Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency.

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.

Quality of life improvement after a three-year course of sublingual immunotherapy in patients with house dust mite and grass pollen induced allergic rhinitis: results from real-life.

BACKGROUND: Along with its high prevalence, the burden of allergic rhinitis rests upon the serious impact on quality of life of patients. Allergic rhinitis is associated with impairments in daily activities, work and school performance, and practical problems. Patients suffer from sleep disorders and emotional problems. Тhe advantages of sublingual immunotherapy on quality of life have only recently begun to emerge. The objective of this prospective real-life study was to evaluate the effect of a three-year course of sublingual immunotherapy with house dust mite (HDM) and grass pollen extracts on quality of life in adults with allergic rhinitis. METHODS: A total number of 191 adult patients [105 (54,979%) men; mean age 27.3 years (SD-6.14)] with moderate to severe allergic rhinitis and clinically relevant sensitization to house dust mites or grass pollen were prospectively evaluated in the course of management of their disease. Health-related quality of life was assessed by Rhinoconjunctivitis Quality of Life Questionnaire at baseline and after three-year course of sublingual immunotherapy. RESULTS: The mean overall Qol score assessed at baseline and at the end of the third year of treatment decreased significantly in patients treated with HDM extract (from 2.95 to 0.76) as well as with Grass pollen extract (from 2.83 to 1.22) (р < 0.001). The improvements in treated with HDM extract were as followed: activities - 3.52 to 0.68; sleep- 2.48 to 0.31; general problems - 1.79 to 0.49; practical problems - 3.57 to 0.68; nasal symptoms - 3.91 to 0.74; eye symptoms - 2.92 to 0.39; emotions - 3.03 to 0.39. The improvements in grass pollen group were: activities - 3.68 to 1.69; sleep- 1.85 to 0.84; general problems - 1.74 to 0.97; practical problems - 3.52 to 1.37; nasal symptoms - 3.72 to 1.57; eye symptoms - 3.58 to 1.3; emotions - 2.48 to 1.19. CONCLUSION: Our study conducted in real life provided evidence that a three-year course of SLIT with HDM extract as well as with grass pollen extract significantly increased QoL in patients with allergic rhinitis.

Effect of micronized cellulose powder on the efficacy of topical oxymetazoline in allergic rhinitis.

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.

Objective approach for fending off the sublingual immunotherapy placebo effect in subjects with pollenosis: double-blinded, placebo-controlled trial.

BACKGROUND: Symptom scoring for the assessment of allergen immunotherapy is associated with a substantial placebo effect. OBJECTIVE: To assess the ability of exhaled breath temperature (EBT), a putative marker of airway inflammation, to evaluate objectively the efficacy of grass pollen sublingual immunotherapy in a proof-of-concept study. METHODS: This was a double-blinded, placebo-controlled clinical trial in 56 subjects (mean ± SD 30 ± 12 years old, 33 men) sensitized to grass pollen. The objective measurements were EBT, spirometry, and periostin and high-sensitivity C-reactive protein in blood. Overall discomfort scored on a visual analog scale was used as a proxy for subjective symptoms. Evaluations were performed before, during, and after the grass pollen season. RESULTS: Fifty-one subjects (25 and 26 in the active treatment and placebo groups, respectively) were assessed before and during the pollen season. The mean pre- vs in-season increase in EBT was significantly smaller (by 59.1%) in the active treatment than in the placebo group (P = .030). Of the other objective markers, only the blood periostin level increased significantly during the pollen season (P = .047), but without intergroup differences. Subjectively, the mean pre- vs in-season increase in the visual analog scale score was 32.3% smaller in the active treatment than in the placebo group, although this difference did not reach statistical significance (P = .116). CONCLUSION: These results suggest that the efficacy of grass pollen sublingual immunotherapy can be assessed by EBT, a putative quantitative measurement of airway inflammation, which is superior in its power to discriminate between active and placebo treatment than a subjective assessment of symptoms assessed on a visual analog scale. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01785394.

Characteristics of a patient population seeking medical advice for nasal symptoms in Bulgaria.

BACKGROUND: The proportion of patients visiting general practitioners (GPs), otorhinolaryngologists (ORLs), and allergologists (ALRGs) for nasal complaints is unknown but important in estimating the number of subjects with nasal symptoms bothersome enough to warrant physician consultations and assessing nasal pathological conditions' burden on a national health care system. OBJECTIVE: The Symptoms of Nasal Inconvenience Fact Finding (SNIFF) survey was developed to (1) assess incidence of physician visits attributable to nasal complaints; (2) characterize patients' nasal conditions; and (3) outline differences across physician categories. METHODS: The SNIFF survey was completed over 20 days by Bulgarian GPs, ORLs, and ALRGs whom patients consulted for nasal symptoms. Survey forms differentiated type and severity of patients' conditions according to Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines and ranked bothersome symptoms. Smell impairment, comorbidities, and prescription practices were documented. RESULTS: Sixty-nine physicians (30 GPs, 8 ORLs, 31 ALRGs) completed 1,685 surveys. The proportion of patients with nasal symptoms over the total patients seen was 15.7%: ALRGs, 18.0%; GPs, 14.6%; ORLs, 13.1%. Patients were classified as having intermittent (38.8%) or persistent (61.2%) rhinitis, with most having moderate/severe symptoms (94.4%). Congestion was the leading symptom in 59.1%. Smell was impaired in 69.8% of patients, asthma was present in 21.4%, and cough in 62.9%. ALRGs were more likely to diagnose and manage patients per ARIA guidelines than were ORLs or GPs. CONCLUSION: The SNIFF survey results demonstrate congestion's role as a leading symptom motivating patients to seek medical advice. SNIFF also uncovered differences in practices among different categories of health care providers.

Safety Aspects and Rational Use of Lanadelumab Injections in the Treatment of Hereditary Angioedema (HAE): Clinical Insights.

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.

Searching for Genetic Biomarkers for Hereditary Angioedema Due to C1-Inhibitor Deficiency (C1-INH-HAE).

Existing evidence indicates that modifier genes could change the phenotypic outcome of the causal SERPING1 variant and thus explain the expression variability of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). To further examine this hypothesis, we investigated the presence or absence of 18 functional variants of genes encoding proteins involved in the metabolism and function of bradykinin, the main mediator of C1-INH-HAE attacks, in relation to three distinct phenotypic traits of patients with C1-INH-HAE, i.e., the age at disease onset, the need for long-term prophylaxis (LTP), and the severity of the disease. Genetic analyses were performed by a validated next-generation sequencing platform. In total, 233 patients with C1-INH-HAE from 144 unrelated families from five European countries were enrolled in the study. Already described correlations between five common functional variants [F12-rs1801020, KLKB1-rs3733402, CPN1-rs61751507, and two in SERPING1 (rs4926 and rs28362944)] and C1-INH-HAE severity were confirmed. Furthermore, significant correlations were found between either the age at disease onset, the LTP, or the severity score of the disease and a series of other functional variants (F13B-rs6003, PLAU-rs2227564, SERPINA1-rs28929474, SERPINA1-rs17580, KLK1-rs5515, SERPINE1-rs6092, and F2-rs1799963). Interestingly, correlations uncovered in the entire cohort of patients were different from those discovered in the cohort of patients carrying missense causal SERPING1 variants. Our findings indicate that variants other than the SERPING1 causal variants act as independent modifiers of C1-INH-HAE severity and could be tested as possible prognostic biomarkers.

The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria.

BACKGROUND: H(1)-antihistamines are first line treatment of chronic urticaria, but many patients do not get satisfactory relief with recommended doses. European guidelines recommend increased antihistamine doses of up to 4-fold. OBJECTIVE: To provide supportive evidence for the European guidelines. METHODS: Eighty tertiary referral patients with chronic urticaria (age range, 19-67 years) were randomized for double-blind treatment with levocetirizine or desloratadine (40/40). Treatment started at the conventional daily dose of 5 mg and then increased weekly to 10 mg, 20 mg, or 20 mg of the opposite drug if relief of symptoms was incomplete. Wheal and pruritus scores, quality of life, patient discomfort, somnolence, and safety were assessed. RESULTS: Thirteen patients became symptom-free at 5 mg (9 levocetirizine vs 4 desloratadine), compared with 28 subjects on the higher doses of 10 mg (8/7) and 20 mg (5/1). Of the 28 patients nonresponsive to 20 mg desloratadine, 7 became symptom-free with 20 mg levocetirizine. None of the 18 levocetirizine nonresponders benefited with 20 mg desloratadine. Increasing antihistamine doses improved quality of life but did not increase somnolence. Analysis of the effect of treatment on discomfort caused by urticaria showed great individual heterogeneity of antihistamine responsiveness: approximately 15% of patients were good responders, approximately 10% were nonresponders, and approximately 75% were responders to higher than conventional antihistamine doses. No serious or severe adverse effects warranting discontinuation of treatment occurred with either drug. CONCLUSION: Increasing the dosage of levocetirizine and desloratadine up to 4-fold improves chronic urticaria symptoms without compromising safety in approximately three quarters of patients with difficult-to-treat chronic urticaria.

Hormonal Effects on Urticaria and Angioedema Conditions.

Women appear to be more frequently affected with urticaria and angioedema. Sex hormones are believed to have an important mechanistic role in regulating pathways involved in these conditions. This effect is likely nonspecific for chronic spontaneous urticaria (CSU) or many forms of angioedema (AE), because many other chronic diseases such as asthma are also affected by sex hormones. The role of sex hormones has been better elucidated for hereditary AE, because they have been shown to have multiple effects including upregulation of FXII, an important activator of the kallikrein pathway. However, their role in the underlying pathogenesis for CSU is less clear. Autoimmunity is clearly linked to CSU, which is more common in women. This suggests that sex hormones could act as adjuvants in activating or upregulating autoimmune pathways. The purpose of this review is to discuss in detail the role of sex hormones in CSU and AE and how a better understanding of the impact hormones has on these conditions might lead to new treatment advancements with better clinical outcomes.

Therapeutic management of hereditary angioedema: past, present, and future.

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.

Recombinant human C1 esterase inhibitor for hereditary angioedema attacks: A European registry.

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.

The physician and hereditary angioedema friend or foe: 62-year diagnostic delay and iatrogenic procedures.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease characterized by episodes of acute subcutaneous swelling, and/or recurrent severe abdominal pain. The disease is potentially fatal if the upper-airway is involved. Iatrogenic harm can occur if HAE is not considered in the differential diagnosis, the specialists are not aware of the natural history, diagnosis and treatment of HAE, or as a result of unnecessary surgical and other iatrogenic interventions. CASE PRESENTATION: We present the case of a 72-year-old man who began suffering recurrent abdominal pain at the age of 8 years. The pain led to frequent emergency department visits, three emergency surgical interventions, and 5 endoscopies before C1-INH-HAE was diagnosed at the age of 70. Infrequent subcutaneous swellings were attributed to unknown allergic reactions that were not related to the primary diagnosis of abdominal pain. Family history was positive for recurrent abdominal pain and angioedema but was ignored until the propositus' grandson developed recurrent severe oro-facial edema attacks. The boy's mother searched the worldwide web and found educational materials on a patient association website. She suggested complement C4 and C1-INH testing that led to the appropriate diagnosis of C1-INH-HAE type 1 in her son and his grandfather. CONCLUSION: This report emphasizes the importance of accurately evaluating personal and family history in patients with a long history of recurrent, acute, severe but medically unexplained abdominal pain and cutaneous swellings. Here, the diagnosis of HAE was overlooked for 62 years and the focus on abdominal complaints led to numerous surgical interventions without consideration of the full differential diagnosis. Screening family members from all generations for unrecognized angioedema, abdominal pain, and measurement of C1-INH and C4 are essential for accurate and timely diagnosis of HAE.

A Three-Year Course of House Dust Mite Sublingual Immunotherapy Appears Effective in Controlling the Symptoms of Allergic Rhinitis.

Background Allergic rhinitis is the most common allergic disorder. Although the management of the disease is successful in many patients, based on guidelines, some of them remain with symptoms uncontrolled with pharmacotherapy. Presently, there is no substantiated information on the control of allergic rhinitis in patients who underwent sublingual immunotherapy. Objective The purpose of this prospective follow-up study was to assess the control of allergic rhinitis in adults after a three-year course of house dust mite sublingual immunotherapy. Methods This prospective real-life study was designed to include adults with moderate to severe allergic rhinitis sensitized to house dust mite who underwent a three-year course of sublingual immunotherapy. Control of symptoms was assessed by Rhinitis Control Assessment Test (RCAT) after three years of house dust mite sublingual immunotherapy. Additionally, patients assessed their symptoms by utilizing a visual analog scale. Results A total number of 86 consecutively enrolled patients (46 (53.49%) men; mean age 26.10 years (SD = 5.85)) with moderate to severe allergic rhinitis and clinically relevant sensitization to house dust mite were evaluated. When assessed by RCAT on the third year, 74 (86.05%) had well-controlled symptoms and 20 (27.03%) of them were completely controlled. A significant reduction in visual analog scale scores-from 7.52 cm at baseline to 2.31 cm-was established ( P < 0.0001). There was a strong negative correlation between RCAT scores and visual analog scale (r = -0.65; P < 0.01). Conclusion This study provided evidence that a three-year course of house dust mite sublingual immunotherapy appears effective in controlling the symptoms of allergic rhinitis.

Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency.

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.

Clinical characteristics of patients seeking medical advice for nasal symptoms in Bulgaria with special focus on children.

BACKGROUND: In an attempt to circumvent low response rates and high cost of classical epidemiological trials, we carried out a real-life survey among practicing physicians consulting patients for nasal symptoms. In this fragment of our work we analyze similarities and differences between children and adults and within the different strata of pediatric age. METHODS: A survey was carried out by 69 physicians across Bulgaria (general practitioners, allergists and otorhinolaryngologists) and made possible calculation of the proportion of subjects with nasal symptoms from all other patients seen. Its structure allowed classification of rhinitis according the ARIA guidelines. RESULTS: Out of the 1685 completed survey forms, 506 pertained to the age group below 18 years. The gender predominance differed in children and adults: 57.3 % vs. 42.8 % of males respectively, P < 0.001. The prevalence of persistent rhinitis in children was 55.7 %, lower than in adults, 63.3 %, P = 0.004. In both pediatric and adult patients moderately severe and severe forms of rhinitis prevailed, 93.7 % vs. 94.6 %, with nasal obstruction as leading symptom: 59.9 % vs. 58.8 %. Cough was significantly more prevalent among children, 72.5 %, gradually decreasing until reaching adulthood, 58.7 %, P < 0.001. Prevalence of doctor diagnosed asthma was also higher among children, 25.1 %, than in adults, 19.5 %, P = 0.011. A gradient for characteristics, which were different in children, emerged across the pediatric age strata. DISCUSSION: Our study uses an unorthodox design targeting the patient population visiting physicians' offices because of nasal symptoms, achieving a much higher level of credibility of the results at minimal expense. As we base our survey on international guidelines, we believe this approach demonstrates the applicability of such consensus documents for practical purposes when in the hands of qualified physicians. CONCLUSIONS: Moderate and severe rhinitis symptoms motivate patients and their guardians to seek medical advice. While nasal congestion is a leading bothersome symptom in both adults and children, specific other features characterize the pediatric age and differ across its strata.

A real - life observational pilot study to evaluate the effects of two-week treatment with montelukast in patients with chronic cough.

BACKGROUND: Different conditions make the proximal airways susceptible to tussigenic stimuli in the chronic cough (CC) syndrome. Leukotrienes can be implicated in the inflammatory mechanism at play in it. Montelukast is a selective cysteinyl-leukotriene receptor antagonist with proven effectiveness in patients with asthma. The aim of our real-life pilot study was to use montelukast to relieve cough symptoms in patients with CC allegedly due to the two frequent causes other than asthma - upper airway cough syndrome and gastroesophageal reflux (GER). METHODS: 14 consecutive patients with CC were evaluated before and after 2 weeks of treatment with montelukast 10 mg daily. Cough was assessed by validated cough questionnaire. Questionnaires regarding the presence of gastroesophageal reflux were also completed. Cough reflex sensitivity to incremental doubling concentrations of citric acid and capsaicin was measured. Lung function, airway hyperresponsiveness and exhaled breath temperature (EBT), a non-invasive marker of lower airway inflammation, were evaluated to exclude asthma as an underlying cause. Thorough upper-airway examination was also conducted. Cell counts, eosinophil cationic protein (ECP), lactoferrin, myeloperoxidase (MPO) were determined in blood to assess systemic inflammation. RESULTS: Discomfort due to cough was significantly reduced after treatment (P < 0.001). Cough threshold for capsaicin increased significantly (P = 0.001) but not for citric acid. The values of lactoferrin and ECP were significantly reduced, but those of MPO rose. EBT and pulmonary function were not significantly affected by the treatment. CONCLUSION: Patients with CC due to upper airway cough syndrome or gastroesophageal reflux (GER) but not asthma reported significant relief of their symptoms after two weeks of treatment with montelukast. ECP, lactoferrin, MPO altered significantly, highlighting their role in the pathological mechanisms in CC. Clinical trial ID at Clinicaltrials.gov is NCT01754220.