in radiologic scanning for early diagnosis and identification of exacerbations of allergic bronchopulmonary mycosis

TSLP, asthma heterogeneity, and human nuocytes

It seems that the variable presentation of asthma is even more variable than imagined. Just listing some of the known pathological variables in asthma, there is eosinophilic, atopic, IL-13 dominant, IL-5 dominant, treatment-refractory, and now, TSLP-associated asthma, the majority of which characterize the disease in its more severe forms. Shikotra and colleagues report findings in this month’s issue (J Allergy Clin Immunol 2012;129:104-111.e9) of upregulation of the innate Th2 cytokine TSLP in asthmatic epithelium, but also predominant expression of IL-13 protein in non-epithelial CD45+ cells found in the airway mucosa and the lamina propria.

Shikotra et al. demonstrate increased TSLP production in the airway mucosa with mild, moderate and severe asthma. TSLP expression was also found in the lamina propria of subjects with severe asthma. The authors note that increased TSLP production was inversely correlated to FEV1/FVC ratio. Increased TSLP production is associated with increased IL-13 and IL-4 production, but only in a subset of asthma subjects. Shikotra et al. comment that their results suggest that there are Th2-high- and -low- asthma phenotypes.

Interestingly, the authors find that the dominant sources of TSLP are from airway epithelial cells and both mast cells and lineage-negative CD45+ cells within the airway epithelium and the lamina propria. These findings support a previous hypothesis of a TSLP-mast cell pathway in the development of asthma. Additionally, the authors suggest that the CD45+ non-epithelial cells within the airway epithelium and lamina propria, may represent the human equivalent of nuocytes, innate Th2 immune cells characterized by high IL-13 production. Since nuocyte-associated IL-13 would be expected to increase TSLP production in both mast cells and epithelial cells, Shikotra et al. further suggest that this observation implies both TSLP-mast cell and TSLP-nuocyte pathways.

In the final summary, Shikotra et al. note that TSLP is a possible therapeutic target, but caution that like other anti-cytokine drugs, anti-TSLP will most likely be effective in asthma subjects with high TSLP and Th2 cytokine profiles.

Update on biomass smoke and traffic pollution and respiratory health

Laumbach and Kipen (J Allergy Clin Immunol 2012;129: 3-11) present a report this month on the contributions of burning biomass fuels (BMF) and traffic-related air pollution (TRAP) to respiratory disease. The authors begin by noting that both TRAP and BMF burning have become critical factors for increased incidence of respiratory infections, COPD, and asthma in developed and less developed countries (DC & LDC, respectively), with both being very preventable causes.

In their introduction, they point out that global pollution monitoring has been under way for half a century, but the effects of microenvironment pollutants, such as BMF and TRAP, are less studied because of the difficulty of evaluating their impact at the level of the individual. New statistical approaches have begun to close this gap to demonstrate strong correlations between TRAP and allergic respiratory diseases as well as between BMF and COPD.

Laumbach and Kipen delve into exposure patterns for BMF burning and TRAP, commenting that the greatest burdens are on women and children in LDCs and adults and children in inner city, low socioeconomic communities in DCs. BMFs are significantly linked to lower respiratory infection in children and COPD in women in LDCs due to greater exposure to cooking and heating in poorly or unventilated households. TRAP exposure is rising in both DCs and LDCs, with LDC experiencing growth in heavy industries reliant on diesel transport.

The authors review the literature on associations of BMF with COPD, tuberculosis, and asthma, TRAP with COPD, childhood asthma and adult asthma, and indoor air pollution and respiratory infection. They briefly discuss mechanistic evidence as well as intervention studies, such as the Beijing Olympics Intervention Study and the Mexico Patsari stove study.

Laumbach and Kipen conclude by commenting on the highly political nature of reducing BMF and TRAP, pointing out that public policy and individual action will be necessary to alleviate the disparate health burden on citizens of LDCs. They urge clinicians to counsel their patients on immediate impact ways to lessen their exposure, such as improving ventilation and avoiding high traffic roadways while exercising outside.