Preoperative respiratory intervention eliminated the operation cancelations of lobectomy surgery.

In Nagasaki University Hospital, the patients undergoing surgery with abnormal respiratory function have been automatically referred to specialized clinic by Medical Support Center (MSC) since July 2016 to reduce surgery cancellations due to insufficient preoperative evaluation. Whether the MSC system decreased post-hospital surgery cancellation, variance rate, or length of hospital stays in patients received "lobectomy" were retrospectively compared between Period A (n = 264, before MSC introduction) and Period B (n = 264, after MSC introduction). Four patients' operations were cancelled after hospitalization in Period A, while 0 patients in Period B (p < 0.05). The length of hospital stay, operation time, anesthesia time, and postoperative extubation oxygen administration time were all shorten in Period B significantly. "Period B", "operation time", and "postoperation oxygenation time" were independent factors for "hospital days", but chronic obstructive pulmonary disease or age were not. The preoperative intervention eliminated the operation cancellation. Preoperative MSC interventions may have contributed to the reduction in hospital days even for the patients with pulmonary dysfunction.

Determining Response to Treatment for Drug-Induced Bronchocentric Granulomatosis by the Forced Oscillation Technique.

Anti-tumor necrosis factor alpha (TNFα) therapy is widely used to treat various inflammatory conditions. Paradoxically, there are several case reports describing the development of bronchocentric granulomatosis treated with TNFα inhibitors, and it is difficult to determine the effect of treatment using conventional spirometry because the lesions are located in small airways. However, it has been reported that the forced oscillation technique (FOT) is useful in the evaluation of small airway disease in bronchial asthma or chronic obstructive pulmonary disease. We performed the FOT to determine the effect of treatment on bronchocentric granulomatosis and found it to be useful. We report the case of a 55-year-old female with ulcerative colitis who was treated with golimumab and who developed bronchocentric granulomatosis as a sarcoid-like reaction to golimumab. She was successfully treated with prednisone, and the treatment efficacy was confirmed by the FOT. The FOT may be useful in the evaluation of small airway disease in bronchocentric granulomatosis. This case may help inform clinicians of the usefulness of the FOT to assess small airway disease in various diseases.

Clearance of Aspergillus fumigatus is impaired in the airway in allergic inflammation.

BACKGROUND: Aspergillus fumigatus (Af) sometimes colonizes and persists within the respiratory tree in some patients with asthma. To date, the precise reasons why the clearance of Af is impaired in patients with asthma remain unknown. OBJECTIVE: To characterize the effects of allergic airway inflammation on clearance of Af. METHODS: Control and Dermatophagoides farinae (Df) allergen-sensitized BALB/c mice were intranasally infected with Af. After 2 and 9 days of infection, the pathology, fungal burden, and cytokine profile in lung tissue were compared. In a different set of experiments, the phagocytotic activity of alveolar macrophages and the expression of their pathogen recognition receptors also were determined. RESULTS: The Af conidia and neutrophilic airway inflammation disappeared by day 9 after infection in control mice. In Df-sensitized mice, Af conidia and neutrophilic and eosinophilic airway inflammation persisted at day 9 after infection. Compared with control mice, Df allergen-sensitized mice showed significant increases in interleukin (IL)-5 and decreases in IL-12 and interferon-γ in lung tissues at day 2 after infection. Most importantly, compared with Af-infected non-Df-sensitized mice, IL-17 in lung tissues was significantly decreased in Df allergen-sensitized Af-infected mice at day 2 after infection but was significantly increased at day 9. Alveolar macrophages isolated from Df allergen-sensitized mice exhibited significant decreases in phagocytotic activity and expression of Toll-like receptor-4 and dectin-1 compared with those from control mice. CONCLUSION: In the airway of patients with allergy, T-helper cell type 2-dominant immunity potentially affects the expression of pathogen recognition receptors and attenuates cellular defense against Af. Prolonged IL-17 production also could play an important role.

Cysteinyl leukotriene receptor antagonist regulates allergic airway inflammation in an organ- and cytokine-specific manner.

BACKGROUND: Cysteinyl leukotrienes (cys-LTs) are very important factors in the pathophysiology of bronchial asthma. Cys-LT receptor antagonists (LTRAs) decrease allergic airway inflammation. The aim of the present study was to determine the differential effects of LTRAs and corticosteroids on allergic airway inflammation and allergen-specific cytokine production from lymphoid tissues using a murine model of asthma. MATERIAL AND METHODS: Four groups of female BALB/c mice [control (Cont); Dermatophagoides farinae allergen-sensitized (AS); pranlukast (Prl), an LTRA-treated AS; and dexamethasone (Dex)-treated AS] were examined. Lung pathology and cytokine production by prepared mononuclear cells isolated from mediastinal lymph nodes (MLNs) and spleen were compared among these groups. RESULTS: AS mice exhibited allergic airway inflammation and significant increases in allergen-specific Th1 and Th2 cytokines in MLNs and spleen. Prl-treated mice showed significant attenuation of allergic airway inflammation concomitant with reduction of Th2 cytokines and IFN-g in MLNs but not in spleen. In contrast, Dex significantly decreased Th1 and Th2 cytokines in MLNs and also decreased them (except IL-13 and IL-2) in spleen. CONCLUSIONS: The inflammatory effects of cys-LTs could differ in lymphoid organs. LTRAs potentially regulate allergic airway inflammation in an organ- and cytokine-specific manner, while systemic corticosteroid shows nonspecific effects.

Differential airway inflammatory responses in asthma exacerbations induced by respiratory syncytial virus and influenza virus a.

BACKGROUND: Although respiratory viral infections cause acute exacerbations of asthma, the inflammatory responses vary depending on the causative virus. The purpose of this study was to compare the inflammatory responses in the airways of acute exacerbations of asthma induced by respiratory syncytial virus (RSV) and influenza A virus. METHODS: Sputum induction was performed in asthmatic patients with acute exacerbations induced by RSV (n = 6), influenza A (n = 7), and non-upper respiratory infection (URI)-related factors (n = 8). Sputum concentrations of cysteinyl leukotrienes (cysLTs), TNF-α and IFN-γ were measured. RESULTS: Sputum cysLTs were significantly higher in RSV-induced exacerbations than in influenza A- and non-URI-induced exacerbations. Sputum TNF-α was significantly higher in influenza A-induced exacerbations than in RSV- and non-URI-induced exacerbations. Sputum IFN-γ was significantly lower in RSV-induced exacerbations than in the others. CONCLUSIONS: RSV and influenza A cause acute exacerbations and have different effects on airway inflammation in asthmatic patients. RSV significantly increased cysLTs, while influenza A significantly increased TNF-α in the airway. The underlying mechanism in virus-induced asthma might depend on the viral species.

Dissociation between sensitizing and colonizing fungi in patients with allergic bronchopulmonary aspergillosis.

BACKGROUND: Because allergic bronchopulmonary aspergillosis (ABPA) does not require the presence of Aspergillus fumigatus for diagnosis, serological and radiological findings without cultures usually confirm this condition. OBJECTIVE: To determine which fungi colonize the airways of patients with definitive ABPA. METHODS: We enrolled 11 patients (ages 57.5 ± 17.1 years; male: female, 4:7) with ABPA diagnosed by serological and radiological criteria. Fungi colonizing the airway were identified from mucous plugs that were naturally expectorated or obtained by fiberoptic bronchoscopy. RESULTS: Aspergillus spp. (n = 8) was the most frequently isolated, followed by Schizophyllum commune (n = 4), Candida albicans (n = 2), Rhizopus oryzae (n = 1), and Penicillium spp. (n = 1). Among the Aspergillus spp., A. niger, A. terreus, and A. sydowii were more frequently isolated (total, n = 6) than A. fumigatus (n = 2). Many patients were sensitized with several fungi in addition to Aspergillus, which were dissociated with airway-colonizing fungi. CONCLUSION: Multiple fungal species can colonize the airway, and dissociation between colonizing and sensitizing species frequently occurs in definitive ABPA. Considering the increased prevalence of azole-resistant Aspergillus spp., administering antifungal drugs that target A. fumigatus without identifying which fungal species colonize the airway might be problematic.

Differential effects of dexamethasone and itraconazole on Aspergillus fumigatus-exacerbated allergic airway inflammation in a murine model of mite-sensitized asthma.

BACKGROUND: Fungal exposure is associated with particularly severe asthma. Nevertheless, the effects of anti-fungal treatments on fungus-exacerbated asthma need to be determined. OBJECTIVES: The present study aimed to compare the effects of itraconazole (ITCZ) and dexamethasone (Dex) on Aspergillus fumigatus (Af)-exacerbated preexisting Dermatophagoides farinae (Df) allergen-sensitized allergic airway inflammation. METHODS: Four groups of BALB/c mice were prepared: control, Df-sensitized plus Af-infected mice (Df-Af), and Df-Af mice treated with Dex (Df-Af-Dex) or with ITCZ (Df-Af-ITCZ). Pulmonary pathology and cytokine profiles in the airway were evaluated. In a different set of experiments, the effects of Dex on alveolar macrophage (AM) phagocytosis of Af conidia were determined in Df-sensitized mice. RESULTS: Af infection significantly increased the level of eosinophils and neutrophils in the airway of Df-sensitized mice. While Dex significantly decreased eosinophils, ITCZ significantly decreased both eosinophils and neutrophils in Df-Af mice. Dex significantly decreased IL-5, whereas ITCZ significantly reduced MIP-2 in the airway. Compared to controls, AM isolated from Df-sensitized mice had significantly reduced phagocytotic activity of Af conidia. However, Dex significantly improved phagocytotic activity of AM in Df-sensitized mice. CONCLUSIONS: The present study showed that Dex and ITCZ differently regulated Af-exacerbated allergic airway inflammation; the former inhibits eosinophilic inflammation and the latter inhibits neutrophilic as well as eosinophilic inflammation by regulating different cytokines. Additionally, Dex enhanced the phagocytotic activity of AM in allergic asthma. Thus, a combination of Dex and ITCZ might be effective for the management of fungus-exacerbated asthma.

Evaluation of efficacy and safety of lascufloxacin for nursing and healthcare associated pneumonia: single-arm, open-label clinical trial: A study protocol.

BACKGROUND: Lascufloxacin hydrochloride (LSFX) is a quinolone antibiotic that inhibits DNA gyrase and topoisomerase IV of bacteria, it is anticipated to minimize antibiotic resistance in bacteria. It exhibits antibacterial activity against a relatively wide range of bacterial species, including anaerobic bacteria, and its efficacy and safety against community-acquired pneumonia have been shown; however, its efficacy and safety against nursing and healthcare associated pneumonia (NHCAP) have not been verified. METHODS/DESIGN: Here, a single-arm, open-label, uncontrolled study was conducted in which LSFX was administered to patients with NHCAP at 24 facilities. The research subjects (77 cases) were orally administered 75 mg of LSFX once a day for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC) (TOC; 5-10 days after the end of LSFX administration), while the secondary endpoints were the efficacy at the time of end of treatment, early clinical efficacy, microbiological efficacy at the time of TOC and end of treatment, and safety evaluation of LSFX. DISCUSSION: NHCAP is a common pneumonia in clinical settings and a notable pneumonia whose mortality is high compared to community-acquired pneumonia. The present study showed the efficacy and safety of LSFX against NHCAP, which could lead to a larger number of therapeutic options for NHCAP.

Serum Cytokine Changes in a Patient with Chronic Pulmonary Aspergillosis Overlapping with Allergic Bronchopulmonary Aspergillosis: A Case Report.

Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are diseases caused by Aspergillus infection, and CPA can develop from ABPA in some cases. We herein report a patient with CPA overlapping with ABPA. Serum cytokine levels were evaluated at 4 time points: the ABPA diagnosis, CPA diagnosis, 6 months after the start of voriconazole (VRCZ), and 12 months after re-administration of VRCZ. Interleukin (IL)-13 levels decreased upon glucocorticoid treatment, whereas IL-25 and IL-33 levels decreased rapidly with the initiation of antifungals. Early antifungal therapy may be important to control disease progression and prevent CPA overlap.

Effect of respiratory syncytial virus infection on plasmacytoid dendritic cell regulation of allergic airway inflammation.

BACKGROUND: Respiratory syncytial virus (RSV) can infect myeloid dendritic cells (mDCs) and regulate their function in the development of allergy. It has been widely reported that plasmacytoid DCs (pDCs) play a critical role in antiviral innate immunity. In contrast, not much is known about the role of pDCs in the interaction between allergy and viral infection. The purpose of the present study was to investigate the effect of RSV infection on pDC function in the regulation of allergic airway inflammation in a murine model of Dermatophagoides farinae-sensitized allergic asthma. METHODS: Splenic pDCs isolated from D. farinae-sensitized donor mice were infected with live RSV ex vivo. Subsequently, these pDCs were inoculated into the airways of D. farinae-sensitized recipient mice. Lung pathology, lung tissue cytokine profiles, the number of regulatory T cells (T(reg)) and mDCs as well as the effects of IL-10 neutralization in the lung tissue of recipient mice were determined. RESULTS: Intranasal inoculation of D. farinae-sensitized pDCs significantly inhibited the development of allergic airway inflammation and both Th1 and Th2 immunity. Live RSV infection of these pDCs prior to inoculation interfered with their inhibitory effects through decreasing T(reg) and IL-10 and increasing mDCs. CONCLUSIONS: In asthmatic airways, pDCs mediate tolerance to inhaled allergens through the regulation of T(reg), IL-10 and mDCs. RSV infection of pDCs potentially inhibits their immunotolerogenic effects and thus exacerbates allergic airway inflammation.

Effects of a short course of pranlukast combined with systemic corticosteroid on acute asthma exacerbation induced by upper respiratory tract infection.

BACKGROUND: Upper respiratory tract infections (URIs) represent the most frequent cause of acute asthma exacerbation. Systemic corticosteroid (CS) is presently recommended for URI-induced asthma exacerbation, although it might inhibit cellular immunity against respiratory virus infection. OBJECTIVES: To determine the effects of adding a short course (2 weeks) of a leukotriene receptor antagonist (LTRA) to systemic CS on URI-induced acute asthma exacerbation. METHODS: Twenty-three adult asthmatics (mean age, 42.8 ± 9.8 y; Male:Female, 10:13) with URI-induced acute asthma exacerbation confirmed by a questionnaire and physical findings were randomly assigned to receive either oral prednisolone (PSL) alone or oral PSL plus the LTRA pranlukast (PRL) for 2 weeks (PSL + PRL). The cumulative doses of PSL and the amount of time required to clear asthma-related symptoms were determined. Levels of respiratory syncytial virus (RSV) RNA and influenza viral (IV) antigen in nasopharyngeal swabs were also determined. RESULTS: Adding PRL significantly reduced the cumulative dose of PSL and tended to reduce the time required to clear asthma-related symptoms. Either RSV or IV was detected in about one-third of the patients. CONCLUSION: The combination of an LTRA and CS might be more useful than CS alone for treating URI-induced acute exacerbation of asthma and reducing the cumulative CS dose.

Acetaldehyde at a low concentration synergistically exacerbates allergic airway inflammation as an endocrine-disrupting chemical and as a volatile organic compound.

BACKGROUND: Acetaldehyde is an endocrine-disrupting chemical (EDC) and a volatile organic compound (VOC). It is also a carcinogen and teratogen that causes bronchoconstriction in a subset of asthmatics. However, the mechanism through which acetaldehyde acts as an EDC/VOC causing allergic airway inflammation remains unknown. OBJECTIVES: To determine the effects of a low concentration of acetaldehyde, which itself did not trigger airway inflammation, on extant allergic airway inflammation in a murine model of allergic asthma. METHODS: We compared airway hyperresponsiveness (AHR), lung pathology, serum IgE and airway concentrations of cytokines among four groups of BALB/c mice [control, Dermatophagoides farinae(Df) allergen-sensitized (AS), intranasally acetaldehyde-injected (ALD) and AS-ALD mice]. RESULTS: Physiological and histological differences were not evident between ALD and control mice. AS mice developed AHR and allergic airway inflammation characterized by goblet cell hyperplasia and eosinophilic infiltration. Both AHR and airway eosinophilia were significantly enhanced in AS-ALD compared with AS mice. Serum total and Df-specific IgE were significantly increased in both AS and AS-ALD mice compared with control and ALD mice, but comparable between AS and AS-ALD mice. Mite allergen sensitization significantly increased interleukin-5 and granulocyte macrophage colony-stimulating factor, and decreased interferon-γ levels in the airways; injecting acetaldehyde into airways with allergic inflammation significantly increased the levels of these inflammatory cytokines. CONCLUSIONS: Exposure to acetaldehyde can enhance allergic airway inflammation in asthma.

Serum Cytokines Usefulness for Understanding the Pathology in Allergic Bronchopulmonary Aspergillosis and Chronic Pulmonary Aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) are important fungal infections caused by Aspergillus species. An overlap of ABPA and CPA has been reported; therefore, it is critical to determine whether the main pathology is ABPA or CPA and whether antifungals are required. In this study, we investigated whether the serum cytokine profile is useful for understanding the pathology and for differentiating between these diseases. We compared the various serum cytokine levels among healthy subjects and patients diagnosed with asthma, ABPA, or CPA at Nagasaki University Hospital between January 2003 and December 2018. In total, 14 healthy subjects, 19 patients with asthma, 11 with ABPA, and 10 with CPA were enrolled. Interleukin (IL) -5 levels were significantly higher in patients with ABPA than in those with CPA, and IL-33 and tumor necrosis factor (TNF) levels were significantly higher in patients with CPA than in those with asthma (p < 0.05, Dunn's multiple comparison test). The sensitivity and specificity of the IL-10/IL-5 ratio (cutoff index 2.47) for diagnosing CPA were 70% and 100%, respectively. The serum cytokine profile is useful in understanding the pathology of ABPA and CPA, and the IL-10/IL-5 ratio may be a novel supplemental biomarker for indicating the pathology of CPA.

Aspergillus fumigatus synergistically enhances mite-induced allergic airway inflammation.

BACKGROUND: Infection is an important trigger of exacerbation of bronchial asthma. The fact that Aspergillus fumigatus (Af) causes a distinct clinical syndrome, allergic bronchopulmonary aspergillosis (ABPA), suggests unique immunological properties in allergic asthma. The present study aimed to determine how Af enhances preexisting allergic airway inflammation and colonizes the airway in asthma. MATERIAL/METHODS: Six groups of BALB/c mice were prepared: Control; live or dead Af-infected (Live Af or Dead Af); Dermatophagoides farinae (Df) allergen-sensitized (Df); and Df-sensitized plus live or dead Af-infected (Df-live Af or Df-dead Af). Pulmonary pathology, cytokine profiles and mucous production in the airway were evaluated in these groups. RESULTS: Af infection significantly enhanced Df allergen-induced eosinophilic inflammation via enhancement of Th2-like response. Live, but not dead, Af significantly exacerbated neutrophilic inflammation. Induction of IL-13 and Muc5ac proteins by Df allergen sensitization was significantly enhanced by both live and dead Af infection, resulting in mucous hypersecretion. CONCLUSIONS: Collectively, the present study showed that mite allergen sensitization concomitant with Af infection enhanced Th2-dominant immune response in the airway, which induced mucous hypersecretion and potentially permitted further colonization by Af spores. It is likely that Af enhances allergic airway inflammation as an allergen, while it enhances neutrophilic airway inflammation as a pathogen. Future studies on pharmacological intervention in the present murine model utilizing glucocorticoid, and anti-fungal drugs are thus promising.

Randomized, double-blind, placebo-controlled, parallel-group trial of sirolimus for tocilizumab-resistant idiopathic multicentric Castleman disease: Study protocol for clinical trial.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder of unknown etiology with systemic symptoms that include fever, night sweats, weight loss, and fatigue. Although tocilizumab (TCZ), which is a recombinant, humanized, anti-human interleukin 6 receptor monoclonal antibody, has been recommended to treat patients with iMCD, 40% of patients with iMCD do not achieve complete remission with TCZ treatment. METHODS/DESIGN: In this phase II, investigator-initiated, multicenter, double-blind, randomized, parallel-group trial, the efficacy and safety of sirolimus will be compared with placebo in patients with TCZ-resistant iMCD. The study will be conducted in 8 centers in Japan. Participants (n = 20) will be randomly assigned to receive 2 mg of oral sirolimus (n = 10) or placebo (n = 10) once daily for 16 weeks. The primary endpoint is a decrease in CHAP score by ≥1 from baseline at 16 weeks. Secondary endpoints include levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; SF-36 Health Survey Questionnaire; physician global assessment (100 mm visual analog scale); patient global assessment (100 mm visual analog scale) at 2, 4, 8, 12, and 16 weeks; change in lymphadenopathy at 16 weeks; and pharmacodynamic assessment, including the measurement of whole blood sirolimus level. DISCUSSION: This clinical trial will provide evidence of efficacy and safety of sirolimus as a potential new therapeutic agent for patients with TCZ-resistant iMCD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials as jRCT2071190029 on October 8, 2019.

Switching from originator infliximab to biosimilar infliximab in Japanese patients with rheumatoid arthritis achieving clinical remission (the IFX-SIRIUS study I): Study protocol for an interventional, multicenter, open-label, single-arm and noninferiority clinical trial with clinical, ultrasound, and biomarker assessments.

BACKGROUND: The introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) into clinical practice has dramatically improve the clinical outcomes of individuals with rheumatoid arthritis (RA). However, bDMARDs are associated with high costs, which has resulted in restricted treatment access and a burden on medical insurance finances. Although biosimilars offer cost-saving, their effectiveness and safety must be established in Post-Marketing Surveillance (PMS). Infliximab (IFX), a chimeric monoclonal antibody to TNF-alpha, is the first bDMARD; its biosimilar, CT-P13, is the first biosimilar DMARD approved for RA treatment in Japan. We will evaluate whether switching from originator IFX to CT-P13 is not inferior for maintaining non-clinical relapse to continued treatment with originator IFX in RA patients achieving clinical remission. METHODS/DESIGN: This study is an interventional, multicenter, open-label, single-arm against historical control and noninferiority clinical trial with a 24-week follow-up. Eighty RA patients who are treated by originator IFX for ≥24 weeks and are achieving clinical remission will be included. Patients will be switched to CT-P13 with the unchanged dosing regimen. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the ratio of patients who experience a nonclinical relapse during the study period. Important secondary endpoints are the changes from the baseline of the MSUS scores. We will also comprehensively analyze the serum levels of many biomarkers such as cytokines and chemokines. DISCUSSION: The study results are expected to show the noninferiority of switching to CT-P13 over the continuation of originator IFX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices but also MSUS to accurately and objectively evaluate disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will explore whether parameters at baseline can predict a nonclinical relapse after switching from originator IFX to CT-P13 by integrating multilateral assessments, i.e., clinical disease activity indices, MSUS findings, and serum biomarkers. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) on October 11, 2019 as jRCTs071190030.

An open-label continuation trial of sirolimus for tocilizumab-refractory idiopathic multicentric Castleman disease: Study protocol for an investigator-initiated, multicenter, open-label trial (SPIRIT compliant).

BACKGROUND: Interleukin 6 (IL-6) inhibitors are the first-line treatment for idiopathic multicentric Castleman disease (iMCD); however, there is no established treatment for cases that are resistant to IL-6 inhibitors. Although sirolimus, a mammalian target of rapamycin inhibitor, has been suggested to be effective in patients with iMCD, the long-term safety and efficacy of sirolimus on individuals with IL-6 inhibitor-resistant iMCD have not been evaluated. METHODS/DESIGN: In this investigator-initiated, multicenter, open-label trial, the long-term safety of sirolimus will be evaluated in patients participating in a placebo-controlled, randomized, double-blind, parallel-group trial on tocilizumab (TCZ)-resistant iMCD. The study will be conducted in 7 centers in Japan. This trial will be promptly started after the evaluation and examination for 16 weeks in the preceding study. The trial will be completed by the time the drug is approved for iMCD treatment in Japan. The primary endpoint is the incidence of adverse events. The secondary endpoints include the following: the levels of hemoglobin, albumin, and C-reactive protein; change in CHAP score; physician global assessment (100-mm visual analog scale); patient global assessment (100-mm visual analog scale); and lymph node changes in subjects with lymphadenopathy. DISCUSSION: This clinical trial will provide evidence regarding the long-term safety of sirolimus as a potential novel therapeutic agent for patients with tocilizumab-resistant iMCD. TRIAL REGISTRATION NUMBER: jRCT2051200050.

Comparison of 12-Week Additional Effect Features of Formoterol Co-Inhalation and Tulobuterol Patch on Budesonide Inhalation in Elderly Patients With Asthma.

BACKGROUND: For asthma strategy, to avoid the aggravation of bronchial inflammation and contraction, the long acting beta agonist (LABA) addition on inhaled corticosteroids (ICS) has been recommended. OBJECTIVES: To know whether there is any clinical difference between the additional efficacies of Formoterol (FOR) and Tulobuterol (TUL) onto Budesonide (BUD) may be useful for the elderly patients' asthma treatment strategy. METHODS: Eighteen outpatients with mild to moderate bronchial asthma with FEV1.0% < 80% treated by intermediate ICS dosages visited Respiratory Division of Nagasaki University Hospital or Isahaya General Hospital, Japan Community Health care Organization were subjected, and were randomly assigned (9 cases per group) to either the FBC group (BUD/FOR 160/4.5 µg, 2 inhalations twice daily) or BUD + TUL group (BUD 200 mcg: 2 inhalations twice daily + TUL 2 mg daily) and were compared in parallel with 2 arms for 12 weeks prospectively. Peak expiratory flow, forced expiratory volume in 1 second, impulse oscillometry (IOS), fractional exhaled nitric oxide (FeNO), Asthma Control Questionnaire, mini-Asthma Quality of Life Questionnaire (mini-AQLQ), and occurrence of adverse reactions were compared. RESULTS: The "Fres" of IOS was improved in FBC group (p = 0.03). The "emotion" domain of mini-AQLQ was improved in BUD + TUL group (p = 0.03). CONCLUSION: By changing the drug formulation, the patch was superior in terms of satisfaction, but it was thought that the inhaled combination was superior in improving the respiratory function itself. It is necessary to pay attention to the characteristics of the patient when selecting treatment.

An open-label continuation trial of tocilizumab for familial Mediterranean fever with colchicine ineffective or intolerance: Study protocol for investigator-initiated, multicenter, open-label trial.

BACKGROUND: Colchicine is the first-line treatment for familial Mediterranean fever (FMF), but secondary amyloidosis resulting from persistent inflammation is a concern in patients with colchicine-resistant or colchicine-intolerant FMF. Although tocilizumab (TCZ), which is a recombinant, humanized, anti-human interleukin 6 receptor monoclonal antibody, has been reported to prevent FMF attacks, the long-term safety and efficacy of TCZ on individuals with colchicine-resistant or colchicine-intolerant FMF have not been evaluated. METHODS/DESIGN: In this investigator-initiated, multicenter, open-label trial, the long-term safety of TCZ will be evaluated in patients participating in a placebo-controlled, randomized, double-blind, parallel-group trial on colchicine-resistant or colchicine-intolerant FMF. The study will be conducted in 9 centers in Japan. After the evaluation and examination for 24 weeks in the preceding study, this trial will be started promptly. The trial will be completed by the time the drug is approved for FMF treatment in Japan. The primary endpoint is the incidence of adverse events, and the secondary endpoints include the number of FMF attacks, number of occurrences of accompanying symptoms during attacks, serum C-reactive protein and amyloid A levels, general evaluation by a physician (100 mm visual analog scale [VAS]), general evaluation by a patient (100 mm VAS), and body temperature. DISCUSSION: The study is expected to obtain evidence regarding the long-term safety of TCZ as a potential new therapeutic agent for patients with colchicine-resistant or colchicine-intolerant FMF. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000037116) as UMIN000032557 on May 30 2018.