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Hereditary angioedema (HAE) is a rare genetic disease with significant mortbidity and mortality for which early diagnosis and effective therapy are critical. Many Asia-Pacific (AP) countries still lack access to diagnostic tests and evidence-based therapies. Epidemiological data from the AP is needed to formulate regional guidelines to improve standards of care for HAE.To investigate the estimated minimal prevalence, needs and potential interventions for the diagnosis and management of HAE in the AP.A structured questionnaire was distributed to representative experts from member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI). Patient profiles and presence of diagnostic facilities/ tests, regional / national HAE guidelines and patient support groups were reported and compared.Completed questionnaires were received from 14 representatives of 12 member countries/territories, representing 46% of the world population. Overall minimal prevalence of HAE in the AP region was 0.02 per 100,000 population, with significant heterogeneity across different centres. Only half and one-third had registered on-demand and prophylactic medications, respectively. Few had patient support groups (58%) or regional guidelines (33%), and their existence was associated with availability of HAE-specific medications. Availability of C1-inhibitor level testing was associated with a lower age of HAE diagnosis (p=0.017).HAE in the AP differs from Western countries. HAE-specific medications were only registered in a minority of countries/territories, but those with patient support groups or regional guidelines were more likely to have better access. AP specific consensus and guidelines are lacking and urgently needed.

Although asthma is a common chronic airway disease that responds well to anti-inflammatory agents, some patients with asthma are unresponsive to conventional treatment. Mesenchymal stem cells (MSCs) have therapeutic potential for the treatment of inflammatory diseases owing to their immunomodulatory properties. However, the target cells of MSCs are not yet clearly known. This study aimed to determine the effect of human umbilical cord-derived MSCs (hUC-MSCs) on asthmatic lungs by modulating innate immune cells and effector T cells using a murine asthmatic model. Intravenously administered hUC-MSCs reduced airway resistance, mucus production, and inflammation in the murine asthma model. hUC-MSCs attenuated not only T helper (Th) 2 cells and Th17 cells but also augmented regulatory T cells (Tregs). As for innate lymphoid cells (ILC), hUC-MSCs effectively suppressed ILC2s by downregulating master regulators of ILC2s, such as

The development of molecular imaging probes to identify key cellular changes within lung metastases may lead to noninvasive detection of metastatic lesions in the lung. In this study, we constructed a macrophage-targeted clickable albumin nanoplatform (CAN) decorated with mannose as the targeting ligand using a click reaction to maintain the intrinsic properties of albumin

Background With the widespread use of gadolinium-based contrast agents (GBCAs), the incidence of allergic-like hypersensitivity reactions (HSRs) to GBCAs is increasing. Research on the incidence and risk factors for HSRs to GBCAs is needed for their safe use. Purpose To determine the incidence of acute and delayed reactions to GBCAs and to discuss the risk factors and strategies for the prevention of HSRs to GBCAs. Materials and Methods All cases of HSRs to contrast media that occurred at the Seoul National University Hospital from July 1, 2012, to June 30, 2020, were assessed. Information including age, sex, GBCA type, onset, and severity of HSRs was retrospectively analyzed. Results Among the 331070 cases of GBCA exposure in 154539 patients, 1304 cases of HSRs (0.4%) were reported. Acute HSRs accounted for 1178 cases (0.4%), while 126 cases (0.04%) were delayed HSRs. While both premedication (odds ratio [OR] = 0.7

Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that has no cure. Although mesenchymal stem cells (MSCs) have been reported to ameliorate lung inflammation and fibrosis in mouse models, their mechanisms of action remain unknown. Therefore, we aimed to determine the changes in various immune cells, especially macrophages and monocytes, involved in the effects of MSC treatment on pulmonary fibrosis. Methods We collected and analyzed explanted lung tissues and blood from patients with IPF who underwent lung transplantation. After establishing a pulmonary fibrosis model via the intratracheal administration of bleomycin (BLM) to 8-week-old mice, MSCs derived from human umbilical cords were administered intravenously or intratracheally on day 10 and the lungs were immunologically analyzed on days 14 and 21. Flow cytometry was performed to analyze the immune cell characteristics, and gene expression levels were examined using quantitative reverse transcription-polymerase chain reaction. Results In the histological analysis of explanted human lung tissues, the terminally fibrotic areas contained a larger number of macrophages and monocytes than the early fibrotic areas of the lungs. When human monocyte-derived macrophages (MoMs) were stimulated with interleukin-13 in vitro, the expression of type 2 macrophage (M2) markers was more prominent in MoMs from the classical monocyte subset than in those from intermediate or non-classical monocyte subsets, and MSCs suppressed M2 marker expression independent of MoM subsets. In the mouse model, the increased number of inflammatory cells in the bronchoalveolar lavage fluid and the degree of lung fibrosis observed in BLM-treated mice were significantly reduced by MSC treatment, which tended to be more prominent with intravenous administration than intratracheal administration. Both M1 and M2 MoMs were upregulated in BLM-treated mice. The M2c subset of M2 MoMs was significantly reduced by MSC treatment. Among M2 MoMs, M2 MoMs derived from Ly6C+ monocytes were most effectively regulated by the intravenous administration, not intratracheal administration, of MSCs. Conclusions Inflammatory classical monocytes may play a role in lung fibrosis in human IPF and BLM-induced pulmonary fibrosis. Intravenous rather than intratracheal administration of MSCs may ameliorate pulmonary fibrosis by inhibiting monocyte differentiation into M2 macrophages.

The standard treatment for allergic-airway inflammation, which is the dominant asthma endotype, is a steroid. However, steroid-refractory asthma is a significant problem. Innate-lymphoid cells (ILCs) produce type-2 cytokines as Th2 cells and play critical roles in asthma pathogenesis. Limited evidence from the asthma-mouse models and human studies suggests that ILC2s may participate in steroid-resistant asthma. Here, we showed that lung ILC2s, but not Th2 cells, can develop steroid resistance that maintains their survival, cytokine production, and pathogenic activities during steroid treatment. Such steroid-resistant ILC2s are associated with the presence of multiple ILC2-stimulating cytokines and the emergence of multipotent IL-5+IL-13+IL-17A+ ILC2s, and the Janus-kinase (JAK) 3/signal-transducer-and-activator-of-transcription (STAT) 3,5, and 6 pathway participates in the acquisition of steroid-resistant ILC2s. JAK3-inhibitor treatment significantly reduced the survival, proliferation, and cytokine production of multipotent ILC2s in vitro ameliorated ILC2-dependent Alternaria-induced asthma. Moreover, JAK3-inhibitor combined with a steroid strongly inhibited steroid-resistant asthma. Therefore, sustained asthmatic conditions may induce multipotent ILC2s that promote steroid-resistant asthma, and combining JAK3-inhibitor with steroid may be a treatment option for steroid-refractory asthma.

Transforming growth factor beta 1 (TGF-β1) induces pulmonary fibrosis by enhancing epithelial apoptosis and affects the enzymatic activity of transglutaminase 2 (TG2). The aim of this study was to determine the role of TG2 in TGF-β1-induced lung remodeling and alveolar macrophage modulation. We characterized the in vivo effects of TGF-β1 and TG2 on lung inflammation, fibrosis, and macrophage activity using transgenic C57BL/6 mice with wild and null TG2 loci. The effect of TG2 inhibition on in vitro TGF-β1-stimulated alveolar macrophages was assessed through mRNA analysis. TG2 was remarkably upregulated in the lungs of TGF-β1 transgenic (TGF-β1 Tg) mice, especially in alveolar macrophages and epithelial cells. In the absence of TG2, TGF-β1-induced inflammation was suppressed, decreasing the number of macrophages in the bronchoalveolar lavage fluid. In addition, the alveolar destruction and peribronchial fibrosis induced by TGF-β1 overexpression were significantly reduced, which correlated with decreases in the expression of fibroblast growth factor and matrix metallopeptidase 12, respectively. However, TG2 deficiency did not compromise the phagocytic activity of alveolar macrophages in TGF-β1 Tg mice. At the same time, TG2 contributed to the regulation of TGF-β1-induced macrophage activation. Inhibition of TG2 did not affect the TGF-β1-induced expression of CD86, an M1 marker, in macrophages, but it did reverse the TGF-β1-induced expression of CD206. This result suggests that TG2 mediates TGF-β1-induced M2-like polarization but does not contribute to TGF-β1-induced M1 polarization. In conclusion, TG2 regulates macrophage modulation and plays an important role in TGF-β1-induced lung inflammation, destruction, and fibrosis.

Background/Aims: Tuberculosis has incidence and mortality rates that are among the highest for all communicable diseases. Adverse drug reactions (ADRs) to anti-tubercular drugs are common, and have a major impact on treatment maintenance and prognosis. It is important to understand the characteristics of ADRs and establish a suitable management plan. Methods: We retrospectively reviewed patients with ADRs during treatment with first-line antitubercular drugs such as isoniazid, rifampicin, ethambutol, and pyrazinamide from 2009 to 2018. Age, sex, and total treatment period, and the onset, severity, seriousness, and system organ class of ADRs, were analyzed to understand the characteristics of first-line anti-tubercular drug-related ADRs. Results: A total of 1,606 of 5,482 patients (29.3%) experienced ADRs after administration of first-line anti-tubercular drugs. The incidence of ADRs related to isoniazid, rifampicin, ethambutol, and pyrazinamide was 22.2%, 21.3%, 24.5%, and 29.6%, respectively. A total of 2,098 ADR reports were made (mean of 1.3 ± 0.6 per patient). The rates of mild, moderate, and severe ADRs were 32.4%, 61.1%, and 6.5%, respectively. There were 127 reports (6.1%) of serious ADRs. Skin and appendage disorders were most frequently reported (27.5%), followed by gastrointestinal disorders (17.5%), and liver and biliary system disorders (13.1%). The total treatment period was longer in patients who experienced ADRs (224.0 ± 3.1 days vs. 247.0 ± 4.7 days, p = 0.009). Conclusions: The incidence of ADRs to first-line anti-tuberculosis drugs was 29.3%, and 6.5% were severe ADRS. ADRs prolonged the overall treatment duration, indicating the importance of their detection and management.

Patients with severe asthma have unmet clinical needs for effective and safe therapies. One possibility may be mesenchymal stem cell (MSC) therapy, which can improve asthma in murine models. However, it remains unclear how MSCs exert their beneficial effects in asthma. Here, we examined the effect of human umbilical cord blood-derived MSCs (hUC-MSC) on two mouse models of severe asthma, namely, Alternaria alternata-induced and house dust mite (HDM)/diesel exhaust particle (DEP)-induced asthma. hUC-MSC treatment attenuated lung type 2 (Th2 and type 2 innate lymphoid cell) inflammation in both models. However, these effects were only observed with particular treatment routes and timings. In vitro co-culture showed that hUC-MSC directly downregulated the interleukin (IL)-5 and IL-13 production of differentiated mouse Th2 cells and peripheral blood mononuclear cells from asthma patients. Thus, these results showed that hUC-MSC treatment can ameliorate asthma by suppressing the asthmogenic cytokine production of effector cells. However, the successful clinical application of MSCs in the future is likely to require careful optimization of the route, dosage, and timing.

This Practice Advisory presents a comprehensive and evidence-based set of position statements and recommendations for the use of contrast media in interventional pain procedures. The advisory was established by an international panel of experts under the auspices of 11 multinational and multispecialty organizations based on a comprehensive review of the literature up to December 31, 2019. The advisory discusses the risks of using gadolinium-based contrast agents. These include nephrogenic systemic fibrosis, gadolinium brain deposition/retention, and encephalopathy and death after an unintentional intrathecal gadolinium injection. The advisory provides recommendations on the selection of a specific gadolinium-based contrast agent in patients with renal insufficiency, those who had multiple gadolinium-enhanced magnetic resonance imaging examinations, and in cases of paraspinal injections. Additionally, recommendations are made for patients who have a history of mild, moderate, or severe hypersensitivity reactions to contrast medium.

HLA-B*58:01 is a well-known risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs). However, only a minority of HLA-B*58:01 carriers suffer SCARs after taking allopurinol. The aim of this study was to investigate subsidiary genetic markers that could identify those at further increased risk of developing allopurinol-induced drug reaction with eosinophilia and systemic symptoms (DRESS) in subjects with HLA-B*58:01.Subjects with B*58:01 were enrolled (21 allopurinol-induced DRESS and 52 allopurinol-tolerant control). HLA-A, -B, -C and -DRB1 alleles were compared. Comparison of risk between HLAs and allopurinol-induced SCAR in separate populations was performed to support the results. Kruskal-Wallis test, Pearson's chi-square test, Fisher's exact test and binary logistic regression were used to analyze the risk of SCAR development.Frequencies of A*24:02 (71.4 vs. 17.3%,The additional secondary screening with A*24:02 and DRB1*13:02 alleles may identify those at further increased risk of allopurinol-induced DRESS in B*58:01 carriers.

Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the effects of direct MSC administration on asthmatic airways. Umbilical cord MSCs (ucMSCs) were intratracheally administered to six-week-old female BALB/c mice sensitized and challenged with ovalbumin; airway hyperresponsiveness (AHR), analyses of airway inflammatory cells, lung histology, flow cytometry, and quantitative real-time PCR were performed. Furthermore, ex vivo and in vitro experiments were performed to assess the effects of ucMSC on M2 activation. Intratracheally administered ucMSCs decreased degree of airway resistance and the number of inflammatory cells such as T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), and macrophages in the murine asthma model. Particularly, MHCII and CD86 expression diminished in dendritic cells and alveolar macrophages (AMs) following ucMSC treatment. SiglecF+CD11c+CD11b- AMs show a negative correlation with type II inflammatory cells including Th2 cells, ILC2, and eosinophils in asthmatic mice and were restored following intratracheal ucMSCs treatment. In addition, ucMSCs decreased the macrophage polarization to M2, particularly M2a. The expression levels of markers associated with M2 polarization and Th2 inflammation were also decreased. ucMSC reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla ex vivo. Furthermore, the in vitro study using IL-4 treated macrophages confirmed that both direct and indirect MSC treatment significantly reduced the expression of Il-5 and Il-13. In conclusion, ucMSCs appear to suppress type II inflammation by regulating lung macrophages via soluble mediators.

Objective Lamotrigine is one of the most widely used antiepileptic drugs, but it has a critical issue of a skin rash if the starting dose is too high or the escalation rate is too rapid. We investigated the efficacy and safety of a novel and rapid titration protocol for lamotrigine that takes only 11 days to reach a daily dose of 200 mg. Methods We prospectively enrolled 33 adult patients (age 18‐85) who were diagnosed with epilepsy and started lamotrigine administration for the first time at a single tertiary hospital. Our new protocol starts with a subthreshold dose of the drug and then administers a stepwise‐incremental dose until reaching the full therapeutic dose within 11 days. Results Of 29 patients analyzed, only two (6.9%) experienced idiosyncratic skin rash before the first follow‐up visit at 2 weeks (±3 days). In addition, a therapeutic concentration was reached in more than 75% of studied patients after 2 weeks of lamotrigine administration. Significance These findings demonstrate the value of the novel tolerance induction protocol for lamotrigine, which could widen the available application of lamotrigine in various situations. However, this study is a preliminary study limited by a small number of patients and its nonrandomized and open‐label design, so the current protocol needs more rigorous clinical evaluations before the application to the real clinical setting.

To evaluate the epidemiology of adverse drug reactions (ADRs) in the Korean population and to identify their characteristics and factors affecting their severity.The analysis was based on the ADRs reported to the Seoul National University Hospital between 2009 and 2018. Statistical assessment (SPSS Statistics 25) included frequency analysis and the χA total of 44,122 cases were analyzed of which 24,801 (56.2%) cases concerned females and 19,321 (43.8%) males. A total of 47% of cases involved persons aged between 50 and 79 years. Antineoplastic agents, immunomodulating agents, and systemically administered anti-infective agents accounted for 57.6% of all drugs reported. Gastro-intestinal system disorders accounted for the largest proportion (25.8%) of adverse drug reactions reported. A total of 3,429 (7.8%) ADRs were reported as being in the category severe. Multivariate analysis showed that the risk of an ADR being reported as severe is higher in males than in females (OR = 1.25, 95% CI: 1.16 - 1.35), and higher in those aged 0 - 4 years (OR = 1.74, 95% CI: 1.46 - 2.08), in those aged 5 - 19 years (OR = 1.19, 95% CI: 1.07 - 1.31), and in those aged 65 years and over (OR = 1.26, 95% CI: 1.16 - 1.37), compared to those aged 20 - 64 years.From a public health perspective, ADRs are important because they are preventable. Important determinants, such as differences in specific age groups and drug classes, for the occurrence of ADRs and the occurrence of severe ADRs in particular, were identified. These determinants need to be carefully monitored in both private medical practices, clinics and hospitals. This monitoring of specific groups will involve close attention factors associated with gender, age group, and drug classes.

Iodinated contrast media (ICM) have become one of the major causes of drug hypersensitivity reactions (HSRs) related to increasing numbers of ICM-based radiological imaging procedures. Strategies for diagnosing and preventing ICM-induced HSRs have not been uniformly standardized yet. However, advances have been made based on the results of recent research. A previous history of hypersensitivity to ICM is the most significant risk factor for developing HSR by ICM. Avoidance of culprit agents and premedication is the main strategy to prevent recurrences of HSRs in high-risk patients. In addition, we strongly recommend identifying sensitized ICM using skin tests to determine immunoglobulin E-mediated or delayed-type allergy and to guide the choice of an alternative contrast agent. ICM provocation test procedures have been established and are helpful in selected cases. In this paper, we review how to evaluate patients who have experienced immediate or delayed HSRs caused by ICM to minimize the risk of recurrence and discuss unmet needs that require further research.

Background Transcriptomic analysis has been used to elucidate the complex pathogenesis of heterogeneous disease and may also contribute to identify potential therapeutic targets by delineating the hub genes. This study aimed to investigate whether blood transcriptomic clustering can distinguish clinical and immune phenotypes of asthmatics, and microbiome in asthmatics. Methods Transcriptomic expression of peripheral blood mononuclear cells (PBMCs) from 47 asthmatics and 21 non-asthmatics was measured using RNA sequencing. A hierarchical clustering algorithm was used to classify asthmatics. Differentially expressed genes, clinical phenotypes, immune phenotypes, and microbiome of each transcriptomic cluster were assessed. Results In asthmatics, three distinct transcriptomic clusters with numerously different transcriptomic expressions were identified. The proportion of severe asthmatics was highest in cluster 3 as 73.3%, followed by cluster 2 (45.5%) and cluster 1 (28.6%). While cluster 1 represented clinically non-severe T2 asthma, cluster 3 tended to include severe non-T2 asthma. Cluster 2 had features of both T2 and non-T2 asthmatics characterized by the highest serum IgE level and neutrophil-dominant sputum cell population. Compared to non-asthmatics, cluster 1 showed higher CCL23 and IL1RL1 expression while the expression of TREML4 was suppressed in cluster 3. CTSD and ALDH2 showed a significant positive linear relationship across three clusters in the order of cluster 1 to 3. No significant differences in the diversities of lung and gut microbiomes were observed among transcriptomic clusters of asthmatics and non-asthmatics. However, our study has limitations in that small sample size data were analyzed with unmeasured confounding factors and causal relationships or function pathways were not verified. Conclusions Genetic clustering based on the blood transcriptome may provide novel immunological insight, which can be biomarkers of asthma immune phenotypes. Trial registration Retrospectively registered

BackgroundAddiction to prescription narcotics is a global issue, and detection of individuals with a narcotic use disorder (NUD) at an early stage can help prevent narcotics misuse and abuse. We developed a novel index to detect early NUD based on a real-world prescription pattern analysis in a large hospital.MethodsWe analyzed narcotic prescriptions of 221 887 patients prescribed by 8737 doctors from July 2000 to June 2018. For the early detection of patients who could potentially progress to developing NUD after a long history of narcotic prescription, a weighted morphine equivalent daily dose (wt-MEDD) score was developed based on the number of prescription dates on which the actual MEDD was higher than the intended MEDD. Performance of the wt-MEDD scoring system in detecting patients diagnosed with NUD by doctors was compared with that of other NUD high risk indexes such as the MEDD scoring system, number of days on prescribed narcotics, the frequency/duration of prescription, narcotics prescription across multiple doctors, and the number of early refills of narcotics.ResultsA wt-MEDD score cut-off value of 10.5 could detect all outliers, as well as patients diagnosed with NUD with 100% sensitivity and 99.6% specificity. The wt-MEDD score showed the highest sensitivity and specificity in identifying NUD among all indexes. Further, combining the wt-MEDD score with other NUD high risk indexes improved the prediction performance.ConclusionWe developed a novel index to distinguish patients with vulnerable use patterns of narcotics. The wt-MEDD score showed excellent performance in detecting early NUD.

Eosinophilia occurs commonly in many diseases including allergic diseases and helminthic infections. Toxocariasis has been suggested as one cause of eosinophilia. The present study was undertaken to examine the prevalence of toxocariasis in patients with eosinophilia and to identify the risk factors for toxocariasis. This prospective cohort study recruited a total of 81 patients with eosinophilia (34 males and 47 females) who visited the outpatient clinic at Seoul National University Hospital from January 2017 to February 2018 and agreed to participate in this study. The prevalence of toxocariasis was examined by T. canis-specific ELISA, and the various risk factors for toxocariasis were evaluated by a questionnaire survey. Among 81 patients with eosinophilia, 18 were positive for anti-T. canis antibodies (22.2%); 88.9% were male (16/18) and 11.1% were female (2/18). Multivariate statistical analysis revealed that males (OR 21.876, 95% CI: 1.667-287.144) with a history of consuming the raw meat or livers of animals (OR 5.899, 95% CI: 1.004-34.669) and a heavy alcohol-drinking habit (OR 8.767, 95% CI: 1.018-75.497) were at higher risk of toxocariasis in patients with eosinophilia. Toxocariasis should be considered a potential cause of eosinophilia when the patient has a history of eating the raw meat or livers of animals in Korea. A single course of albendazole is recommended to reduce the migration of Toxocara larvae in serologically positive cases with eosinophilia.

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Mesenchymal stem cells (MSCs) are attractive alternatives to conventional anti-asthmatic drugs for severe asthma. Mechanisms underlying the anti-asthmatic effects of MSCs have not yet been elucidated. This study evaluated the anti-asthmatic effects of intravenously administered MSCs, focusing on macrophages and monocytes. Seven-week-old transgenic (Tg) mice with lung-specific overexpression of IL-13 were used to simulate chronic asthma. MSCs were intravenously administered four days before sampling. We examined changes in immune cell subpopulations, gene expression, and histological phenotypes. IL-13 Tg mice exhibited diverse features of chronic asthma, including severe type 2 inflammation, airway fibrosis, and mucus metaplasia. Intravenous administration of MSCs attenuated these asthmatic features just four days after a single treatment. MSC treatment significantly reduced SiglecF