Nasal hyperreactivity in allergic rhinitis and chronic rhinosinusitis with polyps: a role for neuronal pathways.

BACKGROUND: Nasal hyperreactivity (NHR) is prevalent in all chronic upper airway inflammatory phenotypes, including allergic rhinitis (AR) and chronic rhinosinusitis with nasal polyps (CRSwNP). Although NHR in patients with non-allergic rhinitis is mediated by neuronal pathways, AR and CRSwNP are mainly characterized by type 2 inflammation. METHODS: Eighteen healthy controls and 45 patients with symptomatic AR/CRSwNP underwent a cold, dry air (CDA) provocation test for objective diagnosis of NHR. Before and after, questionnaires were filled out and nasal secretions and biopsies were collected. Markers for neurogenic inflammation (substance P, calcitonin gene-related peptide, neurokinin A), epithelial activation (IL-33), and histamine were measured in secretions by ELISA; and expression of neuronal markers PGP9.5, TRPV1, and TRPM8 was studied in biopsies by RT-q-PCR. Effects of histamine on TRPV1/A1 were studied with Ca2+-imaging using murine trigeminal neurons. RESULTS: CDA-provocation reduced peak nasal inspiratory flow (PNIF) of patients with subjective NHR but not of non-NHR controls/ patients (p.

Basophil activation test with progressively less heated forms of egg distinguishes egg allergic from tolerant children.

BACKGROUND AND OBJECTIVE: Diagnosis of egg allergy through basophil activation testing (BAT) has been mainly performed with an egg white extract or individual egg allergens rather than clinically more representative whole-egg extracts. Impact of heating on whole-egg extract allergenicity remains unassessed.Validating BAT with gradually less heated whole-egg extracts in egg allergy diagnosis and as tolerance marker. METHODS: CD63-based BAT was performed with five progressively less heated extracts from cake, hard-boiled egg, omelet, soft-boiled, and raw egg in 10 egg allergic (EA), 10 complete egg tolerant (ET) and 12 non-egg-sensitized non-allergic (NEA) children. Cutoffs and diagnostic accuracy measures were established through ROC analysis. Changes in basophil response were assessed in 12 baked egg tolerant children undergoing an 8-month gradual egg reintroduction protocol with BAT and oral food challenges prior to each reintroduction step. RESULTS: Basophil responses to all egg extracts were increased in EA, but not in ET and NEA children. Responses decreased progressively with more heated egg extracts. Compared to ET children, EA children showed higher basophil sensitivity for all egg extracts. Negative BAT responses predicted clinical tolerance with a 90-100% sensitivity, 100% specificity, and false positive rate of 2.78%. In comparison, egg sIgE's (<0.35 kUA/L) had a lower specificity of 50-78% with a false positive rate of 40%. Basophil reactivity and sensitivity tended to decrease in baked egg tolerant children undergoing gradual egg reintroduction, concurrent with tolerance development. CONCLUSION: BAT with progressively less heated egg preparations is a sensitive and highly specific tool to discriminate EA from ET children.

Hereditary angioedema (HAE) in Belgium: results from a national survey.

Background: Hereditary angioedema (HAE) is a rare heritable disorder that is characterized by recurrent, circumscribed, nonpitting, nonpruritic, often painful subepithelial swellings of sudden unpredictable onset that generally fade during 48-72 h. Epidemiological data of hereditary angioedema patients in Belgium is lacking. Methods: We set up a nation-wide, multicentric study involving the 8 Belgian hospitals known to follow-up patients with Type I and II HAE. All Belgium HAE patients were asked to fill out questionnaires that mainly covered demographic data, family history, and detailed information about diagnosis, treatment and burden of their Type I and II HAE. Results: 112 patients with type I or type II HAE could be included. Median delay between first symptoms and diagnosis was 7 years. 51% of patients had experienced pharyngeal or tongue swelling and 78% had experienced abdominal symptoms, both known to cause an important reduction in quality of life. 60% of symptomatic patients reported to receive long term prophylactic treatment. Human plasma-derived C1-esterase inhibitor concentrate was used by 56.3% of patients. 16.7% and 27.1% of patients used a 17-α-alkylated androgen and tranexamic acid as long term prophylactic therapy. Conclusions: We present the first nation-wide epidemiological study regarding HAE in Belgium. Our data show that the morbidity of HAE is not to be underestimated. Knowledge and dissemination of this data is critical in raising awareness, encouraging development of therapies and optimising nationwide management.

Clinical practice of hereditary angioedema in Belgium: opportunities for optimized care.

INTRODUCTION: Hereditary angioedema (HAE) is a rare disorder characterized by unpredictable painful and potentially life-threatening swelling episodes. The international WAO/EAACI guideline on the diagnosis and management of HAE was recently updated and provides up-to-date guidance for the management of. In this paper, we assessed to what extent the Belgian clinical practice was aligned with the revised guideline, and whether there were opportunities to optimise Belgian clinical practice in HAE. METHODS: We compared the updated international guideline for HAE with information we acquired on Belgian clinical practice, a Belgian patient registry and expert opinion analysis. The Belgian patient registry was developed with the involvement of eight Belgian reference centers for HAE patients. Eight Belgian experts, physicians in the participating centers, included patients in the patient registry and participated in the expert opinion analysis. RESULTS: The main action points to further optimise the Belgian clinical practice of HAE are Work towards total disease control and normalize patients' life by considering the use of new and innovative long-term prophylactic treatment options; (2) inform C1-INH-HAE patients about new long-term prophylactic therapies; (3) assure the availability of on-demand therapy for all C1-INH-HAE patients; (4) implement a more universally used assessment including multiple aspects of the disease (e.g. quality of life assessment) in daily clinical practice; and (5) continue and expand an existing patient registry to assure continued data availability on C1-INH-HAE in Belgium. CONCLUSIONS: In light of the updated WAO/EAACI guideline, five action points were identified and several other suggestions were made to optimise the Belgian clinical practice in C1-INH-HAE.

The clinical and immunological basis of early food introduction in food allergy prevention.

IgE-mediated food allergy has an estimated prevalence of 6%-10% in developed countries. Allergen avoidance has long been the main focus in the prevention of food allergy and late solid food introduction after 6-12 months of age was recommended in high-risk infants. However, the rising prevalence of food allergy despite delayed exposure to allergens and the observations that IgE-mediated sensitization to food products could even occur before the introduction of solid foods resulted in a shift towards early solid food introduction as an attempt to prevent IgE-mediated food allergy. Since then, many trials focused on the clinical outcome of early allergen introduction and overall seem to point to a protective effect on the development of IgE-mediated food allergies. For non-IgE-mediated diseases of food allergy, evidence of early food introduction seems less clear. Moreover, data on the underlying immunological processes in early food introduction is lacking. The goal of this review is to summarize the available data of immunological changes in early food introduction to prevent IgE and non-IgE mediated food allergy.

Terminal Complement Pathway Deficiency in an Adult Patient with Meningococcal Sepsis.

The complement system is an essential part of our innate immune system. Three enzymatic activation pathways are described, all converging into a common terminal pathway which causes lysis of the target cell. Late complement deficiencies (LCDs) are typically diagnosed in children or adolescents with invasive meningococcal disease (IMD). However, IMD can also be a first manifestation in adulthood and should prompt for the evaluation of the LCD. We report the case of a young adult with IMD who was found to have a LCD, caused by a compound heterozygous mutation in C6. His vaccination status was optimized and prophylactic antibiotic treatment was initiated. By means of this case, we would like to raise awareness of underlying LCD in (young) adults presenting with IMD by N. meningitidis. Screening for complement deficiencies after IMD, followed by genetic testing, can be lifesaving and allows for genetic counselling. In addition, we discuss the diagnosis and treatment of LCD.

A retrospective analysis omalizumab treatment patterns in patients with chronic spontaneous urticaria: a real-world study in Belgium.

BACKGROUND: Chronic spontaneous urticaria (CSU) is characterized by the repeated occurrence of persistent hives and/or angioedema for ≥6 weeks, without specific external stimuli. H1 -antihistamines have long been the standard of care of CSU, but many patients remain uncontrolled even at 4× the approved dose. Add-on therapy with omalizumab has proven effective in clinical trials, but little is known about omalizumab treatment in Belgium. OBJECTIVE: To collect real-world clinical data on omalizumab treatment in adults with CSU in Belgium. METHODS: This was an observational, retrospective chart review of adults with CSU, who initiated omalizumab treatment between August 2014 and December 2016 (maximum 28 months follow-up). RESULTS: In total, 235 patients were included (median time from symptom onset to diagnosis, 5.4 months; median time from diagnosis to commencing omalizumab, 6.7 months). Treatments used before/after commencing omalizumab did not always adhere to guidelines; many patients (26.4%/11.1%) received first-generation H1 -antihistamines, while 20.4% used omalizumab monotherapy after initiating treatment. The mean interval between omalizumab administrations was 4.8 (SD 1.7) weeks; 67.8% of patients had ≥1 interval prolongation and/or shortening. Mean baseline 7-day Urticaria Activity Score (UAS7) was 32.0 (SD 6.05); this improved to 12.6 (SD 11.2) after 1 month of omalizumab. About 67.2% of patients reached UAS7 ≤ 6 (well controlled) during the study. A total of 87 patients stopped omalizumab and never restarted before the end of the observation period; the most prevalent reason was remission of symptoms (49.4% of patients), followed by lack of effect (12.6%), lost to follow-up (6.9%) and adverse events (3.4%). Headache was the most common adverse event (n = 8/82). No anaphylaxis was reported. CONCLUSIONS: This study revealed that patients initiated on omalizumab in Belgium had severe CSU at baseline, and showed substantial improvements after 1 month of treatment. Greater adherence to the prescription of guideline-recommended medications is needed for the treatment of CSU.

Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency.

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell-depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

Stepwise approach towards adoption of allergen immunotherapy for allergic rhinitis and asthma patients in daily practice in Belgium: a BelSACI-Abeforcal-EUFOREA statement.

Allergic rhinitis (AR) affects 23-30% of the European population with equal prevalence reported in Belgium. Despite guidelines on the correct use of effective treatment, up to 40% of AR patients remain uncontrolled. Allergen immunotherapy (AIT) has been shown to improve the level of control up to 84% of patients being controlled by AIT. Recently, new guidelines for AIT have been published, supporting the clinical evidence for effectiveness of various subcutaneous and sublingual products for AIT in patients who are allergic to airborne allergens. AIT in AR patients not only reduces nasal and/or ocular symptoms but also induces tolerance and has preventive potential. Adoption of AIT into daily clinical practice in Belgium and other European countries is hampered primarily by reimbursement issues of each of the single products but also by several patient- and physician-related factors. Patients need to be better informed about the effectiveness of AIT and the different routes of administration of AIT. Physicians dealing with AR patients should inform patients on tolerance-inducing effects of AIT and are in the need of a harmonized and practical guide that supports them in selecting eligible patients for AIT, in choosing evidence-based AIT products and in following treatment protocols with proven efficacy. Therefore, a stepwise and holistic approach is needed for better adoption of AIT in the real-life setting in Belgium.

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.