Current developments for improving efficacy of allergy vaccines.

Allergic diseases are prevalent worldwide. Allergen immunotherapy (AIT) is a current treatment for allergy, leading to modification of the natural course of disease. Mechanisms of efficacy include Treg through release of IL-10 and TGF-ß and specific IgG4 blocking antibodies. Subcutaneous and sublingual routes are popular, but uptake is limited by inconvenience and safety concerns. Inclusion criteria limit application to a small proportion of allergic patients. New forms of immunotherapy are being investigated for more efficacious, convenient and safer options with promising advances in recent years. The rationale of reducing vaccine allergenicity to increase safety while improving immunogenicity led to investigation of T-cell epitope-based peptides and recombinant allergen derivatives. Additionally, different routes of administration and adjuvants and adjunct therapies are being explored. This review discusses the current status of AIT and recent advances to improve clinical efficacy, safety and long-term immune tolerance.

Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) often presents with persistently uncontrolled asthma despite the use of corticosteroids and antifungal therapy. Omalizumab is a humanized anti-IgE monoclonal antibody currently used to treat severe asthma. OBJECTIVE: The aim was to assess the clinical and immunologic effects of omalizumab in ABPA in a randomized, placebo-controlled trial. METHODS: Patients with chronic ABPA were randomized to 4-month treatment with omalizumab (750 mg monthly) or placebo followed by a 3-month washout period in a cross-over design. The main endpoint was number of exacerbations. Other clinical endpoints included lung function, exhaled nitric oxide (FeNO), quality of life and symptoms. In vitro basophil activation to Aspergillus fumigatus extract and basophil FcεR1 and surface-bound IgE levels were assessed by flow cytometry. RESULTS: Thirteen patients were recruited with mean total IgE 2314 ± 2125 IU/mL. Exacerbations occurred less frequently during the active treatment phase compared with the placebo period (2 vs 12 events, P = .048). Mean FeNO decreased from 30.5 to 17.1 ppb during omalizumab treatment (P = .03). Basophil sensitivity to A. fumigatus and surface-bound IgE and FcεR1 levels decreased significantly after omalizumab but not after placebo. CONCLUSION: Omalizumab can be used safely to treat ABPA, despite high serum IgE levels. Clinical improvement was accompanied by decreased basophil reactivity to A. fumigatus and FcεR1 and surface-bound IgE levels.

Asbestos and the lung in the 21st century: an update.

The asbestos-related disorders (ARDs) are currently of significant occupational and public health concern. Asbestos usage has been banned in most developed countries, but asbestos is still used in many developing countries and the number of cases of ARDs worldwide is rising. Many countries are now experiencing an epidemic of ARDs that is the legacy of occupational exposure in the 1960s-1980s because of the long latency period between asbestos exposure and manifestation of disease. It is likely that asbestos-related mortality and morbidity will continue to increase. Although the most feared complications of asbestos inhalation are the malignant conditions such as mesothelioma and lung cancer, asbestos inhalation more frequently results in benign conditions such as pleural plaques, diffuse pleural thickening, and asbestosis (pulmonary fibrosis due to asbestos exposure). Over recent years, there have been changes in the epidemiology of mesothelioma, in clinical management of ARDs and developments in new techniques for early detection of malignancy. This review provides an update on the respiratory manifestations of asbestos exposure and also considers advances in screening methods that may affect future management in the workplace.

Fractional exhaled nitric oxide in asthma: an update.

In asthma, clinical symptoms and lung function are insensitive in reflecting the underlying airway inflammation, and monitoring of this process has only recently become available. Fractional exhaled nitric oxide (Fe(NO)) is now recognized as a reliable surrogate marker of eosinophilic airway inflammation and offers the advantage of being completely non-invasive and very easy to obtain. This review summarizes the clinical use of Fe(NO) in asthma. It covers the relationship between Fe(NO) and the underlying eosinophilic inflammation, the pathophysiology and production of Fe(NO), technical aspects of Fe(NO) measurement and potential confounding factors in interpreting levels. Fe(NO) reference values and the role of Fe(NO) in asthma assessment, diagnosis and management are also discussed.

House dust mite sublingual immunotherapy: the role for transforming growth factor-beta and functional regulatory T cells.

RATIONALE: Sublingual allergen-specific immunotherapy is gaining popularity for treatment of allergic diseases, but underlying immunological mechanisms are unresolved. OBJECTIVES: To perform detailed immunological investigation of sublingual house dust mite (HDM) immunotherapy. METHODS: A 12-month randomized double-blind placebo-controlled study of sublingual HDM immunotherapy in 30 HDM-allergic subjects was performed, with 1-year open extension in 9 patients on active treatment. HDM-stimulated blood mononuclear cells were analyzed for proliferation, cytokines, and regulatory T cells (Tregs) by flow cytometry and ELISA. Effects of blocking transforming growth factor (TGF)-beta and IL-10 on proliferation were determined. Treg suppressor function and allergen-specific antibody levels were measured. Clinical efficacy was assessed by symptom, medication, and Juniper quality-of-life scores. MEASUREMENTS AND MAIN RESULTS: Allergen-induced CD4(+) T-cell division and IL-5 production were significantly decreased after 6- and 12-months' active treatment but not placebo. sTGF-betaRII blocked immunotherapy-induced suppression of allergen-specific T-cell proliferation, maximal at 6 months. Decreased allergen-specific CD4(+) T-cell proliferation and increased IL-10 secretion and serum Der p 2-specific IgG(4) were maximal at 24 months' active treatment. Treg (CD4(+)CD25(+)CD127(lo)/Foxp3(+)) function was demonstrated by suppression of allergen-specific effector T-cell (CD4(+)CD25(-)CD127(hi)) proliferation and cytokine production. Clinical efficacy of immunotherapy was supported by significantly decreased rhinitis symptom score, total asthma score, and Juniper quality-of-life score. CONCLUSIONS: This study establishes the novel finding that TGF-beta mediates the immunological suppression seen early in clinically effective sublingual HDM immunotherapy in addition to an increase in Tregs with suppressor function. Clinical trial registered with www.clinicaltrials.gov (NCT00250263).

The controversial role of surveillance bronchoscopy after lung transplantation.

PURPOSE OF REVIEW: Clinically mandated transbronchial biopsy is universally regarded as the most efficient tool to establish pathology in the allograft. However, the utility of surveillance transbronchial biopsy to facilitate early detection and treatment of acute pulmonary allograft rejection is a matter of current debate. The purpose of this review is to summarize the evidence for and against the performance of surveillance bronchoscopy postlung transplantation, to discuss the risk/benefit ratio and the application of this procedure in the individual patient. RECENT FINDINGS: Detection of silent acute rejection of the pulmonary allograft remains an important benefit of surveillance bronchoscopy although definitive evidence for a positive impact on survival or prevention of development of the bronchiolitis syndrome (BOS) is yet to be demonstrated. Perhaps the wrong target has been the focus as new evidence suggests that high grade lymphocytic bronchiolitis is the important independent risk factor for the development of BOS and death after lung transplantation. Providing effective therapies for lymphocytic bronchiolitis can be developed there is now strong support for performance of surveillance transbronchial biopsy. Most studies attest to a low risk of severe complications. SUMMARY: Surveillance bronchoscopy is useful to detect asymptomatic acute rejection but also to determine the presence and severity of lymphocytic bronchiolitis, which should be the new target of therapeutic endeavours. It is acknowledged that the true risk/benefit ratio of surveillance bronchoscopy may differ between programs so each case deserves individual consideration.

Exhaled breath condensate biomarkers in asbestos-related lung disorders.

OBJECTIVES: Asbestos induces generation of reactive oxygen and nitrogen species in laboratory studies. Several such species can be measured non-invasively in humans in exhaled breath condensate (EBC) but few have been evaluated. This study aimed to assess oxidative stress and lung inflammation in vivo. METHODS: Eighty six men were studied: sixty subjects with asbestos-related disorders (asbestosis: 18, diffuse pleural thickening (DPT): 16, pleural plaques (PPs): 26) and twenty six age- and gender-matched normal individuals. RESULTS: Subjects with asbestosis had raised EBC markers of oxidative stress compared with normal controls [8-isoprostane (geometric mean (95% CI) 0.51 (0.17-1.51) vs 0.07 (0.04-0.13) ng/ml, p<0.01); hydrogen peroxide (13.68 (8.63-21.68) vs 5.89 (3.99-8.69) microM, p<0.05), as well as increased EBC total protein (17.27 (10.57-28.23) vs 7.62 (5.13-11.34) microg/ml, p<0.05), and fractional exhaled nitric oxide (mean+/-SD) (9.67+/-3.26 vs 7.57+/-1.89ppb; p<0.05). EBC pH was lower in subjects with asbestosis compared with subjects with DPT (7.26+/-0.31 vs 7.53+/-0.24; p<0.05). There were no significant differences in exhaled carbon monoxide, EBC total nitrogen oxides and 3-nitrotyrosine between any of the asbestos-related disorders, or between these and controls. CONCLUSION: In asbestos-related disorders, markers of inflammation and oxidative stress are significantly elevated in subjects with asbestosis compared with healthy individuals but not in pleural diseases.

Early detection of malignant pleural mesothelioma through measurement of soluble mesothelin-related protein and positron emission tomography.

A 51-year-old man with no known history of asbestos exposure presented with hydropneumothorax. Soluble mesothelin-related protein testing and combined positron emission tomography and computed tomography were used to diagnose malignant pleural mesothelioma. One year after radical surgery and radiotherapy, there was no clinical recurrence.

Clinical consequences of asbestos-related diffuse pleural thickening: A review.

Asbestos-related diffuse pleural thickening (DPT), or extensive fibrosis of the visceral pleura secondary to asbestos exposure, is increasingly common due to the large number of workers previously exposed to asbestos. It may coexist with asbestos related pleural plaques but has a distinctly different pathology. The pathogenesis of this condition as distinct from pleural plaques is gradually becoming understood. Generation of reactive oxygen and nitrogen species, profibrotic cytokines and growth factors in response to asbestos is likely to play a role in the formation of a fibrinous intrapleural matrix. Benign asbestos related pleural effusions commonly antedate the development of diffuse pleural thickening. Environmental as well as occupational exposure to asbestos may also result in pleural fibrosis, particularly in geographic areas with naturally occurring asbestiform soil minerals. Pleural disorders may also occur after household exposure. High resolution computed tomography (CT) is more sensitive and specific than chest radiography for the diagnosis of diffuse pleural thickening, and several classification systems for asbestos-related disorders have been devised. Magnetic resonance imaging and fluorodeoxyglucose positron emission tomography (PET) scanning may be useful in distinguishing between DPT and malignant mesothelioma. DPT may be associated with symptoms such as dyspnoea and chest pain. It causes a restrictive defect on lung function and may rarely result in respiratory failure and death. Treatment is primarily supportive.

Soluble mesothelin-related protein in an asbestos-exposed population: the dust diseases board cohort study.

RATIONALE: Soluble mesothelin-related protein (SMRP) is raised in epithelial-type malignant mesothelioma (MM), but the utility of SMRP in screening for MM is unknown. OBJECTIVES: We aimed to evaluate SMRP in an asbestos-exposed cohort. METHODS: A total of 538 subjects were studied. Those with elevated SMRP (> or =2.5 nM) underwent further investigation including positron emission tomography/computed tomography. MEASUREMENTS AND MAIN RESULTS: Mean (+/-SD) SMRP in healthy subjects exposed to asbestos (n = 223) was 0.79 (+/-0.45) nM. Fifteen subjects had elevated SMRP, of whom one had lung cancer, which was successfully resected. Another with lung cancer was undetected by SMRP. No subjects were diagnosed with MM. Mean SMRP in healthy subjects was significantly lower than in subjects with pleural plaques alone (P < 0.01). CONCLUSIONS: This is the first large-scale prospective study of SMRP for screening for malignancy in asbestos-exposed individuals. A high false-positive rate was observed. SMRP seems unlikely to prove useful in screening for MM.

Nitric oxide and exhaled breath nitrite/nitrates in chronic obstructive pulmonary disease patients.

BACKGROUND: Measurement of nitric oxide (NO) and nitrite/nitrates (NOx) levels in exhaled breath condensate (EBC) are non-invasive techniques, which can be used to monitor airway inflammatory diseases. Production of NO is often increased in inflammatory diseases of the airways, including exacerbations of chronic obstructive pulmonary disease (COPD). COPD-associated airway inflammation may be affected by multiple factors, including cigarette smoking and glucocorticosteroid (GCS) treatment. OBJECTIVES: To test the hypothesis that total NOx levels in EBC and exhaled NO levels would be affected by cigarette smoking or the presence of COPD. METHODS: Exhaled NO levels and NOx levels in EBC were measured in 96 COPD patients and in 80 normal subjects. RESULTS: Exhaled NO levels in COPD patients were significantly higher than those of normal subjects when comparing either the total groups (9.8 +/- 0.7 vs. 5.5 +/- 0.4 ppb, p < 0.0005) or 2 appropriate subgroups, ex-smokers (10.3 +/- 1.0 vs. 5.4 +/- 0.6 ppb, p < 0.0005) and smokers (9.2 +/- 1.2 vs. 5.7 +/- 0.5 ppb, p = 0.002). There was no significant difference in NOx levels in EBC, however, between COPD patients and healthy subjects when analysed either together or as subgroups. No significant difference was found in either exhaled NO levels or NOx levels in EBC between GCS-naive subjects and those on GCS treatment in the ex-smoking or smoking COPD subgroups. CONCLUSIONS: COPD patients have higher exhaled NO levels than control subjects when either combined or analysed as non-smoking, ex-smoking and smoking subgroups. GCS treatment did not appear to affect these non-invasive markers of airway inflammation in COPD.

Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage.

RATIONALE: Exhaled breath condensate (EBC) is increasingly studied as a noninvasive research method of sampling the lungs, measuring several biomarkers. The exact site of origin of substances measured in EBC is unknown, as is the clinical applicability of the technique. Special techniques might be needed to measure EBC biomarkers. OBJECTIVES: To assess biomarker concentrations in clinical disease and investigate the site of origin of EBC, we compared EBC and bronchoalveolar lavage (BAL) biomarkers in 49 patients undergoing bronchoscopy for clinical indications. MEASUREMENTS: We measured exhaled nitric oxide, 8-isoprostane, hydrogen peroxide, total nitrogen oxides, pH, total protein, and phospholipid (n = 33) and keratin (n = 15) to assess alveolar and mucinous compartments, respectively. EBC was collected over 10 min using a refrigerated condenser according to European Respiratory Society/American Thoracic Society recommendations, and BAL performed immediately thereafter. RESULTS: 8-Isoprostane, nitrogen oxides, and pH were significantly higher in EBC than in BAL (3.845 vs. 0.027 ng/ml, 28.4 vs. 3.8 microM, and 7.35 vs. 6.4, respectively; p < 0.001). Hydrogen peroxide showed no difference between EBC and BAL (17.5 vs. 20.6 microM, p = not significant), whereas protein was significantly higher in BAL (33.8 vs. 183.2 microg/ml, p < 0.001). Total phospholipid was also higher in EBC, but keratin showed no difference. No significant correlation was found between EBC and BAL for any of the biomarkers evaluated either before or after correction for dilution. CONCLUSIONS: In clinical disease, markers of inflammation and oxidative stress are easily measurable in EBC using standard laboratory techniques and EBC is readily obtained. However, EBC and BAL markers do not correlate.

Fractional exhaled nitric oxide concentration is increased in asbestosis and pleural plaques.

OBJECTIVE AND BACKGROUND: Asbestos exposure induces generation of reactive oxygen and nitrogen species. Nitric oxide is involved in asbestos-related lung toxicity in vitro and can be measured non-invasively in humans in exhaled breath. The authors hypothesized that fractional exhaled nitric oxide concentration (FENO) would be increased in subjects with asbestos-related lung disorders. METHODS: FENO was measured in 56 subjects with asbestos-related disorders (asbestosis: 12; pleural plaques: 32; asbestos-related diffuse pleural thickening: 12) and in 35 normal subjects. The authors also measured exhaled carbon monoxide, another marker of lung inflammation. RESULTS: Median (25-75 percentile) FENO was increased in subjects with asbestosis (7.9 (6.6-15.7) p.p.b.; P=0.001) and pleural plaques (6.3 (5.3-9) p.p.b.; P=0.03) compared with normal controls (4.6 (3.5-6) p.p.b.). Subjects with DPT had a median FENO of 5.6 p.p.b., similar to controls. No significant differences in exhaled carbon monoxide were observed between controls (1.0+/-0.3 p.p.m.) and subjects with asbestosis (1.3+/-0.3 p.p.m.), pleural plaques (1.2+/-0.3 p.p.m.) or diffuse pleural thickening (1.1+/-0.3 p.p.m.). CONCLUSIONS: FENO is raised in asbestosis consistent with lung inflammation, and also in pleural plaques.

Diffuse panbronchiolitis in a Caucasian man in Canada.

Diffuse panbronchiolitis (DPB) is a rare, chronic bronchiolar disease in non-Asian populations and is therefore commonly overlooked in Western countries. It usually affects nonsmokers and manifests as persistent air flow obstruction, chronic cough and interstitial nodular opacities. Untreated, the prognosis is poor. In this report the authors describe a Caucasian man of Canadian descent who presented with progressive clinical and lung function impairment despite three years of bronchodilator and corticosteroid treatment with presumed asthma. His chest computed tomography scan showed diffuse centrilobular opacities. Lung biopsy revealed chronic bronchiolitis characterized by infiltration of lymphocytes, plasma cells and foam cells in respiratory and terminal bronchioles, compatible with a diagnosis of DPB. After two months of therapy with clarithromycin, the patient had already shown improvement. Physicians should be aware that DPB may occur in Western countries, and that DPB should be considered in the differential diagnosis of patients with persistent air flow obstruction and nodular shadows on chest radiograms.

Effect of montelukast on exhaled nitric oxide and nonvolatile markers of inflammation in mild asthma.

STUDY OBJECTIVES: Leukotriene receptor antagonists appear to exert anti-inflammatory activity in asthma. We undertook the present study to evaluate the effect of montelukast on levels of exhaled nitric oxide (ENO) and two inflammatory markers, hydrogen peroxide (H(2)O(2)), and cysteinyl leukotrienes (cys-LTs), in the exhaled breath condensate of subjects with mild asthma. PATIENTS: Twenty stable subjects with mild asthma (15 women and 5 men; mean [+/- SD] age, 34.8 +/- 12.6 years) were included in the study. INTERVENTION: A 1-week run-in period was followed by 2 weeks of treatment (with montelukast or placebo) that was administered in randomized, double-blind, crossover fashion. One week of washout followed each treatment arm. RESULTS: Montelukast significantly reduced the levels of ENO from baseline (median, 52.5 parts per billion [ppb]; 25th to 75th percentile, 37.8 to 101.8 ppb) during the entire treatment period (ie, day 1 to day 14), with the effect measurable as early as day 1 (median, 45.9 ppb; 25th to 75th percentile, 29.3 to 92.5 ppb) and with the maximal effect being observed on day 7 (median, 35.7 ppb; 25th to 75th percentile, 27.6 to 66.6 ppb). The levels of ENO did not change significantly with placebo therapy. Montelukast improved symptom score and reduced peak expiratory flow (PEF) variability. Changes in PEF variability correlated positively with changes in ENO (r = 0.46; p = 0.04). No significant changes in FEV(1) or concentration of H(2)O(2) in the exhaled breath condensate were observed. Levels of cys-LTs were undetectable in the exhaled breath condensate. CONCLUSIONS: We concluded that montelukast reduces the levels of ENO in patients with mild asthma, a finding that is compatible with an anti-inflammatory effect of montelukast, and that ENO appears to be more sensitive in detecting this effect than FEV(1) and H(2)O(2) levels in the exhaled breath condensate.

Effect of nasal triamcinolone acetonide on lower airway inflammatory markers in patients with allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) and asthma are commonly associated, and similar underlying inflammatory processes link both diseases. AR, even in the absence of asthma, is associated with increased levels of exhaled nitric oxide (ENO) and hydrogen peroxide (H(2)O(2)) in exhaled breath condensate, 2 noninvasive markers of lower airway inflammation. OBJECTIVE: We sought to evaluate the effect of treatment with the nasal steroid triamcinolone acetonide on ENO and exhaled H(2)O(2) in subjects with AR. METHODS: We allocated 23 subjects in a randomized, double-blind, parallel-controlled fashion to 4-week treatment with triamcinolone acetonide (220 microg/d) or matching placebo. RESULTS: ENO levels were greater in the subgroup with concomitant asthma (16/23 subjects) and decreased significantly with triamcinolone acetonide treatment in this subgroup of patients in comparison with patients receiving placebo. Breath condensate levels of H(2)O(2) were higher in patients with AR without asthma than in those with asthma but decreased significantly with triamcinolone acetonide treatment in both subgroups. No changes were observed in bronchial hyperresponsiveness, nasal and asthma symptoms, or peak expiratory flow with active treatment or placebo. CONCLUSION: We conclude that treatment of AR with triamcinolone acetonide results in decrease of 2 noninvasive markers of lower airway inflammation, ENO and H(2)O(2), supporting that upper and lower airway inflammation should be seen as a continuum in subjects with AR with and without asthma. ENO might be a more specific marker of the lower airway inflammation present in asthma.

Efeito da terapêutica anti-inflamatória em marcadores da inflamaçäo das vias aéreas no ar expirado / Effect of antinflammatory therapy on markers od airway inflammation in the exhaled breath

Introdução: Óxido nítrico expirado (ENO) é considerado um marcador inflamatório na asma estando aumentado na ausência de terapia anti-inflamatória. Peróxido de hidrogênio (H202) e leucotrienos cisteínicos (LT-cis) são substâncias inflamatórias não voláteis que ocorrem no ar expirado condensado de pacientes com asma. Montelucaste, um antagonista de receptores de leucotrienos cisteínicos (LT-cis) resulta em melhora de controle da asma e influencia a inflamação eosinofilica brônquica. Objetivo: A hipótese principal deste estudo foi que a terapia com montelucaste', 10 mg/dia) administrado por duas semanas diminui os níveis de ENO em adultos com asma leve estável. Material e Métodos: Este estudo é um modelo randomizado, duplo-cego, cruzado, placebo-controlado, tendo um período de uma semana de 'washout" seguida a cada período de tratamento. As concentrações de LT-cis e H202 foram medidas no ar expirado condensado. Vinte pacientes (15 F, 5 M), média de idade de 34,8 anos foram estudados. Resultados: Montelucaste reduziu significativamente os níveis de ENO em comparação aos níveis basais (d0 52,5 ppb) durante todo o período de tratamento (dl a d14), com o efeito iniciando no dia; (45,9 ppb) e o efeito máximo sendo observado no dia 7 35,7 ppb). Os níveis de ENO não mudaram com placebo. Montelucaste reduziu o escore de sintomas e a variabilidade de pico de fluxo expiratório (PEF`)1 A redução da variablidade do PEF correlacionou positivamente com a redução no ENO. Nenhuma mudança no VEP, ou concentração de H202 no ar condensado foram observados Os níveis de leucotrienos cisteínicos nao foram detectados. Conclusão: Estes achados são consistentes com um efeito...(au)