Clinical implications of isolated troponinemia following immune checkpoint inhibitor therapy.

Cardiovascular adverse events induced by immune checkpoint inhibitors (ICIs) have gained significant interest over the past decade due to their impact on short- and long-term outcomes. They were initially thought to be rare, but the increasing use of ICIs in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in their incidence. Different guidelines have proposed screening measures for ICI-induced myocarditis by incorporating troponin measurements at baseline and during the first few weeks of treatment. However, no specific guidelines have been developed yet regarding the interpretation of an asymptomatic rise in troponins. This state-of-the art review aims to provide an overview of the clinical relevance of elevated troponins during checkpoint inhibition and recommendations on how to manage elevated troponin levels during ICI therapy.

Variable content of Fel d 1 variants in house dust and cat extracts may have an impact on allergen measurement.

BACKGROUND: The major cat allergen, Fel d 1, is a tetrameric glycoprotein composed of 2 heterodimers. Polymorphisms in this allergen are well documented. Recent work shows that Fel d 1 samples can contain core fragments of variable immunoreactivity. OBJECTIVES: Our objective was to compare Fel d 1 polymorphism in cat extracts and house dust, which is used as an indicator of allergen exposure and to understand how the combination of individual Fel d 1 variants can affect cat allergen measurement. METHODS: Natural Fel d 1 allergens were water-extracted from house dust and from the chest area and anal sacs of a cat. Recombinant Fel d 1 was provided commercially. The samples were analyzed by immunoblotting; variants were isolated using gel electrophoresis and tested using enzyme-linked immunosorbent assay. RESULTS: Four Fel d 1 variants of 40, 30, 19-21, and 14-16 kDa were consistently identified in Fel d 1 samples. Fel d 1 patterns found in house dust and the chest area wash were similar. Dimers were shown to be the major variant, while intact or truncated tetramers and core fragments were found in variable amounts. Intact and truncated dimers of Fel d 1 displayed similar antibody binding. Conversely, the intact tetramer-but not the core tetramer-was found to bind twice the antibody amount as the dimers and core fragments. CONCLUSIONS: Despite a common pattern of Fel d 1 variants in cat extracts and house dust, variations in the tetramer-to-dimer ratio among samples may introduce major discordances in cat allergen measurements using immunoassays. Our findings indicate the need for further harmonization of allergen immunoassays.

Histamine induces Th2 activation through the histamine receptor 1 in house dust mite rhinitic but not asthmatic patients.

BACKGROUND: Effects of mast cell-released histamine on smooth muscle and endothelial cells are considered as responsible of immediate symptoms of anaphylaxis. However, little is known about histamine effects on Th2 lymphocytes, which orchestrate the allergic reaction upstream of mast cells. OBJECTIVE: We addressed this question in house dust mite (HDM) allergics, according to the presence of rhinitis or asthma and allergen stimulation. METHODS: Peripheral blood mononuclear cell from 15 rhinitic and 14 asthmatic HDM-allergic subjects and 16 controls were cultured with Der p 1 or histamine. The effect of Der p 1 on histamine receptor (H1R and H2R) expression was studied. T-cell cytokine production was studied upon Der p 1 or histamine stimulation. The role of H1R in histamine effects was assessed with levocetirizine. RESULTS: H1R and H2R are overexpressed on T cells from asthmatic but not from rhinitic subjects. Der p 1 increases H1R expression on CD4(+) cells from both allergic groups, and decreases it in controls, on CD4(+) and CD8(+) subsets. Der p 1 decreases T-cell H2R expression in asthmatics. Allergen increases IL-4 and IL-13 in both allergic groups. Histamine increases Th2 cytokines in rhinitics only, and levocetirizine abolishes this effect. In asthmatics and controls, histamine decreases T-cell cytokines through a non-H1R dependent pathway. CONCLUSION: In rhinitis but not in asthma, histamine is able to increase allergic inflammation by increasing Th2 cytokine production in a positive feedback dependent on H1R. This result could explain in part why H1R antagonists, are very efficient in rhinitis, but not in asthma.

17q21 variants modify the association between early respiratory infections and asthma.

Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset

T-cell activation during exacerbations: a longitudinal study in refractory asthma.

BACKGROUND: Asthma exacerbations represent the main source of costs and morbidity in asthma care, and drugs specifically designed to prevent exacerbations are needed. A prerequisite is to dispose of a precise knowledge of inflammatory events leading to exacerbations. OBJECTIVE: To study T-cell activation during exacerbations from severe refractory asthmatics. METHODS: Proportions of blood T-cell interleukin (IL)-13, interferon-gamma, IL-4, IL-5, IL-10 production and of CD4+CD25+(high)CD62L+CD45RO+ [T regulatory (Treg)] cells were determined by flow cytometry. Blood cytokine mRNA was studied by reverse transcription-polymerase chain reaction and the respective protein levels were determined by cytokine beads array. Depletion of Treg cells was performed to study their activation. T-cell cytokines were detected in parallel in induced sputum. RESULTS: At baseline, T helper 2 (Th2) cells were increased in asthmatics, whereas T helper 1 (Th1) and Treg T cells were decreased. T helper 2 cells increased before exacerbations, followed by Th1 cells, in blood and induced sputum, albeit Treg cells decreased in parallel with IL-10-producing T cells. Concordant results were found at the mRNA level. The suppressive activity of Treg cells was impaired during exacerbations compared to baseline. CONCLUSIONS: New insights are given into pathophysiology of asthma exacerbations: Although at baseline T-cell activation is Th2-biased, a mixed Th1/Th2 activation occurs during exacerbations. The Treg cell deficiency found at baseline in SRA increases during exacerbations.

[Environmental factors for asthma severity and allergy: results from the EGEA study]. / Facteurs environnementaux de l'asthme sévère et de l'allergie: résultats de l'étude EGEA.

INTRODUCTION: EGEA (Epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), a case control and family study including 2048 individuals, was initiated to look for environmental and genetic risk factors for asthma. A synthesis of the results obtained since 2002 on phenotypic and environmental aspects of asthma severity and allergy are presented in this article. METHODS AND RESULTS: The results support a role for hormonal factors in asthma severity and in various allergic markers of asthma. A greater body mass index was related to a more severe asthma in women with early menarche. Associations between markers of allergy (eosinophils, IgE and atopy) and hormonal dependent events in women (premenstrual asthma, menopause and oral contraceptive use) have been found. In asthmatics, exposure to agents known to be associated with occupational asthma, active and passive smoking were associated with an increased clinical asthma severity score. The study underlines the protective role of country living and exposure to pets in early life on allergy markers in adulthood, supporting the hygiene hypothesis. CONCLUSIONS: New hypothesis will be tested in the near future from the second stage of this survey.

T-cell activation in occupational asthma and rhinitis.

BACKGROUND: Allergic asthma and rhinitis are described as associated with a Th2 activation. However, recent works indicate that a Th1 activation can also be associated with these diseases, concomitantly to a defect in regulatory T (Treg) cell activation. Occupational asthma (OA) and occupational rhinitis (OR) are peculiar cases of these diseases in which the T-cell activation profile is largely unknown. OBJECTIVE: To characterize T-cell activation induced after a specific inhalation test (SIT) in OA and OR. MATERIAL AND METHODS: A total of 21 subjects with OA, 10 subjects with OR, 10 exposed nonallergic (ENA) subjects, and 14 healthy volunteers were included. The SIT with the incriminated substance was performed in patients and ENA subjects. Blood and induced sputum were obtained before and after SIT. T cells were analysed for CD69, CD25, IL-13, and IFN-gamma expression by flow cytometry. IL-4 and IFN-gamma were assayed by enzyme-linked immunosorbent assay (ELISA) in cell culture supernatants. Treg cells were identified as CD4(+)CD25(+high)CD45RO(+)CD69(-) T cells in peripheral blood. RESULTS: Baseline IFN-gamma production was decreased in OA and OR compared with controls. The SIT induced an increase in both Th1 and Th2 cells in blood and sputum from OA. In this group, the proportion of peripheral Treg cells decreased after SIT. Similar results were found in the CD8(+) population. ELISA assays were concordant with flow cytometry. In OR, an attenuated activation profile was found, with an increase in the proportion of IL-13-producing T cells after SIT. By contrast, in ENA subjects, SIT induced Th2 activation, with an increase in Treg cells and a decrease in Th1 cells. CONCLUSIONS: Our results demonstrate a gradient of T-cell activation from a tolerating profile in ENA subjects to an inflammatory profile in OA, with an intermediate stage in OR.

Safety and efficacy of Juniperus ashei sublingual-swallow ultra-rush pollen immunotherapy in cypress rhinoconjunctivitis. A double-blind, placebo-controlled study.

BACKGROUND: The safety and efficacy of high-dose sublingual-swallow immunotherapy (SLIT) has been established in pollen rhinoconjunctivitis. This treatment has now been evaluated using an ultra-rush incremental dose regimen with a Juniperus ashei allergen extract in patients allergic to Cupressus sempervirens and Cupressus arizonica. METHODS: Patients received either placebo or SLIT. Evaluation of safety was based on the frequency of adverse events during the incremental dose period (half a day) and during maintenance therapy (4 months). Evaluation of efficacy was based on symptom and medication scores at the pollen peak. RESULTS: Seventy of the 76 patients included completed the study. There were no drop-outs during the rush procedure. One patient in the active group dropped out during the maintenance therapy due to adverse events: gastric pain and vomiting. There was also 1 drop-out in the placebo group due to pregnancy. Adverse events were infrequent, local and mild. Symptom scores for rhinitis and conjunctivitis were not statistically different between groups, but there was a marked and significant (p < 0.03) decrease of the medication score (about 50%) and nasal steroid consumption (about 75%) in the active treatment group. An increase from baseline of serum IgE and IgG4 J. ashei-specific antibodies was only observed in actively treated patients (p < 0.04 and p < 0.01, respectively). CONCLUSIONS: The tolerability and safety of high-dose ultra-rush SLIT were comparable to those reported in previous SLIT studies. SLIT with J. ashei extract, due to its high Jun a 1 content, significantly reduced nasal steroid consumption in patients allergic to European cypress.

Ultra-rush venom immunotherapy induces differential T cell activation and regulatory patterns according to the severity of allergy.

BACKGROUND: Venom immunotherapy (VIT) induces immune tolerance to hymenoptera venom antigens in allergic patients and is therefore a helpful model for studying modulation of allergic immune response. The objectives were to assess the early effects of ultra-rush VIT on T lymphocyte activation and regulatory profile induction, in all subjects combined and according to the four severity grades of the Mueller classification. MATERIALS AND METHODS: Blood samples from 30 vespid-allergic patients were taken before and after the first day of treatment, and before day 15 and day 45 booster injections. IFN-gamma and IL-4 levels were assayed by ELISA, in whole-blood supernatants. IFN-gamma and IL-13-producing T cells, but also natural CD4+CD25+high regulatory T cells and acquired regulatory T cell proportions were assessed by flow cytometry. Results were analysed in the whole population and compared between patients with I-II or III-IV allergic reactions. RESULTS: During VIT, IFN-gamma increased in whole blood when IL-4 decreased. Among T cells, the percentage of CD3+IFN-gamma+ cells increased while IL-13-producing T cells decreased. Proportions of CD4+CD25+high cells and IL-10-producing T cells increased with VIT. In I-II subjects, IFN-gamma increased gradually, whereas it remained at low levels in III-IV patients. By contrast, IL-4 decrease was more pronounced in III-IV patients. Increase in CD4+CD25+high T cells occurred early in I-II patients but was delayed in III-IV patients. IL-10-producing T cells increased gradually in both groups but were in a lower proportion in III-IV patients. CONCLUSION: A T helper type 2 (Th2)-to-Th1 switch occurs during ultra-rush VIT, in parallel with natural and acquired regulatory T cell increase. These events occur earlier and at a higher level in less severe subjects, suggesting that VIT tolerance induction is easier to achieve in these patients.

Do patients with skin allergies have higher levels of anxiety than patients with allergic respiratory diseases? Results of a large-scale cross-sectional study in a French population.

BACKGROUND: Psychological comorbidity is a known aspect of allergic disease. However, there is recent evidence that a large proportion of allergic patients remains undiagnosed and untreated for psychological disease. In addition, the complexities of the anxiety-allergy relationship, i.e. differences for current and past disease, or differences among allergic disease types, are not well understood. OBJECTIVES: To measure the level of anxiety in a large allergic population in France using a standardized measure, the State/Trait Anxiety Inventory (STAI). METHODS: Allergy patients in France (n = 3939) who visited their allergy specialists participated in the study. The patients completed a questionnaire which was then linked to the questionnaire completed by their physician. Only patients with both subject and physician questionnaire were kept in the analyses. Mean STAI scores for the State (S) and Trait (T) scales were obtained for each allergic disease. ANCOVA models testing group differences on the mean scores, using the categories "current disease", "past disease" and "allergic disease ever", were assessed along with relevant confounders. RESULTS: Allergic rhinitis (AR), asthma and atopic dermatitis (AD) were the most prevalent conditions of the 12 allergic diseases assessed in the study. Women had higher mean STAI S/T scores than men and age was also found to be associated with higher S scores; therefore, both age and gender were included as covariates where relevant. A single ANCOVA model for each STAI scale showed a statistical difference among the various allergic diseases. Using the category "current disease" each allergic disease was assessed separately regarding the presence or absence of that disease. Higher, statistically significant mean STAI scores were found for AD and allergic urticaria on the S scale and for AD on the T scale. Similarly, for the category "allergic disease ever", AD and allergic urticaria reached statistical significance on the S scale, while on the T scale only AD was statistically significant. When patients were assessed for anxiety based on their past disease, asthma, AR and sinusitis were significant on the S scale while asthma and nasal polyps were statistically significant on the T scale. When asthma and AD were tested simultaneously, only the latter was significant. CONCLUSIONS: High mean scores for State and Trait anxiety were mostly associated with AD.

Diesel exhaust particles enhance T-cell activation in severe asthmatics.

Prevalence of asthma is increasing in westernized countries. Epidemiological studies showed the impact of traffic pollution on the triggering of asthma symptoms and exacerbations, and this effect is mainly attributed to the polycyclic aromatic hydrocarbon core of diesel exhaust particles (DEP). However, although DEP induce IgE synthesis, little is known of their role on T-cell activation, the main cells orchestrating asthma inflammation. We assessed the effect of DEP on T-cell activation in severe uncontrolled asthmatics during (n = 13) and outside (n = 19) exacerbations. Results were compared with data obtained in healthy controls (n = 14). Peripheral blood mononuclear cells were cultured in the presence of low-dose DEP. T-cell activation markers, CD69 and CD25, interleukin-4 (IL-4) and interferon (IFN)-gamma production and T-cell proliferation were assessed by flow cytometry. DEP exposure increased the proportion of CD3+CD69+ T cells in all subjects. The proportion of CD25+ T cells increased under DEP stimulation in the exacerbation group only. IFN-gamma- and IL-4-producing T cells increased in both asthmatic groups, especially during exacerbations, but not in controls. This effect was more pronounced for IL-4. In response to DEP stimulation, T-cell proliferation increased in higher proportion in asthmatics compared with controls. These results show that DEP activate T cells in asthmatics only, with a higher effect during exacerbations. This is in keeping with epidemiological data which demonstrated that DEP trigger respiratory symptoms in asthmatics but not in controls. The higher effect of DEP in exacerbated asthmatics suggests that uncontrolled asthma is a risk factor for aggravation under exposure to traffic pollutants.

Variation of T-cell activation in allergic subjects during natural pollen exposure.

BACKGROUND: Allergic inflammation is characterized by a Th2 activation. However, little is known about dynamics of T-cell cytokine production during natural allergen exposure. The aim of this study was to assess the Th1/Th2 balance in cypress allergic patients compared with controls, and variations of this balance over the pollen season. METHODS: Twenty cypress allergic patients and 10 controls were studied, distributed during two consecutive pollen seasons. Cytokine production was assessed by flow cytometry and ELISA. The variation of cytokine production during the pollen season was analyzed among patients in four occasions, and the preseason values were compared with controls. IL-13 and IFN-gamma-containing T cells were assessed among whole blood cells and PBMC. In addition the effect of specific stimulation by Juniperus ashei pollen extract was studied. RESULTS: Compared with controls, IL-13-producing T cells were increased in allergics in any case. By contrast, compared with controls, allergic IFN-gamma-producing T cells were decreased in whole blood, but not in PBMC, and were increased after specific stimulation. During the season, an increase in IFN-gamma- and a decrease in IL-13-producing T cells occurred in patients, whatever the culture conditions. CONCLUSION: These results show that the allergic T-cell activation is not limited to a Th2 profile: allergen-stimulated T cells are able to produce IFN-gamma at baseline, and the Th1/Th2 ratio increases during the pollen season.

[Economic burden of COPD: the SCOPE study]. / Impact economique de la BPCO en France: etude SCOPE.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a major health problem. Few data about COPD economic burden are available. METHODS: SCOPE was an observational economical retrospective and prospective study conducted in France in 2001, by 114 general practitioners (GPs) and 57 lung specialists. The aim was to describe the burden of COPD patients and to estimate the annual cost according to severity stages. Health resource utilization was collected by questionnaires over a 12-month period for 285 patients. RESULTS: It was a cost-of-illness analysis. COPD patients followed by a lung specialist were more severe than patients followed by a GP and had a higher level of medical resource consumption. The COPD disease and its complications explained 66% of the total cost. The main cost drivers were inpatient care (35%, or 1509,9 euros/year/patient) and prescription medications (31%, or 1340,6 euros/year/patient). The direct total cost varied according to COPD severity on account of inpatient care and respiratory assistance. DISCUSSION: This study confirmed the economic burden of COPD in France. Actions allowed to slow down the disease's evolution and to anticipate the exacerbation could reduce the cost.

[T regulatory lymphocytes, atopy and asthma: a new concept in three dimensions]. / Lymphocytes T régulateurs, atopie et asthme: un nouveau concept en trois dimensions.

BACKGROUND: Allergic inflammation is considered to be the result of a pattern of Th2 lymphocyte activation. However this inflammation, relevant for atopy and infiltration of affected tissues by eosinophils, is insufficient by itself to explain the clinical features of asthma. Several studies have demonstrated that Th2 type inflammation was also associated in asthma with a Th1 response, with production of gamma interferon. It has recently been shown that the regulatory T lymphocytes (Treg) which produce IL-10 and/or TGF-beta and induce tolerance are defective in allergic patients. In addition, these lymphocytes increase during specific immunotherapy. Their decrease could explain the Th2 activation found in atopic patients. PERSPECTIVE: We review the potential importance of Treg cells in atopy and also asthma, and propose a concept whereby the allergic inflammatory response would not be due to a Th1/Th2 imbalance, but rather to a Treg deficiency progressively rising from normal to atopic, from atopy to asthma and from asthma to acute exacerbations. CONCLUSION: Three dimensions of inflammation need therefore to be taken into account: Th1, Th2 and Treg.

Dog factor differences in Can f 1 allergen production.

BACKGROUND: The clinical importance of dog allergy is well known, but it is unknown if all types of dogs represent the same risk for allergic patients. The purpose of this work was to evaluate among 288 healthy dogs if the levels of Can f 1 on fur vary between breeds (German Shepherd, Pyrenean Shepherd, Poodle, Cocker spaniel, Spaniel, Griffon, Labrador retriever and Yorkshire terrier), gender, hormonal status, hair length, and according to the presence of seborrhea. METHODS: Each dog was shaved in a limited area and Can f 1 concentrations were measured in mug/g fur by ELISA. The results (geometric mean values and 95% confidence intervals) were analyzed using analysis of variance and with nonparametric tests. RESULTS: A wide variability in Can f 1 levels was found between dog breeds, from Labradors [1.99 (0.03-129.91)] to Yorkshires [16.72 (3.67-76.16)] and Poodles [17.04 (2.79-103.94)] but only the Labrador levels were significantly different from each other breed. Males produced more Can f 1 than females, 11.75 (1.27-108.40) vs 8.89 (0.91-86.39). No difference was found according to hair length or hormonal status. The seborrheic status highly (P = 0.0019) influenced the presence of Can f 1 on hair: 16.66 (1.59-173.96) vs 9.40 (1.03-85.70). CONCLUSION: Breeds (Labrador retriever), sex and seborrhea seem to influence the levels of Can f 1 on fur.