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Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin/mucosal swelling, and/or attacks of severe abdominal pain when it affects the gastrointestinal tract. The disease might be unexpectedly fatal when the upper airways are compromised. HAE clinical presentation, disease course and prognosis are associated with significant disease burden and severely impaired quality of life. Lanadelumab is a breakthrough therapy for the prevention of attacks in HAE type 1 and 2 patients. This revolutionary approach to administer a single subcutaneous injection (once every two to four weeks) and achieve complete disease control has dramatically improved patient care resulting in significant change in the life of affected families. Current data support the drug's tolerability in adult and adolescent patients without notable safety concerns in both clinical research and real-world settings. Rational use of prophylactic treatments of HAE searches for a socio-economic balance, taking into account the life-long course of the disease, the public health funds who pay the monetary price, and the patients who might need to receive the therapy for a period longer than investigated during the development program. In this review, we address the current evidence on lanadelumab's tolerability, highlighting aspects of the drug's rationale use in clinical practice. Further studies need to investigate whether this therapy might be appropriate in other forms of angioedema, such as idiopathic primary angioedema and HAE with normal C1 inhibitor. Future efforts must focus to improve modern drugs' accessibility in more countries. Although modern prophylactic options lessen the risk of fatal laryngeal attacks, patients must be equipped with reliable on-demand therapies and be trained how to use them as such a risk cannot be fully diminished with potentially life-threatening attacks occurring even in subjects with successful and stable long-term prophylaxis. Notwithstanding, further studies are needed to identify early responders from non-responders and develop therapies for the latter.

Background In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. Methods C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. Results In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. Conclusions For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.

Hereditary angioedema (HAE), an inherited deficiency offunctional C1 esterase inhibitor (C1-INH), is characterized byrecurrent episodes of disabling and often painful swelling insubcutaneous and/or submucosal tissues.1HAE attacks aregenerally unpredictable, but triggers for an attack can includehaving a dental or medical procedure (eg, surgery), other trauma,or stress. A preemptive management plan for patients under-going these types of situations may reduce the risk of HAE at-tacks. Recommendations include administration of short-termprophylaxis in patients with HAE before invasive medical pro-cedures, especially those involving the upper airways or digestivetract, with C1-INH concentrate typically the medication ofchoice.

Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.

Introduction Hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is a rare disease with unpredictable, self-limiting and localized swelling episodes involving the cutaneous and subcutaneous tissues. In the last decade, the spectrum of the possibilities to control the disease has considerably changed with the development of biologic therapies making necessary a careful evaluation of the differences among current and emerging treatments to properly optimize the management of patients. Areas covered This review serves to summarize the literature regarding the use of biologics for the treatment of C1-INH-HAE. Medications already available on the market and new drugs in different phases of development are addressed. Expert opinion The advent of biologic therapies dramatically improved the lives of patients with C1-INH-HAE although further improvement is still needed. Whether this is cost/effective will be answered in the next years when we will see if these major advances will benefit the majority of the patients.

Hereditary angioedema is a rare disease that can often be disabling or even life threatening because of the unpredictable, self-limiting, and localized swelling episodes involving cutaneous, subcutaneous, and mucosal sites. The last decades revealed a spectrum of possibilities to control the disease through the development of effective therapies that changed the life of many patients and families worldwide. This review summarizes the current literature regarding the general management and therapeutic approach in patients with hereditary angioedema, both with and without C1 inhibitor deficiency. Medications already available in the market and new drugs in different research stages of development are addressed. Recent decades saw a huge leap in identifying mechanisms of angioedema and developing modern safe and effective medications to both treat acute angioedema manifestations and control disease activity via prophylactic therapy. Further improvement is still needed, together with improving global accessibility of diagnostic tools and effective medications. Whether novel drugs will demonstrate a sustained cost/effectiveness ratio will be answered in the years to come when we will witness whether a majority of the patients will benefit from these major advances.

Background Hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency (C1-INH-HAE) is characterized by recurrent swelling attacks. A European treatment registry was established to review the adverse event profile and efficacy of recombinant human C1 esterase inhibitor (rhC1-INH) for HAE attacks. Methods Individuals with C1-INH-HAE were enrolled following a decision to treat with rhC1-INH and provision of written informed consent. Medical history and baseline HAE information were collected at screening. Healthcare providers entered data on HAE attacks, response to treatment, and adverse events using a web-based questionnaire. Results From July 1, 2011, through December 1, 2019, 71 patients with C1-INH-HAE (30 male/41 female; mean age, 47.3 years; age range, 19–78 years) in 9 countries reported 2356 attacks and were treated with rhC1-INH. Before registry entry, patients, including 20 (28.2%) who were on maintenance therapy/prophylaxis at registry enrollment, experienced a mean of 25 HAE attacks per year (median, 16 [range, 0–185]). Most treated HAE attacks were abdominal (46.1%), followed by peripheral (38.3%), oro-facial-pharyngeal (14.8%), urogenital (3.2%), and laryngeal (2.6%). The mean rhC1-INH dose was 3307 U (43.3 U/kg). Patients reported symptom improvement within 4 h for 97.8% of attacks (2305/2356) with rhC1-INH; most attacks (99.8%; 2351/2356) required only 1 dose. Five attacks were treated with a second dose (total rhC1-INH dose administered for attack, 4200 U). No hypersensitivity, thrombotic/thromboembolic events, or drug-related serious adverse events were reported. Conclusion The rhC1-INH treatment registry provided real-world data on the treatment of 2356 HAE attacks that were consistent with clinical trial data of rhC1-INH in patients with C1-INH-HAE.

Introduction: Hereditary angioedema (HAE) with C1 esterase inhibitor deficiency (C1-INH-HAE) is a rare disease that manifests with cutaneous and/or submucosal swellings due to uncontrolled activation of the contact/kinin system. Attacks recur with unpredictable frequency and severity, laryngeal edema is potentially lethal, and the disease burden may severely disrupt patients' lives.Areas covered: This review provides an overview of lanadelumab, a human monoclonal antibody targeted against plasma kallikrein that was recently approved for prevention of symptoms in C1-INH-HAE.Expert opinion: The phase III HELP Study demonstrated the efficacy of lanadelumab in reducing HAE attacks. These positive results are being further confirmed in the open-label extension study. This agent addresses some of the limitations of existing prophylactic options as tolerability issues, the need for intravenous administration and frequent dosing. Therefore, lanadelumab can profoundly improve the quality of life of patients with C1-INH-HAE.

Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.

Hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency is a debilitating and potentially lethal disease. Management includes on-demand treatment of angioedema and their prophylaxis. Plasma derived C1-INH is an established treatment for both on demand and prophylaxis of HAE. Conestat alfa is a recombinant form of human C1-INH (rhC1-INH) produced in transgenic rabbits. It has granted drug's registration as treatment option for acute HAE attacks in adults and adolescents in Europe, America, and other countries. Long-term prophylaxis with rhC1-INH received recent consideration in clinical trials. Areas covered: This review will critically appraise available information about rhC1-INH (conestat alfa) prophylactic treatment in adult and adolescent patients with congenital C1-INH deficiency. Results from a phase II randomized placebo-controlled trial for prophylaxis of severe HAE evidenced positive treatment outcomes for its application, both twice or once weekly. Expert commentary: Phase II clinical studies suggest that rhC1-INH is a viable option for prophylaxis of HAE. Safety and tolerability data are comparable to other available HAE specific drugs, zeroing the possibility for blood-born viral transmission. Sustainability of modern technologies is granting a practically stable and continuous recombinant production process. With other available options, rhC1-INH facilitates tailoring HAE treatment to patients' needs.

C-C motif chemokine ligand 2 (CCL2), also called monocyte chemoattractant protein-1 (MCP-1) is a key β-chemokine involved in the migration of monocytes and macrophages, playing a significant role in the inflammatory responses in the airways. We aimed to assess the serum levels of MCP-1/CCL2 in a pilot cross-sectional study of Bulgarian children with bronchial asthma (BA) and cystic fibrosis (CF). Forty-two children were recruited to the study as follows: twenty with BA, twelve with CF and ten healthy children. Serum MCP-1/CCL2 levels were measured using ELISA. We found higher serum level of MCP-1/CCL2 in children with BA (191.09±64.96 pg/ml) and CF (258.51±76.45 pg/ml) compared to healthy children (70.30±64.30 pg/ml, p=0.022, and p=0.068, respectively). Younger patients with BA had higher levels of MCP-1/CCL2, as well as children with CF, with levels decreasing gradually with age. We observed also higher levels of MCP-1/CCL2 in children with moderate to severe BA compared to mild BA. We documented the significantly higher level of MCP-1/CCL2 in children with these chronic pulmonary diseases than in healthy controls, which suggesting that investigation of serum MCP-1/CCL2 levels could turn out to be beneficial for the severity of the disease.

Background Defective nasal barrier function is implicated in allergic rhinitis, which results in persistent inflammation and clinical symptoms, among which congestion plays a prominent role. In searching ways to improve the efficacy of nasally applied drugs in this condition, we tested the hypothesis that hydroxypropylmethylcellulose (HPMC), known as a mucoprotective agent, could enhance the efficacy of a decongestant (oxymetazoline nasal spray, 0.05%) by "sealing" it to the mucosa. Methods This double-blind placebo-controlled study was conducted with 40 patients (mean age, 35 years; 23 women) with persistent allergic rhinitis. The patients were randomized to receive 1 puff of oxymetazoline, followed by 1 puff of either HPMC or lactose powder (placebo) twice a day for 7 days and then only oxymetazoline rescue medication for another week. Peak inspiratory nasal flow (PNIF) was measured for 360 minutes after oxymetazoline and HPMC or placebo insufflation on days 1 and 8, and at a single point on day 15. Symptoms assessments involve visual analog scales and total nasal symptom scores. Results HPMC significantly enhanced oxymetazoline-increased PNIF at days 1 (p = 0.042) and 8 (p = 0.006). Baseline PNIF was greater in the HPMC group at day 15 (p = 0.014), indicative of further reduced nasal congestion. All nasal symptoms improved in both groups at day 8, but only the HPMC group showed further amelioration at day 15. Rescue medication was smaller in the HPMC group between days 8 and 15. Conclusion HPMC enhances decongestion through mucoadhesion but may also be augmenting the mucosal barrier in allergic rhinitis, which explains the carryover efficacy of oxymetazoline for a week after its discontinuation. Clinical trial registration clinicaltrials.gov identifier: NCT01986582.

SERPING1 genotyping of subjects suspicious for hereditary angioedema due to C1-INH deficiency (C1-INH-HAE) is important for clinical practice as well as for research reasons. Conventional approaches towards the detection of C1-INH-HAE-associated SERPING1 variants are cumbersome and time-demanding with many pitfalls. To take advantage of the benefits of next-generation sequencing (NGS) technology, we developed and validated a custom NGS platform that, by targeting the entire SERPING1 gene, facilitates genetic testing of C1-INH-HAE patients in clinical practice. In total, 135 different C1-INH-HAE-associated SERPING1 variants, out of the approximately 450 reported, along with 115 negative controls and 95 randomly selected DNA samples from affected family members of C1-INH-HAE index patients, were included in the forward and reverse validation processes of this platform. Our platform's performance, i.e. analytical sensitivity of 98.96%, a false negative rate of 1.05%, analytical specificity 100%, a false positive rate equal to zero, accuracy of 99.35%, and repeatability of 100% recommends its implementation as a first line approach for the genetic testing of C1-INH-HAE patients or as a confirmatory method. A noteworthy advantage of our platform is the concomitant detection of single nucleotide variants and copy number variations throughout the whole length of the SERPING1 gene, moreover providing information about the size and the localization of the latter. During our study, 15 novel C1-INH-HAE-related SERPING1 variants were detected.

Introduction Patients with hereditary angioedema (HAE) are at risk for an acute attack after medical procedures. Short-term prophylaxis may minimize this risk. This study evaluated recombinant C1 esterase inhibitor (rhC1-INH) as short-term prophylaxis. Methods Patients with angioedema were treated with rhC1-INH prior to medical procedures/stressful life events; HAE attacks were recorded through 2 days and >2-7 days postprocedure. Results Fifty-one patients (median age, 44 years [range, 17-73 years]; 62.7% female; 92.2% HAE type 1) were included. A median rhC1-INH dose of 3075 IU (range, 2100-4200 IU) was administered as prophylaxis, median of 60 minutes prior, for 70 procedures (52.9% [n=37] dental [median, 60 minutes preprocedure]); 30.0% [n=21] surgical [median, 45 minutes preprocedure]; 15.7% [n=11] endoscopy [median, 30 minutes preprocedure, and 1.4% [n=1] stressful life event). Majority (n=48; 68.6%) of 70 cases had rhC1-INH administered 10-65 minutes preprocedure: 25 of 48 (52.1%) dental, 16 (33.3%) surgical, and 7 (14.6%) endoscopy. Nineteen (27.1%) cases involved long-term prophylaxis (danazol/tranexamic acid). Overall, 97.1% (68/70) of cases did not have an HAE attack within 2 days postprocedure; 91.4% (64/70) during >2-7 days postprocedure. For 2 attacks occurring within 2 days, rhC1-INH was administered 230 minutes and ≥24 hours preprocedure, respectively. No adverse events were reported. As a self-control group, 76.9% of 26 cases with no long-term/short-term prophylaxis preprocedure had an attack within 2 days postprocedure. Conclusions Short-term prophylaxis with rhC1-INH, administered within several hours preprocedure, was efficacious and safe in adolescents/adults and reduced the risk of an HAE attack postprocedure.

Background:Bronchial asthma is a heterogeneous disease that includes various subtypes. They may share similar clinical characteristics, but probably have different pathological mechanisms.Aim:To identify phenotypes using cluster analysis in moderate to severe bronchial asthma and to compare differences in clinical, physiological, immunological and inflammatory data between the clusters.Patients and methods:Forty adult patients with moderate to severe bronchial asthma out of exacerbation were included. All underwent clinical assessment, anthropometric measurements, skin prick testing, standard spirometry and measurement fraction of exhaled nitric oxide. Blood eosinophilic count, serum total IgE and periostin levels were determined. Two-step cluster approach, hierarchical clustering method and k-mean analysis were used for identification of the clusters.Results:We have identified four clusters. Cluster 1 (n=14) - late-onset, non-atopic asthma with impaired lung function, Cluster 2 (n=13) - late-onset, atopic asthma, Cluster 3 (n=6) - late-onset, aspirin sensitivity, eosinophilic asthma, and Cluster 4 (n=7) - early-onset, atopic asthma.Conclusions:Our study is the first in Bulgaria in which cluster analysis is applied to asthmatic patients. We identified four clusters. The variables with greatest force for differentiation in our study were: age of asthma onset, duration of diseases, atopy, smoking, blood eosinophils, nonsteroidal anti-inflammatory drugs hypersensitivity, baseline FEV1/FVC and symptoms severity. Our results support the concept of heterogeneity of bronchial asthma and demonstrate that cluster analysis can be an useful tool for phenotyping of disease and personalized approach to the treatment of patients.

Triazole antifungals are commonly used in the treatment of candidiasis. Fluconazole (FCZ) is one of the most frequently prescribed therapy for vaginal fungal infections. Rarely, FCZ has been shown to cause fixed drug eruptions (FDE).

Lamotrigine (LTG), an aromatic antiepileptic drug, is mainly used to manage epilepsy and bipolar / mood disorders. Skin rashes are the most common adverse reaction to this drug that typically develop in the first 8 weeks of treatment.