A case of diffuse aspiration bronchiolitis due to oesophageal stenosis after radiation therapy.

A 66-year-old woman was hospitalized for recurrent pneumonia twice in 1 year. After treatment for pneumonia, chronic coughing, sputum and low-grade fever continued, so she was referred and admitted to our hospital for investigation. Chest computed tomography revealed a lung infiltrative shadow and diffuse centrilobular micronodules. Histological findings from transbronchial lung biopsy showed chronic inflammation and giant cells in the bronchiole. These findings were compatible with diffuse aspiration bronchiolitis (DAB), which is characterized by chronic inflammation of the bronchioles caused by recurrent aspiration of foreign bodies. Oesophagogastroduodenoscopy revealed stenosis of the oesophageal entrance, which was thought to be caused by radiation therapy for hypopharyngeal cancer 20 years before. Antibiotic treatment ameliorated the centrilobular nodule shadow. After discharge, there was no recurrence. This is the first case report of DAB resulting from oesophageal stenosis associated with hypopharyngeal cancer and will serve as an educational case.

Assessment of the rapid effect of dupilumab in two cases of severe asthma comorbid with recurrent eosinophilic chronic rhinosinusitis after endoscopic sinus surgery.

Dupilumab, a human monoclonal antibody against interleukin-4 (IL-4) and IL-13, has been approved for treating severe asthma and eosinophilic chronic rhinosinusitis (ECRS). Patients with ECRS are often candidates for endoscopic sinus surgery (ESS). However, a considerable number of patients have recurrent ECRS. ECRS is an important factor influencing asthma control. Here, we present two cases of severe asthma and recurrent ECRS after ESS. Although they had been treated with inhaled corticosteroids and a long-acting ß2-agonist, they experienced frequent asthma exacerbations. Laboratory examinations revealed increased serum eosinophils and immunoglobulin E (IgE). Furthermore, the Asthma Control Test (ACT) score and forced expiratory volume in 1 sec (FEV1) were indicative of airway obstruction. After treatment with dupilumab, asthma, rhinosinusitis symptoms, and pulmonary function improved remarkably. Dupilumab therapy improved quality of life in these patients with severe asthma and ECRS.

Remarkable response of non-small cell lung cancer to nintedanib treatment in a patient with idiopathic pulmonary fibrosis.

Nintedanib is a multi-target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82-year-old man with non-small cell lung carcinoma complicated by IPF who was treated with nintedanib. High-resolution computed tomography (HRCT) showed a subpleural basal-predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6-min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non-small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF.

The impact of obstructive sleep apnea and nasal CPAP on circulating adiponectin levels.

PURPOSE: Although obstructive sleep apnea syndrome (OSAS) is known to be an important risk factor for cardiovascular diseases, the mechanism behind this association has not been fully elucidated. Transendothelial migration of monocytes mediated by adhesion molecules is a crucial step in the pathogenesis of atherosclerosis. We investigated the effect of hypoxic stress on plasma adiponectin and tumor necrosis factor-α (TNF-α) levels and whether adiponectin and TNF-α modulate adhesion molecules in patients with OSAS. METHODS: In 22 patients, plasma adiponectin and TNF-α levels and serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) were determined early in the morning after polysomnography and after nasal continuous positive airway pressure (nCPAP) treatment. RESULTS: Plasma adiponectin levels were inversely correlated with the apnea-hypopnea index (AHI) (r = -0.582, p < 0.005) and % time in SpO2 <90 % (r = -0.539, p < 0.01) but not with the body mass index (BMI). TNF-α levels were positively correlated with the AHI (r = 0.462, p < 0.05) and BMI (r = 0.452, p < 0.05). Serum sICAM-1 levels were inversely correlated with plasma adiponectin levels (r = -0.476, p < 0.05) but not with TNF-α levels. Although plasma TNF-α levels decreased after overnight nCPAP treatment (p < 0.05), plasma adiponectin levels increased after long-term nCPAP (3 months) treatment (p < 0.02) in ten patients. CONCLUSIONS: Our findings suggest that reduced adiponectin and elevated TNF-α levels in plasma are associated with OSAS-induced hypoxic stress. Decreased adiponectin levels are associated with sICAM-1 levels.

Distribution of bone mineral content is associated with body weight and exercise capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND: Although low bone mineral density is highly prevalent in patients with chronic obstructive pulmonary disease (COPD), the distribution of the reduced bone mass has not been fully elucidated. OBJECTIVES: To determine regional bone mass loss in patients with COPD and investigate whether the change in distribution may be associated with body weight loss and functional capacity. METHODS: Body mass index (BMI) was assessed, and height squared indices were derived for the bone mineral content index (BMCI) of the arms, legs and trunk by dual-energy X-ray absorptiometry in 45 male patients with COPD and 12 age- and sex-matched control subjects. Pulmonary function tests were performed, and maximal oxygen uptake (VO2max) was measured. RESULTS: The BMCI was lower in the total bone, legs and trunk of patients with COPD than in control subjects, although the BMCI in the arms was similar between the groups. BMI correlated significantly with the BMCI in all 3 segments. Bone mineral content (BMC) in the trunk, expressed as a percentage of total BMC (BMC trunk/total BMC), correlated significantly with BMI. The BMCI in the trunk was closely related with VO2max but not with airflow limitation. CONCLUSIONS: There was a regional difference in BMC reduction, but a predominant reduction of bone mass in the trunk was not associated with the severity of airflow limitation but rather with body weight loss and exercise intolerance. These data suggest that body weight loss and exercise intolerance are important risk factors for vertebral fracture in patients with COPD.

[Classification and the staging of chronic obstructive pulmonary disease and assessment of determinant factors of prognosis].

Classification of the stage of COPD is based on flow limitation such as post-bronchodilator FEV1. GOLD guideline and JRS guideline, and other guidelines are almost similar standards. But prognosis is not determined only FEV1. COPD is recognized not only lung disease but also systemic disease. This is a reason why the multidimensional estimation is needed. Prognostic factors are proposed for many studies, for example exercise capacity (6MWD, VO2max), BMI, dyspnea score, BODE index, and so on. BODE index is a multidimensional index, consist of 4 categories such as BMI, airflow obstruction, dyspnea, and exercise capacity. High BODE index means poor prognosis. Exacerbation frequency and fibronectin/CRP ratio proposed as prognostic factors too.

Production of inflammatory mediators by monocytes in patients with obstructive sleep apnea syndrome.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is known to be a risk factor of cardiovascular events. However, the precise mechanism linking the two has not been fully elucidated. OBJECTIVE: The aim of this study was to investigate the effect of hypoxic stress on the production of tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9) by monocytes. METHODS: Thirty-three OSAS patients and 13 healthy control subjects were enrolled. The OSAS patients were classified as mild-to-moderate (13) and severe (20). Venous blood samples were collected before and after sleep as well as after long-term nasal continuous positive airway pressure (CPAP) treatment for the purpose of isolation of monocytes. Peripheral blood monocytes were isolated using standard methods. Monocytes were cultured under lipopolysaccharide stimulation for 24 hours, and TNF-alpha, MCP-1, and MMP-9 in the culture supernatants were determined by ELISA. RESULTS: In severe patients, the TNF-alpha production by monocytes was significantly elevated as compared to that before sleep (p<0.01). In all OSAS patients, the TNF-alpha production after sleep was significantly correlated with AHI (p<0.01), ODI (p<0.01) and % time in SpO(2)<90% (p<0.05), and inversely correlated with the lowest SpO(2) (p<0.01). The production of MCP-1 and MMP-9 by monocytes was significantly elevated compared to that before sleep in severe patients (p<0.05). The production of these mediators by monocytes was significantly decreased after long-term nasal CPAP treatment (p<0.05). CONCLUSION: These results indicate that OSAS-induced hypoxic stress activates the production of inflammatory mediators by monocytes.

Nocturnal hypoxic stress activates invasive ability of monocytes in patients with obstructive sleep apnoea syndrome.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea syndrome (OSAS) is known to be a risk factor for cardiovascular events. However, the precise mechanism has not been fully elucidated. OSAS-induced hypoxic stress may promote the production of inflammatory cytokines and chemokines by monocytes, which has a crucial role in the development of atherosclerosis. In addition, adhesion to the vascular endothelium and transendothelial migration of monocytes are considered to induce atherosclerosis. The aim of this study was to investigate the effects of hypoxic stress on the invasive ability of monocytes in OSAS. METHODS: Twenty-one male patients with OSAS and 17 healthy male control subjects, who were matched for age and BMI, were enrolled. Venous blood samples were collected before and after sleep, and also after CPAP titration, for the purpose of monocyte isolation. The invasive ability of monocytes was evaluated by counting the number of invading cells using a BD BioCoat Matrigel Invasion Chamber. RESULTS: The number of cells, which represents the invasive ability of monocytes, was significantly higher in patients with OSAS compared with control subjects, in the early morning (P < 0.001). In patients with OSAS, invasive ability in the early morning after sleep was significantly elevated as compared with that before sleep (P < 0.001), and was positively correlated with the oxygen desaturation index (P < 0.05). CPAP titration led to a decrease in the invasive ability (P < 0.001). CONCLUSIONS: These results indicate that OSAS-induced hypoxic stress activates the invasive ability of monocytes, and that the occurrence of this phenomenon during sleep may contribute to the development of atherosclerosis in OSAS.

Effect of serum leptin levels on hypercapnic ventilatory response in obstructive sleep apnea.

BACKGROUND: Leptin levels have been reported to be higher in patients with obstructive sleep apnea (OSA) than in control subjects with matching age and body mass index (BMI). Although animal studies have shown that leptin augments hypercapnic ventilatory response (HCVR), the effect of leptin on HCVR has not been clarified in OSA. OBJECTIVES: To investigate whether leptin could augment HCVR during wakefulness in patients with OSA. METHODS: Of 134 consecutive patients with OSA, 13 eucapnic and 16 hypercapnic patients with OSA, and 12 control subjects matched for sex, age, and BMI were selected. Fasting serum leptin levels were collected, and HCVR during wakefulness assessed by the slope between minute ventilation and end-tidal PCO(2). RESULTS: There was a significant positive relationship between serum leptin levels and HCVR in the group including control subjects and eucapnic patients with OSA (r = 0.42, p < 0.05). Subgroup analyses suggest that serum leptin levels and HCVR were significantly higher in eucapnic patients with OSA than in control subjects. On the other hand, hypercapnic patients had lower HCVR than eucapnic patients (p < 0.05), whereas serum leptin levels were similar between the two OSA subgroups. CONCLUSION: Leptin levels and HCVR are correlated as long as the eucapnic condition is maintained. We speculate that a stimulating effect of leptin on HCVR may be masked by the hypoventilation state.

Elevated circulating plasma adiponectin in underweight patients with COPD.

BACKGROUND: Adiponectin is an adipose tissue-derived specific protein that has antiinflammatory as well as anti-atherosclerotic effects. In the United States, many patients with COPD are obese and die of cardiovascular diseases. However, in Japan, patients with COPD are frequently cachexic and die of respiratory failure. This study was designed to investigate the role of adiponectin in these differences in characteristics of COPD. METHODS: We enrolled normal-weight and underweight male patients with COPD (n = 31; age, 71 +/- 1 years; body mass index [BMI], 20.1 +/- 0.6 kg/m(2)) and age-matched, healthy, male, control subjects (n = 12). The adiponectin levels were measured by enzyme-linked immunosorbent assay. Correlation of adiponectin levels with pulmonary function and serum levels of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin-6) were estimated. RESULTS: Adiponectin levels in patients with COPD were significantly higher than those in control subjects (p<0.01) and inversely correlated with BMI (r = - 0.55, p<0.01). Even in the normal-weight patients with COPD, adiponectin levels were significantly higher than those in control subjects (p<0.01). Adiponectin levels in patients with COPD significantly correlated with percentage of predicted residual volume (r = 0.40, p<0.05). In patients with TNF-alpha levels > 5 pg/mL, there was a significant correlation between plasma adiponectin and serum TNF-alpha levels (r = 0.68, p<0.05). CONCLUSIONS: Plasma adiponectin levels in patients with COPD were elevated and correlated with body weight loss, hyperinflation, and systemic inflammation. Increased adiponectin may reduce cardiovascular events in underweight patients with COPD.

Evidence for activation of nuclear factor kappaB in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a risk factor for atherosclerosis, and atherosclerosis evolves from activation of the inflammatory cascade. We propose that activation of the nuclear factor kappaB (NF-kappaB), a key transcription factor in the inflammatory cascade, occurs in OSA. Nine age-matched, nonsmoking, and non-hypertensive men with OSA symptoms and seven similar healthy subjects were recruited for standard polysomnography followed by the collection of blood samples for monocyte nuclear p65 concentrations (OSA and healthy groups). In the OSA group, p65 and of monocyte production of tumor necrosis factor alpha (TNF-alpha) were measured at the same time and after the next night of continuous positive airway pressure (CPAP). p65 Concentrations in the OSA group were significantly higher than in the control group [median, 0.037 ng/microl (interquartile range, 0.034 to 0.051) vs 0.019 ng/microl (interquartile range, 0.013 to 0.032); p = 0.008], and in the OSA group were significantly correlated with apnea-hypopnea index and time spent below an oxygen saturation of 90% (r = 0.77 and 0.88, respectively) after adjustment for age and BMI. One night of CPAP resulted in a reduction in p65 [to 0.020 ng/mul (interquartile range, 0.010 to 0.036), p = 0.04] and levels of TNF-alpha production in cultured monocytes [16.26 (interquartile range, 7.75 to 24.85) to 7.59 ng/ml (interquartile range, 5.19 to 12.95), p = 0.01]. NF-kappaB activation occurs with sleep-disordered breathing. Such activation of NF-kappaB may contribute to the pathogenesis of atherosclerosis in OSA patients.

[A familial case of summer-type hypersensitivity pneumonitis possibly associated with bird breeder's lung diagnosed by bronchoalveolar lavage fluid].

Case 1: A 32-year-old woman had cough and exertional dyspnea in August 2002, and chest computed tomographic scan revealed diffuse centrilobular nodules. Bronchoalveolar lavage fluid (BALF) showed a high proportion of lymphocytes with a decreased CD 4/CD 8 ratio. Transbronchial lung biopsy (TBLB) specimens showed alveolitis. Summer-type hypersensitivity pneumonitis was diagnosed on the basis of positive findings of anti-Trichosporon antibodies in the serum. Case 2: A 64-year-old man, the father of Case 1, also had cough and exertional dyspnea in August 2003. He had been in close contact with pigeons. Chest computed tomographic scan revealed bilateral map-like ground-glass opacities predominantly in the upper lobes. BALF showed a high proportion of lymphocytes with a decreased CD 4/CD 8 ratio. TBLB specimens showed alveolitis, granuloma and Masson body in the air spaces. Specific IgG and IgA antibodies against Trichosporon asahii, IgA antibodies against Trichosporon mucoides, and IgA antibodies against pigeon dropping extracts were found only in the BALF but not in the serum. Although a positive finding of returning-home provocation test was definitive in diagnosing summer-type hypersensitivity pneumonitis, he was also suspected of having bird fancier's lung.

Tuberculous peritonitis developing during chemotherapy for pulmonary and intestinal tuberculosis: a case report.

This report is of a case of tuberculous peritonitis that developed during antituberculous chemotherapy. A 54-year-old man had been diagnosed as all-drug susceptible pulmonary and intestinal tuberculosis, and treatment with isoniazid, ethambutol and rifampicin had been initiated. About 5 months later, while still undergoing therapy, a large amount of ascites developed. A diagnostic laparoscopy was performed but due to the adhesion between the greater omentum and the parietal peritoneum, intestinal perforation occurred. An emergency operation was performed and the diagnosis of tuberculous peritonitis was confirmed. There are few reports of abdominal tuberculosis developing during antituberculous chemotherapy. In this case a paradoxical response may have been involved in the pathogenesis.

Elevated plasma ghrelin level in underweight patients with chronic obstructive pulmonary disease.

Ghrelin, a novel growth hormone-releasing peptide, has been shown to cause a positive energy balance by reducing fat use and stimulating food intake. This study investigated whether plasma ghrelin is associated with clinical parameters in patients with chronic obstructive pulmonary disease. Plasma ghrelin was measured in 50 patients and 13 control subjects, together with anabolic and catabolic factors. Patients were divided into two groups based on body mass index: underweight patients (n = 26) or normal weight patients (n = 24). Plasma ghrelin was significantly higher in underweight patients than in normal weight patients and healthy control subjects. Circulating tumor necrosis factor-alpha, interleukin-6, and norepinephrine were significantly higher in underweight patients than in normal weight patients. Plasma ghrelin correlated negatively with body mass index and correlated positively with catabolic factors such as tumor necrosis factor-alpha and norepinephrine. In addition, plasma ghrelin correlated positively with percent predicted residual volume and residual volume-to-total lung capacity ratio. In conclusion, plasma ghrelin was elevated in underweight patients with chronic obstructive pulmonary disease, and the level was associated with a cachectic state and abnormality of pulmonary function.

[A case of pleural malignant lymphoma associated with chronic tuberculous pyothorax].

We report a case of pleural malignant lymphoma associated with chronic tuberculous pyothorax. A 67-year-old male was hospitalized because of left lateral chest swelling and pain. He had suffered from pulmonary tuberculosis at the age of six and tuberculous pleurisy at the age of 24. We made a histologic diagnosis of malignant lymphoma diffuse large B-cell type. He was medicated THP-COP (THP, CY, VCR, PSL) therapy and his chest pain and swelling has improved gradually. From the view point of molecular biology, we detected Epstein-Barr virus (EBV) infection in the pyothorax wall. In conclusion, we should be more careful about medical examination in patients with EBV positive tuberculous pyothorax considering the complication of malignant lymphoma.