The Relationship Between Zonulin and Asthma: A Mouse Model Study

Background and Objectives@#Zonulin is a human protein that regulates intercellular tight junctions and increases the permeability of the intestinal epithelium. In light of the increasing focus on zonulin’s role in numerous chronic inflammatory diseases, this study aimed to investigate whether differences exist in serum zonulin levels and bronchial epithelium zonulin expression in vivo between asthma and normal groups, using a mouse model. @*Methods@#Sixteen mice were utilized in this study, divided evenly between the normal and asthma groups. Serum zonulin levels, the expression of zonulin antibody in the bronchial epithelium, and serum cytokine levels were evaluated in both groups. Enzyme-linked immunosorbent assay and RNA in situ hybridization were utilized for the analysis. @*Results@#The asthma group exhibited significantly higher levels of serum zonulin. High zonulin antibody expression was also observed in the bronchial epithelium of the asthma group. Given that our mouse model demonstrated a significant difference in interleukin (IL)-4 and IL-6 between the normal and asthma groups, zonulin may be associated not only with type 2 responses but also with various subtypes of asthma. Further studies are required to investigate this relationship in greater detail. @*Conclusion@#Zonulin may play a role in the complex pathophysiology of asthma and could serve as a biomarker in various asthma-related situations.

KAAACI Allergic Rhinitis Guidelines: Part 1. Update in pharmacotherapy

The prevalence of allergic rhinitis (AR) and the socioeconomic burden associated with the medical cost and quality of life of AR have progressively increased. Therefore, practical guidelines for the appropriate management of AR need to be developed based on scientific evidence considering the real-world environment, values, and preferences of patients and physicians. The Korean Academy of Asthma, Allergy and Clinical Immunology revised clinical guidelines for AR to address key clinical questions of the management of AR. Part 1 of the revised guideline covers the pharmacological management of patients with AR in Korea. Through a meta-analysis and a systematic review, we made 4 recommendations for AR pharmacotherapy, including intranasal corticosteroid (INCS)/intranasal antihistamine combination therapy, oral antihistamine/INCS combination therapy, leukotriene receptor antagonist treatment in AR patients with asthma, and prophylactic treatment for patients with pollen-induced AR. However, all recommendations are conditional because of the low or very low evidence of certainty. Well-designed and strictly executed randomized controlled trials are needed to measure and report appropriate outcomes.

KAAACI Allergic Rhinitis Guidelines: Part 2. Update in nonpharmacotherapy

Allergic rhinitis is the most common chronic disease worldwide. Various upper airway symptoms lower quality of life, and due to the recurrent symptoms, multiple treatments are usually attempted rather than one definitive treatment. There are alternatives to medical (medication-based) and nonmedical treatments. A guideline is needed to understand allergic rhinitis and develop an appropriate treatment plan. We have developed guidelines for medical treatment based on previous reports. The current guidelines herein are associated with the “KAAACI Evidence-Based Guidelines for Allergic Rhinitis in Korea, Part 1: Update in pharmacotherapy” in which we aimed to provide evidence-based recommendations for the medical treatment of allergic rhinitis. Part 2 focuses on nonpharmacological management, including allergen-specific immunotherapy, subcutaneous or sublingual immunotherapy, nasal saline irrigation, environmental management strategies, companion animal management, and nasal turbinate surgery. The evidence to support the treatment efficacy, safety, and selection has been systematically reviewed. However, larger controlled studies are needed to elevate the level of evidence to select rational non-medical therapeutic options for patients with allergic rhinitis.

Sodium-Glucose Cotransporter-2 Inhibitor-Related Diabetic Ketoacidosis: Accuracy Verification of Operational Definition

Background@#The most important aspect of a retrospective cohort study is the operational definition (OP) of the disease. We developed a detailed OP for the detection of sodiumglucose cotransporter-2 inhibitors (SGLT2i) related to diabetic ketoacidosis (DKA). The OP was systemically verified and analyzed. @*Methods@#All patients prescribed SGLT2i at four university hospitals were enrolled in this experiment. A DKA diagnostic algorithm was created and distributed to each hospital;subsequently, the number of SGLT2i-related DKAs was confirmed. Then, the algorithm functionality was verified through manual chart reviews by an endocrinologist using the same OP. @*Results@#A total of 8,958 patients were initially prescribed SGLT2i. According to the algorithm, 0.18% (16/8,958) were confirmed to have SGLT2i-related DKA. However, based on manual chart reviews of these 16 cases, there was only one case of SGLT2i-related DKA (positive predictive value = 6.3%). Even after repeatedly narrowing the diagnosis range of the algorithm, the effect of a positive predictive value was insignificant (6.3–10.0%, P > 0.999). @*Conclusion@#Owing to the nature of electronic medical record data, we could not create an algorithm that clearly differentiates SGLT2i-related DKA despite repeated attempts. In all retrospective studies, a portion of the samples should be randomly selected to confirm the accuracy of the OP through chart review. In retrospective cohort studies in which chart review is not possible, it will be difficult to guarantee the reliability of the results.

Analysis of Adverse Drug Reactions to First-Line Anti-Tuberculosis Drugs Using the Korea Adverse Event Reporting System

Background@#Adverse drug reactions (ADRs) to first-line anti-tuberculosis (TB) drugs are common; however, there have been few reports of nationwide epidemiologic studies on ADRs to anti-TB drugs in Korea. This study aimed to investigate the clinical characteristics of various ADRs to first-line anti-TB drugs using a nationwide database of ADRs. @*Methods@#We used the Korea Adverse Event Reporting System (KAERS) database (2009– 2018). The study subjects were selected using the Korean Standard Classification of Diseases codes for pulmonary and extrapulmonary TB and electronic data interchange codes for isoniazid (INH), rifampicin (RIF), ethambutol (ETB), and pyrazinamide (PZA). The causality assessment of “possible,” “probable,” or “certain” by World Health Organization-Uppsala Monitoring Center System causality category was selected. @*Results@#A total of 1,562,024 ADRs were reported in the KIDS-KAERS database from 2009 to 2018, where ADRs to first-line anti-TB drugs were 17,843 cases (1.14%). The most common causative drugs were RIF (28.7%), INH (24.0%), ETB (23.4%), and PZA (23.9%) in that order. 48.5% of cases were reported in the older patients (≥ 60 years). According to organ system, gastro-intestinal system disorder was most common (32.0%), followed by skin and appendage (25.9%), liver and biliary system (14.2%). Nausea was the most common ADR (14.6%), followed by hepatic enzyme elevation (14.2%), rash (11.7%), pruritus (9.1%), vomiting (8.9%), and urticaria (4.2%). Most ADRs appeared within 1 month, but ADRs such as neuropathy, paresthesia, hematologic abnormalities, renal function abnormalities and liver enzyme abnormality were also often reported after 2 months. @*Conclusion@#Our data are clinically informative for recognizing and coping with ADRs of antiTB drugs.

Hypereosinophilia secondary to Sézary syndrome

The Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma characterized by the presence of erythroderma covering at least 80% of the body-surface area, lymphadenopathy, and the presence of clonally related neoplastic T cells with cerebriform nuclei (Sézary cells) in the blood, skin, and lymph nodes. Hypereosinophilia can be caused by hematologic malignancy with clonal abnormality, which is often associated with Sézary syndrome. Sézary syndrome has rarely been reported in Korea. However, hypereosinophilia in the Sézary syndrome has not been reported in Korea. Here, we report a case of 75-year-old man with hypereosinophila, erythroderma, and cutaneous T-cell lymphoma which was finally diagnosed as Sézary syndrome.

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 1. Definition, Methodology and First-line Management

Chronic spontaneous urticaria (CSU) is defined as the occurrence of spontaneous wheals, angioedema, or both for >6 weeks in the absence of specific causes. It is a common condition associated with substantial disease burden both for affected individuals and societies in many countries, including Korea. CSU frequently persists for several years and requires high-intensity treatment; therefore, patients experience deteriorations in quality of life and medication-associated complications. During the last decade, there have been major advances in the pharmacological treatment of CSU and there is an outstanding need for evidence-based guidelines that reflect clinical practice in Korea. The guidelines reported here represent a joint initiative of the Korean Academy of Asthma, Allergy and Clinical Immunology and the Korean Dermatological Association, and aim to provide evidence-based guidance for the management of CSU in Korean adults and children. In Part 1, disease definition, guideline scope and development methodology as well as evidence-based recommendations on the use of antihistamines and corticosteroids are summarized.

A Prospective Observation of Psychological Distress in Patients With Anaphylaxis

PURPOSE: Anaphylaxis is an immediate allergic reaction characterized by potentially life-threatening, severe, systemic manifestations. While studies have evaluated links between serious illness and posttraumatic stress disorder (PTSD), few have investigated PTSD after anaphylaxis in adults. We sought to investigate the psychosocial burden of recent anaphylaxis in Korean adults.METHODS: A total of 203 (mean age of 44 years, 120 females) patients with anaphylaxis were recruited from 15 university hospitals in Korea. Questionnaires, including the Impact of Event Scale-Revised-Korean version (IES-R-K), the Korean version of the Beck Anxiety Inventory (K-BAI), and the Korean version of the Beck Depression Inventory (K-BDI), were administered. Demographic characteristics, causes and clinical features of anaphylaxis, and serum inflammatory markers, including tryptase, platelet-activating factor, interleukin-6, tumor necrosis factor-α, and C-reactive protein, were evaluated.RESULTS: PTSD (IES-R-K ≥ 25) was noted in 84 (41.4%) patients with anaphylaxis. Of them, 56.0% had severe PTSD (IES-R-K ≥ 40). Additionally, 23.2% and 28.1% of the patients had anxiety (K-BAI ≥ 22) and depression (K-BDI ≥ 17), respectively. IES-R-K was significantly correlated with both K-BAI (r = 0.609, P < 0.0001) and K-BDI (r = 0.550, P < 0.0001). Among the inflammatory mediators, tryptase levels were lower in patients exhibiting PTSD; meanwhile, platelet-activating factor levels were lower in patients exhibiting anxiety and depression while recovering from anaphylaxis. In multivariate analysis, K-BAI and K-BDI were identified as major predictive variables of PTSD in patients with anaphylaxis.CONCLUSIONS: In patients with anaphylaxis, we found a remarkably high prevalence of PTSD and associated psychological distresses, including anxiety and depression. Physicians ought to be aware of the potential for psychological distress in anaphylactic patients and to consider psychological evaluation.

The Relation of Autologous Serum Skin Test andAutologous Plasma Skin Test Result with VariousClinical and Laboratory Findings in Patients withChronic Spontaneous Urticaria

Background@#Despite the autologous serum skin test (ASST)and autologous plasma skin test (APST) is widely used test accessingwhether a patient with chronic spontaneous urticaria(CSU) has autoreactivity or not, the clinician often encounterdifficulty making correlation between the test result and clinicalimplications. @*Objective@#This study was aimed to findany clinical and laboratory findings related to the ASST andAPST response. Agreement and correlation between the twotests was also analyzed. @*Methods@#A retrospective study wasconducted on 300 CSU patients who underwent ASST, APST.The subjects were divided into four groups according to theskin test result. Also, the degree of serum and plasma responsewas recorded. @*Results@#Both ASST and APST positivegroup had shorter duration of the disease, higher incidenceof at least one episode of angioedema than negative group.There were no significant differences in the positivity for autoantibodiesincluding antinuclear, ds-DNA, and thyroid-relatedbetween the two groups. The predicted positive rate ofASST and APST according to age showed bimodal peak and decreasing pattern according to disease duration. Predictedpositivity of both tests declined with increase in total immunoglobulineE (IgE) level. In the correlation study, the twotests showed high correlation coefficients. @*Conclusion@#ASSTand APST positivity may be related to disease duration andseverity of CSU. The two tests showed a generally consistentresult. Autoreactivity may be gradually lost as disease continues.We suggest the autoreactivity in CSU could arise independentlyfrom IgE mediated immune process.

The KAAACI/KDA Evidence-Based Practice Guidelines for Chronic Spontaneous Urticaria in Korean Adults and Children: Part 1. Definition, Methodology and First-line Management

Chronic spontaneous urticaria (CSU) is defined as the occurrence of spontaneous wheals, angioedema, or both for >6 weeks in the absence of specific causes. It is a common condition associated with substantial disease burden both for affected individuals and societies in many countries, including Korea. CSU frequently persists for several years and requires high-intensity treatment; therefore, patients experience deteriorations in quality of life and medication-associated complications. During the last decade, there have been major advances in the pharmacological treatment of CSU and there is an outstanding need for evidence-based guidelines that reflect clinical practice in Korea. The guidelines reported here represent a joint initiative of the Korean Academy of Asthma, Allergy and Clinical Immunology and the Korean Dermatological Association, and aim to provide evidence-based guidance for the management of CSU in Korean adults and children. In Part 1, disease definition, guideline scope and development methodology as well as evidence-based recommendations on the use of antihistamines and corticosteroids are summarized.

Clinical Efficacy of Allergen-Specific Immunotherapy from Patient and Physician Perspectives

PURPOSE: Allergen-specific immunotherapy (AIT) is the only curative treatment for allergic diseases, but a few allergic patients receive AIT. In this multicenter cross-sectional study, we aimed to explore patient and physician perspectives on AIT through a questionnaire survey. MATERIALS AND METHODS: Allergic patients who received subcutaneous immunotherapy for at least 1 year were asked to answer a questionnaire developed by an expert panel of allergen and immunotherapy workgroup in Korea. RESULTS: A total of 267 patients (adults, 60.3%) with allergic rhinitis (91.4%), asthma (42.7%), or atopic dermatitis (20.2%) from referred hospitals completed the survey. Among patients and physicians, respectively, the overall rates of satisfaction with AIT for allergic rhinitis were 86.4% and 83.3% (kappa agreement=0.234, p<0.001), and those for asthma were 85.3% and 72.9% (kappa agreement=0.373, p<0.001). Moreover, pediatric asthmatic patients reported a significantly higher satisfaction rate than adult asthmatic patients after AIT (p=0.040). Symptom severity (p<0.001, respectively) and drug use for allergic rhinitis and asthma decreased after AIT. However, there was no significant difference in satisfaction rates between children and adults in allergic rhinitis (p=0.736). Interestingly, 35.7% and 35% of allergic rhinitis and asthma patients, respectively, reported experiencing improvement in their symptoms within 6 months of starting AIT. CONCLUSION: In this study evaluating the perspectives of patients and physicians on AIT, the majority of patients were satisfied with the efficacy and safety of AIT, but not its cost. AIT should be recommended for AR and allergic patients.

Severe Cutaneous Adverse Reactions to Antiepileptic Drugs: A Nationwide Registry-Based Study in Korea

PURPOSE: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) to antiepileptic drug (AED), are rare, but result in significant morbidity and mortality. We investigated the major culprit drugs, clinical characteristics, and clinical course and outcomes of AED-induced SCARs using a nationwide registry in Korea. METHODS: A total of 161 patients with AED-induced SCARs from 28 referral hospitals were analyzed. The causative AEDs, clinical characteristics, organ involvements, details of treatment, and outcomes were evaluated. We compared the clinical and laboratory parameters between SJS/TEN and DRESS according to the leading causative drugs. We further determined risk factors for prolonged hospitalization in AED-induced SCARs. RESULTS: Carbamazepine and lamotrigine were the most common culprit drugs causing SCARs. Valproic acid and levetiracetam also emerged as the major causative agents. The disease duration and hospital stay in carbamazepine-induced SJS/TEN were shorter than those in other AEDs (P< 0.05, respectively). In younger patients, lamotrigine caused higher incidences of DRESS than other drugs (P= 0.045). Carbamazepine, the most common culprit drug for SCARs, was associated with a favorable outcome related with prolonged hospitalization in SJS (odds ratio, 0.12; 95% confidence interval, 0.02-0.63, P= 0.12), and thrombocytopenia was found to be a risk factor for prolonged hospitalization in DRESS. CONCLUSION: This was the first large-scale epidemiological study of AED-induced SCARs in Korea. Valproic acid and levetiracetam were the significant emerging AEDs causing SCARs in addition to the well-known offending AEDs such as carbamazepine and lamotrigine. Carbamazepine was associated with reduced hospitalization, but thrombocytopenia was a risk factor for prolonged hospitalization. Our results suggest that the clinical characteristics and clinical courses of AED-induced SCARs might vary according to the individual AEDs.

Clinical Manifestations and Risk Factors of Anaphylaxis in Pollen-Food Allergy Syndrome

PURPOSE: Many studies have reported that pollen-food allergy syndrome (PFAS) can cause anaphylaxis. No comprehensive investigations into anaphylaxis in PFAS have been conducted, however. In this study, we investigated the clinical manifestations and risk factors for anaphylaxis in PFAS in Korean patients with pollinosis. MATERIALS AND METHODS: Data were obtained from a nationwide cross-sectional study that previously reported on PFAS in Korean patients with pollinosis. Data from 273 patients with PFAS were collected, including demographics, list of culprit fruits and vegetables, and clinical manifestations of food allergy. We analyzed 27 anaphylaxis patients and compared them with patients with PFAS with oropharyngeal symptoms only (n=130). RESULTS: The most common cause of anaphylaxis in PFAS was peanut (33.3%), apple (22.2%), walnut (22.2%), pine nut (18.5%), peach (14.8%), and ginseng (14.8%). Anaphylaxis was significantly associated with the strength of sensitization to alder, hazel, willow, poplar, timothy, and ragweed (p<0.05, respectively). Multivariable analysis revealed that the presence of atopic dermatitis [odds ratio (OR), 3.58; 95% confidence interval (CI), 1.25–10.23; p=0.017]; sensitization to hazel (OR, 5.27; 95% CI, 1.79–15.53; p=0.003), timothy (OR, 11.8; 95% CI, 2.70–51.64; p=0.001), or ragweed (OR, 3.18; 95% CI, 1.03–9.87; p=0.045); and the number of culprit foods (OR, 1.25; 95% CI, 1.15–1.37; p<0.001) were related to the development of anaphylaxis in PFAS. CONCLUSION: The most common culprit foods causing anaphylaxis in PFAS were peanut and apple. The presence of atopic dermatitis; sensitization to hazel, timothy, or ragweed; and a greater number of culprit foods were risk factors for anaphylaxis in PFAS.

Erratum: Pollen-Food Allergy Syndrome in Korean Pollinosis Patients: A Nationwide Survey

This erratum is being published to correct the error on page 650 of the article. The number of participating research institution should be corrected.

Does Cephalosporin Skin Test Predict Immediate Hypersensitivity to Cephalosporin?

No abstract available.

Pollen-Food Allergy Syndrome in Korean Pollinosis Patients: A Nationwide Survey

PURPOSE: Pollen-food allergy syndrome (PFAS) is an immunoglobulin E (IgE)-mediated allergy in pollinosis patients caused by raw fruits and vegetables and is the most common food allergy in adults. However, there has been no nationwide study on PFAS in Korea. In this study, we investigated the prevalence and clinical characteristics of PFAS in Korea. METHODS: Twenty-two investigators participated in this study, in which patients with allergic rhinoconjunctivitis and/or bronchial asthma with pollen allergy were enrolled. The questionnaires included demographic characteristics, a list of fruits and vegetables, and clinical manifestations of food allergy. Pollen allergy was diagnosed by skin prick test and/or measurement of the serum level of specific IgE. RESULTS: A total of 648 pollinosis patients were enrolled. The prevalence of PFAS was 41.7% (n = 270). PFAS patients exhibited cutaneous (43.0%), respiratory (20.0%), cardiovascular (3.7%) or neurologic symptoms (4.8%) in addition to oropharyngeal symptoms. Anaphylaxis was noted in 8.9% of the PFAS patients. Seventy types of foods were linked to PFAS; e.g., peach (48.5%), apple (46.7%), kiwi (30.4%), peanut (17.4%), plum (16.3%), chestnut (14.8%), pineapple (13.7%), walnut (14.1%), Korean melon (12.6%), tomato (11.9%), melon (11.5%) and apricot (10.7%). Korean foods such as taro/taro stem (8.9%), ginseong (8.2%), perilla leaf (4.4%), bellflower root (4.4%), crown daisy (3.0%), deodeok (3.3%), kudzu root (3.0%) and lotus root (2.6%) were also linked to PFAS. CONCLUSIONS: This was the first nationwide study of PFAS in Korea. The prevalence of PFAS was 41.7%, and 8.9% of the PFAS patients had anaphylaxis. These results will provide clinically useful information to physicians.

Oral allergy syndrome

Oral allergy syndrome (OAS) is an IgE-mediated allergy caused by cross-reacting antigenic determinants in pollens and various fruits, vegetables, and nuts which are known as the most common food allergy in adults. Cross-reactive antigenic proteins include pathogenesis-related-10 protein, profilin, cross-reactive carbohydrate determinant and lipid transfer protein. The prevalence of OAS has been reported at up to 70% of birch pollen allergy. A nationwide multicenter study in our country has recently reported that the prevalence of OAS in Korea is 41.7% of pollen allergy. Typical symptoms of OAS are tingling, itching sense and edema of lips, mouth, and throat immediately after ingestion of raw fruits, vegetables, or nuts. These can progress to systemic symptoms including anaphylaxis. The diagnosis can be made by typical clinical history in patients with pollen allergy. Skin prick test using fresh fruits extracts can be helpful in confirming sensitization to foods, which has better sensitivity than commercial skin prick test or serum specific IgE test. Treatment of OAS is to avoid causative foods. Self-injectable epinephrine should be considered in the case of anaphylaxis. Allergen-specific immunotherapy to pollens has also been tried.

Radiocontrast media-induced acute generalized exanthematous pustulosis: A safe administration of alternative radiocontrast media using patch tests

Acute generalized exanthematous pustulosis (AGEP) is rarely caused by radiocontrast media (RCM). The role of skin tests for the diagnosis and evaluation of cross-reactivity in a delayed type of RCM-induced hypersensitivity have yet to be determined. Here, we report a case of iodixanol-induced AGEP where we safely administered alternative RCM using patch tests. A 44-year-old woman had coronary artery angiography (CAG) for the evaluation of ischemic heart disease. She was on regular hemodialysis because of end-stage renal disease. She was given iodixanol (Visipaque) during CAG. Approximately 1 day after CAG, she developed AGEP. The patient was rehospitalized for CAG again after 1 year. We performed skin tests to choose safe alternative RCM. Intradermal tests with iodixanol, iohexol (Bonorex) and Iopamidol (Pamiray) showed negative responses. Patch tests showed a positive response to iodixanol, equivocal to iohexol, and negative to Iopamidol. We finally chose Iopamidol and performed CAG successfully without any adverse reaction. Patch tests may be a useful tool for the diagnosis and choice of safe alternatives in RCM-induced delayed-type hypersensitivity reactions such as AGEP.

Clinical diagnostic guidelines of allergic rhinitis: comprehensive treatment and consideration of special circumstances

In order to prevent sensitization to a new allergen and the development of asthma, practitioners may consider allergen-specific immunotherapy in patients with allergic rhinitis. Additionally, in patients with severe allergic rhinitis refractory to medication, practitioners can also consider surgical management for improving the patients' nasal symptoms. However, there are still no practical guidelines regarding the indications for immunotherapy, the appropriate selection of the allergen, and the optimal duration of therapy. Moreover, no clear indications exist for surgical treatment. Pregnant or lactating women frequently complain of symptoms of rhinitis. However, due to the fear of potential complications to their babies, they avoid medical treatment despite significant discomfort. Therefore, we present 14 answers to core questions about immunotherapy, surgical treatment, and considerations for special circumstances, such as pregnancy and lactation.

Clinical diagnostic guidelines for allergic rhinitis: diagnosis

As the prevalence and socioeconomic burden of allergic rhinitis is steadily increasing every year, it is essential that clinical practitioners diagnose and manage allergic rhinitis in an evidence-based manner. Therefore, the Korean Academy of Asthma, Allergy and Clinical Immunology developed new clinical guidelines for Korean patients and practitioners. We first performed a questionnaire survey to address the core questions, about which clinical practitioners are the most curious. A large group of physicians (allergists), pediatricians, and otorhinolaryngologists developed answers for those questions by performing a systematic literature review and determining the appropriate levels of recommendation. In this article, we propose 11 answers for core questions regarding the diagnosis and differential diagnosis of allergic rhinitis.