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