Relationship between serum IgA levels and low percentage forced expiratory volume in the first second in asthma.

Objective: Immunoglobulin A (IgA) is suggested to have pathogenic effects in respiratory inflammatory diseases, including asthma. We aimed to analyze the relationship between serum IgA, and clinical indicators and biomarkers of asthma.Methods: This study was a post hoc analysis of the NHOM Asthma Study. In this study, serum IgA was measured using serum samples stored. We determined an association between the serum IgA level and clinical variables and biomarkers using multivariate linear regression and analyzed the differences in clinical indices between IgA high- and IgA low-asthma.Results: In this study, 572 patients with asthma were included in the final analysis. Lower percentage forced expiratory volume in the first second (%FEV1), higher serum eotaxin levels, lower serum ST2 levels, and higher serum MIP-1ß levels, were independently and significantly associated with higher serum IgA levels among asthma patients by multivariate linear regression analysis (%FEV1, 95% confidence interval [CI], -8.18- -0.613, p < 0.05; eotaxin, 95% CI, 8.95-46.69, p < 0.001; ST2, 95% CI, -73.71- -7.37, p < 0.05; and MIP-1ß, 95% CI, 1.47-18.71, p < 0.05). Furthermore, IgA high-asthma (serum IgA ≥ 238 mg/dL, n = 270) and IgA low-asthma (serum IgA < 238 mg/dL, n = 302) were compared separately. %FEV1 was significantly lower, the percentage of atopy was higher, and serum MIP-1ß level was higher in IgA high-asthma.Conclusions: This study suggests that serum IgA may be involved in the worsening of asthma outcomes, as assessed by %FEV1 and enhanced inflammation via elevated serum MIP-1ß.

Differences in asthma-related outcomes by anti-IL-5 biologics, omalizumab, and dupilumab based on blood eosinophil counts.

BACKGROUND: Selecting optimal biologics based on type 2 biomarkers has been of interest in severe asthma treatment. However, few direct biomarker stratification-based comparisons have been made. OBJECTIVE: To compare the effectiveness of anti-IL-5 (mepolizumab, benralizumab), omalizumab, and dupilumab in reducing the number of hospitalizations from asthma and exacerbations across all and eosinophil-stratified subgroups. METHODS: A retrospective cohort study using the National Hospital Organization database (2016-2020) was performed. Asthmatic patients using biologics were selected, and the baseline backgrounds of the groups were balanced using inverse probability treatment weighting for propensity scores. Weighted rate ratios (RRs) were obtained using a Poisson regression model. RESULTS: Among the 320 patients with asthma using biologics, 205 (64.1%), 75 (23.4%), and 40 (12.5%) were categorized into the anti-IL-5, omalizumab, and dupilumab groups, respectively. After weighting, there were 47.1, 30.0, and 62.6 hospitalizations per 100 person-years [omalizumab vs. anti-IL-5: weighted RR, 0.61 (0.34-1.08); dupilumab vs. anti-IL-5: 1.48 (0.81-2.72)], and 117.0, 134.6, and 287.3 exacerbations per 100 person-years [omalizumab vs. anti-IL-5: 1.13 (0.83-1.54); dupilumab vs. anti-IL-5: 2.69 (1.91-3.78)] in these respective groups. In patients with eosinophil of ≥ 300/µL, the dupilumab group had more exacerbations compared with the anti-IL-5 group [weighted RR, 2.85 (1.82-4.46)]. In patients with eosinophil of < 300/µL, the omalizumab group had fewer hospitalizations compared with the anti-IL-5 group [weighted RR, 0.32 (0.13-0.51)]. CONCLUSION: Anti-IL-5 biologics may be more effective than dupilumab in patients with high blood eosinophil counts, while less effective than omalizumab in patients with low eosinophil counts.

Identification of exhaled volatile organic compounds that characterize asthma phenotypes: A J-VOCSA study.

BACKGROUND: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma. METHODS: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS). RESULTS: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1-5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p < 0.05 adjusted by false discovery rate (FDR). Comparison of these phenotypes yielded several VOCs showing different trends (p < 0.05); however, no VOCs showed p < 0.05 adjusted by FDR. CONCLUSIONS: Exhaled VOC profiles may be useful for distinguishing asthma and asthma phenotypes; however, these findings need to be validated, and their pathological roles should be clarified.

Serum IgA augments adhesiveness of cultured lung microvascular endothelial cells and suppresses angiogenesis.

Immunoglobulin A (IgA) is important in local immunity and is also abundant in the blood. This study aimed to evaluate the effects of serum IgA on cultured lung microvascular endothelial cells (HMVEC-Ls), which are involved in the pathogenesis of inflammatory lung diseases. Serum IgA induced adhesion molecules and inflammatory cytokine production from HMVEC-Ls, and enhanced adhesion of peripheral blood mononuclear cells to HMVEC-Ls. In contrast, migration, proliferation, and tube formation of HMVEC-Ls were significantly suppressed by serum IgA. Experiments with siRNAs and western blotting revealed that two known IgA receptors, ß1,4-galactosyltransferase 1 (b4GALT1) and asialoglycoprotein receptor 1 (ASGR1), and mitogen-activated protein kinase and nuclear factor-kappa B pathways were partly involved in serum IgA-induced cytokine production by HMVEC-Ls. Collectively, serum IgA enhanced cytokine production and adhesiveness of HMVEC-L, with b4GALT1 and ASGR1 partially being involved, and suppressed angiogenesis. Thus, serum IgA may be targeted to treat inflammatory lung diseases.

Allergic bronchopulmonary aspergillosis with atopic, nonatopic, and sans asthma-Factor analysis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma. METHODS: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA. RESULTS: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p < .001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups. CONCLUSION: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition.

Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria.

Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n(-/-) BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n(-/-) mice were resistant. Upon mycobacterial infection, Clec4n(-/-) mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM.

Characterization and cluster analyses of elderly asthma in comparison with nonelderly patients with asthma in Japan.

BACKGROUND: Asthma is a heterogeneous disease with multiple phenotypes that are useful in precision medicine. As the population ages, the elderly asthma (EA, aged ≥ 65 years) population is growing, and EA is now a major health problem worldwide. OBJECTIVE: To characterize EA and identify its phenotypes. METHODS: In adult patients with asthma (aged ≥ 18 years) who had been diagnosed with having asthma at least 1 year before study enrollment, 1925 were included in the NHOM-Asthma (registered in UMIN-CTR; UMIN000027776), and the data were used for this study, JFGE-Asthma (registered in UMIN-CTR; UMIN000036912). Data from EA and non-EA (NEA) groups were compared, and Ward's minimum-variance hierarchical clustering method and principal component analysis were performed. RESULTS: EA was characterized by older asthma onset, longer asthma duration and smoking history, more comorbidities, lower pulmonary function, less atopic, lower adherence, and more hospital admissions because of asthma. In contrast, the number of eosinophils, total immunoglobulin E level, oral corticosteroid use, and asthma control questionnaire scores were equivalent between EA and NEA. There were 3 distinct phenotypes in EA, which are as follows: EA1: youngest, late onset, short duration, mild; EA2: early onset, long duration, atopic, low lung function, moderate; and EA3: oldest, eosinophilic, overweight, low lung function, most severe. The classification factors of the EA phenotypes included the age of onset and asthma control questionnaire-6. Similarities were observed between EA and NEA phenotypes after principal component analysis. CONCLUSION: The EA in Japan may be unique because of the population's high longevity. Characterization of EA phenotypes from the present cohort indicated the need for distinct precision medicine for EA. TRIAL REGISTRATION: JFGE-Asthma registered in UMIN-CTR (https://www.umin.ac.jp/ctr/); UMIN000036912.

Phenotype characterization and biomarker evaluation in moderate to severe type 2-high asthma.

BACKGROUND: There are two major pathological phenotypes of asthma, type 2 (T2)-high and T2-low asthma, which are important in determining treatment strategies. However, the characteristics and phenotypes of T2-high asthma have not yet been fully identified. OBJECTIVE: This study aimed to identify the clinical characteristics and phenotypes of patients with T2-high asthma. METHODS: This study used data from a nationwide asthma cohort study in Japan, NHOM Asthma Study. T2-high asthma was defined as a blood eosinophils count ≥ 300 /µL and/or fractional exhaled nitric oxide level ≥ 25 ppb, and the clinical characteristics and biomarkers were compared between T2-high and T2-low asthma. Furthermore, T2-high asthma was phenotyped via hierarchical cluster analysis using Ward's method. RESULTS: Patients with T2-high asthma were older, less likely to be female, had longer asthma duration, had lower pulmonary function, and had more comorbidities, including sinusitis and SAS. Patients with T2-high asthma showed higher serum thymus and activation-regulated chemokine and urinary leukotriene E4 levels and lower serum ST2 levels than those with T2-low asthma. There were four phenotypes among patients with T2-high asthma: Cluster 1 (youngest, early-onset, and atopic), Cluster 2 (long duration, eosinophilic, and low lung function), Cluster 3 (elderly, female-dominant, and late-onset), and Cluster 4 (elderly, late-onset, and asthma-COPD overlap-dominant). CONCLUSIONS: Patients with T2-high asthma have distinct characteristics and four distinct phenotypes, in which eosinophil-dominant Cluster 2 is the most severe phenotype. The present findings may be useful in precision medicine for asthma treatment in the future.

Biologics for severe asthma: The real-world evidence, effectiveness of switching, and prediction factors for the efficacy.

Biologics have been a key component of severe asthma treatment, and there are currently biologics available that target IgE, IL-5, IL-4/IL-13, and TSLP. Randomized controlled trials have established clinical evidence, but a significant portion of patients with severe asthma in real-life settings would have been excluded from those trials. Therefore, real-world research is necessary, and there is a growing body of information about the long-term efficacy and safety of biologics. Multiple clinical phenotypes of severe asthma exist, and it is crucial to choose patients based on their phenotypes. Blood eosinophil count is an important biomarker for anti-IL-5 therapies, and FeNO and eosinophil counts serve as prediction markers for dupilumab. Reliable markers for predicting response, however, have not yet been fully established for omalizumab. Identification of clinical or biological prediction factors is crucial for the path toward clinical remission because the current treatment goal includes clinical remission, which is defined as a realistic goal for remission off treatment. Additionally, since there are now multiple biologic options and overlaps in eligibility for biologics in clinical practice, the evidence regarding the effectiveness of switching the biologics is crucial. Investigations into the clinical trajectory following the cessation of biologics are another important issue. Recent research on omalizumab, mepolizumab, benralizumab and dupilumab's real-world effectiveness, the prediction factor for the efficacy, and the impact of switching or discontinuation will be reviewed and discussed in this review.

Classifications of moderate to severe asthma phenotypes in Japan and analysis of serum biomarkers: A Nationwide Cohort Study in Japan (NHOM Asthma Study).

BACKGROUND: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes. METHODS: Adult asthma patients (n = 1925) from 27 national hospitals in Japan were enrolled and divided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1-3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5 patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis were performed for phenotyping. Analysis of variance, the Kruskal-Wallis, and chi-square tests were used to compare cluster differences. RESULTS: The following five clusters were identified: 1) late-onset, old, less-atopic; 2) late-onset, old, eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young, female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers, FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined by tree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4, 5 phenotypes. CONCLUSIONS: Five distinct phenotypes were identified for moderate to severe asthma and may be classified using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.).

Identification of ANXA2 on epithelial cells as a new receptor for secretory IgA using immunoprecipitation and mass spectrometry.

Secretory immunoglobulin A plays an important role in the protection against exogenous pathogens and antigens, but it has also been reported to have pathogenic potential. We previously found that secretory immunoglobulin A accumulated in the peripheral lungs during idiopathic pulmonary fibrosis and that transferrin receptor/CD71 was partially involved in secretory immunoglobulin A-induced inflammatory cytokine production in A549 cells. This study aimed to identify the receptor responsible for the induction of cytokine production by secretory immunoglobulin A-stimulated airway epithelial cells. To this end, immunoprecipitation followed by time-of-flight mass spectrometry and peptide mass fingerprinting were performed and Annexin A2 was detected as a novel receptor for secretory immunoglobulin A. Enzyme-linked immunosorbent assay demonstrated binding of secretory immunoglobulin A to Annexin A2, and flow cytometry showed robust expression of Annexin A2 on the surface of BEAS-2B cells, A549 cells, and normal human bronchial/tracheal epithelial cells. Experiments in A549 cells using Annexin A2 small interfering RNA and neutralizing antibodies suggested that Annexin A2 was partially involved in the production of interleukin-8/CXCL8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 induced by secretory immunoglobulin A. Immunohistochemistry using lung sections revealed clear expression of Annexin A2 on airway epithelial cells, although the staining remained equivalent in idiopathic pulmonary fibrosis, asthma, and healthy control lungs. In conclusion, we identified that Annexin A2 expressed in airway epithelial cells is a novel receptor for secretory immunoglobulin A, which is involved in cytokine synthesis.

Immunoglobulin A promotes IL-6 and IL-8 production, proliferation, and migration by the human bronchial smooth muscle cells.

Immunoglobulin A (IgA) is important in biological defense, mainly in the mucosal area, and plays pathogenic roles in various diseases by activating both inflammatory and structural cells. The current study aimed to validate the effects of IgA on the human bronchial smooth muscle cell (BSMC), which plays a major role in airway inflammation and remodeling. Serum IgA induced interleukin (IL)-6 and IL-8 production at both mRNA and protein levels, and enhanced cell proliferation and migration by the BSMCs. The synthetic phenotype markers were regulated and the contractile phenotype markers were downregulated by serum IgA. Mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt, and nuclear factor-κB pathways were involved in IgA-induced IL-6 and IL-8 production. The BSMCs expressed transferrin receptor (TfR), and TfR siRNA transfection inhibited IL-6 and IL-8 production by serum IgA. In summary, serum IgA is a potent activator of the BSMCs at least partially via TfR.

Evaluation of cytokine levels in response to mitogen among HIV-1-infected blood cells and their relationships to the number of T cells.

BACKGROUND: Human immunodeficiency virus-1 (HIV-1) infection causes loss and anergy of CD4+ and CD8+ T cells, leading to opportunistic infections, including tuberculosis (TB). QuantiFERON®-TB (QFT) is used as a diagnostic tool to detect TB, but it exhibits limited accuracy among subjects with low CD4+ T cell numbers, including HIV-1-infected individuals. The present study aimed to determine the effect of HIV-1 infection and patients' blood T cell numbers on cytokine production in response to mitogen (Mit) stimulation. METHODS: The number of CD4+ and CD8+ T cells in HIV-1-infected individuals was quantified. Levels of various cytokines in Mit-stimulated and un-stimulated (Nil) supernatants of QFT gold "in tube" were assessed using a MAGPIX System. The correlation between cytokine levels and CD4+/CD8+ T cell counts in response to Mit was analyzed. The cytokine levels were compared between HIV-1-infected and healthy subjects. RESULTS: HIV-1-infected individuals (110) and control subjects (27) were enrolled. Interferon (IFN)-γ, interleukin-1 receptor antagonist (IL-1RA), IL-6, IL-8, and regulated on activation, normal T cell expressed and secreted (RANTES) values in Mit-Nil tubes showed a significant correlation with CD4+ T cell counts, while IFN-γ, IL-6, and IFN-γ-induced protein 10 (IP-10) values in Mit-Nil tubes had significant correlation with CD8+ T cell counts. IL-1RA, IL-8, IP-10, platelet-derived growth factor (PDGF)-BB, and RANTES levels in Nil tubes were significantly higher in the HIV-1-infected group. IFN-γ, IL-2, IL-5, IL-6, IP-10, and macrophage inflammatory protein-1ß values in Mit-Nil tubes were significantly higher, and PDGF-BB and RANTES levels were significantly lower in the HIV-1-infected group. CONCLUSION: The functions of HIV-1-infected T cells and uninfected T cells, such as spontaneous and responsive cytokine production in response to Mit, were different. Our findings may be useful for developing new clinical tools for patients with low T cell counts. Additionally, the study provides new insights into the pathogenesis of HIV-1 infection.

Serum total IgE may be a biomarker among chronic pulmonary aspergillosis patients with elevated serum total IgE levels: A cohort study with pathological evaluations.

High serum total immunoglobulin E (IgE) levels have been reported in chronic pulmonary aspergillosis (CPA). However, researchers have not verified if they reflect the disease activity. We aimed to compare the serum total IgE levels in CPA cases with high serum IgE during an exacerbation or when stable and examined the IgE expression patterns in the lesions via immunofluorescence staining. From April 2016 to September 2019, we extracted CPA cases with elevated serum total IgE levels based on the criteria of the Infectious Diseases Society of America. We retrospectively analyzed serum total IgE levels and other parameters and eventually extracted 32 cases. The patients' serum total IgE levels were significantly higher in the exacerbation period than in the stable period (P < .0001). The median rate of change was 1.76 times (quartile 1.41-3.25). In addition, we used surgical specimens of CPA cases with high serum total IgE levels, normal serum total IgE CPA cases, and control surgical specimens and performed immunofluorescence staining with IgE, mast cell tryptase, CD138, and 4,6-diamidino-2-phenylindole. We observed multiple mast cells and plasma cells in the CPA cases regardless of the serum total IgE level. In contrast, multiple IgE-positive cells co-stained with tryptase were observed in CPA cases with high serum total IgE levels. This finding suggested that serum total IgE could serve as a biomarker for evaluating disease severity. Immunofluorescence staining suggested that IgE may play a role in pathogenesis through activation of mast cells by cross-linking in cases of CPA with high serum total IgE levels. LAY SUMMARY: High serum total IgE levels are common in chronic pulmonary aspergillosis. This novel study indicated that serum total IgE is a possible biomarker of the disease activity in the aforementioned condition. Immunofluorescence staining indicated a possible role of IgE in disease pathogenesis.

High serum cytokine levels may predict the responsiveness of patients with severe asthma to benralizumab.

OBJECTIVE: Benralizumab, a humanized monoclonal antibody against human IL-5 receptor alpha, is effective in treating eosinophilic severe asthma. However, patients' response to benralizumab varies widely. In this study, we aimed to identify a new serum biomarker to accurately predict benralizumab response. METHODS: Seventeen benralizumab-treated patients with severe eosinophilic asthma were enrolled. Blood samples were collected; pulmonary function tests were performed and questionnaires were disseminated at baseline and after 1, 2, 4, and 6 months of treatment. Blood cytokine levels were measured. Response was defined as an elevation in forced expiratory volume in 1 s of at least 10.4% from baseline after 4 months of treatment. RESULTS: There were nine respondents and eight non-respondents. The non-responders showed significantly higher baseline serum interferon-γ; interleukin (IL)-4, -5, -6, -7, and -12p70; IL-17/IL-17A; IL-17E/IL-25; IL-18/IL-1F4; chemokine (C-C motif) ligand (CCL)3/macrophage inflammatory protein (MIP)-1α; CCL4/MIP-1ß; CCL11/eotaxin; matrix metalloproteinase-12; tumor necrosis factor-α, and thymic stromal lymphopoietin levels. After benralizumab administration, the serum CCL3/MIP-1α and CCL11/eotaxin levels significantly and persistently increased in the responders (CCL3/MIP-1α, responders: 144.5 ± 37.9 pg/ml (baseline) vs. 210.3 ± 59.4 pg/ml (4 months), p = 0.009; non-responders: 270.8 ± 139.8 pg/ml (baseline) vs. 299.5 ± 159.9 pg/ml (4 months), p = 0.33; CCL11/eotaxin, responders: 167.9 ± 62.6 pg/ml (baseline) vs. 326.7 ± 134.4 pg/ml (4 months), p = 0.038; non-responders: 420.9 ± 323.1 pg/ml (baseline) vs. 502.1 ± 406.0 pg/ml (4 months), p = 0.30). CONCLUSION: Low baseline serum inflammatory cytokine levels may be useful in predicting a good benralizumab response.Supplemental data for this article is available online at at www.tandfonline.com/ijas .

High serum free IL-18 is associated with decreased omalizumab efficacy: findings from a 2-year omalizumab treatment study.

OBJECTIVE: Omalizumab is more effective in severe allergic patients with eosinophilic asthma than those with non-eosinophilic asthma. IL-18, a unique cytokine involved in allergic but non-eosinophilic inflammation, might be associated with the latter condition. We aimed to clarify the roles of IL-18 related pathways in insufficient response to omalizumab treatment. METHODS: Patients with severe allergic asthma who completed 2-year omalizumab treatments at Kyoto University Hospital were included in this study (UMIN000002389). Associations between pretreatment levels of serum free IL-18 in addition to other mediators and asthma phenotypes including responses to omalizumab treatment were analyzed. Changes in serum free IL-18, periostin and total IgE levels during the treatment were also examined. RESULTS: Twenty-seven patients (19 females, average age of 55.7 years) were examined. Fifteen incomplete responders who experienced exacerbations in the second year, were significantly and more frequently obese and showed significantly earlier asthma onset, lower blood eosinophils and more exacerbations before omalizumab treatment than complete responders. Significantly more patients showed high baseline serum free IL-18 levels (≥141 pg/mL, a threshold for the highest tertile) among the incomplete responders than complete responders. Patients with high serum free IL-18 levels shared similar characteristics with incomplete responders, showing significant reductions in serum total IgE levels during omalizumab treatment. Finally, serum free IL-18 levels negatively correlated with serum periostin levels at baseline and in change ratios. CONCLUSIONS: High baseline serum free IL-18 levels may predict reduced omalizumab efficacy in severe allergic patients with type-2 low asthma, regarding reduction of exacerbations.

IL-1RA in the supernatant of QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold Plus is useful for discriminating active tuberculosis from latent infection.

INTRODUCTION: The new-generation QuantiFERON (QFT)-TB Gold Plus (QFT-Plus) is expected to be useful because it includes a new peptide that is supposed to induce a CD8+ T cell response. There is a need for a new marker with sensitivity higher than that of the conventional IFN-γ release assays owing to false-negative results in the latter. This study aimed to compare cytokines in QFT-plus and QuantiFERON-Gold In-Tube (QFT-GIT) supernatants to discriminate between active tuberculosis and latent tuberculosis infection (LTBI). METHODS: A cross-sectional study was conducted at Tokyo National Hospital, wherein 21 LTBI patients and age and sex-matched active TB patients were randomly selected. The levels of various cytokines were measured and compared using the MAGPIX System, and receiver operating characteristic (ROC) curves were generated. RESULTS: IL-1RA, IFN-γ, CXCL10/IP-10, and CCL4/MIP-1ß levels were higher in the active TB group than in the LTBI group in QFT-GIT antigen (GIT Ag) tubes. In QFT-plus tubes, IL-1RA was higher in TB1 and TB2 tubes, while CCL2/MCP-1 was higher only in TB2 tubes. In Nil tubes, CCL5/RANTES, TNF-α, PDGF-BB, and IL-2 levels were significantly higher in the active TB group. IL-1RA in GIT Ag tubes showed the highest area under the curve of 0.8367. The sensitivity and specificity of IL-1RA were 66.7% (95% confidence interval [CI]: 43.0-85.4) and 90.5% (95% CI: 69.6-98.8), respectively, which were the highest among the cytokines. CONCLUSIONS: IL-1RA level in the QFT-GIT supernatant can be a good marker for discriminating active TB from LTBI.

FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms.

Fibroblasts provide a structural framework for multiple organs and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of FOXL1 (forkhead box L1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high FOXL1 transcripts associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, which is in contrast with fibroblasts derived from other organs. RNA in situ hybridization and immunohistochemistry in normal lung tissue indicated that FOXL1 mRNA and protein are expressed in submucosal interstitial cells together with airway epithelial cells. Transcriptome analysis revealed that FOXL1 could control a broad array of genes that potentiate fibroblast function, including TAZ (transcriptional coactivator with PDZ-binding motif)/YAP (Yes-associated protein) signature genes and PDGFRα (platelet-derived growth factor receptor-α). FOXL1 silencing in lung fibroblasts attenuated cell growth and collagen gel contraction capacity, underscoring the functional importance of FOXL1 in fibroproliferative reactions. Of clinical importance, increased FOXL1 mRNA expression was found in fibroblasts of idiopathic pulmonary fibrosis lung tissue. Our observations suggest that FOXL1 regulates multiple functional aspects of lung fibroblasts as a key transcription factor and is involved in idiopathic pulmonary fibrosis pathogenesis.

Early Arterial Embolization and Mortality in Mechanically Ventilated Patients With Hemoptysis: A Nationwide Retrospective Cohort Study.

OBJECTIVES: Hemoptysis, a symptom common across various respiratory diseases, can cause airway obstruction leading to a life-threatening condition. Arterial embolization has been used to control bleeding from the lower airways. However, limited studies have evaluated its effects on in-hospital mortality in patients with hemoptysis requiring mechanical ventilation. The objective of this study was to clarify whether early intervention by arterial embolization reduced mortality in mechanically ventilated patients with hemoptysis. DESIGN: Retrospective cohort study from July 2010 to March 2017. SETTING: More than 1,200 acute-care hospitals, comprising approximately 90% of all tertiary-care emergency hospitals in Japan. PATIENTS: The study cohort was patients with pulmonary diseases hospitalized for hemoptysis and mechanically ventilated within 2 days of admission. INTERVENTIONS: We compared patients who had undergone arterial embolization within 3 days of endotracheal intubation (early embolization group) with patients who did not (control group). MEASUREMENTS AND MAIN RESULTS: A total of 12,287 patients with hemoptysis requiring mechanical ventilation were analyzed. After 1:4 propensity score matching, there were 226 and 904 patients in the early embolization and control groups, respectively. The early embolization group was associated with lower 7-day and 30-day mortalities (7-d mortality: 1.3% vs 4.0%; odds ratio, 0.39; 95% CI, 0.16-0.97; p = 0.044 and 30-d mortality: 7.5% vs 16.8%; odds ratio, 0.45; 95% CI, 0.28-0.73; p = 0.001) and shorter duration of mechanical ventilation (median 6 d, interquartile range 4-13 d vs 8 d, interquartile range 4-19 d; p = 0.003) compared with the control group. CONCLUSIONS: Our results show that early intervention by arterial embolization may be effective in reducing 7-day and 30-day mortalities in patients with life-threatening hemoptysis requiring mechanical ventilation.

Comparison of QuantiFERON-TB Gold Plus, QuantiFERON-TB Gold In-Tube, and T-SPOT.TB among patients with tuberculosis.

OBJECTIVES: This study evaluated the efficacy of the following interferon (IFN)-γ release assays (IGRAs): QuantiFERON-TB Gold Plus (QFT-Plus), QFT-Gold In-Tube (QFT-GIT), and T-SPOT. TB (T-SPOT) with the quantitative values of IFN-γ response. METHODS: Blood samples were collected from patients with active tuberculosis (TB), latent TB infection (LTBI), individuals with previous TB infection, and healthy volunteers enrolled between May 2017 and June 2018. RESULTS: IGRAs results were analyzed in 175 subjects (76 had active TB, 14 had LTBI, 35 had prior TB infection, and 50 were healthy). QFT-Plus and QFT-GIT revealed equal efficacy for IFN-γ values, and the IFN-γ response in QFTs tended to increase with the spot counts in T-SPOT, with similar high sensitivities (approximately 90%) in the active TB group. The test concordance of two of three IGRAs was optimal among all subjects (κ coefficients: 0.82-0.96). Additionally, the median quantitative values of IFN-γ with QFT-Plus and QFT-GIT were higher in the active TB group than in the LTBI and previous TB groups. CONCLUSION: Three IGRAs showed equivalent efficacy with high sensitivities and higher IFN-γ response in active TB group than that in non-active TB group.