Small and large airway reactions to osmotic stimuli in asthma and chronic idiopathic cough.

BACKGROUND: Chronic cough is a common symptom and related to several pulmonary, airway and heart diseases. When all likely medical explanations for the coughing are excluded, there remains a large group of patients with chronic coughing, which is mostly a cough reflex easily triggered by environmental irritants and noxious stimuli. The main aim of this study was to improve the diagnostic ability to differentiate chronic idiopathic cough (CIC) from asthma. METHODS: Twenty-three patients with CIC, 16 patients with mild asthma and 21 control participants were included. The study consisted of three randomised bronchial provocations with osmotic stimuli: mannitol, eucapnic dry air and hypertonic saline. At each provocation lung function was assessed by spirometry and impulse oscillometry (IOS). RESULTS: In a comparison of the groups, while the FEV1 measurements did not differ, the CIC group had increased airway resistance and reactance after provocation with hypertonic saline compared to the control subjects. After mannitol provocation the patients with asthma had significantly increased airway resistance compared to the controls and from eucapnic dry air provocations these patients had a significant reduction in spirometry values and increased airway resistance compared to both the patients with CIC and the controls. CONCLUSION: The asthma group reacted in a predictable way with impaired lung function from osmotic provocations, whereas the patients with CIC demonstrated peripheral airway changes from hypertonic saline, also known to be a noxious stimulus. The IOS method uncovers differences between patients with CIC and control participants that contribute to our ability to provide a correct diagnosis.

The Use of DAO as a Marker for Histamine Intolerance: Measurements and Determinants in a Large Random Population-Based Survey.

Histamine intolerance (HIT) is a common adverse reaction to food where elimination and reintroduction of histamine-rich food is part of the investigation. Analysis of the enzyme diamine oxidase (DAO) is sometimes used as an additional tool for diagnosis. This study aimed to describe the distribution of DAO in a large representative cohort of adults and to determine the association between DAO activity and possible associated factors. The study is based on the population-based West Sweden Asthma Study and includes 1051 subjects. Subjects underwent structured interviews including questions on demography, asthma, allergy symptoms, and lifestyle factors. Subjects were assessed for specific-IgE-antibodies and measurement of DAO activity in serum. Previously suggested cut-off levels for low values (<3 U/mL), normal values (>10 U/mL), and median levels of DAO were used. In the group of 1051 subjects, only a few presented reactions upon histamine intake, whereas 44% presented DAO levels below the suggested normal cut-off levels. BMI and age were shown to have an impact on DAO activity among women with increasing activity of DAO with increasing BMI and age. Among men, only increasing age was seen to have an impact on DAO levels. There was no difference in DAO levels with different sensitization status to common foods or airborne allergens. No association between DAO levels and reported symptoms to histamine-rich foods could be found. In conclusion, the determination of the DAO enzyme needs to be re-evaluated and may not be used as a valuable tool for histamine intolerance using current cut-off values. Further studies are needed to improve the use of DAO as a biomarker for histamine intolerance.

Regional variation in intensity of inhaled asthma medication and oral corticosteroid use in Denmark, Finland, and Sweden.

Oral corticosteroids (OCS) are often prescribed to patients with asthma that remains uncontrolled with maintenance therapy. We performed a real-world analysis to describe the geographic distributions of patients with asthma and OCS dispensed in Nordic countries. This observational, retrospective study examined patient-level data from nationally prescribed drug registries from January to December 2018 for individuals aged ≥12 years in Denmark, Finland, and Sweden. Using an algorithm based on asthma treatment combinations defined by the Global Initiative for Asthma (GINA), we identified patients with asthma, those on GINA Step 4-5 treatments, and those being dispensed ≥2 courses of OCS and determined volumes of OCS dispensed to these patients over the 1-year analysis period. Data were plotted geographically within each country using colour-coded heat maps. The overall asthma prevalence rates were 7.4% in Denmark, 11.6% in Finland, and 8.1% in Sweden. In Denmark, Finland, and Sweden, respectively, the frequencies of patients on GINA Step 4-5 treatments were 19%, 15%, and 16%; among whom 10%, 23%, and 5% received ≥2 courses of OCS. The rates of patients on GINA Step 4-5 treatments who were dispensed OCS in each country were 23%, 30%, and 46%, of which 22%, 17%, and 10% were dispensed doses averaging ≥5 mg/day over the year. Heat maps revealed considerable heterogeneity in geographic densities of patients with asthma and OCS claims within each country. Taken together, these results demonstrate regional variations in estimated asthma severity, control, and OCS dispensed within and between countries. Patterns of medication use suggest that a high proportion of patients in Denmark, Finland, and Sweden are on GINA Step 4-5 treatments, many of whom are dispensed OCS; this poses a considerable corticosteroid burden to these patients. Geographic differences in medication use within and between Nordic countries may reflect variations in population characteristics and/or treatment approaches.

Sensitivity to environmental irritants and capsaicin cough reaction in patients with a positive methacholine provocation test before and after treatment with inhaled corticosteroids.

BACKGROUND: Increasing evidence points to a potential role for members of the transient receptor potential family of cation channels on several features of asthmatic disease. The cough sensitivity to inhaled capsaicin is known to reflect the reactivity of these airway sensory nerves. OBJECTIVE: The aim was to study, among patients having a positive methacholine provocation and diagnosed with asthma, capsaicin cough sensitivity, sensitivity to methacholine, and levels of exhaled nitric oxide before and after treatment with inhaled steroids, and further, to measure the self-reported impact from environmental irritants. METHODS: Eighteen steroid-naïve patients with a positive methacholine test underwent capsaicin inhalation provocation on two occasions, before and after regular use of inhaled steroids over at least 3 months. Comparisons were made to 21 healthy controls. Sensitivity to methacholine and levels of exhaled nitric oxide were measured before and after the treatment. The participants also answered a validated questionnaire regarding environmental irritants. RESULTS: The patients displayed higher capsaicin cough sensitivity than the controls before the treatment period, but not afterward. Before treatment, capsaicin cough answer correlated significantly with levels of exhaled nitric oxide, but not with methacholine sensitivity. After treatment with inhaled corticosteroids, the capsaicin cough sensitivity and the inflammatory parameters were normalized. In comparison to the control group, the patients reported more affective reactions to and behavioral disruptions induced by environmental irritants. CONCLUSIONS: In steroid-naïve patients with a positive methacholine test, there is a link between that part of the airway inflammation that is reflected by exhaled nitric oxide and that followed by an augmented reactivity of capsaicin-sensitive sensory nerves. This association disappears after steroid treatment.

The triad of current asthma, rhinitis and eczema is uncommon among adults: Prevalence, sensitization profiles, and risk factors.

BACKGROUND: Coexistence of asthma, rhinitis, and eczema has been studied in children, but data are lacking in adults. As new treatments emerge, epidemiological data on the coexistence are needed. AIMS: To study the prevalence of concomitant asthma, rhinitis and eczema in the general adult population and among those sensitized to aeroallergens, and to study associations between background characteristics and risks of phenotypes of asthma, rhinitis, and eczema. METHODS: In the West Sweden Asthma Study, phenotypes and sensitization profiles of 1103 randomly selected adults (16-75 years) were assessed. The methods included measures of serum-IgE and structured interviews on asthma, rhinitis, eczema, their associated symptoms, and relevant risk factors. RESULTS: Among all participants and in those sensitized, 2% and 6% had concomitant asthma, rhinitis, and eczema, respectively, and the condition did not differ by age or sex. Corresponding figures for asthma and rhinitis, but not eczema, was 8% and 19%, respectively. Determinants of coexistence of the three conditions were family history of asthma/allergy, body mass index, and occupational exposure to gas, dust and fumes. Allergic sensitization in those with asthma, rhinitis and eczema was found in 78%, in those with asthma and rhinitis but not eczema in 65%, in those with asthma and eczema but not rhinitis in 40%, while only 5% were sensitized among those having asthma only. CONCLUSIONS: In the general adult population about 2% have concomitant asthma, rhinitis, and eczema. Of sensitized adults, about 6% has coexistence of the three conditions.

Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis.

BACKGROUND: Recombinant DNA technology has the potential to produce allergen-specific immunotherapy vaccines with defined composition. OBJECTIVE: To evaluate the effectiveness of a new recombinant birch pollen allergen vaccine in patients with birch pollen allergy. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial was undertaken to compare the following 3 vaccines in 134 adults with birch pollen allergy: recombinant birch pollen allergen vaccine (rBet v 1a), licensed birch pollen extract, natural purified birch pollen allergen (nBet v 1), and placebo. Patients received 12 weekly injections followed by monthly injections of the maintenance dose containing 15 microg Bet v 1 for 2 years. RESULTS: Significant reductions (about 50%) in rhinoconjunctivitis symptoms (rBet v 1, P = .0002; nBet v 1, P = .0006; birch extract, P = .0024), rescue medication (rBet v 1, P = .0011; nBet v 1, P = .0025; birch extract, P = .0063), and skin sensitivities (P < .0001) were observed in the 3 actively treated groups compared with placebo during 2 consecutive pollen seasons. Clinical improvement was accompanied by marked increases in Bet v 1-specific IgG levels, which were higher in the rBet v 1-treated group than in the birch and nBet v 1-treated groups. New IgE specificities were induced in 3 of 29 patients treated with birch pollen extract, but in none of the 32 rBet v 1-treated or 29 nBet v 1-treated patients. No severe systemic adverse events were observed in the rBet v 1-treated group. CONCLUSION: The rBet v 1-based vaccine was safe and effective in treating birch pollen allergy, and induced a highly specific immune response.

[Allergen-specific immunotherapy provides long-lasting symptom relief]. / Allergenspecifik immunterapi ger långvarig symtomlindring - Ändå är behandlingen inte tillgänglig för alla patienter som behöver den.

Allergen immunotherapy (AIT) to patients with allergy towards pollens, cats or house dust mite provides longstanding improvement of symptoms of rhinoconjunctivitis and allergic asthma and reduces the need for symptomatic medication. In addition, some studies suggest that AIT can protect from the development of asthma in children with allergic rhinitis. The clinical effects of AIT are explained by a shift from a Th2 to a Th1-mediated immune response upon allergen exposure. In Sweden the treatment is given as sublingual tablets (grass) or subcutaneous injections, and a treatment period of 3-4 years is necessary to ensure longstanding effect of the treatment. Serious side-effects such as asthma attacks or anaphylaxis are uncommon, if the treatment is provided by staff specifically trained to administer AIT. Intralymphatic administration of the allergen extract is a novel and promising approach that might shorten the treatment period with similar clinical effects.

Anti-apoptotic BFL-1 is the major effector in activation-induced human mast cell survival.

Mast cells are best known for their role in allergic reactions, where aggregation of FcεRI leads to the release of mast cell mediators causing allergic symptoms. The activation also induces a survival program in the cells, i.e., activation-induced mast cell survival. The aim of the present study was to investigate how the activation-induced survival is mediated. Cord blood-derived mast cells and the mast cell line LAD-2 were activated through FcεRI crosslinking, with or without addition of chemicals that inhibit the activity or expression of selected Bcl-2 family members (ABT-737; roscovitine). Cell viability was assessed using staining and flow cytometry. The expression and function of Bcl-2 family members BFL-1 and MCL-1 were investigated using real-time quantitative PCR and siRNA treatment. The mast cell expression of Bfl-1 was investigated in skin biopsies. FcεRI crosslinking promotes activation-induced survival of human mast cells and this is associated with an upregulation of the anti-apoptotic Bcl-2 family member Bfl-1. ABT-737 alone or in combination with roscovitine decreases viability of human mast cells although activation-induced survival is sustained, indicating a minor role for Bcl-X(L), Bcl-2, Bcl-w and Mcl-1. Reducing BFL-1 but not MCL-1 levels by siRNA inhibited activation-induced mast cell survival. We also demonstrate that mast cell expression of Bfl-1 is elevated in birch-pollen-provocated skin and in lesions of atopic dermatitis and psoriasis patients. Taken together, our results highlight Bfl-1 as a major effector in activation-induced human mast cell survival.

Production of interleukin-12 by monocytes and interferon-gamma by natural killer cells in allergic patients during rush immunotherapy.

BACKGROUND: Allergen specific immunotherapy modifies the immunologic response to allergen exposure; however, the role of cells composing the innate immune system, such as monocytes and natural killer (NK) cells, in this mechanism is still unclear. OBJECTIVE: To examine the effect of rush immunotherapy (RIT) on early allergen-induced cytokine production by peripheral blood mononuclear cells from treated cat- and birch-allergic patients. METHODS: Twelve allergic patients received RIT, and another 4 served as controls. Blood samples were taken before the start and after 3 days, 1 week, 3 weeks, and 3 months of RIT. Allergen-induced production of interleukin-12 (IL-12) by monocytes and interferon-gamma (IFN-gamma) by NK cells was evaluated by means of flow cytometry. RESULTS: Before the start of RIT, allergic patients had significantly lower numbers of IL-12+ monocytes compared with healthy subjects (P = .01). The percentage of IL-12+ monocytes increased after 3 months of RIT (P = .003). In the allergic control group, the proportion of IL-12+ monocytes evaluated after 3 months was not different from baseline and was significantly lower compared with that in the RIT group (P = .005). Before treatment, the percentage of IFN-gamma+ NK cells was lower in allergic patients than in healthy subjects (P = .04). The percentage of IFN-gamma+ NK cells increased after 3 weeks (P = .03) and 3 months (P = .01) of RIT. CONCLUSIONS: Restoration of the cytokine imbalance by immunotherapy is not only restricted to the cells of the adaptive immune system but also concerns cells composing the innate immune system.

Basophil interleukin 4 and interleukin 13 production is suppressed during the early phase of rush immunotherapy.

BACKGROUND: Studies using rush immunotherapy (RIT) have shown that rapid protection can be achieved using protocols allowing a fast increment of allergen dose. We examined the early effects of RIT on basophil numbers and expression of CD203c, production of interleukin (IL)-4 and IL-13 and histamine release by basophils in the peripheral blood of patients treated with immunotherapy and controls. METHODS: Twelve patients treated with RIT and 4 untreated controls were included in the study. Any adverse events were evaluated during the incremental phase of RIT. Mononuclear cells were isolated before the start of RIT and 3 days, 1 week, 4 weeks and 3 months after the beginning of the treatment. Histamine release upon allergen stimulation, expression of CD203c and allergen-induced production of IL-4 and IL-13 by basophils were examined. RESULTS: Significant decreases in blood basophil count (p = 0.02) were observed early in the treatment, returning to baseline values 1 week after the start of RIT. Similarly, histamine release decreased at day 3 (p = 0.02), but returned to pretreatment levels after 1 week. Also, the percentage of IL-4+ and IL-13+ basophils and levels of CD203c expression were markedly reduced early in the treatment. IL-4 and IL-13 production correlated with histamine release and CD203c expression. Histamine release and production of IL-4 and IL-13 by basophils before the treatment correlated with the severity of adverse events during the incremental phase of RIT. CONCLUSION: We report the decrease in blood basophil numbers, their lower activation status and the reduced production of IL-4 and IL-13 early in the course of RIT. This early suppression of basophil activation could be one mechanism behind the protective effect of RIT.

Effect of 2-year placebo-controlled immunotherapy on airway symptoms and medication in patients with birch pollen allergy.

BACKGROUND: Birch pollen is a common allergen in northern, central, and eastern Europe. Earlier studies of specific immunotherapy using birch pollen extract were not placebo-controlled or were only preseasonal. Long-term, placebo-controlled studies with subcutaneously administered standardized birch pollen extract are lacking. OBJECTIVE: The aim of this study was to evaluate the effect of immunotherapy with birch pollen extract on airway symptoms and use of medication in adult birch pollen-allergic patients in a double-blind, placebo-controlled trial. METHODS: Forty-nine patients with histories of birch pollen allergy from the upper and lower airways, positive skin prick test and conjunctival provocation test results, and in vitro specific IgE to birch pollen (Betula verrucosa ) extract were included. Immunotherapy with birch pollen extract was given during 2 consecutive years in a double-blind, randomized, placebo-controlled study. Clinical symptom scores from the upper and lower airways and use of rescue medication were registered throughout the pollen season. RESULTS: Forty-six patients reached the maintenance dose and were maintained on that dose during the 2-year study. The median symptom scores during the 1997 and 1998 seasons were 1.3 and 2.6, respectively, in the specific immunotherapy group and 2.1 and 4.3, respectively, in the placebo group. The differences between the groups were significant (P =.05 in 1997 and P =.005 in 1998). The placebo group used significantly more rescue medication during both seasons than the specific immunotherapy group (P =.004 for 1997 and P =.004 for 1998). CONCLUSION: Specific immunotherapy with birch pollen extract is an effective and safe treatment for reducing clinical allergy symptoms and medication use in birch pollen-allergic patients during the pollen season.

The effect of omalizumab on nasal allergic inflammation.

BACKGROUND: In sensitized patients, coupling between IgE and FcepsilonRI receptors on mast cells leads to release of proinflammatory mediators and a subsequent influx of inflammatory cells to the affected organ. Omalizumab (Xolair; formerly rhuMAb-E25) binds to circulating IgE, thus preventing induction of the allergic process. OBJECTIVE: We investigated the effect of treatment with omalizumab on seasonal allergic rhinitis and related changes in inflammatory cell numbers in nasal biopsy specimens. METHODS: Patients were randomized to treatment with omalizumab or placebo before the pollen season; the treatment was started and continued during season. Symptoms and use of medication were recorded, and blood samples and nasal biopsy specimens were obtained before and during season. Immunocytochemistry was performed on biopsy sections through use of the following antibodies: anti-CD4, CD8 (T lymphocytes), EG2, and anti-eosinophil peroxidase (eosinophils), anti-tryptase (mast cells), human neutrophil lipocalin (neutrophils), and antibodies against IgE and FcepsilonRI. RESULTS: During the season, blood eosinophils increased in placebo-treated patients but not in omalizumab-treated patients (P =.01); the difference between the treatment groups was significant (P =.04). Free IgE in serum decreased significantly (P =.0002) in omalizumab-treated patients but not in placebo-treated patients; the difference between the groups was significant (P =.0001). In nasal biopsy specimens, the number of eosinophil peroxidase-positive staining cells increased in the placebo-treated patients (P =.003) but not in the actively treated patients during the season; the difference between the groups was significant (P =.0001). The number of IgE(+) staining cells decreased significantly in the omalizumab group during the season in comparison with the placebo group (P =.04). CONCLUSION: The clinical benefit of treatment with omalizumab is associated with an anti-inflammatory effect on cellular markers in blood and nasal tissue.