Factors associated with improvements in subjective symptoms of obstructive sleep apnea syndrome after continuous positive airway pressure therapy.

PURPOSE: Continuous positive airway pressure (CPAP) therapy improves subjective symptoms in obstructive sleep apnea syndrome (OSAS) patients; however, factors predicting symptom improvement post-CPAP therapy and the CPAP duration necessary for improving subjective symptoms are unclear. This study aimed to identify these factors and the appropriate nightly CPAP duration for improving subjective symptoms. METHODS: We recruited 359 subjects who completed both overnight polysomnography and subjective symptom assessments using the Epworth Sleepiness Scale (ESS), Zung Self-Depression Scale (SDS), and Pittsburgh Sleep Quality Index (PSQI). Firstly, we analyzed subject characteristics, and the associations between each assessment score and the Apnea-Hypopnea Index. These assessments were then repeated for 138 subjects who could continue for 3 months after starting CPAP. Secondly, associations between changes in self-reported outcome measures and nightly CPAP duration were analyzed. We identified subjects with abnormal initial ESS, PSQI, and SDS scores and divided them into "improvement" and "non-improvement" groups to examine factors associated with a positive outcome after CPAP therapy. RESULTS: Subjective symptom scores and proportions of subjects exceeding the cutoff values of each symptom score were not significantly related to OSAS severity. ESS, SDS, and PSQI scores improved 3 months after CPAP treatment, and factors involved in each improvement were found. Remarkably, longer CPAP nightly duration resulted in improvements in all subjective symptom scores. Furthermore, minimum durations between 4.75 and 5.40 h were necessary for improvements in subjective symptoms based on ROC curve analysis. CONCLUSIONS: Longer nightly CPAP use significantly improved OSAS subjective symptoms.

Association between severity of obstructive sleep apnea and glycated hemoglobin level in Japanese individuals with and without diabetes.

Aim of this study was to examine the association between the severity of obstructive sleep apnea (OSA) and dysglycemia in Japanese individuals with and without type 2 diabetes (T2DM). We enrolled 115 individuals diagnosed with OSA with an apnea hypopnea-index (AHI) ≥ 20 in whom continuous positive airway pressure (CPAP) therapy was introduced (N = 115, 44 with T2DM, age 62 ± 11 years, BMI 27.0 ± 4.4 kg/m2 and AHI median 36.1; interquartile range 27.2-48.1). During admission, the severity of OSA was evaluated by polysomnography, and its association with glycated hemoglobin (HbA1c) level was examined. Continuous glucose monitoring (CGM) was also conducted during the admission in 94 individuals. Apnea-hypopnea index (AHI), non-rapid eye movement (REM) AHI, minimum peripheral capillary oxygen saturation (SpO2) and percentage of sleep time (%TST) with SpO2 < 90% were significantly associated with HbA1c level in total and non-diabetic individuals (all p < 0.05) but not in those with T2DM, the majority of whom were treated with anti-diabetic medications. The associations of the non-REM AHI and %TST with SpO2 < 90% with HbA1c level remained significant after adjustment for age, sex and BMI in non-diabetic and T2DM subjects treated with dietary therapy only. Mean glucose level, but not SD or coefficient of variation of glucose, assessed by CGM was significantly associated with AHI and non-REM AHI in non-diabetic subjects after adjustment for age, sex and BMI. In conclusion, the severity of OSA was associated with increased HbA1c level independently of BMI in Japanese individuals, especially in those without diabetes.

Pneumococcal Infection Aggravates Elastase-Induced Emphysema via Matrix Metalloproteinase 12 Overexpression.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (COPD)--typically caused by bacterial or viral infection--is associated with poor prognosis and emphysema progression through unknown mechanisms. We aimed to elucidate the mechanisms responsible for the poor prognosis and emphysema progression associated with COPD exacerbation. METHODS: We established a mouse model mimicking acute human COPD exacerbation, wherein mice with elastase-induced emphysema were intranasally infected with Streptococcus pneumoniae. RESULTS: In mice with elastase-induced emphysema, infection with S. pneumoniae resulted in increased mortality, an increased number of inflammatory cells in bronchoalveolar lavage fluid (BALF), and increased matrix metalloproteinase 12 (MMP-12) production in the lungs, as well as enhanced emphysema progression. The increased MMP-12 production was mostly due to alveolar type II cells, alveolar macrophages, and lymphocytes that aggregated around vessels and bronchioles. Dexamethasone treatment suppressed the mortality rate and number of inflammatory cells in BALF but not emphysema progression, possibly owing to the failure of MMP-12 suppression in the lungs, whereas treatment with the MMP inhibitor ONO-4817 dramatically suppressed both mortality rate and emphysema progression. CONCLUSIONS: These results suggest that MMP-12 production during COPD exacerbation results in increased mortality and emphysema progression. Our study identifies MMP-12 as a target to prevent further aggravation of COPD.

Evaluation of cigarette smoke-induced emphysema in mice using quantitative micro-computed tomography.

Chronic cigarette smoke (CS) exposure provokes variable changes in the lungs, and emphysema is an important feature of chronic obstructive pulmonary disease. The usefulness of micro-computed tomography (CT) to assess emphysema in different mouse models has been investigated, but few studies evaluated the dynamic structural changes in a CS-induced emphysema mouse model. A novel micro-CT technique with respiratory and cardiac gating has resulted in high-quality images that enable processing for further quantitative and qualitative analyses. Adult female C57BL/6J mice were repeatedly exposed to mainstream CS, and micro-CT scans were performed at 0, 4, 12, and 20 wk. Emphysema was also histologically quantified at each time point. Air-exposed mice and mice treated with intratracheal elastase served as controls and comparisons, respectively. End-expiratory lung volume, corresponding to functional residual volume, was defined as the calculated volume at the phase of end-expiration, and it evaluated air trapping. The end-expiratory lung volumes of CS-exposed mice were significantly larger than those of air controls at 12 and 20 wk, which was in line with alveolar enlargement and destruction by histological quantification. However, CS exposure neither increased low attenuation volume nor decreased the average lung CT value at any time point, unlike the elastase-instilled emphysema model. CS-exposed mice had rather higher average lung CT values at 4 and 12 wk. This is the first study characterizing a CS-induced emphysema model on micro-CT over time in mice. Moreover, these findings extend our understanding of the distinct pathophysiology of CS-induced emphysema in mice.

Polymorphism of LRP5 gene and emphysema severity are associated with osteoporosis in Japanese patients with or at risk for COPD.

BACKGROUND AND OBJECTIVE: Osteoporosis is an important systemic comorbidity of chronic obstructive pulmonary disease (COPD). However, neither its mechanisms nor its risk factors have been fully elucidated. With regard to genetic factors, low-density lipoprotein receptor-related protein 5 (LRP5) A1330V is known to be associated with osteoporosis in the general population, but the influence of this polymorphism in COPD is unknown. The aim of this study was to investigate the potential risk factors of COPD-related bone loss and fracture. METHODS: Keio University and affiliated hospitals have enrolled an observational cohort to investigate the management of COPD comorbidities. To assess risk factors for osteopenia and osteoporosis, bone mineral density (BMD) of the hip and lumbar spine, presence of vertebral fracture, quantitative data on emphysema and airway wall on computed tomography, as well as LRP5 genotype were analysed in patients with or at risk for COPD (n = 270). RESULTS: The percentage of subjects with osteoporosis (T-score ≤ -2.5), osteopenia (T-score between -1 and -2.5) and a normal BMD (T-score ≥ -1) was 15.2%, 35.9% and 48.9%, respectively. T-score was significantly decreased in subjects with LRP5 TT genotype (n = 15) compared with that in those with CC/CT genotype (n = 255) (-1.83 vs. -0.98, P = 0.0167). On multivariate logistic regression analysis, female gender (odds ratio (OR) 10.4; P < 0.0001), severe emphysema (OR 2.3; P = 0.013) and LRP5 TT genotype (OR 3.7; P = 0.031) independently increased the risk of osteopenia/osteoporosis. CONCLUSIONS: This study confirmed the complex pathophysiology of COPD-related osteoporosis, including the influence of gender, clinical phenotype and genetic factors.

Immune reconstitution inflammatory syndrome due to Mycobacterium avium complex successfully followed up using 18 F-fluorodeoxyglucose positron emission tomography-computed tomography in a patient with human immunodeficiency virus infection: A case report.

BACKGROUND: In human immunodeficiency virus (HIV)-infected patients, immune reconstitution inflammatory syndrome (IRIS) due to nontuberculous mycobacteria (NTM) infection is one of the most difficult types of IRIS to manage. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been suggested as a useful tool for evaluating the inflammatory status of HIV-infected patients. We present the first case of Mycobacterium avium complex (MAC)-associated IRIS (MAC-IRIS) that was successfully followed up using 18F-FDG PET/CT. CASE PRESENTATION: A 44-year-old homosexual Japanese man was referred to our hospital with fever and dyspnea. He was diagnosed with Pneumocystis jiroveci pneumonia and found to be HIV positive. After the initiation of combined antiretroviral therapy (cART), the patient's mediastinal and bilateral hilar lymphadenopathy gradually enlarged, and bilateral infiltrates appeared in the upper lung fields. 18F-FDG PET/CT was performed five months after the initiation of cART and showed intense accumulation of fluorodeoxyglucose (FDG) corresponding to the lesions of infiltration as well as the mediastinal and bilateral hilar lymphadenopathy. A bronchial wash culture and pathology findings led to a diagnosis of MAC-IRIS. Anti-mycobacterial chemotherapy with rifampicin, ethambutol, clarithromycin, and levofloxacin was started. One year after the chemotherapy was initiated, there was a significant reduction in FDG uptake in the area of the lesions except in the mediastinal lymph node. This implied incomplete resolution of the MAC-IRIS-related inflammation. Anti-mycobacterial chemotherapy was continued because of the residual lesion. To date, the patient has not experienced a recurrence of MAC-IRIS, a period of nine months. CONCLUSION: We present a case of MAC-IRIS in an HIV-infected patient whose disease activity was successfully followed up using 18F-FDG PET/CT. Our data suggest that 18F-FDG PET/CT is useful for evaluating the disease activity of NTM-IRIS and assessing the appropriate duration of anti-mycobacterial chemotherapy for NTM-IRIS in HIV-infected patients.

Analysis of comorbid factors that increase the COPD assessment test scores.

BACKGROUND: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD. COPD patients have a variety of comorbidities, but little is known about their impact on quality of life. This study was designed to investigate comorbid factors that may contribute to high CAT scores. METHODS: An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects. Health status was assessed by the CAT, the St. Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health. Comorbidities were identified based on patients' reports, physicians' records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale. Dual X-ray absorptiometry measurements of bone mineral density were performed. RESULTS: The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36. The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients. CONCLUSIONS: Symptomatic COPD patients have a high prevalence of comorbidities. A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized. TRIAL REGISTRATION: Clinical trial registered with UMIN (UMIN000003470).

[Early diagnosis of metastatic spinal tumor is a key for effective palliative radiotherapy in patients with lung cancer].

Patients with metastatic spinal tumor are the largest in number among the patients with bone tumor. It causes a severe bone pain, pathological fracture and spinal cord compression. Thus it harshly hampers patient's quality of life. We report 3 patients with lung cancer whose initial manifestation was metastatic spinal tumor. We treated the 3 patients with palliative radiotherapy and medication. Although the severe pain has improved on a numerical rating scale(NRS), but performance status(PS)and activity of daily living(ADL)of the 3 patients got worse because the disease was progressed and complicated. Generally, PS of cancer patients found by bone matastasis is low. However, it is difficult to take an effective treatment, which leads to ADL improvement. There are many choices for treating metastatic bone tumors including pain control, bisphosphonate administration, radiation therapy, strontium radiotherapy, bone cement, palliative surgery and orthotics. In addition, a development of molecular target drugs, such as Denosmab, is expected as future modality of palliative care. In conclusion, we should detect a bone metastasis in the patient with lung cancer as early as possible, and select an appropriate treatment in collaboration with each specialist for achieving the ADL and PS improvement.

Effects of long-term cigarette smoke exposure on bone metabolism, structure, and quality in a mouse model of emphysema.

Smoking is a common risk factor for both chronic obstructive pulmonary disease (COPD) and osteoporosis. In patients with COPD, severe emphysema is a risk factor for vertebral fracture; however, the effects of smoking or emphysema on bone health remain largely unknown. We report bone deterioration in a mouse model of emphysema induced by nose-only cigarette smoke (CS) exposure. Unexpectedly, short-term exposure for 4-weeks decreased bone turnover and increased bone volume in mice. However, prolonged exposure for 20- and 40-weeks reversed the effects from suppression to promotion of bone resorption. This long-term CS exposure increased osteoclast number and impaired bone growth, while it increased bone volume. Strikingly, long-term CS exposure deteriorated bone quality of the lumbar vertebrae as illustrated by disorientation of collagen fibers and the biological apatite c-axis. This animal model may provide a better understanding of the mechanisms underlying the deterioration of bone quality in pulmonary emphysema caused by smoking.

Impact of mild exacerbation on COPD symptoms in a Japanese cohort.

BACKGROUND: Patients with COPD might not report mild exacerbation. The frequency, risk factors, and impact of mild exacerbation on COPD status are unknown. OBJECTIVES: The present study was performed to compare features between mild exacerbation and moderate or severe exacerbation in Japanese patients with COPD. PATIENTS AND METHODS: An observational COPD cohort was designed at Keio University and affiliated hospitals to prospectively investigate the management of COPD comorbidities. This study analyzes data only from patients with COPD who had completed annual examinations and questionnaires over a period of 2 years (n=311). RESULTS: Among 59 patients with mild exacerbations during the first year, 32.2% also experienced only mild exacerbations in the second year. Among 60 patients with moderate or severe exacerbations during the first year, 40% also had the same severity of exacerbation during the second year. Findings of the COPD assessment test and the symptom component of the St George's Respiratory Questionnaire at steady state were worse in patients with mild exacerbations than in those who were exacerbation free during the 2-year study period, although the severity of the ratio of predicted forced expiratory volume in 1 second did not differ between them. Severe airflow limitation (the ratio of predicted forced expiratory volume in 1 second <50%) and experience of mild exacerbations independently advanced the likelihood of an elevated COPD assessment test score to ≥2 per year. CONCLUSION: The severity of COPD exacerbation seemed to be temporally stable over 2 years, and even mild exacerbations adversely impacted the health-related quality of life of patients with COPD.

Obstructive sleep apnea syndrome should be considered as a cause of nocturia in younger patients without other voiding symptoms.

INTRODUCTION: This study aimed to evaluate urination frequency among patients with obstructive sleep apnea syndrome (OSAS) and the effect of continuous positive airway pressure (CPAP) treatment. METHODS: We evaluated 138 men with moderate-to-severe OSAS by using polysomnography. Urination status was assessed at baseline and three months using the International Prostate Symptom Score and Overactive Bladder Symptom Score. Nocturia was defined as ≥2 nighttime urinations and patients were classified into Group A (<50 years old with nocturia), Group B (≥50 years old with nocturia), and Group C (patients without nocturia). OSAS severity and other urinary symptoms were also evaluated. RESULTS: Patients with nocturia exhibited more severe OSAS, compared to patients without nocturia (apnea-hypopnea index [AHI]: 52.0 vs. 44.7; p=0.021). Group A had the worst AHI, but did not have additional voiding symptoms, compared to Group B (p<0.001). The number of urinations was significantly correlated with OSAS severity in <50-year-old patients (p=0.013). CPAP reduced the number of urinations in Group A (75% of patients) and Group B (90% of patients). Patients with and without improved nocturia exhibited significant differences in their baseline OSAS severity (AHI: 53.7 vs. 37.3; p=0.042). CONCLUSIONS: OSAS severity was associated with the number of urinations in <50-year-old patients. CPAP decreased the nocturia frequency in 85% of patients with nocturia and was most effective in patients with severe AHI. However, additional studies should evaluate voiding volume in order to elucidate the mechanism of nocturia in patients with OSAS.

Determinants of chronic obstructive pulmonary disease severity in the late-elderly differ from those in younger patients.

BACKGROUND: Although the age range of chronic obstructive pulmonary disease (COPD) patients is broad, few studies have focused on the effects of age on disease characteristics. METHODS: Keio University and affiliated hospitals established an observational COPD cohort. Patients were assessed using high resolution computed tomography (CT) to quantify emphysema, health status using the COPD assessment test (CAT) and the St. George's Respiratory Questionnaire (SGRQ), spirometry, echocardiogram, dual X-ray absorption of bone, biomarkers and comorbid diagnoses. We examined the characteristics of COPD patients aged 75 and over compared with patients below 75. RESULTS: A total of 443 patients comprising 252 patients aged <75 years and 191 patients aged ≥75 years, were enrolled. Emphysematous changes on CT and prevalence of possible pulmonary hypertension were greater in late-elderly patients. The slope of the relationship between CT emphysema densitometry score and forced expiratory volume in 1 s was significantly less steep in the late-elderly than the younger patients (p = 0.002). CAT and total SGRQ scores and the frequency of long-term oxygen therapy were significantly higher in the late-elderly with moderate airflow obstruction compared to those of the younger in the same grade, although the opposite was seen in late-elderly patients with very severe airflow obstruction. Hypertension, aortic aneurysm, prostatic hypertrophy, anemia, and cataract are more prevalent in late-elderly patients. CONCLUSIONS: Elderly COPD patients show a varied age-related pattern of disease that warrants specific attention in clinical practice above and beyond assessment of airflow limitation. Trial registration Clinical trial registered with the University Hospital Medical Information Network (UMIN000003470, April 10, 2010).

The reasons for triple therapy in stable COPD patients in Japanese clinical practice.

BACKGROUND: Triple combination therapy involving long-acting muscarinic antagonists long-acting ß2 agonists, and inhaled corticosteroids has recently become an option for maintenance treatment of COPD. Some add-on clinical trials have reported the benefits of these combinations. However, the process to step up to triple therapy varies for individual cases. METHODS: Keio University and affiliated hospitals conducted an observational COPD cohort study, recruiting patients diagnosed as having COPD by pulmonary physicians and those referred for investigation of possible COPD. Their prescription history and clinical course were retrospectively analyzed based on the physicians' medical records and patient questionnaires. This study was registered with UMIN (UMIN000003470, April 10, 2010). RESULTS: A total of 95 of the 445 COPD patients (21%) were treated with inhaled corticosteroids/long-acting ß2 agonists/long-acting muscarinic antagonists as maintenance therapy, including 12 in COPD Grade I, 31 in Grade II, 38 in Grade III, and 14 in Grade IV, based on the Global Initiative for Chronic Obstructive Lung Disease spirometric grading. For more than half of the patients on triple therapy, the treatment had been intensified due to unsatisfactory improvement of symptoms, and 32% were treated with triple therapy due to comorbid asthma. In contrast, there were COPD patients whose therapy was maintained after starting with triple therapy because of their serious conditions or concurrent exacerbation at diagnosis (8%). CONCLUSION: Triple therapy was often prescribed in the real-life management of COPD, even in patients whose airflow limitation was not severe. To better control symptoms was the major reason for choosing triple therapy, regardless of the severity of COPD, in Japan.

Dry pleurisy complicating solitary pulmonary nodules caused by Mycobacterium avium: a case report.

INTRODUCTION: Mycobacterium avium complex (MAC) lung disease presenting as a solitary pulmonary nodule (MAC-SPN) is often asymptomatic, is more common in middle to old age, and mimics lung cancer or tuberculoma. We report herein a case of MAC-SPN in an immunocompetent young adult patient, presenting with persistent chest pain and a subacutely progressive nodule with high intense (18)F-fluorodeoxyglucose uptake. Histological examination of resected specimens revealed pleurisy, which is a rare finding of MAC-SPN. CASE PRESENTATION: A 36-year-old Japanese male presented with chest pain and a subacutely progressive pulmonary nodule. Positron emission tomography-computed tomography showed high intense (18)F-fluorodeoxyglucose uptake in the nodule. Owing to his continuous chest pain and subacutely progressive nodules, wedge resection was performed using video-assisted thoracoscopic surgery. Histological examination revealed an epithelioid granuloma and pleurisy, and the lung tissue culture was positive for mycobacteria identified as M. avium. CONCLUSION: This is the first report of MAC-SPN occurring with persistent chest pain, suggesting that MAC should be considered in the differential diagnosis of a solitary pulmonary nodule, even for patients who experience persistent chest pain. As in the present case, surgical resection with video-assisted thoracoscopic surgery is a reasonable approach to the diagnosis and treatment of MAC-SPN with possible malignancy, especially as MAC can be diagnosed using resected lung tissue culture with histological confirmation.

Tuberous sclerosis diagnosed by incidental computed tomography findings of multifocal micronodular pneumocyte hyperplasia: a case report.

INTRODUCTION: The majority of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis complex is diagnosed with the classical clinical triad of seizures, mental retardation, and skin lesions. We report a rare case of tuberous sclerosis complex with no classical clinical findings, which was diagnosed through incidental computed tomography findings of multiple nodular lesions of multifocal micronodular pneumocyte hyperplasia. CASE PRESENTATION: A chest computed tomography scan of a 51-year-old Japanese woman showed multiple nodular ground-glass opacities that were not seen on chest X-ray. Video-assisted thoracoscopic surgery was performed. A histological examination demonstrated type II pneumocyte hyperplasia with thickened fibrotic alveolar septa, which was consistent with multifocal micronodular pneumocyte hyperplasia. Brain magnetic resonance imaging displayed multiple cortical tubers, and abdominal computed tomography showed bilateral renal angiomyolipoma. Our patient was finally diagnosed as having tuberous sclerosis complex with multifocal micronodular pneumocyte hyperplasia, although she had no episodes of epilepsy, no skin lesions, and no family history. CONCLUSIONS: Multifocal micronodular pneumocyte hyperplasia with latent tuberous sclerosis complex should be considered in the differential diagnosis of multiple ground-glass opacities.