Case of uncontrolled asthma with Ceriporia lacerata-related broncholithiasis.

An 81-year-old Japanese male patient was treated for asthma. He complained of persistent cough and wheezing. Chest computed tomography scan revealed atelectasis in the right middle lobe. Fiberoptic bronchoscopy was performed. Results showed a calcified stone with filamentous fungi with septa in the right middle lobe bronchus, which was subsequently removed. Ceriporia lacerata was detected repeatedly on sputum culture. Thus, the filamentous fungi were suspected as C. lacerata. Broncholithiasis possibly caused mucous membrane damage owing to C. lacerata colonization, resulting in allergic airway inflammation. Herein, we report a rare case of C. lacerata-related broncholithiasis associated with asthma exacerbation.

Effects of Dupilumab for Asthma-chronic Obstructive Pulmonary Disease Overlap.

No Abstract.

Waterproofing Spray-Associated Lung Injury Review: Differences between Cases of Early and Delayed Improvement of Waterproofing Spray-Associated Lung Injury.

Waterproofing spray-associated lung injury (WALI) is an acute respiratory disorder characterized by bilateral diffuse lung injury on chest computed tomography (CT). In most cases, the symptoms and abnormal radiographic findings of WALI patients improve spontaneously over several days; however, some cases have persistent symptoms and abnormal shadows for >1 week. The distinctive features of each WALI are unknown. Herein, we present two new cases of WALI that we encountered in our hospital, and we previously reported two other cases of WALI. We examined the characteristics of WALI in our cases and 39 other cases of WALI definitively diagnosed and reported in PubMed and the Japan medical board with verifiable data during a 15-year period. We compared the clinical characteristics of the 22 cases in which the patients' symptoms were resolved within 1 week (early improvement) to those of the 21 cases in which the symptoms were resolved after >1 week (delayed improvement). The WALI cases with delayed improvement had significantly more shadowing that extended over the entire lung field and was not biased in intensity toward the upper or lower lung field. In addition, the serum white blood cell (WBC) counts and serum Krebs von den Lungen-6 (KL-6) levels differed significantly between the cases of early and delayed improvement of WALI.

RSV infection-elicited high MMP-12-producing macrophages exacerbate allergic airway inflammation with neutrophil infiltration.

Respiratory syncytial virus (RSV) infection often exacerbates bronchial asthma, but there is no licensed RSV vaccine or specific treatments. Here we show that RSV-induced alveolar macrophages, which produce high levels of matrix metalloproteinase-12 (MMP-12), exacerbate allergic airway inflammation with increased neutrophil infiltration. When mice subjected to allergic airway inflammation via exposure to the house dust mite antigen (HDM) were infected with RSV (HDM/RSV), MMP-12 expression, viral load, neutrophil infiltration, and airway hyperresponsiveness (AHR) were increased compared to those in the HDM and RSV groups. These exacerbations in the HDM/RSV group were attenuated in MMP-12-deficient mice and mice treated with MMP408, a selective MMP-12 inhibitor, but not in mice treated with dexamethasone. Finally, M2-like macrophages produced MMP-12, and its production was promoted by increase of IFN-ß-induced IL-4 receptor expression with RSV infection. Thus, targeting MMP-12 represents a potentially novel therapeutic strategy for the exacerbation of asthma.

Association between serum anti-glycopeptidolipid-core IgA antibody titers and clinical characteristics of Mycobacterium avium complex pulmonary disease.

OBJECTIVES: Mycobacterium avium complex pulmonary disease (MAC-PD) can be serologically diagnosed according to the presence of anti-glycopeptidolipid (GPL)-core IgA antibodies. However, few studies have examined the association between serum anti-GPL-core IgA antibody titers and the clinical characteristics of patients with MAC-PD. METHODS: From April 2014 to June 2019, the levels of anti-GPL-core IgA antibodies in 489 MAC-PD patients were determined at the current institute. Of them, 89 patients fulfilled the criteria of the American Thoracic Society and the Infectious Diseases Society of America statement on the diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Patients were categorized into the antibody strong-positive (n = 27), weak-positive (n = 32), and negative (n = 30) groups according to their serum anti-GPL-core IgA antibody results. Their clinical characteristics were retrospectively compared. RESULTS: Disease progression requiring treatment and extensive radiological findings were significantly abundant in the strong-positive group compared with the weak-positive group. Clinical characteristics of the antibody weak-positive and negative groups did not significantly differ. CONCLUSIONS: The findings revealed that serum anti-GPL-core IgA antibody titers are useful for diagnosing MAC-PD and also for predicting the risk of exacerbation.

Exacerbating factors in elderly patients with Mycobacterium avium complex pulmonary disease.

No previous studies have examined Mycobacterium avium complex pulmonary disease (MAC-PD) in only elderly patients ⩾75 years old. Here, we investigated the exacerbating factors of MAC-PD in elderly patients and clarified cases that can be followed up without MAC medication. From April 2011 to March 2019, 126 advanced aged patients at our institute were newly diagnosed with MAC-PD, and could be observed based on radiological findings for over a year. Their medical records were retrospectively examined for clinical and radiological findings at the time of diagnosis and 1 year later. To identify the predictors of exacerbation, clinical characteristics of 109 treatment-naïve patients were compared between exacerbated and unchanged groups. Additionally, the unchanged group was followed for one more year. In the current study, positive acid-fast bacilli smears from the sputum test, the presence of cavitary lesions and extensive radiological findings, particularly abnormal shadows in ⩾3 lobes, were predictive of exacerbation among treatment-naïve elderly MAC-PD patients. In the unchanged group, <10% showed exacerbation of radiological findings within the subsequent year. In conclusion, if the sputum smear is negative, no cavitary lesions are present, and abnormal shadows are restricted to ⩽2 lobes, elderly patients with MAC-PD may remain untreated for a few years.

Predictors of radiological aggravations of pulmonary MAC disease.

BACKGROUND AND OBJECTIVES: The number of patients with pulmonary Mycobacterium avium complex (MAC) disease is increasing worldwide, especially among middle-aged women and never-smokers. However, little is known about the factors causing exacerbations of pulmonary MAC disease in untreated patients. The aim of the present study was to identify the predictors of radiological aggravations of pulmonary MAC disease. METHODS: From April 2011 to December 2018, 238 MAC patients at our institute were newly diagnosed with pulmonary MAC disease according to the 2007 American Thoracic Society/Infectious Disease Society guideline. Their medical records were examined retrospectively for their clinical findings. The radiological findings at the time of the diagnosis and 1 year later were evaluated. To identify the predictors of radiological aggravation, multivariable analysis was performed with the data of 167 treatment-naïve patients. RESULTS: Female, never-smoker, and nodular/bronchiectatic (NB) type were predominant in patients with pulmonary MAC disease. Univariate analysis of data from treatment-naïve subjects showed that no lung diseases other than MAC, extensive radiological findings, and a positive acid-fast bacilli (AFB) smear were significantly associated with radiological aggravations. On multivariate analysis, the radiological factor (larger affected area) and absence of other lung disease were significantly associated with radiological aggravations. In particular, the presence of abnormal shadows in more than 3 lobes was significantly associated with radiological aggravations. CONCLUSIONS: In this study, the presence of extensive radiological findings and the absence of lung diseases other than MAC were predictors of radiological aggravations of treatment-naïve pulmonary MAC disease. In particular, the presence of abnormal shadows in more than 3 lobes was significantly associated with radiological aggravations.

A retrospective clinical research of relapsed organizing pneumonia.

BACKGROUND: Organizing pneumonia (OP) usually responds spectacularly well to initial treatment, but relapses can occur and some cases run a fatal course. Still, the issue of relapse has been addressed in relatively few studies, and predictors have not been clarified. The purpose of this study was to examine the pattern of relapses in OP, to determine whether relapse affects morbidity and mortality, and to identify possible predictors of relapse. METHODS: Blood sampling, pulmonary function testing, computed tomography (CT) of the chest, and bronchofiberscopy were performed for all patients and were retrospectively reviewed along with clinical information. Periodical chest CT was conducted and additional chest CT was performed when relapse of OP was clinically suspected. All patients were followed regarding treatment response, treatment duration, and presence of relapse. Results were compared between two groups based on serum concentrations of surfactant protein (SP)-D: normal SP-D and high SP-D. RESULTS: Twenty-two patients were analyzed in this study. SP-D showed a negative correlation with percutaneous oxygen saturation and positive correlations with serum lactate dehydrogenase, Krebs von den Lungen (KL)-6, and percentage of lymphocytes in bronchoalveolar lavage (BAL). Prognosis was good for all patients, but relapse was significantly more frequent in the high SP-D group (6 cases) than in the normal SP-D group (0 cases; P = 0.049). Serum KL-6 and percentage of monocytes in BAL were significantly higher, and pulmonary vital capacity and forced expiratory volume in 1 s were significantly lower in the high SP-D group than in the low SP-D group. CONCLUSIONS: When treating cases of OP with high serum concentrations of SP-D, attention should be paid to the possibility of relapse.

A Previously Unknown Drug-Drug Interaction Is Suspected in Delayed Elimination of Plasma Methotrexate in High-Dose Methotrexate Therapy.

Background: High-dose methotrexate (HD-MTX) therapy is widely implemented for leukemia, osteosarcoma, and lymphoma. Although various measures have been taken to avoid toxicity from high serum MTX concentrations, there are many cases of delayed elimination of MTX. Objective: We suspected that delayed elimination of serum MTX was caused by unknown interactions between MTX and concomitant drugs. Methods: Concerning concomitant drugs in the case of delayed elimination of MTX, we performed screening tests in 35 patients who had undergone HD-MTX therapy. We then investigated the risk factors for delayed MTX elimination in 94 patients with leukemia, lymphoma, or osteosarcoma retrospectively. Results: The percentages of concomitant use of Stronger Neo-Minophagen C (SNMC), a glycyrrhizin preparation, and vincristine were higher in the delayed group. The percentage of delayed MTX elimination in patients receiving HD-MTX therapy was 41%. Multiple logistic regression analysis revealed that the concomitant use of SNMC solely was a significant risk factor for delayed MTX (odds ratio = 12.20; 95% CI = 1.06-139.84). Conclusion and Relevance: Concomitant use of SNMC was shown to be related to delayed elimination of serum MTX, and our results suggested a previously unknown drug-drug interaction between MTX and SNMC.

Evaluation of Inhaled Procaterol for Potential Assist Use in Patients with Stable Chronic Obstructive Pulmonary Disease.

OBJECTIVES: International guidelines recommend the use of long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease (COPD), but the usefulness of short-acting bronchodilator assist use for stable COPD remains uncertain. The purpose of the present study was to objectively demonstrate the effects of assist use of procaterol, a short-acting ß2-agonist, on the respiratory mechanics of stable COPD patients treated with a long-acting bronchodilator using forced oscillation technique (FOT) and conventional spirometry. We also confirmed the length of time for which procaterol assist could significantly improve the pulmonary function. METHODS: We enrolled 28 outpatients with mild to severe COPD (Global Initiative for Obstructive Lung Disease stages I-III), who had used the same long-acting bronchodilator for longer than 3 months and who were in stable condition. All measures were performed using both FOT and spirometry sequentially from 15 min to 2 h after inhalation. RESULTS: Compared to baseline, inhaled procaterol assist use modestly but significantly improved spirometric and FOT measurements within 2 h after inhalation. These significant effects continued for at least 2 h. -Significant correlations were found between parameters -measured by spirometry and those measured by FOT. CONCLUSIONS: Procaterol assist use modestly but significantly improved pulmonary function determined by spirometry and respiratory mechanics in patients with stable COPD treated with long-acting bronchodilators. Thus, inhaled procaterol has the potential for assist use for COPD.

Analysis of predictive parameters for the development of radiation-induced pneumonitis.

INTRODUCTION: Prevention and effective treatment of radiation-induced pneumonitis (RP) could facilitate greater use of radiation therapy (RT) for lung cancer. The purpose of this study was to determine clinical parameters useful for early prediction of RP. METHODS: Blood sampling, pulmonary function testing, chest computed tomography, and bronchoalveolar lavage (BAL) were performed in patients with pathologically confirmed lung cancer who had completed ≥60 Gy of RT, at baseline, shortly after RT, and at 1 month posttreatment. RESULTS: By 3 months post-RT, 11 patients developed RP (RP group) and the remaining 11 patients did not (NRP group). RT significantly increased total cell counts and alveolar macrophages in BAL of the NRP group, whereas lymphocyte count was increased in both groups. Matrix metallopeptidase-9 (MMP-9) increased and vascular endothelial growth factor decreased significantly in the BAL fluid (BALF) of the RP group following RT. Serum surfactant protein D (SP-D) increased significantly in the NRP group. SP-D in BALF from the RP group increased significantly with a subsequent increase in serum SP-D. Pulmonary dilution decreased similarly in both groups of patients. CONCLUSIONS: Increased SP-D in BALF, rather than that in serum, could be useful biomarkers in predicting RP. The MMP-9 in BALF might play a role in the pathogenesis of RP. Pulmonary dilution test may not be predictive of the development of RP.

Decreased expression levels of cell cycle regulators and matrix metalloproteinases in melanoma from RET-transgenic mice by single irradiation of non-equilibrium atmospheric pressure plasmas.

Since effective therapies for melanoma with BRAF(V600E) mutation are being developed, interest has been shown in the development of therapies for melanoma without BRAF(V600E) mutation. Recently, interest has also been shown in medical application of non-nequilibrium atmospheric pressure plasmas (NEAPPs). We previously suggested that repeated NEAPP irradiation to spontaneously developed benign melanocytic tumors in RFP-RET-transgenic mice (RET-mice) not only suppresses tumor growth but also prevents malignant transformation. In this study, we first confirmed that transcript expression levels of tumor growth regulators (CyclinD1, D2, E1, E2, G2 and PCNA but not CyclinG1) and tumor invasion regulators [Matrix metalloproteinase (MMP)-2, -9 and -14 and melanoma cell adhesion molecule (MCAM)] in melanomas were significantly higher than those in benign melanocytic tumors in RET-mice. We then showed that transcript expression levels of CyclinE1, G1 and G2 and MMP-2 and -9 in melanomas from RET-mice were significantly decreased by single NEAPP irradiation, whereas transcript expression levels of CyclinD1, D2, E2, PCNA, MCAM and MMP-14 were comparable in untreated and NEAPP-treated melanomas. Since no Braf(V600E) mutation melanomas have been found in RET-mice, our results suggest that single NEAPP irradiation is a potential therapeutic tool for melanoma without BRAF(V600E) mutation through modulation of the expression levels of tumor growth and invasion regulators.

[Development of Preventive Therapy by Clarification of Mechanisms of Environmental-Factor-Mediated Diseases].

Environmental factors affecting human health are generally classified into physical, chemical and biological factors. In this review article, we focus on ultraviolet (UV) as a physical factor, heavy metals as a chemical factor and Japanese cedar pollens as a biological factor. Since we believe that progress based on both fieldwork research and experimental research is essential in hygiene study, we included the results of both the research approached. We first introduced the mechanism of development of and prevention of UV-mediated skin melanoma in our experimental research after showing our epidemiological research on UV-mediated DNA damage in humans. We then introduced our evaluation of toxicity and development of a remediation system in our experimental research on heavy metals after showing our fieldwork research for the monitoring of drinking water from wells in Asian countries. We finally introduced the results of pathogenic analysis of pollinosis in our clinical study. We would be very happy if young researchers would re-realize the importance of experimental research as well as epidemiological research in hygiene study.

Carcinogenic risk of chromium, copper and arsenic in CCA-treated wood.

We showed that 2.1% of 233 pieces of lumber debris after the Great East Japan Earthquake was chromated copper arsenate (CCA)-treated wood. Since hexavalent chromium (Cr), copper (Cu) and pentavalent arsenic (As) in the debris may be diffused in the air via incineration, we exposed human lung normal (BEAS-2B) and carcinoma (A549) cells to Cr, Cu and As at the molar ratio in a representative CCA-treated wood. Co-exposure to 0.10 µM Cr and 0.06 µM As, which solely had no effect on colony formation, synergistically promoted colony formation in BEAS-2B cells, but not A549 cells, with activation of the PI3K/AKT pathway. Sole exposure and co-exposure to Cu showed limited effects. Since previous reports showed Cr and As concentrations to which human lungs might be exposed, our results suggest the importance to avoid diffusion of Cr and As in the air via incineration of debris including CCA-treated wood after the disaster.

[Analysis of Environmental-Stress-Related Impairments of Inner Ear].

Noise stress generated in industry is one of the environmental factors that physically affects the functions of the inner ear. Exposure to noise can cause hearing loss, resulting in serious problems in occupational and daily life. At present, however, there are very limited ways to prevent hearing impairments. The inner ear consists of the organ of Corti, vestibule and semicircular canal. Functional or morphological damage of these tissues in the inner ear caused by genetic factors, aging or environmental factors can result in hearing or balance impairments. In this review, we first introduce a deafness-related molecule found by our clinical research. Our experimental research using genetically engineered mice further demonstrated that impaired activity of the target molecule caused congenital and age-related hearing loss with neurodegeneration of spiral ganglion neurons in the inner ears. We also describe impaired balance in mice caused by exposure to low-frequency noise under experimental conditions with indoor environmental monitoring. We believe that our approaches to pursue both experimental research and fieldwork research complementarily are crucial for the development of a method for prevention of impairments of the inner ear.

Tiotropium bromide as add-on therapy to inhaled corticosteroids for treating asthma.

INTRODUCTION: Bronchial asthma is becoming increasingly prevalent worldwide. Although first-line therapy with inhaled corticosteroids (ICS) with or without long-acting ß2 agonists (LABA) has significantly improved the clinical outcomes of asthma, they cannot provide all asthmatics with good control and thus alternatives or add-on drugs are required. Tiotropium is a long-acting muscarinic antagonist that has been used to treat chronic obstructive pulmonary disease and it has been approved for treating asthma in some countries. This agent has similar bronchodilatory effects to those of LABA and might also have anti-inflammatory and anti-remodeling effects. AREAS COVERED: Some pivotal clinical trials have found tiotropium effective as an add-on medication for low-to-medium doses of ICS for treating symptomatic asthma and asthma that remains uncontrolled despite ICS plus LABA therapy. EXPERT OPINION: Whether or not tiotropium has anti-inflammatory and anti-remodeling effects in humans with asthma is an important issue. Predictors that would identify patients who would derive the maximal potential benefit from treatment with tiotropium in addition to their current therapy are also needed. Although the cardiovascular toxicity of tiotropium is less remarkable in asthma than in chronic obstructive pulmonary disease, longer and larger studies are still needed to confirm the safety of tiotropium for treating asthma.