Successful treatment of chronic lower respiratory tract infection by macrolide administration in a patient with intralobar pulmonary sequestration and primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic disease associated with abnormalities in ciliary structure and function. Although recurrent respiratory infection associated with ciliary dysfunction is a common clinical feature, there is no standardized treatment or management of respiratory infection in PCD patients. Here, we report that respiratory infection with PCD and intralobar sequestration (ILS) were treated successfully with clarithromycin before the surgical resection of ILS. A 15-year-old non-smoking Japanese woman was admitted for productive cough and dyspnea on exertion. Chest CT scan on admission showed complex cystic LESIONS with air-fluid level in the right lower lobe, and diffuse nodular shadows in the whole lobe of the lung. On flexible bronchoscopy examination, sputum and bronchiolar fluid cultures revealed Staphylococcus aureus (S. aureus). An electron microscopic examination of the cilia showed inner dynein arm deficiency. Administration of clarithromycin improved the lower respiratory tract infection associated with S. aureus. CT angiography after clarithromycin treatment demonstrated an aberrant systemic artery arising from the celiac trunk and supplying the cystic mass lesions that were incorporated into the normal pulmonary parenchyma without their own pleural covering. Based on these results, the patient was diagnosed with PCD and ILS. Because of the clarithromycin treatment, resection of the ILS was performed safely without any complications. Although further observation of clarithromycin treatment is needed, we believe that clarithromycin may be considered one of the agents for treating PCD.

Ghrelin ameliorates bleomycin-induced acute lung injury by protecting alveolar epithelial cells and suppressing lung inflammation.

Acute lung injury is a critical illness syndrome consisting of acute respiratory failure with bilateral pulmonary infiltrates that is refractory to current therapies. Acute lung injury is characterized by injury of the alveolar capillary barrier, neutrophil accumulation, and induction of pro-inflammatory cytokines followed by devastating lung fibrosis. Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation, and promotes cell survival. We investigated the pharmacological potential of ghrelin in the treatment of acute lung injury by using a bleomycin-induced acute lung injury model in mice. Ghrelin or saline was given to mice daily starting 1 day after bleomycin administration. Ghrelin-treated mice showed a definitively higher survival rate than saline-treated ones. They also had smaller reductions in body weight and food intake. The amelioration of neutrophil alveolar infiltration, pulmonary vascular permeability, induction of pro-inflammatory cytokines, and subsequent lung fibrosis were notable in ghrelin-treated mice. Additionally, ghrelin administration reduced the injury-induced apoptosis of alveolar epithelial cells. Our results indicate that ghrelin administration exerts a protective effect against acute lung injury by protecting the alveolar epithelial cells and regulating lung inflammation, and highlight ghrelin as a promising therapeutic agent for the management of this intractable disease.

[A case of diffuse alveolar hemorrhage occurring during the course of rheumatoid arthritis].

A 70-year-old woman, who underwent treatment with prednisolone and methotrexate for rheumatoid arthritis, was admitted to our hospital due to rapidly progressive dyspnea. A chest CT scan showed diffuse ground-glass opacities and reticulonodular shadows in both lungs. Intubation was performed due to severe hypoxia. The color of the bronchoalveolar lavage, using three sequential aliquots, became progressively more reddish, suggesting alveolar hemorrhage. Based on this, we made a diagnosis of diffuse alveolar hemorrhage. To the best of our knowledge, few studies have reported cases of diffuse alveolar hemorrhage associated with rheumatoid arthritis as an underlying disease. We consider that diffuse alveolar hemorrhage may occur as a complication of rheumatoid arthritis.

[Pulmonary Langerhans cell histiocytosis in identical twins].

Case 1 was a 22-year-old younger sister of identical twins who had smoked 10 cigarettes per day for 4 years since she was 18. She was admitted to our hospital due to dyspnea on exertion, dry cough and bilateral diffuse reticulonodular infiltrates on chest computed tomography (CT). Histological findings of transbronchial lung biopsy demonstrated nodular lesions consisting of spindle-shaped mononuclear cells. Immunohistochemical studies revealed that the cytoplasm of these mononuclear cells showed positive reactions to CD1a. Based on these findings, she was given a diagnosis of pulmonary Langerhans cell histiocytosis (LCH). She reduced the number of cigarettes smoked to 1 cigarette per week. After 6 months, her respiratory symptoms and radiographic abnormalities had improved. Case 2 was the elder twin sister of case 1. She had smoked 5 cigarettes per day for 4 years since she was 18. She presented no respiratory symptoms. However, as the diagnosis in case 1 was LCH, a chest CT was taken which revealed 3 small nodular lesions. After six months, there were no significant changes on chest CT. At the time of writing, she is 23-years-old and continues to smoke, however, has no respiratory symptoms.

[A case of pulmonary epithelioid hemangioendothelioma that required differentiation from malignant mesothelioma].

A 77-year-old woman presented with a 3-month history of right chest pain and a low-grade fever. Right pleural effusion had been detected at another hospital. Her chest CT scan revealed right pleural effusion, right pleural thickening, and bilateral multiple lung nodules. No specific findings were obtained from an examination of the pleural effusion. Thoracoscopic pleural and lung biopsies were conducted. Histologically, the tumor had an infiltrative growth pattern in the fibrously-thickened parietal pleura, visceral pleura, and lung parenchyma. The tumor was composed of epithelioid and spindle cells, and in some sections, the tumor cells had intracytoplasmic vacuoles, and had formed an immature vascular lumen. Proliferation in a papillary fashion in the alveolar spaces and vascular involvement of tumor were also seen. Immunohistochemically, the tumor cells were positive for factor VIII-related antigen, CD31, and CD34, and negative for calretinin and WT-1. The tumor was therefore diagnosed as pulmonary epithelioid hemangioendothelioma (PEH), which is a rare, low-to-moderate grade vascular tumor of the lung. This disease should be included in the differential diagnosis together with malignant pleural mesothelioma, in cases demonstrating unusual pleural thickening.

[A case of Hodgkin's lymphoma in a patient with sarcoidosis].

A 61-year-old woman was admitted to our hospital for examination of an abnormal shadow on her chest X-ray film taken in October 2006. Chest CT film taken in November 2006 revealed lymphadenopathy in the left side of the neck, as well as in the supraclavicular, axillary, mediastinal, and hilar areas, as well as around the pancreas. Diffuse small nodules were seen along the bronchovascular bundles and interlobular pleura. Bronchoscopic examination revealed lymphocyte accumulation and increased CD4/8 ratio in bronchoalveolar lavage fluid. Based on noncaseating epithelioid cell granulomas seen in transbronchial lung biopsy, we diagnosed having sarcoidosis. In April 2008, she complained of abdominal discomfort and a skin lesion. New lymphadenopathy was palpated on the right side of the neck and the left axillary region. On a chest X-ray film and chest CT film, multiple swollen lymph nodes which became even more swollen than those in November 2006 were observed. She received surgical resection of the neck lymph nodes and a pathological diagnosis of Hodgkin's lymphoma was established. This was a rare case of sarcoidosis-lymphoma syndrome.

Ghrelin and its therapeutic potential for cachectic patients.

The discovery of ghrelin has resulted in the development of approaches to appetite, enabling a better understanding of the mechanisms regulating appetite through molecular analyses. Ghrelin is a 28-amino acid peptide that was isolated from the stomach only a decade ago, and has recently been investigated as a potential therapeutic endogenous agent. This peptide increases appetite, adjusts energy balance, suppresses inflammation, and enhances the release of growth hormone from the pituitary gland. Although many bioactive substances such as peptide YY, leptin, adiponectin and obestatin are involved in appetite control, ghrelin is the only known peptide to signal starvation information from a peripheral organ to the central nervous system, contributing to an increase in appetite. Clinical trials have revealed the effectiveness of ghrelin in increasing lean body mass and activity in cachectic patients. As shown in clinical research on humans and basic research using animal models, cachexia often occurs in response to excess release of proinflammatory cytokines and induces further appetite loss, which aggravates the physiological status of underlying diseases. Ghrelin functions as a protector against the vicious cycle of the cachectic paradigm through orexigenic, anabolic and anti-inflammatory effects, so administration of ghrelin may be able to improve quality of life in cachectic patients. We show here a significant role of ghrelin in the pathophysiology of cachectic diseases and the possibility of clinical applications.

Effect of octanoic acid-rich formula on plasma ghrelin levels in cachectic patients with chronic respiratory disease.

BACKGROUND: For cachectic patients with chronic respiratory disease (CRD), conventional enteral nutrition formula is an optional treatment to maintain energy balance. The molecular mechanisms by which enteral nutrition formula controls appetite and weight remain unknown. We examined whether enteral nutrition formula rich in octanoic acids would increase plasma levels of ghrelin, an appetite-stimulating hormone produced in the stomach, in cachectic patients with CRD. METHODS: Plasma ghrelin profiles in cachectic patients with CRD were assessed and compared with those in age- and sex-matched controls. Plasma levels of acyl-ghrelin, an active ghrelin modified by octanoic acids, and desacyl-ghrelin were measured separately. We examined changes in 24-h plasma ghrelin profiles before and after single administration of the formula. We also evaluated the effects of 2-week administration of the formula on plasma ghrelin levels and nutritional status in patients. RESULTS: The ratio of acyl-ghrelin to desacyl-ghrelin in plasma was lower in patients than in controls. Single administration of the formula did not change plasma desacyl-ghrelin levels, but induced an increase in acyl-ghrelin levels. Two-week treatment with the formula was effective in increasing weight and acyl-ghrelin, along with improving nutritional status in patients. CONCLUSION: These results show that the formula contributes to increased weight, which may be associated with induction of acyl-ghrelin production in cachectic patients with CRD.

[Case of multiple pulmonary arteriovenous fistulas detected during treatment for severe pneumonia].

A 55-year-old woman who developed severe hypoxemia associated with severe pneumonia was admitted to our hospital for mechanical ventilation. She was treated with antibiotics under a diagnosis of mycoplasma pneumonia. Although most clinical findings improved, hypoxemia remained. As a chest CT film showed multiple nodules and an enhanced CT film revealed arterial filling in the nodules, multiple pulmonary arteriovenous fistulas (PAVFs) were considered to be an underlying cause of hypoxemia. Transcatheter coil embolization for 5 PAVFs, significantly ameliorated hypoxemia in the patient. PAVF is a congenital desease, and in many cases, is asymptomatic. Therefore, it was rare for PAVFs to be detected in a middle-aged patient with prolonged hypoxemia associated with pneumonia.

[A case of lung cancer with hyperthyroidism].

We here report a case of metastasis from lung cancer to the thyroid. On presentation, this patient showed painful anterior cervical swelling and right supraclavicular lymph node swelling. Laboratory data showed primary hyperthyroidism. Although subacute thyroiditis was suspected, echo-guided needle aspiration biopsy and lymph node biopsy revealed poorly differentiated squamous cell carcinoma. As a result, primary lung cancer with thyroid metastasis was diagnosed based on mediastinal enlargement on chest X ray films and normal findings in organs other than the lung and thyroid. Chemotherapy for lung cancer induced a decrease in the size of tumor and the normalization of thyroid function. However, 2 months after the normalization, cervical swelling enlarged and a lung mass in right upper lobe and skin tumor appeared. Despite treatment with chemotherapy, she died. Postmortem revealed that the right upper lung carcinoma was the primary lesion and immunohistochemical staining for surfactant protein was positive in the thyroid, skin tumor and lymph node, which revealed these carcinomas had metastasized from lung cancer. To the best of our knowledge, thyrotoxicosis induced by thyroid metastasis of lung cancer is an uncommon case.

Ghrelin treatment suppresses neutrophil-dominant inflammation in airways of patients with chronic respiratory infection.

BACKGROUND: Persistent neutrophil influx into the airways is a characteristic of chronic respiratory infection and contributes to the deterioration of pulmonary function. Ghrelin is a novel growth hormone (GH)-releasing peptide with potential anti-inflammatory activities. The present study investigated whether or not ghrelin can reduce neutrophil-dominant inflammation in airways of patients with chronic respiratory infection. POPULATIONS AND METHODS: Synthesized ghrelin was administered intravenously for 3 weeks to 7 cachectic patients with chronic respiratory infection to confirm ghrelin's effects on airway inflammation and nutrition state. Neutrophils, neutrophil products and inflammatory cytokines in sputum were used as markers of airway inflammation. Changes in serum protein levels were also evaluated along with plasma catecholamine levels. Exercise tolerance was assessed by measuring 6-min walking distance before and after 3 weeks of ghrelin treatment. RESULTS: Three-week ghrelin administration decreased neutrophil density and inflammatory cytokine levels in sputum, reduced plasma norepinephrine level, and increased body weight, serum protein level, and 6-min walking distance. CONCLUSIONS: Ghrelin administration suppressed airway inflammation by decreasing neutrophil accumulation in lungs and increased body weight. These findings may contribute to the development of supportive therapies for patients with refractory chronic respiratory infection.

Elevated levels of beta-D-glucan in bronchoalveolar lavage fluid in patients with farmer's lung in Miyazaki, Japan.

BACKGROUND: Farmers may be often exposed to beta-D-glucan in moldy hay, since straw for feed can be stored throughout the year. OBJECTIVES: The aim of the present study was to clarify whether levels of beta-D-glucan, which modifies immune responses, are high in the respiratory tract in farmer's lung and whether beta-D-glucan participates in the pathogenesis of this condition. METHODS: We measured beta-D-glucan levels in the bronchoalveolar lavage fluid (BALF) of 10 patients with farmer's lung, 4 with summer-type hypersensitivity pneumonitis (HP) and 10 healthy volunteers. Interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha levels in BALF were measured by enzyme-linked immunosorbent assay (ELISA). We investigated the effects of beta-D-glucan on nuclear factor (NF)-kappaB activation and on the release of IL-8 and TNF-alpha from small airway epithelial cells (SAECs) in vitro. RESULTS: beta-D-Glucan levels in the BALF of farmer's lung patients were increased compared to those in patients with summer-type HP and in healthy volunteers. Additionally, IL-8 levels in BALF were higher in farmer's lung than in summer-type HP, and TNF-alpha levels were equal in the two patient groups but raised compared to those in healthy volunteers. High, but not low, concentrations of beta-D-glucan were found to induce NF-kappaB activation in SAECs. IL-8 levels in the supernatant obtained from SAEC cultures were increased following the addition of beta-D-glucan in vitro. CONCLUSION: BALF from farmer's lung patients showed high beta-D-glucan levels, which may enhance the expression and release of cytokines through NF-kappaB activation in respiratory epithelial cells.

[Bilateral pulmonary mucormycosis with diabetic ketoacidosis].

A 38 year-old woman admitted for bilateral infiltrates with a cavity and treated diabetic ketoacidosis and elevated inflammatory reaction in clinical examination was found in transbronchial lung biopsy specimens to have bilateral pulmonary mucormycosis. We controlled blood glucose with insulin and removed bilateral pulmonary lesions separately. Pulmonary mucormycosis with diabetic ketoacidosis is a rare but fatal fungal infection. Early diagnosis, intensive insulin therapy, and surgical resection may save patients with pulmonary mucormycosis even if lesions are bilateral.

Elevated alpha-defensin levels in plasma of patients with pulmonary sarcoidosis.

BACKGROUND AND OBJECTIVES: Pathogens such as mycobacteria and proprionibacterium have been implicated in the pathogenesis of sarcoidosis. alpha-Defensins (DF) are naturally occurring antimicrobial peptides. The aim of the present study was to assess whether DF are increased in the airway and/or systemic circulation in patients with pulmonary sarcoidosis and whether DF levels are related to sarcoidosis disease activity. METHODS: DF levels in plasma and BAL fluid (BALF) were measured in 30 patients with pulmonary sarcoidosis and in 10 controls. Plasma and BALF DF levels were compared according to disease activity. Molecular forms were analysed using reverse-phase (RP) HPLC to confirm plasma and BALF DF kinetics in pulmonary sarcoidosis. RESULTS: DF concentrations in plasma and BALF were higher in patients with pulmonary sarcoidosis than in the controls. Plasma DF levels correlated with lysozyme but not with angiotensin-converting enzyme. These levels were high in patients in whom more organs were involved, whereas BALF DF levels were higher in patients at stage II or III than with those at sarcoidosis I. RP-HPLC showed high plasma levels of pro-defensins, DF precursors from the bone marrow, in sarcoidosis, although DF in peripheral neutrophils and BALF were the mature type. CONCLUSIONS: High plasma DF concentrations resulted from bone marrow stimulation and seemed to be associated with disease activity, whereas BALF DF were released from accumulated neutrophils in the lungs and may contribute to parenchymal involvement in sarcoidosis.

Elevated BALF concentrations of alpha- and beta-defensins in patients with pulmonary alveolar proteinosis.

Defensins are endogenous antibiotics and regulators of inflammation, immunity and wound repair. Their concentrations are substantially increased in bronchoalveolar lavage fluid (BALF) of patients with infectious lung diseases. alpha-defensin (HAD) levels are also elevated in patients with idiopathic pulmonary fibrosis (IPF) and correlated with the decline in pulmonary function tests, suggesting the association of defensins with the pathogenesis of interstitial lung diseases. The aim of this study was to determine the profile of defensins in interstitial lung diseases. Serum and BALF levels of HAD and beta-defensin 1 and 2 (HBD-1, and -2) were measured by radioimmunoassay in 63 patients with interstitial lung diseases, including idiopathic pulmonary alveolar proteinosis (PAP), IPF, nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) and pulmonary sarcoidosis, and in 9 healthy volunteers as controls. Levels of HAD in BALF of patients with PAP were significantly higher than those in controls and patients with COP and sarcoidosis. Serum levels of HAD in all groups were significantly higher than those in controls. Levels of HBD-1 and -2 in BALF of patients with PAP were extremely high in all subjects. Serum levels of HBD-1 were higher in all patient groups, with the exception of those with PAP, and those of HBD-2 were also higher in patients with IPF and sarcoidosis, compared with controls. BALF of PAP patients, but not IPF patients and controls, expressed antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus. Our findings suggest different kinetics of HAD and HBD-1 and -2 in serum and BALF of interstitial lung diseases and that these antimicrobial peptides in the airway lumen may contribute to prevention of bacterial airway infections in PAP.

Long-term treatment with theophylline reduces neutrophils, interleukin-8 and tumor necrosis factor-alpha in the sputum of patients with chronic obstructive pulmonary disease.

BACKGROUND: The non-selective phosphodiesterase inhibitor theophylline has bronchodilator/anti-inflammatory properties and is widely used in the treatment of airways diseases. We determined the effect of long-term theophylline treatment on airway inflammation in patients with chronic obstructive pulmonary disease (COPD). POPULATIONS AND METHODS: Seventeen stable COPD patients were enrolled in the 12-month study. Theophylline was administered at 400mg/day. We studied changes in symptoms, spirometry, sputum volume, and sputum inflammatory cytokines levels. We also examined the effects of theophylline on the release of inflammatory cytokines in vitro by measuring interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha levels from lipopolysaccharide (LPS)-stimulated neutrophils and THP-1 cells. RESULTS: Forced vital capacity was increased and sputum IL-8 levels decreased after 4 weeks of theophylline treatment. After 6 months of theophylline treatment, forced expiratory volume in 1s was increased, and neutrophils counts and TNF-alpha levels in sputum were reduced. Levels of IL-8 and TNF-alpha released by LPS-stimulated THP-1 cells were reduced by treatment with theophylline at 10microg/ml. In contrast, IL-8 levels released by LPS-stimulated neutrophils were reduced by treatment with theophylline at 100microg/ml. CONCLUSION: Our clinical study of small population showed that long-term treatment with theophylline seems to reduce airway inflammation in stable COPD patients.

Elevated levels of antimicrobial peptides in bronchoalveolar lavage fluid in patients with chronic eosinophilic pneumonia.

BACKGROUND: Chronic eosinophilic pneumonia (CEP) is an idiopathic pulmonary disease. As the lung is in direct communication with the environment, inhaled antigen may activate immune mechanisms in the airway that may participate in the pathogenesis of idiopathic pulmonary diseases. Defensins are antimicrobial peptides that consist of alpha-defensin (HAD) in neutrophils and beta-defensin (HBD) in epithelial cells. Defensins act as innate immunity against pathogens acquired from the environment and as mediators to induce local inflammation. OBJECTIVES: The aim of the present study was to determine whether immune mechanisms in the airway are induced in CEP patients. METHODS: We measured BALF defensin levels in patients with CEP, acute EP (AEP) and drug-induced eosinophilic pneumonia (drug-EP). We also measured BALF levels of IL-5, GM-CSF, eotaxin and RANTES. These substances can recruit eosinophils. RESULTS: BALF HAD levels were higher in patients with CEP than in those with drug-EP and normal controls. HBD-2 was detected in BALF of 10 of 11 CEP patients and in 3 of 5 AEP patients while its level was below detection in drug-EP patients and normal controls. BALF HBD-2 levels correlated with the proportion of lymphocytes in CEP patients. CONCLUSION: The defensin-linked immune system is activated in CEP but not in drug-EP. This suggests that inhaled antigen(s) may be involved in the pathogenesis of CEP.

Isolation of human beta-defensin-4 in lung tissue and its increase in lower respiratory tract infection.

BACKGROUND: Human beta-defensin-4 (hBD-4), a new member of the beta-defensin family, was discovered by an analysis of the genomic sequence. The objective of this study was to clarify hBD-4 expression in human lung tissue, along with the inducible expression in response to infectious stimuli, localization, and antimicrobial activities of hBD-4 peptides. We also investigated the participation of hBD-4 in chronic lower respiratory tract infections (LRTI) by measuring the concentrations of hBD-4 peptides in human bronchial epithelial lining fluid (ELF). METHODS: The antimicrobial activity of synthetic hBD-4 peptides against E. coli and P. aeruginosa was measured by radial diffusion and colony count assays. We identified hBD-4 in homogenated human lung tissue by reverse-phase high-performance liquid chromatography coupled with a radioimmunoassay (RIA). Localization of hBD-4 was studied through immunohistochemical analysis (IHC). We investigated the effects of lipopolysaccharide (LPS) on hBD-4 expression and its release from small airway epithelial cells (SAEC). We collected ELF from patients with chronic LRTI using bronchoscopic microsampling to measure hBD-4 concentrations by RIA. RESULTS: hBD-4 exhibited salt-sensitive antimicrobial activity against P. aeruginosa. We detected the presence of hBD-4 peptides in human lung tissue. IHC demonstrated the localization of hBD-4-producing cells in bronchial and bronchiolar epithelium. The levels of hBD-4 peptides released from LPS-treated SAECs were higher than those of untreated control cells. ELF hBD-4 was detectable in 4 of 6 patients with chronic LRTI, while the amounts in controls were all below the detectable level. CONCLUSION: This study suggested that hBD-4 plays a significant role in the innate immunity of the lower respiratory tract.

Increased levels of interleukin-18 in bronchoalveolar lavage fluid of patients with idiopathic nonspecific interstitial pneumonia.

BACKGROUND: Interleukin-18 (IL-18) is a proinflammatory cytokine that can induce interferon-gamma (IFN-gamma), and it plays an important role in T-helper 1 responses. Among idiopathic interstitial pneumonia (IIP), nonspecific interstitial pneumonia (NSIP) has an increased number of lymphocytes in bronchoalveolar lavage (BAL) fluid compared with usual interstitial pneumonia (UIP). However, the difference in their pathogenesis is unclear. OBJECTIVE: The present study aims to investigate the roles of IL-18 in patients with idiopathic UIP and idiopathic NSIP. METHODS: We measured the serum and BAL fluid (BALF) levels of IL-18 and IFN-gamma in 22 patients with IIP (12 with UIP, 10 with NSIP) and 9 healthy volunteers. RESULTS: Lymphocyte proportions in BALF were significantly higher in NSIP than in UIP and healthy subjects. No significant differences were observed in the serum IL-18 levels of all subjects, while the BALF levels of IL-18 in patients with NSIP were significantly higher than in patients with UIP (p < 0.005) and in healthy subjects (p < 0.005). Among all subjects, the levels of IL-18 in BALF correlated significantly with those in serum and the lymphocyte proportions in BALF. The serum IFN-gamma levels of all subjects were below sensitivity, but there was significant reverse correlation between the levels of IFN-gamma and the lymphocyte proportions in BALF. CONCLUSION: The lymphocytosis in BALF of patients with idiopathic NSIP and a part of idiopathic UIP might be associated with the high levels of IL-18.