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.

Chinese herbal formula shows promise for protection from peanut-allergy anaphylaxis

Traditional Chinese medicine (TCM) has been practiced in humans for thousands of years, and is growing in popularity in the US. Herbal remedies, in particular, are attractive for their low cost and favorable side effect profiles. Recently, animal research on an herbal preparation, derived from a TCM formula called Wu Mei Wan, demonstrated 100% protection from peanut allergy anaphylaxis that persisted for 6 months. In the mouse-model peanut allergy study, mast cell and basophil activation and numbers were significantly decreased as well.

In this issue, Patil et al. (J Allergy Clin Immunol 2011;128:1259-1265.e2) report promising results from an extended safety study in peanut allergic subjects of Food Allergy Herbal Formula 2 (FAHF 2), an FDA-approved botanical drug, in which they also evaluated the immunomodulatory effects of FAHF 2 on basophils. After 6 months of treatment with FAHF 2, significant reductions in basophil activation markers and circulating basophil titers were demonstrated in peripheral blood allergen stimulation tests. Patil et al. also report a concomitant decrease in eosinophils, though no change in specific IgE from baseline values. They speculate that the effect on basophils is independent of IgE-mediated basophil activation and related to FAHF 2.

They report that FAHF 2 is safe based on the absence of change from baseline of laboratory values, pulmonary function testing, and electrocardiographic results. Among 14 subjects that completed the trial, the authors report one adverse event: exacerbation of eosinophilic esophagitis. The subject stopped FAHF 2 and was able to return to the study after gastroenterologic consultation.

In conclusion, FAHF 2 therapy results in reductions in basophil activation, hyperreleasibility, and circulating titers. Patil et al. note that a double-blind, placebo-controlled efficacy study is in planning stages.

We asked senior authors Xiu-Min Li and Hugh Sampson, from Mount Sinai School of Medicine, New York, to tell us about the implications of this study and future research directions:

Li and Sampson: FAHF-2 appeared safe and well-tolerated in this long-term clinical trial of food allergic patients. Although patients were not challenged in this phase I trial, basophil activation was inhibited following therapy as anticipated, suggesting that this formulation may provide a safe immunotherapeutic option for food allergic patients. A phase II trial of FAHF-2 is now underway and if it demonstrates protection against food allergic reactions, the goal is to conduct further studies to obtain FDA approval for FAHF-2 as a prescription botanical drug.

The search for reliable predictors for developing asthma

In the context of the increasing prevalence and public health burden of asthma, reliable predictors of asthma development are being sought in order to prevent or mitigate the impact of the disease. Recent research findings of the asthma risk predictive value of infant-onset eczema combined with presence of filaggrin (FLG) null mutation and food sensitization are very promising. This month’s issue presents a report by Filipiak-Pittroff and colleagues (J Allergy Clin Immunol 2011;128:1235-1241.e5), on behalf of 2 large European birth cohort studies of nutritional and environmental factors in the development of allergic diseases, in which they sought to validate the eczema+FLG+food allergy predictors and to determine if the combination was useful in predicting persistent eczema.

Filipiak-Pittroff et al. assembled a dataset of almost 300 children with infant-onset eczema and known FLG and food allergy status and retrospectively examined the relation of these conditions with the presence of asthma and persistent eczema at age 10. The authors report that all three factors are risk factors for asthma, and their combination is highly specific, but not sensitive, for predicting asthma. This finding implies that a prediction cannot be made with sufficient confidence based on these criteria only, since there might be many false negatives, i.e. many children at risk for asthma development would not be identified correctly.

Thus, their findings did not corroborate previous research suggesting a nearly 100% predictive value for asthma development for the combined presence of early eczema, food allergy, and FLG null mutation, and shows that for a precise prediction of asthma more than these three variables are needed.

Filipiak-Pittroff et al. conclude that their results underscore the complex presentation of atopic diseases and reinforce the need to identify reliable methods for prediction.

Do the NAEPP Guidelines need updating?

Stanley Szefler, MD, Deputy Editor of the JACI, provides much food-for-thought in an editorial in this month’s issue focusing on the asthma guidelines (J Allergy Clin Immunol 2011;128:937-938). Dr. Szefler asks whether our current understanding of asthma compels a review of the NAEPP EPR-3 guidelines, which were last updated in 2007. He points out accumulated evidence has changed our thinking on add-on therapy, the role of vitamin D, and the public health implications of severe asthma. Additionally, Dr. Szefler highlights recent contributions focused on biomarkers in asthma management and skin prick testing in young children as predictive of wheezing in later childhood, as well as the conundrum of asthma heterogeneity that confounds our efforts to alleviate disease burden.

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