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The emerging field of gut-lung axis research has revealed a complex interplay between the gut microbiota and respiratory health, particularly in asthma. This review comprehensively explored the intricate relationship between these two systems, focusing on their influence on immune responses, inflammation, and the pathogenesis of respiratory diseases. Recent studies have demonstrated that gut microbiota dysbiosis can contribute to asthma onset and exacerbation, prompting investigations into therapeutic strategies to correct this imbalance. Probiotics and prebiotics, known for their ability to modulate gut microbial compositions, were discussed as potential interventions to restore immune homeostasis. The impact of antibiotics and metabolites, including short-chain fatty acids produced by the gut microbiota, on immune regulation was examined. Fecal microbiota transplantation has shown promise in various diseases, but its role in respiratory disorders is not established. Innovative approaches, including mucus transplants, inhaled probiotics, and microencapsulation strategies, have been proposed as novel therapeutic avenues. Despite challenges, including the sophisticated adaptability of microbial communities and the need for mechanistic clarity, the potential for microbiota-based interventions is considerable. Collaboration between researchers, clinicians, and other experts is essential to unravel the complexities of the gut-lung axis, paving a way for innovative strategies that could transform the management of respiratory diseases.

Abstract 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.

Abstract 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

Abstract 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.

Abstract Despite numerous previous studies, the full action mechanism of the pathogenesis of asthma remains undiscovered, and the need for further investigation is increasing in order to identify more effective target molecules. Recent attempts to develop more efficacious treatments for asthma have incorporated mesenchymal stem cell (MSC)-based cell therapies. This study aimed to evaluate the anti-asthmatic effects of MSCs primed with Liproxstatin-1, a potent ferroptosis inhibitor. In addition, we sought to examine the changes within macrophage populations and their characteristics in asthmatic conditions. Seven-week-old transgenic mice, constitutively overexpressing lung-specific interleukin (IL)-13, were used to simulate chronic asthma. Human umbilical cord-derived MSCs (hUC-MSCs) primed with Liproxstatin-1 were intratracheally administered four days prior to sampling. IL-13 transgenic mice demonstrated phenotypes of chronic asthma, including severe inflammation, goblet cell hyperplasia, and subepithelial fibrosis. Ly6C+M2 macrophages, found within the pro-inflammatory CD11c+CD11b+ macrophages, were upregulated and showed a strong correlation with lung eosinophil counts. Liproxstatin-1-primed hUC-MSCs showed enhanced ability to downregulate the activation of T helper type 2 cells compared to naïve MSCs in vitro and reduced airway inflammation, particularly Ly6C+M2 macrophages population, and fibrosis in vivo. In conclusion, intratracheal administration is an effective method of MSC delivery, and macrophages hold great potential as an additional therapeutic target for asthma.

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca2+ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal antiinflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Background: Although beta-lactams are 1 of the major causative agents of severe cutaneous adverse reactions (SCAR), their epidemiology and clinical aspects have been poorly studied. This study aimed to investigate the characteristics of SCAR caused by beta-lactams in the Korean SCAR registry. Methods: We retrospectively analyzed beta-lactam-induced SCAR cases collected from 28 tertiary university hospitals in Korea between 2010 and 2015. The SCAR phenotypes included Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), SJS-TEN overlap, and drug reaction with eosinophilia and systemic symptoms (DRESS). Beta-lactams were classified according to their chemical structures: penicillins, cephalosporins, and carbapenems. The causative beta-lactams, clinical and laboratory features, treatments, and outcomes were evaluated. Results: Among the 275 antibiotic-induced SCAR cases, 170 patients developed SCAR induced by beta-lactams. Beta-lactam antibiotic-induced SCAR showed more frequent SJS/TEN compared to SCAR induced by non-beta-lactam antibiotics (SJS/TEN/SJS-TEN overlap/DRESS: 36.5/11.2/5.9/46.5% vs. 23.8/10.5/2.9/62.9%, P = 0.049). Cephalosporin was the most common culprit drug. Particularly, 91 and 79 patients presented with SJS/TEN and DRESS, respectively. The odds ratio (OR) for poor prognosis, such as sequelae and death, was significantly increased in subjects with SJS-TEN overlap and TEN and carbapenem as culprit drug in the multivariate analysis (OR, 35.61; P = 0.016, OR, 28.07; P = 0.006, OR 30.46; P = 0.027). Conclusion: Among antibiotic-induced SCAR, clinical features were different depending on whether the culprit drug was a beta-lactam antibiotic or SCAR type. The poor prognosis was related to SJS-TEN overlap, TEN type, and carbapenem as the culprit drug.

Abstract Background Transglutaminase 2 (TG2), a multifunctional calcium‐dependent acyltransferase, is upregulated in asthmatic airways and reported to play a role in the pathogenesis of allergic asthma. However, the underlying mechanism is not fully understood. Objective To investigate the role of TG2 in alternative activation of alveolar macrophages by using murine asthma model. Methods TG2 expression was assessed in induced sputum of 21 asthma patients and 19 healthy controls, and lung tissue of ovalbumin (OVA)‐induced murine asthma model. To evaluate the role of TG2 in asthma, we developed an OVA asthma model in both TG2 null and wild‐type mice. The expression of M2 macrophage markers was measured by fluorescence‐activated cell sorting (FACS) after OVA sensitization and challenge. To evaluate the effect of TG2 inhibition in vitro, interleukin 4 (IL‐4) or IL‐13‐stimulated expression of M2 macrophage markers was measured in CRL‐2456 cells in the presence and absence of a TG2 inhibitor. Results The expression of both TG2 and M2 markers was increased in the sputum of asthmatics compared with that of healthy controls. The expression of TG2 was increased in macrophages of OVA mice. Airway hyperresponsiveness, and the number of inflammatory cells, including eosinophils, was significantly reduced in TG2 null mice compared with wild‐type mice. Enhanced expression of M2 markers in OVA mice was normalized by TG2 knockout. IL‐4 or IL‐13‐stimulated expression of M2 markers in alveolar macrophages was also attenuated by TG2 inhibitor treatment in vitro. Conclusion Our results suggest that TG2‐mediated modulation of alveolar macrophage polarization plays important roles in the pathogenesis of asthma.

Abstract In vivo presentation of airway hyper-responsiveness (AHR) at the different time points of the allergic reaction is not clearly understood. The purpose of this study was to investigate how AHR manifests in the airway and the lung parenchyma in vivo following exposure to different stimuli and in the early and late phases of asthma after allergen exposure. Ovalbumin (OVA)-induced allergic asthma model was established using 6-week female BALB/c mice. Enhanced pause was measured with a non-invasive method to assess AHR. The dynamic changes of the airway and lung parenchyma were evaluated with ultra-high-resolution computed tomography (128 multi-detector, 1024 × 1024 matrix) for 10 h. While the methacholine challenge showed no grossly visible changes in the proximal airway and lung parenchyma despite provoking AHR, the OVA challenge induced significant immediate changes manifesting as peribronchial ground glass opacities, consolidations, air-trapping, and paradoxical proximal airway dilatations. After resolution of immediate response, multiple episodes of AHRs occurred with paradoxical proximal airway dilatation and peripheral air-trapping in late phase over a prolonged time period in vivo. Understanding of airflow limitation based on the structural changes of asthmatic airway would be helpful to make an appropriate drug delivery strategy for the treatment of asthma.

Abstract Background 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. Methods 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. Results Frequencies of A*24:02 (71.4 vs. 17.3%, p < 0.001, odds ratio [OR] = 12.0; 95% confidence interval [CI], 3.6–39.2) were significantly higher in B*58:01 (+) DRESS than B*58:01 (+) tolerant controls. In addition, DRB1*13:02 further increased the risk of DRESS. The phenotype frequency of A*24:02/DRB1*13:02 was significantly higher in the B*58:01 (+) DRESS group than in the B*58:01 (+) tolerant controls (52.4% vs. 5.8%, p < 0.001, OR, 66.0; 95% CI, 6.1–716.2). In 2782 allopurinol user cohort, the overall prevalence of DRESS was 0.22%, which increased to 1.62% and 2.86% in the presence of B*58:01 and B*58:01/A*24:02, respectively. Conclusion 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.

Abstract 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.

Drug hypersensitivity reactions (DHRs) to intravenous drugs can be severe and might leave patients and doctors in a difficult position where an essential treatment or intervention has to be suspended. Even if virtually any intravenous medication can potentially trigger a life-threatening DHR, chemotherapeutics, biologics, and antibiotics are amongst the intravenous drugs most frequently involved in these reactions. Admittedly, suspending such treatments may negatively impact the survival outcomes or the quality of life of affected patients.Delabeling pathways and rapid drug desensitization (RDD) can help reactive patients stay on first-choice therapies instead of turning to less efficacious, less cost-effective, or more toxic alternatives. However, these are high-complexity and high-risk techniques, which usually need expert teams and allergy-specific techniques (skin testing, in vitro testing, drug provocation testing) to ensure safety, an accurate diagnosis, and personalized management. Unfortunately, there are significant inequalities within and among countries in access to allergy departments with the necessary expertise and resources to offer these techniques and tackle these DHRs optimally.The main objective of this consensus document is to create a great benefit for patients worldwide by aiding allergists to expand the scope of their practice and support them with evidence, data, and experience from leading groups from around the globe.This statement of the Drug Hypersensitivity Committee of the World Allergy Organization (WAO) aims to be a comprehensive practical guide on the technical aspects of implementing acute-onset intravenous hypersensitivity delabeling and RDD for a wide range of drugs. Thus, the manuscript does not only focus on clinical pathways. Instead, it also provides guidance on topics usually left unaddressed, namely, internal validation, continuous quality improvement, creating a healthy multidisciplinary environment, and redesigning care (including a specific supplemental section on a real-life example of how to design a dedicated space that can combine basic and complex diagnostic and therapeutic techniques in allergy).

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? 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.

BackgroundDrug desensitization is helpful for patients who have experienced significant hypersensitivity reactions (HSRs) to antineoplastic agents. One-bag desensitization protocols, attracting attention in recent years, need to be validated on their safety and efficacy in a large number.MethodsOne-bag desensitization procedures conducted from 2018 to 2020 were analyzed; their outcomes and the risk factors for breakthrough reactions (BTRs) were assessed in desensitization procedures to major drug types (platins, taxanes, and monoclonal antibodies).ResultsA total of 1,143 procedures of one-bag desensitization were performed in 228 patients with 99% completion rate. BTRs occurred in 26% of the total desensitization procedures—34% in platins, 12% in taxanes, and 18% in mAbs. BTR occurrence rate decreased along the desensitization process with 80% of BTRs occurring within the 6th desensitization attempts. Severe BTR occurred more frequently with severe initial HSRs (1% in mild to moderate initial HSRs vs. 16% in severe). Severe initial HSR was also a significant risk factor for moderate to severe BTR in platins (odds ratio 1.56, 95% confidence interval [CI] 1.06–2.29, p = 0.025). The use of steroid was also associated with lower occurrence of moderate to severe BTR (odds ratio 0.50, 95% CI 0.35–0.72, p < 0.001).ConclusionMost patients with HSRs to antineoplastic agents can safely receive chemotherapy through a one-bag desensitization protocol. Further studies on each drug with larger sample size can help verify the risk factors of BTRs and evaluate the efficacy of steroid premedication in improving the safety of desensitization in high-risk patients.

Background: Asthma is a heterogeneous inflammatory airway disorder with various phenotypes. Quantitative computed tomography (QCT) methods can differentiate among lung diseases through accurate assessment of the location, extent, and severity of the disease. The purpose of this study was to identify asthma clusters using QCT metrics of airway and parenchymal structure, and to identify associations with visual analyses conducted by radiologists. Methods: This prospective study used input from QCT-based metrics including hydraulic diameter (Dh), luminal wall thickness (WT), functional small airway disease (fSAD), and emphysematous lung (Emph) to perform a cluster analysis and made comparisons with the visual grouping analysis conducted by radiologists based on site of airway involvement and remodeling evaluated. Results: A total of 61 asthmatics of varying severities were grouped into 4 clusters. From C1 to C4, more severe lung function deterioration, higher fixed obstruction rate, and more frequent asthma exacerbations were observed in the 5-year follow-up period. C1 presented non-severe asthma with increased WT, Dh of proximal airways, and fSAD. C2 was mixed with non-severe and severe asthmatics, and showed bronchodilator responses limited to the proximal airways. C3 and C4 included severe asthmatics that showed a reduced Dh of the proximal airway and diminished bronchodilator responses. While C3 was characterized by severe allergic asthma without fSAD, C4 included ex-smokers with high fSAD% and Emph%. These clusters correlated well with the grouping done by radiologists and clinical outcomes. Conclusions: Four QCT imaging-based clusters with distinct structural and functional changes in proximal and small airways can stratify heterogeneous asthmatics and can be a complementary tool to predict clinical outcomes.

Abstract Background Several type B adverse drug reactions (ADRs), especially severe cutaneous adverse reactions (SCARs), are associated with particular human leukocyte antigen (HLA) genotypes. However, pre‐stored HLA information obtained from other clinical workups has not been used to prevent ADRs. We aimed to simulate the preemptive use of pre‐stored HLA information in electronic medical records to evaluate whether this information can prevent ADRs. Methods We analyzed the incidence and the risk of ADRs for selected HLA alleles (HLA‐B*57:01, HLA‐B*58:01, HLA‐A*31:01, HLA‐B*15:02, HLA‐B*15:11, HLA‐B*13:01, HLA‐B*59:01, and HLA‐A*32:01) and seven drugs (abacavir, allopurinol, carbamazepine, oxcarbazepine, dapsone, methazolamide, and vancomycin) using pre‐stored HLA information of transplant patients based on the Pharmacogenomics Knowledge Base guidelines and experts' consensus. Results Among 11,988 HLA‐tested transplant patients, 4092 (34.1%) had high‐risk HLA alleles, 4583 (38.2%) were prescribed risk drugs, and 580 (4.8%) experienced type B ADRs. Patients with HLA‐B*58:01 had a significantly higher incidence of type B ADR and SCARs associated with allopurinol use than that of patients without HLA‐B*58:01 (17.2% vs. 11.9%, odds ratio [OR] 1.53 [95% confidence interval {CI} 1.09–2.13], p = 0.001, 2.3% versus 0.3%, OR 7.13 [95% CI 2.19–22.69], p

Background: Beta-lactams (BLs) are commonly used antibiotics and leading causative agents of drug-induced anaphylaxis. Few studies on the culprit drugs and risk factors of BL-induced anaphylaxis are available. Our goal was to evaluate the culprit drugs and compare the risk factors in patients with BL-induced anaphylaxis to matched tolerant controls in a hospital setting. Methods: We retrospectively enrolled all patients who developed anaphylaxis from intravenous BL during hospitalization from 9 Korean hospitals. We compared clinical parameters between patients with BL-induced anaphylaxis and 4-fold BL-tolerant controls matched by age, sex, BL use, and the purpose of BL administration. Results: Seventy-four cases of BL-induced anaphylaxis and 296 BL-tolerant controls were enrolled. Cephalosporin accounted for 77% of total BL-induced anaphylaxis, and the top derivatives were ceftriaxone (23.0%), cefazedone (10.8%), and cefbuperazone (9.5%). Among penicillin derivatives, piperacillin (16.2%) was the most common, followed by ampicillin (2.7%). History of drug allergy (odds ratio [OR], 19.91; 95% confidence interval [CI] 5.33–74.44), previous exposure to the causative BL (OR, 7.71; 95% CI, 1.62–36.76), and concurrent administration of angiotensin-converting enzyme inhibitors (ACEIs) (OR, 5.97; 95% CI, 1.28–27.91) were independent risk factors associated with BL-induced anaphylaxis. Food allergy (OR, 13.93; 95% CI 1.31–148.9) and previous exposure to BL (OR, 6.59; 95% CI, 1.30–33.31) were identified as risk factors for cephalosporin-induced anaphylaxis. Conclusions: To prevent BL-induced anaphylaxis, attention should be paid to histories of drug or food allergy, previous exposure to BLs, and ACEI use. The risk factors and clinical outcomes might vary according to the BL classes.

Background/Aims This study was to evaluate the clinical significance of infusion-related reaction (IRR) of rituximab in diffuse large B-cell lymphoma (DLBCL) patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) as a first-line chemotherapy. Methods The medical records of 326 patients diagnosed with DLBCL were re trospectively analyzed. Both doctor’s progress records and nursing records were reviewed. IRR was graded according to the National Cancer Institute Common Terminology Criteria. Results IRR was not associated with overall survival (OS) or progression-free survival (PFS) of DLBCL patients as compared to those who did not have IRR (OS: median 78.0 months vs. 69.0 months, p = 0.700; PFS: median 65.4 months vs. 64.0 months, p = 0.901). IRR grade did not affect OS or PFS. B symptoms was independently associated with IRR (hazard ratio [HR], 1.850; 95% confidence interval [CI], 1.041 to 3.290; p = 0.036). Further, bone marrow involvement was independently associated with re-IRR (HR, 4.904; 95% CI, 0.767 to 3.118; p = 0.029). Conclusions Our study shows that IRR of rituximab is not associated with OS or PFS of DLBCL patients who received R-CHOP. Furthermore, our study suggests a need for more careful observation for IRR in patients with B symptoms or bone marrow involvement.

Background/Aims There are only a few reports on the direct costs of severe cutaneous adverse reactions (SCARs), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), despite the tremendous negative impact these reactions can have on patients. We estimated the direct costs of treating SCARs. Methods Patients admitted to a tertiary teaching hospital for the treatment of SCARs from January 1, 2005 to December 31, 2010 were included. Patients who had experienced SCARs during their admission for other medical conditions were excluded. The direct costs of hospitalization and outpatient department visits were collected. Inpatient and outpatient care costs were calculated, and factors affecting inpatient care costs were analyzed. Results The total healthcare cost for the management of 73 SCAR patients (36 with DRESS, 21 with SJS, and 16 with TEN) was 752,067 US dollars (USD). Most of the costs were spent on inpatient care (703,832 USD). The median inpatient care cost per person was 3,720 (range, 1,133 to 107,490) USD for DRESS, 4,457 (range, 1,224 to 21,428) USD for SJS, and 8,061 (range, 1,127 to 52,220) USD for TEN. Longer hospitalization significantly increased the inpatient care costs of the patients with DRESS (by 428 USD [range, 395 to 461] per day). Longer hospitalization and death significantly increased the inpatient care costs of the patients with SJS/TEN (179 USD [range, 148 to 210] per day and an additional 14,425 USD [range, 9,513 to 19,337] for the deceased). Conclusions The management of SCARs required considerable direct medical costs. SCARs are not only a health problem but also a significant financial burden for the affected individuals.

Chronic rhinosinusitis (CRS) is characterized according to the presence or absence of nasal polyps (NPs) and displays nasal microbiota dysbiosis. However, optimal sampling methods of the nasal microbiome in CRS have not been identified. We aimed to assess the microbial composition in patients with CRS, comparing different sampling methods (swab and tissue biopsy), tissue types (uncinate tissue and NP), and disease subtypes. Samples were obtained by swabbing the middle meatus and taking a biopsy of uncinate tissue (UT) in patients with CRS with (CRSwNP, N = 8) or without NP (CRSsNP, N = 6) and controls (N = 8). NPs were also harvested in CRSwNP. DNAs were extracted from fifty-two samples and analyzed by 16S rRNA gene amplicon sequencing. As a result, a great interpersonal variance was observed in nasal swabs, while UT samples presented distinct microbiome with low inter-personal differences. Moreover, the UT microbiomes were further differentiated into three clusters which are associated with disease status (control, CRSsNP, and CRSwNP). Compared to UT, NP revealed a unique microbiome profile with significantly less bacterial diversity. Prevotella was the genus whose abundance was negatively correlated with disease severity in NP. In conclusion, tissue samples are better specimens than nasal swabs for assessing the microbiomes of CRS patients. Several bacteria in UT and NP tissues revealed an association with clinical severity of CRSwNP.

Background: Epidemiology and risk factors of drug-induced anaphylaxis are difficult to estimate due to lack of confirmative diagnosis and under reporting. Here we report the current state of drug-induced anaphylaxis in Korea based on an in-hospital pharmacovigilance database in a tertiary hospital. Methods: This study is a retrospective analysis of drug-induced anaphylaxis, reported to an in-hospital pharmacovigilance center in Seoul National University Hospital from June 2009 to May 2013. Anaphylaxis occurred in patients under 18 years of age or developed by medications administered from outside pharmacies or hospitals were excluded. We assessed causative drug, incidence per use of each drug and risk factors of fatal anaphylactic shock. Results: A total of 152 in-hospital drug-induced anaphylaxis cases were reported during the study period. The single most frequently reported drug was platinum compound and the incidence of anaphylaxis and anaphylactic shock in platinum compounds users was 2.84 and 1.39 per 1000 patients use. Risk factors of anaphylactic shock among total anaphylaxis cases were identified as older age ≥70 years [Odd's ratio (OR), 5.86; 95% confidence interval (CI), 1.70–20.14]. The use of iodinated contrast media (OR, 6.19; 95% CI, 1.87–20.53) and aminosteroid neuromuscular blocking agent (NMBA) (OR, 12.82; 95% CI, 1.50–109.92) were also a risk factor for the development of anaphylactic shock. Conclusions: Platinum compounds are the most commonly reported causative agents of in-hospital drug-induced anaphylaxis. Older age ≥70 years and drugs such as iodinated contrast media and aminosteroid NMBA are related with high risk of anaphylactic shock.

Acute hypersensitivity reactions to gadolinium-based magnetic resonance (MR) contrast media have been shown to have a much lower incidence and they are generally milder in terms of severity than acute adverse reactions associated with the use of iodinated contrast media for computed tomography scans. However, even though it is rare, a severe hypersensitivity reaction to MR contrast media can occur. Here we present the case of a 66-year-old woman who experienced a severe hypersensitivity reaction after administration of gadolinium-based contrast media without a previous history of allergies.

Background: Some western countries recently have shown a slowdown in the incidence of allergic diseases after worldwide increasing trends, but there are few data from Asian populations concerning changing trend of allergic diseases. We evaluated the recent trends in the prevalence of asthma and other allergic diseases in Korea. Methods: From the database of Korean National Health Insurance, a nationwide diagnostic data from 2009 to 2014 were extracted and the national prevalence was analyzed. Results: The prevalence per 1000 people of atopic dermatitis, allergic rhinitis, and asthma in 2014 was 19.0, 133.1, and 36.3, respectively. The prevalence of three diseases was highest in the age group under 10 as, 95.0, 384.1, and 132.1 per 1000 people, while the prevalence in the over-10-year-group was only 11.6, 109.5, and 27.3, respectively. The prevalence of atopic dermatitis and allergic rhinitis gradually decreased with older age, but the prevalence of asthma showed a re-increasing pattern from the age group 30–39 and reached another peak for the age group 70–79. During the study period, the prevalence of asthma and atopic dermatitis showed decreasing tendency. In contrast, the prevalence of allergic rhinitis steadily increased until 2013, especially in the age group under 10. Conclusions: The national prevalence of atopic dermatitis, and asthma did not show noticeable increase any more in Korea. However, the prevalence of allergic rhinitis still on the rise until recently, especially in the age group under 10. This is the first report in Asia suggesting a slowdown of the incidence of allergic diseases.

Idiopathic hypereosinophilia (IHE)/idiopathic hypereosinophilic syndrome (IHES) has been defined by a persistent elevation of the blood eosinophil count exceeding 1.5×103/μL, without evidence of reactive or clonal causes. While T-cell clonality assessment has been recommended for unexplained hypereosinophilia, this approach is not often applied to routine practice in the clinic. We hypothesized that the clonality would exist in a subset of IHE/IHES patients. We aimed to investigate the candidate mutations and T-cell clonality in IHE/IHES and to explore the role of mutations in eosinophil proliferation. We performed targeted capture sequencing for 88 genes using next-generation sequencing, T-cell receptor (TCR) gene rearrangement assays, and pathway network analysis in relation to eosinophil proliferation. By targeted sequencing, 140 variants in 59 genes were identified. Sixteen out of 30 patients (53.3%) harbored at least one candidate mutation. The most frequently affected genes were NOTCH1 (26.7%), SCRIB and STAG2 (16.7%), and SH2B3 (13.3%). Network analysis revealed that our 21 candidate genes (BIRC3, BRD4, CSF3R, DNMT3A, EGR2, EZH2, FAT4, FLT3, GATA2, IKZF, JAK2, MAPK1, MPL, NF1, NOTCH1, PTEN, RB1, RUNX1, TET2, TP53 and WT1) are functionally linked to the eosinophilopoietic pathway. Among the 21 candidate genes, five genes (MAPK1, RUNX1, GATA2, NOTCH1 and TP53) with the highest number of linkages were considered major genes. A TCR assay revealed that four patients (13.3%) had a clonal TCR rearrangement. NOTCH1 was the most frequently mutated gene and was shown to be a common node for eosinophilopoiesis in our network analysis, while the possibility of hidden T cell malignancy was indwelling in the presence of NOTCH1 mutation, though not revealed by aberrant T cell study. Collectively, these results provide new evidence that mutations affecting eosinophilopoiesis underlie a subset of IHE/IHES, and the candidate genes are inferred to act their potential roles in the eosinophilopoietic pathway.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases; however, it is hard to estimate their incidence due to the rarity of these diseases. We evaluated the incidence of SJS and TEN using a nationwide administrative database.We used a national medical insurance review system (Health Insurance Review and Assessment) database which contained the claim data of the entire nation from 2009 to 2013 to estimate the accurate incidence of SJS and TEN in Korea. The diagnostic codes of L511 (SJS) or L512 (TEN) from the International Classification of Diseases-10th revision were used to define the target study population. We also retrospectively followed up a 2011 SJS and TEN cohort for 24 months in order to assess the in-hospital mortality, related complications and total claims cost due to SJS and TEN.A total of 1,167 (938 SJS and 229 TEN) cases were newly diagnosed from 2010 to 2013. The age- and sex-standardized annual incidences estimated in this study were 3.96 to 5.03 in SJS and 0.94 to 1.45 in TEN per million. There was no significant change in annual incidence throughout the study periods. When analyzed by 10-year age groups, the annual incidence was the lowest in group 20-29 years and the highest in group 70 for both SJS and TEN. Based on the 2011 cohort analysis, the in-hospital mortality were 5.7 and 15.1% for SJS and TEN, respectively. The mortality increased with age, particularly, after 40 years of age. Among the complications related with SJS or TEN, ocular sequelae was the most common (43.1 and 43.4% of SJS and TEN patients, respectively) followed by urethral sequelae (5.7 and 9.4% of SJS and TEN patients, respectively).Overall, our data suggest that SJS, and TEN are infrequent but constantly arise throughout the years.

Thalidomide is known to have anti-inflammatory and immunomodulatory actions. However, the effect and the anti-asthmatic mechanism of thalidomide in the pathogenesis of asthmatic airways are not fully understood.This study is designed to determine the effect and the potential mechanism of thalidomide in the pathogenesis of asthmatic airways using animal model of allergic asthma.Six-week-old female BALB/C mice were sensitized with alum plus ovalbumin (OVA) and were exposed to OVA via intranasal route for 3 days for challenge. Thalidomide 200 mg/kg was given via gavage twice a day from a day before the challenge and airway hyperresponsivenss (AHR), airway inflammatory cells, and cytokines in bronchoalveolar lavage fluids (BALF) were evaluated. The expression levels of pro-inflammatory cytokines and other mediators were evaluated using ELISA, real time (RT)-qPCR, and flow cytometry. CRL-2456, alveolar macrophage cell line, was used to test the direct effect of thalidomide on the activation of macrophages in vitro.The mice with thalidomide treatment showed significantly reduced levels of allergen-induced BALF and lung inflammation, AHR, and the expression of a number of pro-inflammatory cytokines and mediators including Th2 related, IL-17 cytokines, and altered levels of allergen-specific IgG1/IgG2a. Of interesting note, thalidomide treatment significantly reduced expression levels of allergen- or Th2 cytokine-stimulated alternative activation of macrophages in vivo and in vitro.These studies highlight a potential use of thalidomide in the treatment of allergic diseases including asthma. This study further identified a novel inhibitory effect of thalidomide on alternative activation of macrophages as a potential mechanism of anti-asthmatic effect of thalidomide.

Oriental natural plants have been used as medical herbs for the treatment of various diseases for over 2,000 years. In this study, we evaluated the effect of several natural plants on the preservation of male fertility by assessing the ability of plant extracts to stimulate spermatogonial stem cell (SSC) proliferation by using a serum-free culture method. In vitro assays showed that Petasites japonicus extracts, especially the butanol fraction, have a significant effect on germ cells proliferation including SSCs. The activity of SSCs cultured in the presence of the Petasites japonicus butanol fraction was confirmed by normal colony formation and spermatogenesis following germ cell transplantation of the treated SSCs. Our findings could lead to the discovery of novel factors that activate SSCs and could be useful for the development of technologies for the prevention of male infertility.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) was recently classified into EIB alone and EIB with asthma, based on the presence of concurrent asthma. OBJECTIVE: Differences between EIB alone and EIB with asthma have not been fully described. METHODS: We retrospectively reviewed who visited an allergy clinic for respiratory symptoms after exercise and underwent exercise bronchial provocation testing. More than a 15% decrease of forced expiratory volume in 1 second (FEV1) from baseline to the end of a 6 min free-running challenge test was interpreted as positive EIB. RESULTS: EIB was observed in 66.9% of the study subjects (89/133). EIB-positive subjects showed higher positivity to methacholine provocation testing (61.4% vs. 18.9%, p

Anaphylaxis is the most severe form of radiocontrast media (RCM) induced hypersensitivity and can be life-threatening if profound hypotension is combined. With increased use of iodine based RCM, related hypersensitivity is rapidly growing. However, the clinical characteristics and risk factors of RCM induced anaphylaxis accompanied by hypotension (anaphylactic shock) are not clearly defined. This study was performed to investigate the risk factors of RCM induced anaphylactic shock and the clinical value of RCM skin testing to identify causative agents in affected patients.We analyzed the data of RCM induced anaphylaxis monitored by an inhospital pharmacovigilance center at a tertiary teaching hospital from January 2005 to December 2012 and compared the clinical features and skin test results according to the accompanying hypotension.Among total of 104 cases of RCM induced anaphylaxis, 34.6% of patients, developed anaphylaxis on their first exposure to RCM. Anaphylactic patients presenting with shock were older (57.4 vs. 50.1 years, p = 0.026) and had a history of more frequently exposure to RCM (5.1±7.8 vs. 1.9±3.3, p = 0.004) compared to those without hypotension. Among RCMs, hypotension was more frequent in anaphylaxis related to iopromide compared to other agents (85.0% vs. 61.4%, p = 0.011). Skin tests were performed in 51 patients after development of RCM induced anaphylaxis. Overall skin test positivity to RCM was 64.7% and 81.8% in patients with anaphylactic shock.RCM induced anaphylactic shock is related to multiple exposures to RCM and most patients showed skin test positivity to RCM.

BACKGROUND: Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). METHODS: Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. RESULTS: Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. CONCLUSION: Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways.

Trimebutine maleate [2-dimethylamino-2-phenylbutyl 3,4,5-trimethoxybenzoic acid] has been demonstrated to be active for relieving abdominal pain and it is widely used for patients with irritable bowel syndrome. Adverse drug reactions are mostly mild and well-tolerated. To our knowledge, only two cases of trimebutine induced hypersensitivity have been reported, and both were delayed type reactions. Here, we report the first case of trimebutine maleate-induced anaphylaxis.