Biologic agents for asthma treatment

Most treatment strategies for asthma currently include inhaled corticosteroids, with the addition of long-acting beta-2-agonists or leukotriene modifiers, if necessary. However, some patients may not respond to conventional treatment. A better understanding of the pathophysiology of asthma has recently led to the development of biological agents, which have shown promising results for symptom control and future risk reduction in severe asthmatics. This article reviews currently available biologic agents, introduces related studies, and describes the subgroup of patients benefitting from each of biologic agents in the view point of precision medicine.ope

Application of Impulse Oscillometry in Adult Asthmatic Patients With Preserved Lung Function

Purpose: It is difficult to assess airway obstruction using spirometry in adult asthmatic patients with preserved lung function. Impulse oscillometry (IOS) can detect not only airway resistance but also reactance. Therefore, IOS may be useful in assessing pulmonary function in such patients. We investigated the applicability of IOS for asthma patients with preserved lung function. Methods: Between 2015 and 2018, 1,248 adult asthmatic patients suspected of having asthma who visited the Allergy and Asthma Center of Severance Hospital underwent both spirometry and IOS. Consequently, 784 patients had asthma, 111 had chronic obstructive lung disease (COPD) or asthma-COPD overlap, and 7 had parenchymal lung disease. The remaining 346 patients had chronic cough without underlying lung or airway disease. Among the 784 asthmatic patients, 191 with decreased lung function (predicted forced expiratory volume in 1 second [FEV1] < 80%) were excluded. Propensity score matching was performed to adjust baseline characteristics between 346 non-asthmatic and 593 asthmatic patients with preserved lung function. Subsequently, we compared the spirometry and IOS parameters between the 329 asthmatic and 329 non-asthmatic patients. Results: Multiple logistic regression analysis showed that the area of reactance (AX) was associated with asthma with preserved lung function. In receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) of AX (AUC = 0.6823) for asthma was not significantly different from that of FEV1 (AUC = 0.6758). However, the AUC of a combination of AX and FEV1 (AUC = 0.7437) for asthma was significantly higher than that of FEV1 alone. The cutoff value of AX was 0.51 kPa/L in univariate ROC analysis. Conclusions: AX is associated with adult asthma with preserved lung function. Performing spirometry together with IOS is more beneficial than performing spirometry alone for diagnosing asthma in adult patients with preserved lung function.ope

Empagliflozin and Dulaglutide are Effective against Obesity-induced Airway Hyperresponsiveness and Fibrosis in A Murine Model

Patients with asthma with obesity experience severe symptoms, are unresponsive to conventional asthma treatment, and lack proper pharmacotherapy. Empagliflozin and dulaglutide, developed for diabetes, reduce weight, decrease insulin resistance, and exert additive effects. We evaluated the efficacy of empagliflozin, dulaglutide, and their combination on obesity-induced airway hyperresponsiveness (AHR) and lung fibrosis using a murine model. We assigned C57BL/6J mice to five groups: control, high-fat diet (HFD), and HFD with empagliflozin, dulaglutide, or both. Mice received a 12-week HFD, empagliflozin (5 days/week, oral gavage), and dulaglutide (once weekly, intraperitoneally). Both drugs significantly attenuated HFD-induced weight increase, abnormal glucose metabolism, and abnormal serum levels of leptin and insulin, and co-treatment was more effective. Both drugs significantly alleviated HFD-induced AHR, increased macrophages in bronchoalveolar lavage fluid (BALF), and co-treatment was more effective on AHR. HFD-induced lung fibrosis was decreased by both drugs alone and combined. HFD induced interleukin (IL)-17, transforming growth factor (TGF)-β1, and IL-1β mRNA and protein expression, which was significantly reduced by empagliflozin, dulaglutide, and their combination. Tumour necrosis factor (TNF)-α and IL-6 showed similar patterns without significant differences. HFD-enhanced T helper (Th) 1 and Th17 cell differentiation was improved by both drugs. Empagliflozin and dulaglutide could be a promising therapy for obesity-induced asthma and showed additive effects in combination.ope

Effects of Air Purifiers on Patients with Allergic Rhinitis: a Multicenter, Randomized, Double-Blind, and Placebo-Controlled Study

Purpose: Exposure to particulate matter (PM) is a well-known risk factor in the triggering and exacerbation of allergic airway disease. Indoor environments, where people spend most of their time, are of utmost importance. To assess the effects of air purifiers [equipped with high-efficiency particulate air (HEPA) filters] on allergic rhinitis (AR) in adult patients, we performed a multicenter, randomized, double-blind, and placebo-controlled study. Materials and methods: Patients with house dust mite (HDM)-induced AR were randomly assigned to either active or mockup (placebo) air-purification groups. Two air purifiers (placed in living room and bedroom) were operated for 6 weeks in each home environment. The primary study endpoint was to achieve improvement in AR symptoms and medication scores. Secondary endpoints were to achieve improvement in the quality of life (QoL) and visual analog scale (VAS) scores, as well as in the indoor (bedroom and living room) concentrations of PM2.5 and PM10. Results: After 6 weeks of air purifier use, medication scores improved significantly in the active (vs. placebo) group, although subjective measures (symptoms, VAS, and QoL scores) did not differ. Bedroom PM2.5 concentrations initially exceeded living room or outdoor levels, but declined (by up to 51.8%) following active purifier operation. Concentrations of PM2.5 in living room and PM10 in bedroom and living room were also significantly reduced through active purification. Conclusion: The use of air purifiers with HEPA filters significantly reduced medication requirements for patients with HDM-induced AR and significantly lowered indoor PM2.5 concentrations, regardless of room placement. Active intervention to reduce household air pollutants may help improve allergic airway disease (clinicaltrials.gov NCT03313453).ope

A Case of Azathioprine Induced Warfarin Resistance in Behçet’s Disease

Behçet’s disease is characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Thrombosis associated with vascular inflammation in patients with Behçet’s disease presents various clinical symptoms. Warfarin is usually administered for treatment of thrombosis. However, warfarin can interact with many medications that cause various problems. A 43-year-old woman with Behçet’s disease presented with a swollen right leg. Deep vein thrombosis (DVT) was confirmed, and treated with warfarin. Due to exacerbation of Behçet’s disease, she received azathioprine along with warfarin. Subsequently, the international normalized ratio (INR) decreased and DVT was exacerbated. Despite an increase in the warfarin dose, the patient did not reach the target INR. After discontinuation of azathioprine, DVT improved and the warfarin dose was decreased. There were no specific findings associated with a hypercoagulable status. This finding suggests the interaction of azathioprine and warfarin. Therefore, clinicians should be cautious regarding the possibility of drug interactions between azathioprine and warfarin.ope

Validation of a Multiplex Assay for Measuring Specific IgG4

Purpose: Specific IgG4 (sIgG4) increases with allergen specific immunotherapy and may reflect a state of immune tolerance in food allergy. While ImmunoCAP® has been widely used to measure sIgG4 to a single allergen, PROTIA™ Specific IgG4® has been designed as a multiplex assay for measuring sIgG4. This study sought to validate this assay in comparison to ImmunoCAP®. Materials and methods: Measurements of sIgG4 were compared between PROTIA™ Specific IgG4® and ImmunoCAP® using sera from 519 allergy patients (asthma: 114, allergic rhinitis: 318, food allergy: 146) with 731 paired tests. sIgG4 was measured against nine inhalant allergens (Dermatophagoides pteronyssinus, Dermatophagoides farinae, cat dander, dog dander, birch pollen, oak pollen, ragweed pollen, mugwort pollen, and Alternaria alternata spores) and nine food allergens (egg white, casein, wheat, peanut, walnut, crab, shrimp, apple, and peach). Results: PROTIA™ Specific IgG4® showed 95.6% agreement rate with ImmunoCAP® in the positivity comparison. For sIgG4 positivity to each individual allergen, an agreement rate of more than 84.8% was observed. In Cohen's kappa analysis, these assays displayed substantial correlations [Cohen's kappa coefficient (κ) ≥0.699], except for shrimp (κ=0.448). Furthermore, both assays displayed strong correlations in quantitative comparisons [correlation coefficients value (ρ) ≥0.8014], except for apple (ρ=0.6571, p=0.175). Serial dilution tests also showed consistency between the assays. Conclusion: PROTIA™ Specific IgG4® showed high consistency with ImmunoCAP® in measuring sIgG4. This assay is applicable to various clinical fields, including allergen immunotherapy and food allergy.ope

Validation of PROTIA™ Allergy-Q 64 Atopy® as a Specific IgE Measurement Assay for 10 Major Allergen Components

PURPOSE: Component-resolved diagnostics (CRD) is expected to provide additional diagnostic information in allergic patients. PROTIA™ Allergy-Q 64 Atopy®, a recently developed CRD-based multiplex specific immunoglobulin E (sIgE) assay, can quantitatively measure sIgE to major allergen components. METHODS: The sIgE detection by PROTIA™ Allergy-Q 64 Atopy® and ImmunoCAP® assays was compared using the sera of 125 Korean allergic patients. Group 1 and 2 allergens of house dust mites (HDMs; Dermatophagoides farinae (Der f) 1 and Der f 2 in PROTIA™ Allergy-Q 64 Atopy®, Dermatophagoides pteronyssinus (Der p) 1 and Der p 2 in ImmunoCAP®), Bet v 1, Fel d 1, Que a 1, ω-5 gliadin, α-lactalbumin, β-lactoglobulin, casein and α-Gal were measured by both assays. RESULTS: Comparing the results from the 2 assays, the agreement rate for all the 10 allergens was > 88% (group 1 HDM allergen, 100%; group 2 HDM allergen, 94.6%; Bet v 1, 97.4%; Fel d 1, 90.5%; Que a 1, 89.2%; α-lactalbumin, 96%; β-lactoglobulin, 88%; casein, 88%; ω-5 gliadin, 96%; α-Gal, 100%). Correlation analysis indicated that, all the 10 allergen sIgEs showed more than moderate positive correlation (Pearson correlation coefficients > 0.640). Additionally, intra-class comparison showed more than high correlation for all the 10 allergens (Spearman's rank correlation coefficients > 0.743). CONCLUSIONS: PROTIA™ Allergy-Q 64 Atopy® is reliable and comparable to the ImmunoCAP® assay for component-resolved diagnosis.ope

Influence of government-driven quality assessment program on patients with chronic obstructive pulmonary disease

Background: The Korean Health Insurance Review and Assessment Service (HIRA) has launched the Chronic Obstructive Pulmonary Disease (COPD) Quality Assessment Program (CQAP) since 2014. We aimed to reveal the influence of this national program on clinical outcomes and the burden of COPD in Korea. Methods: The CQAP is conducted annually. We used healthcare claims data linked with the results of the program provided by HIRA between May 2014 and April 2017. Patients were considered to have COPD if they visited a hospital for COPD management during the assessment term. Those who visited a medical institution for COPD and were prescribed COPD medications at least twice were assessed by the CQAP (assessed subjects, AS; not-assessed subjects, NAS). CQAP evaluated the pulmonary function test conduction rate, regular visitation rate, and prescription rates of COPD medications. Results: Among the 560,000 patients with COPD, about 140,000 were assessed by the CQAP annually. In both groups, the pulmonary function test conduction rate and inhaled bronchodilator prescription rate improved since 2014. Compared to the NAS group, the risk of admission and all-cause mortality rate in the AS group were significantly reduced by 21.2% and 40.7%, respectively. In patients who were assessed for 3 consecutive years, all of the above variables were high at baseline and were not improved much from implementation of CQAP. In matching analysis, we observed this improvement to be limited in the COPD quality assessment year. Conclusions: The CQAP by the health insurance bureau has improved the management protocol and prognosis of COPD.ope

Clinical Features and Culprit Food Allergens of Korean Adult Food Allergy Patients: A Cross-Sectional Single-Institute Study

PURPOSE: To investigate the causative allergens and clinical characteristics of Korean adult patients with food allergy (FA). METHODS: This retrospective, cross-sectional single-institutional study enrolled Korean adult patients (n = 812) suspected of having FA. For diagnosis, causality assessment history taking, ImmunoCAP specific immunoglobulin E measurement and/or skin prick test were performed. RESULTS: Among 812 patients, 415 were diagnosed as having FA. The most common causative allergen was fruit, with a diagnosis of pollen food allergy syndrome (PFAS: 155, 37.3%), followed by crustaceans (111, 26.7%), wheat (63, 15.1%), fruits in patients without PFAS(43, 10.3%), buckwheat (31, 7.4%), peanut (31, 7.4%), walnut (25, 6.0%), red meat due to reaction to galactose-α-1,3-galactose (α-Gal) (8, 1.9%), and silkworm pupa (13, 3.1%). Allergy to egg, milk, fish, or shellfish was rare in Korean adults. One-third of patients with FA exhibited multiple FAs (238/415, 57.3%); the average number of causative allergens was 2.39. About 129 patients (31.0%) were diagnosed as having anaphylaxis; in these patients, wheat was the most frequent causative food. Twenty patients were further diagnosed with food-dependent exercise-induced anaphylaxis (FDEIA); all were due to wheat. In particular, crustaceans, wheat, PFAS, buckwheat, and red meat (α-Gal) were also frequent causes of anaphylaxis. CONCLUSIONS: Wheat, fruits with or without PFAS, and crustaceans are important and frequent causative allergens in Korean adult FA; these allergens differ from those found in childhood FA. It is notable that non-classic allergies, such as PFAS, FDEIA, and α-Gal allergy, are the important causes of anaphylaxis in Korean adult FA.ope

IgE Sensitization Patterns to Commonly Consumed Foods Determined by Skin Prick Test in Korean Adults

Offending food allergens can vary with regional preferences in food consumption. In this study, we analysed sensitization rates to commonly consumed foods in Korean adults suspected of having food allergy. One hundred and thirty four subjects underwent a skin prick test (SPT) with 55 food allergens, of which 13 were made by our laboratory and the rest were commercially purchased. Of the 134 patients, 73 (54.5%) were sensitized to one or more food allergens. Sensitization to chrysalis was detected most frequently, at a rate of 25.4%. Sensitization rates to other food allergens were as follows: maize grain (13.4%), shrimp (11.9%), almond (11.1%), wheat flour (8.2%), lobster (8.2%), buckwheat (8.2%), mackerel (5.2%), pollack (5.2%), halibut (4.5%), peanut (4.5%), anchovy (4.4%), squid (3.7%), saury (3.0%), common eel (3.0%), yellow corvina (3.0%), hairtail (2.2%), octopus (2.2%), and others. In addition to well-known food allergens, sensitivity to mackerel, chrysalis, pollack, and halibut, which are popular foods in Korea, was observed at high rates in Korean adults. We suggest that the SPT panel for food allergy in Korea should include these allergens.ope