Effect of Dupilumab on Depression in Asthma with Eosinophilic Chronic Rhinosinusitis in the Japanese Population.

INTRODUCTION: Psychological disorders, such as depression, are markedly prevalent in patients with airway diseases. In this study, we assessed the effect of treatment with dupilumab, an IL-4 receptor α chain antibody, on depressive symptoms in a cohort of patients with asthma with eosinophilic chronic rhinosinusitis (ECRS). METHODS: The study participants, diagnosed with asthma and ECRS, were assessed for symptoms and quality of life (QOL) scores for asthma and ECRS and medications. The Patient Health Questionnaire-9 (PHQ-9) scores were used to evaluate the depressive state. The depressive symptoms were compared with asthma and ECRS symptoms both at the time of initiation and after 4 months of dupilumab treatment. RESULTS: Ultimately, 31 patients were included in the study. Most patients demonstrated a depressive state that was correlated with the nasal symptom score. In the evaluation 4 months after dupilumab treatment, the PHQ-9 score was significantly reduced, and the decrease was remarkable in patients whose nasal symptom score was reduced by 50% or more. Additionally, the PHQ-9 scores in patients with improved nasal and asthma symptoms were significantly reduced. DISCUSSION/CONCLUSION: Dupilumab may improve QOL in patients with bronchial asthma with ECRS by reducing depressive symptoms through the improvement of clinical symptoms.

Clinical Significance of Interferon-γ Neutralizing Autoantibodies Against Disseminated Nontuberculous Mycobacterial Disease.

Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.

Effect of inhaled corticosteroids on bronchial asthma in Japanese athletes.

BACKGROUND: Asthma has a higher prevalence in athlete populations such as Olympic athletes than in the general population. Correct diagnosis and management of asthma in athletes is important for symptom control and avoidance of doping accusations. However, few reports are available on asthma treatment in the athlete population in clinical practice. In this study, we focused on the clinical efficacy of inhaled corticosteroid (ICS) for asthma in a Japanese athlete population. METHODS: The study subjects included athletes who visited the Niigata Institute for Health and Sports Medicine, Niigata, Japan for athletic tests and who were diagnosed with asthma on the basis of respiratory symptoms and positive results in a bronchodilator or bronchial provocation test such as exercise, hypertonic saline, or methacholine provocation. The athletes received ICS alone for at least 3 months, and the clinical background, sports type, and treatment efficacy were analyzed. RESULTS: The study population comprised 80 athletes (59 men and 21 women) with a median age of 16.0 years. Regarding sports type, 28 athletes engaged in winter sports (35%), 22 in endurance sports (27.5%), and 25 in indoor sports (31.3%). Although ICS is the primary treatment in athlete asthma, 16.3% of the athletes showed an unsatisfactory response to treatment according to the Global Evaluation of Treatment Effectiveness (GETE). These subjects were characterized by a decreased response to methacholine and lower values for FEV1/FVC and type 2 helper T cell (Th2)-associated biomarkers relative to responsive athletes. In multivariate analysis, FEV1/FVC and the logarithm to the base 10 of the IgE level were independently associated with the ICS response. CONCLUSIONS: These data suggest that ICS is effective for asthma in most athletes. However, certain asthmatic athletes are less responsive to ICS than expected. The pathogenesis in these subjects may differ from that of conventional asthma characterized by chronic allergic airway inflammation.

Characteristics of eosinophilic and non-eosinophilic asthma during treatment with inhaled corticosteroids.

OBJECTIVE: Eosinophilic inflammation in the respiratory tract is a hallmark of bronchial asthma. In naïve cases, the inflammatory profile is associated with disease severity and reactivity to inhaled corticosteroids (ICS). Sustained airway eosinophilia has been reported during ICS treatment. However, the immunological characteristics of these cases are not known and it is unclear if this situation contributes to asthma control. This study was performed to determine the answer of these questions. METHODS: To compare phenotypes of eosinophilic and non-eosinophilic asthma (EA and NEA, respectively) under ICS treatment, clinical data were obtained from asthmatic subjects (n = 22) and healthy controls (n = 10), and the leukocyte compositions of induced sputum and peripheral blood were determined. T lymphocyte profiles in systemic blood were assessed by flow cytometry. RESULTS: A higher frequency of emergency room visits was observed in the NEA group, which had a higher neutrophil count relative to the total inflammatory cell population in induced sputum than the EA group (59.5 versus 36.6%; p < 0.01). The fraction of helper T (Th)17 lymphocytes as well as the ratio of Th17 to regulatory T cells (Treg) in the peripheral blood was higher in the NEA than in the EA group (0.24 versus 0.13; p < 0.05). CONCLUSIONS: Th17 were more prevalent than Treg cells in the peripheral blood of NEA patients under ICS treatment, corresponding to neutrophil-dominant airway inflammation and a severe asthmatic phenotype. Thus, an imbalance in Th17/Treg may be associated with the pathogenesis of NEA in patients undergoing ICS treatment.

Depression's influence on the Asthma Control Test, Japanese version.

BACKGROUND: Depression has been linked to poorer asthma control in asthmatic patients. Although the Japanese version of the Asthma Control Test (ACT-J) is frequently used as a simple, practical evaluation tool in clinical care settings in Japan, knowledge regarding its efficacy for assessing asthma control in asthmatic patients with depression is limited. Thus, we retrospectively investigated cut-off values of the ACT-J for well-controlled asthma, and explored depression's influence on the test with a questionnaire survey. METHODS: Data were analyzed on 1,962 adult asthmatic patients who had completed both the ACT-J and the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) in 2008 questionnaire survey conducted by the Niigata Asthma Treatment Study Group. Patients were classified into low (LD: J-PHQ-9 score of 0-4) or high depression (HD: J-PHQ-9 score of 5-27) groups. In both groups, the efficacy of the ACT-J was confirmed. We then compared the optimal cut-off points for uncontrolled asthma in both groups by performing a receiver operating characteristic (ROC) analysis, using the original classification referred to the GINA classification as the "true" classification. RESULTS: Cronbach's alpha in the LD and HD group was 0.808 and 0.740 respectively. In both groups, the sub-group with existence of work absenteeism or frequent attacks during the previous 12 months scored lower on the ACT-J. The area under the curve and optimal cut-off point for patients with LD and HD were 0.821 and 0.846, and 23 and 20 respectively. CONCLUSIONS: The efficacy of the ACT-J was confirmed in depressive patients with asthma. Because asthma control as evaluated with the ACT-J can be worse than actual control under depressive states, physicians should also pay attention to a patient's depressive state at evaluation. Further investigations focus on the association between the ACT-J and depression are required.

Mizoribine as a safe and effective combined maintenance therapy with prednisolone for anti-neutrophil cytoplasmic antibody-associated vasculitis in a hemodialysis patient.

A 77-year-old man developed severe renal insufficiency due to proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, and was started on hemodialysis (HD). Because his renal insufficiency appeared to be irreversible, he was maintained on oral prednisolone (PSL) at 5 mg/day. However, a disease flare-up with alveolar hemorrhage occurred. Serology revealed elevated levels of PR3-ANCA and C-reactive protein (CRP). The patient was given pulse therapy with a quarter dose of methylprednisolone (m-PSL) (250 mg, 3 days), followed by oral PSL at 15 mg/day. As a supplemental treatment, he was given 25 mg of mizoribine (MZR) immediately after each HD session. Subsequently, the levels of PR3-ANCA and CRP decreased, and the alveolar hemorrhage resolved. The dose of MZR to be given was determined by measuring the patient's serum concentrations of MZR at various time points after the HD session. The maintenance dose of MZR was finally set at 50 mg. At present, the oral PSL dosage has been tapered to 10 mg/day, and the patient has achieved a state of remission without any side effects.