Chitinase-Induced Airway Hyperreactivity and Inflammation in a Mouse Model of Nonallergic Asthma.

INTRODUCTION: Environmental exposure to mites and fungi has been proposed to critically contribute to the development of IgE-mediated asthma. A common denominator of such organisms is chitin. Human chitinases have been reported to be upregulated by interleukin-13 secreted in the context of Th2-type immune responses and to induce asthma. We assessed whether chitin-containing components induced chitinases in an innate immune-dependent way and whether this results in bronchial hyperresponsiveness. MATERIALS AND METHODS: Monocyte/macrophage cell lines were stimulated with chitin-containing or bacterial components in vitro. Chitinase activity in the supernatant and the expression of the chitotriosidase gene were measured by enzyme assay and quantitative PCR, respectively. Non-sensitized mice were stimulated with chitin-containing components intranasally, and a chitinase inhibitor was administered intraperitoneally. As markers for inflammation leukocytes were counted in the bronchoalveolar lavage (BAL) fluid, and airway hyperresponsiveness was assessed via methacholine challenge. RESULTS: We found both whole chitin-containing dust mites as well as the fungal cell wall component zymosan A but not endotoxin-induced chitinase activity and chitotriosidase gene expression in vitro. The intranasal application of zymosan A into mice led to the induction of chitinase activity in the BAL fluid and to bronchial hyperresponsiveness, which could be reduced by applying the chitinase inhibitor allosamidin. DISCUSSION: We propose that environmental exposure to mites and fungi leads to the induction of chitinase, which in turn favors the development of bronchial hyperreactivity in an IgE-independent manner.

Hereditary angioedema in children and adolescents - A consensus update on therapeutic strategies for German-speaking countries.

BACKGROUND/METHODS: At a consensus meeting in August 2018, pediatricians and dermatologists from German-speaking countries discussed the therapeutic strategy for the treatment of pediatric patients with type I and II hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) for Germany, Austria, and Switzerland, taking into account the current marketing approval status. HAE-C1-INH is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible and an optimal management of the disease are important to avoid ineffective therapies and to properly treat swelling attacks. This article provides recommendations for developing appropriate treatment strategies in the management of HAE-C1-INH in pediatric patients in German-speaking countries. An overview of available drugs in this age-group is provided, together with their approval status, and study results obtained in adults and pediatric patients. RESULTS/CONCLUSION: Currently, plasma-derived C1 inhibitor concentrates have the broadest approval status and are considered the best available option for on-demand treatment of HAE-C1-INH attacks and for short- and long-term prophylaxis across all pediatric age-groups in German-speaking countries. For on-demand treatment of children aged 2 years and older, recombinant C1-INH and bradykinin-receptor antagonist icatibant are alternatives. For long-term prophylaxis in adolescents, the parenteral kallikrein inhibitor lanadelumab has recently been approved and can be recommended due to proven efficacy and safety.

Childhood fish oil supplementation modifies associations between traffic related air pollution and allergic sensitisation.

BACKGROUND: Studies of potential adverse effects of traffic related air pollution (TRAP) on allergic disease have had mixed findings. Nutritional studies to examine whether fish oil supplementation may protect against development of allergic disease through their anti-inflammatory actions have also had mixed findings. Extremely few studies to date have considered whether air pollution and dietary factors such as fish oil intake may interact, which was the rationale for this study. METHODS: We conducted a secondary analysis of the Childhood Asthma Prevention Study (CAPS) birth cohort, where children were randomised to fish oil supplementation or placebo from early life to age 5 years. We examined interactions between supplementation and TRAP (using weighted road density at place of residence as our measure of traffic related air pollution exposure) with allergic disease and lung function outcomes at age 5 and 8 years. RESULTS: Outcome information was available on approximately 400 children (~ 70% of the original birth cohort). Statistically significant interactions between fish oil supplementation and TRAP were seen for house dust mite (HDM), inhalant and all-allergen skin prick tests (SPTs) and for HDM-specific interleukin-5 response at age 5. Adjusting for relevant confounders, relative risks (RRs) for positive HDM SPT were RR 1.74 (95% CI 1.22-2.48) per 100 m local road or 33.3 m of motorway within 50 m of the home for those randomised to the control group and 1.03 (0.76-1.41) for those randomised to receive the fish oil supplement. The risk differential was highest in an analysis restricted to those who did not change address between ages 5 and 8 years. In this sub-group, supplementation also protected against the effect of traffic exposure on pre-bronchodilator FEV1/FVC ratio. CONCLUSIONS: Results suggest that fish oil supplementation may protect against pro-allergic sensitisation effects of TRAP exposure. Strengths of this analysis are that supplementation was randomised and independent of TRAP exposure, however, findings need to be confirmed in a larger experimental study with the interaction investigated as a primary hypothesis, potentially also exploring epigenetic mechanisms. More generally, studies of adverse health effects of air pollution may benefit from considering potential effect modification by diet and other factors. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry. www.anzctr.org.au Registration: ACTRN12605000042640 , Date: 26th July 2005. Retrospectively registered, trial commenced prior to registry availability.

Could it be hereditary angioedema?-Perspectives from different medical specialties.

Hereditary angioedema (HAE) is a rare autosomal dominant disease, with patients often suffering with associated symptoms for many years before receiving a correct diagnosis. The symptoms greatly impact a patient's quality of life (QoL) and include excruciating abdominal pain and angioedema of the skin and submucosa. Angioedema of the larynx represents a significant mortality risk in undiagnosed patients, and a large proportion of patients with HAE receive incorrect diagnoses and undergo unnecessary surgery. HAE-specific treatments can control and prevent acute life-threatening episodes, in addition to improving QoL, emphasizing the value of early diagnosis for patients. Diagnostic delay may be due to a lack of HAE awareness by healthcare professionals and the similarity of HAE symptoms with those of more common conditions, complicating differential diagnosis. The multifaceted nature of the condition may result in visits to one of many different medical settings, for example: the Emergency Room, pediatrics, general practice, otolaryngology, gastroenterology, and dermatology. Therefore, it is crucial that physicians in multiple healthcare specialties are aware of the disease to ensure that patients with HAE receive a timely diagnosis. Using patient cases from various medical specialties, this review highlights the necessity for cross-specialty awareness of HAE and outlines the essential information for the various healthcare professionals that may encounter a patient with HAE symptoms, in order to effectively treat and/or diagnose HAE.

Food as a trigger for abdominal angioedema attacks in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare inherited disease. In most HAE-affected subjects, defined trigger factors precede angioedema attacks. Mechanisms of how trigger factors stimulate the contact activation pathway with bradykinin generation are not well elucidated. In recent studies, hypersensitivity reactions and food were stated as relevant triggers. We investigated HAE affected people for possible hypersensitivity reactions or intolerances and their relation in triggering angioedema attacks. METHODS: A questionnaire was filled in, recording date of birth, gender, and self-reported angioedema attacks associated with the ingestion of foodstuffs, administration of drugs, hymenoptera stings and hypersensitivity reactions against inhalation allergens. All participants performed a skin prick test against inhalation allergens and food. In patients who stated an association of possible hypersensitivity with angioedema, a serological ImmunoCAP test was also performed. RESULTS: From the 27 women and 15 men analyzed, 79% stated trigger factors. From those food was mentioned in 36%. The suspected food included tomato, green salad, fish, citrus fruits, apple, onion, garlic, cheese, chili, kiwi, milk, tree nuts, strawberry, pineapple, shrimps, bread, banana, leek, chicken and alcohol, and were associated with abdominal angioedema. Neither the skin prick test nor the ImmunoCAP-test turned out positive for the tested food allergens. CONCLUSION: Food seems to be a relevant trigger factor, causing angioedema in HAE affected patients. The reason, however, is not IgE-mediated hypersensitivity, but most probably an intolerance reaction to food products.

Hereditary angioedema due to C1 - inhibitor deficiency in Switzerland: clinical characteristics and therapeutic modalities within a cohort study.

BACKGROUND: Registration of trigger factors, prodromal symptoms, swelling localization, therapeutic behavior and gender-specific differences of the largest cohort of patients with hereditary angioedema due to C1-Inhibitor deficiency (C1-INH-HAE) in Switzerland. METHODS: Questionnaire survey within a cohort study: Consenting eligible patients with diagnosed HAE according to clinical history, physical examination and laboratory results, including plasma values for C1-INH and C4 were selected. To each participant we sent a questionnaire assessing patients' birthday, sex, date of first symptoms and diagnosis, trigger factors, prodromal symptoms, frequency and localization of angioedema, medication use and co-morbidities. Clinical information was collected in each center and then transmitted to the cohort database. Frequencies and distributions were summarized. Associations between gender and trigger factors or prodromal symptoms or localization of angioedema were assessed in multivariate analyses correcting for patients' age. RESULTS: Of 135 patients, data from 104 patients (77%) were available for analysis. Fifty- four percent were female, mean age at diagnosis was 19.5 years (SD 14.1), Mean age when completing the questionnaire was 44.0 (SD 19.8). More women than men were symptomatic (44/57 vs. 36/47; p = 0.005). This association remained when correcting for age at diagnosis (16.10. 95%CI (5.17 to 26.70); p = 0.004). Swelling episodes ranged between 1 and 136 episodes/year. Swelling was more common among female than among male (-13.15 (95% CI; -23.10 to -3.22), p = 0.010). Age at diagnosis was inversely associated with the total number of attacks 0.50 (-0.88 to -.011); p = 0.012). One third of patients were on danazol prophylaxis. CONCLUSION: We found large differences of HAE in male and female both in terms of symptom number and swelling episodes. Women are more affected by intensity and frequency of angioedema episodes than men. Danazol treatment remains widely used as effective prophylaxis despite its side effects. New therapies which selectively influence the hormonal estrogen balance could open new therapeutic options mainly for women and maybe also for men.

Allergen-specific IL-5 responses in early childhood predict asthma at age eight.

BACKGROUND: The pattern of development of allergen-specific T cell cytokine responses in early childhood and their relation to later disease is poorly understood. Here we describe longitudinal changes in allergen-stimulated T cell cytokine responses and their relation to asthma and allergic disease during the first 8 years of life. METHODS: Subjects with a family history of asthma, who were enrolled antenatally in the Childhood Asthma Prevention Study (public trials registration number ACTRN12605000042640), had skin prick tests, clinical evaluation for asthma and eczema, and in vitro assessment of T cell cytokine responses to HDM extract performed at ages 18 months (n = 281), 3 years (n = 349), 5 years (n = 370) and 8 years (n = 275). We measured interleukin (IL-) 13 at 3, 5 and 8 years, and IL-5, IL-10, and interferon-γ (IFN-γ), at 18 months, 3, 5 and 8 years by ELISA. A cohort analysis was undertaken. Independent effects of cytokine responses at each age on the risk of asthma and allergic outcomes at age 8 years were estimated by multivariable logistic regression. RESULTS: HDM-specific IL-5 responses increased with age. HDM-specific IL-13 and IL-10 responses peaked at age 5 years. HDM-specific IL-5 responses at 3 years, 5 years and 8 years were significantly associated with the presence of asthma and atopy at 8 years. IL-13 responses at 3 years, 5 years and 8 years were significantly associated with atopy at 8 years, but this association was not independent of the effect of IL-5. Other HDM-specific cytokine responses were not independently related to asthma or eczema at 8 years. CONCLUSION: HDM-specific IL-5 responses at age 3 years or later are the best measure of T cell function for predicting asthma at age 8 years.

Pelvic osteomyelitis: a diagnostic challenge in children.

BACKGROUND: Acute hematogenous osteomyelitis (AHOM) in children usually occurs in tubular bones. Acute hematogenous osteomyelitis of the pelvis is rare and is often not recognized primarily. METHODS: To review the experience with pelvic AHOM at our institution, we analyzed records from children diagnosed with pelvic AHOM (1984-2003) and compared with those reported in the literature. RESULTS: Among 220 children with AHOM (median age, 6.4 years), those 19 (9%) with pelvic AHOM were significantly older (median age, 9.0 years; range, 0.04-15.6). All children presented with limping or refused to walk. Twelve of 19 patients were febrile, 16 of 18 had elevated C-reactive protein (>20 mg/L), and 6 of 19 had leukocytes greater than 12 G/L. Staphylococcus aureus was isolated from blood or bone aspirates in 9 of 17 patients, and Streptococcus pneumoniae was isolated in 1. Scintigraphy was diagnostic in 15 of 15 children, and magnetic resonance imaging in 7 of 7 children. The mean time between initial symptoms and diagnosis was 3 days (range, 1-8 days). Infection resolved completely in all children after antibiotic therapy. CONCLUSION: Pelvic AHOM should be considered in children with limping and pain referred to the hip, thigh, or abdomen. Diagnosis by scintigraphy or magnetic resonance imaging followed by local puncture and microbiological workup allows for specific antibiotic treatment and results in an excellent outcome of pelvic AHOM.

IL-5 T-cell responses to house dust mite are associated with the development of allergen-specific IgE responses and asthma in the first 5 years of life.

BACKGROUND: Allergen-specific T(H)2-like cytokine responses are considered to be important in sensitization and allergic diseases. OBJECTIVE: To examine the profile of house dust mite (HDM) stimulated T-cell cytokines and their relationship to allergic disease in children over the period of the first 5 years of life. METHODS: Subjects with a family history of asthma who were enrolled antenatally in the Childhood Asthma Prevention Study and had skin prick tests, clinical evaluation for asthma and eczema, and in vitro assessment of lymphocyte cytokine responses to HDM extract performed at ages 18 months (n = 281), 3 years (n = 349), and 5 years (n = 370). IL-13 at 3 and 5 years and IL-5, IL-10, and IFN- gamma at 18 months, 3 years, and 5 years were measured by ELISA. RESULTS: House dust mite-specific cytokine responses increased with age for all cytokines except IFN-gamma. HDM-specific IL-5 responses at 3 years and 5 years were significantly positively related to skin prick test positivity at 5 years. IL-5 responses at 5 years were also significantly related to asthma at 5 years. Other HDM-specific cytokine responses were not related to asthma or eczema at 5 years. Responses were not altered by a HDM avoidance intervention. CONCLUSION: IL-5 responses to HDM, the dominant local inhalant allergen, are related to the expression of clinical illness at age 5 years. CLINICAL IMPLICATIONS: The T-cell response to HDM, as reflected in IL-5 production, is acquired over the first years of life and may play a role in the expression of allergic airways disease.