Propionibacterium acnes-associated sarcoidosis complicated by acute bird-related hypersensitivity pneumonitis.

BACKGROUND: The number of reports on sarcoidosis complicated by hypersensitivity pneumonitis (HP) is limited, and most describe cases complicated by chronic bird-related HP. Here, we present for the first time a case with Propionibacterium acnes-associated sarcoidosis complicated by acute bird-related HP. CASE PRESENTATION: A 62-year-old man with a past medical history of sarcoidosis was admitted to our department, and chest computed tomography showed diffuse ground-glass opacities, which appeared as he rapidly increased the number of pigeons he kept for a competition. Random transbronchial lung biopsy revealed well-formed non-caseating epithelioid granulomas, which contained positively stained substances on immunohistochemistry using the PAB antibody, a specific monoclonal antibody against P. acnes lipoteichoic acid. Poorly formed non-caseating granulomas without positively stained substances were also detected. CONCLUSION: We describe the successful identification of this exceptionally rare case of sarcoidosis complicated by acute bird-related HP in which two morphologically and immunohistologically different types of granulomas were present in the same lung.

NLRP3 protein deficiency exacerbates hyperoxia-induced lethality through Stat3 protein signaling independent of interleukin-1ß.

Supplemental oxygen inhalation is frequently used to treat severe respiratory failure; however, prolonged exposure to hyperoxia causes hyperoxic acute lung injury (HALI), which induces acute respiratory distress syndrome and leads to high mortality rates. Recent investigations suggest the possible role of NLRP3 inflammasomes, which regulate IL-1ß production and lead to inflammatory responses, in the pathophysiology of HALI; however, their role is not fully understood. In this study, we investigated the role of NLRP3 inflammasomes in mice with HALI. Under hyperoxic conditions, NLRP3(-/-) mice died at a higher rate compared with wild-type and IL-1ß(-/-) mice, and there was no difference in IL-1ß production in their lungs. Under hyperoxic conditions, the lungs of NLRP3(-/-) mice exhibited reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, as well as increased and decreased expression of MMP-9 and Bcl-2, respectively. NLRP3(-/-) mice exhibited diminished expression and activation of Stat3, which regulates MMP-9 and Bcl-2, in addition to increased numbers of apoptotic alveolar epithelial cells. In vitro experiments revealed that alveolar macrophages and neutrophils promoted Stat3 activation in alveolar epithelial cells. Furthermore, NLRP3 deficiency impaired the migration of neutrophils and chemokine expression by macrophages. These findings demonstrate that NLRP3 regulates Stat3 signaling in alveolar epithelial cells by affecting macrophage and neutrophil function independent of IL-1ß production and contributes to the pathophysiology of HALI.

Physical activity in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Physical activity is an important parameter in patients with chronic obstructive pulmonary disease, but has not been studied in detail in patients with interstitial lung disease. This study aimed to evaluate physical activity in patients with idiopathic pulmonary fibrosis (IPF). METHODS: Physical activity was monitored in 31 stable IPF patients using an accelerometer for 1 month. The following factors reflecting physical activity were measured: the number of steps, walking distance, the time spent at magnitude of movement (MM) 1-6, physical activity-related energy expenditure (PAEE) and total energy expenditure. We also measured the following clinical parameters: the modified Medical Research Council (MRC) scale, Krebs von den Lungen-6 (KL-6), pulmonary function parameters, 6-min walk test (6MWT) results and high-resolution computed tomography (HRCT) findings of the chest. We determined the relationship between these parameters and physical activity. RESULTS: We recorded 24 days of physical activity data. The time spent at MM < 1 was more than 10 h per day, whereas that at MM > 1 was approximately 1 h per day. The modified MRC scale, serum KL-6 levels, 6MWT distance, and the extent of honeycomb and reticular abnormality on HRCT were associated with several facets of physical activity. In particular, lower KL-6 levels were correlated with higher physical activity based on the number of steps, walking distance, the time spent at MM 1-4 and PAEE. CONCLUSIONS: The modified MRC scale, 6MWT distance, extent of fibrosis on HRCT and serum KL-6 levels are strongly associated with physical activity.

Clinical significance of interleukin 33 (IL-33) in patients with eosinophilic pneumonia.

BACKGROUND: Interleukin 33 (IL-33) works as a functional mediator in allergic disease by enhancing the activity of eosinophils and inducing expression of T helper 2 (Th2)-associated cytokines. However, the role of IL-33 in pulmonary eosinophilia has not been elucidated. We investigated the levels of IL-33 in eosinophilic pneumonia (EP) together with associated cytokines, and discussed the clinical significance of IL-33 in EP. METHODS: Sera and bronchoalveolar lavage fluid (BALF) were obtained from 16 patients with EP, including acute eosinophilic pneumonia (AEP) and chronic eosinophilic pneumonia (CEP). Twelve patients with acute respiratory distress syndrome (ARDS) were also included for comparison. The concentration of IL-33 and Th2 cytokines (IL-4, IL-5, IL-13) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The concentration of serum IL-33 was significantly higher in patients with AEP than in CEP. In CEP, only patients with atopic factors showed mild increase of serum IL-33. The concentration of BALF IL-33 was also significantly elevated in AEP, however, it remained quite low in CEP. Among Th2 cytokines, IL-5 was significantly increased in both serum and BALF in AEP, and the level of IL-5 was positively correlated with that of IL-33. ARDS showed no increase of serum and BALF IL-33. CONCLUSIONS: The remarkable increase of BALF IL-33 in AEP indicated the local production of IL-33 in lungs. IL-33 is considered to be a local key molecule for triggering pulmonary eosinophilia, together with IL-5. BALF IL-33 appears to be a useful marker for discriminating AEP from CEP and ARDS.

Impaired inflammatory responses to multiple toll-like receptor ligands in alveolar macrophages of streptozotocin-induced diabetic mice.

OBJECTIVE: To investigate the effect of hyperglycemic state on the activation of alveolar macrophages (AMs) mediated via Toll-like receptors (TLRs) typically associated with bacterial infection. METHODS: AMs obtained from normoglycemic control mice and streptozotocin-induced diabetic mice were stimulated ex vivo with the following: a TLR2 ligand, peptidoglycan (PGN); a TLR4 ligand, lipopolysaccharide (LPS); or a TLR5 ligand, flagellin (FLG). Cytokine production and mRNA expression were measured by ELISA and real-time PCR, respectively. TLR expression was assessed by real-time PCR and flow cytometry. RESULTS: AMs from diabetic mice produced significantly less TNF-α after PGN or FLG stimulation, and less IL-6 after FLG stimulation, compared with AMs from control mice. The decrease in the production of these cytokines was associated with reduced mRNA expression of the corresponding cytokines. In contrast, production of TNF-α and IL-6 after LPS stimulation did not differ between groups. Furthermore, there was no substantial difference in the expression of TLR2, TLR4, and TLR5 in AMs between the groups. The increased JNK phosphorylation induced by PGN or FLG stimulation was downregulated in AMs from diabetic mice. CONCLUSIONS: Hyperglycemic state impairs the reactivity of AMs to multiple TLR ligands. This effect might result from hyperglycemia-induced alteration of intracellular signaling and is unlikely due to the modulation of TLR expression.

[A case of chronic lower respiratory tract infection in which the traditional herbal medicine Hochuekkito was effective to prevent exacerbation].

A thin, 63-year-old man was receiving low-dose macrolide therapy for a diagnosis of chronic lower respiratory tract infection, but frequent exacerbations due to Streptococcus pneumoniae were observed. High-resolution computed tomography (CT) of the chest showed bronchiectasis and small centrilobular nodules in the right lower lobe. He had previously had several episodes of exacerbation of chronic lower respiratory tract infection, for which he had received antibiotic treatments (oral fluoroquinolones or intravenous cephems). However, he continued to experience recurrent exacerbations, and Pseudomonas aeruginosa was also isolated from his sputum. To improve his general condition, Hochuekkito, a herbal medicine, was initiated. His body weight and serum albumin level gradually increased, and after 6 months of administration, neither S. pneumoniae nor P. aeruginosa were isolated from his

[Interstitial pneumonia with anti-PL-7 antibody difficult to distinguish from rheumatoid lung].

A 63-year-old woman had abnormal shadows on a chest radiograph taken on a medical examination during treatment for rheumatoid arthritis. The chest radiograph showed linear and reticular shadows and ground glass opacities in the bibasilar lung fields. Though we considered rheumatoid arthritis due to joint disorder and a positive reaction for serum anti-CCP antibody, there were no bone lesions or articular narrowing on radiographs of the fingers. We diagnosed antisynthetase syndrome after we obtained a positive reaction for serum anti-PL-7 antibody. Antisynthetase syndrome demonstrates findings similar to those of rheumatoid arthritis, and this disease should be taken into consideration if chest computed tomography demonstrates consolidation with predominant patchy and irregular bronchovascular bundle thickening with a subpleural distribution.

[Role of IL-33 in bronchial asthma].

IL-33 is a member of the IL-1 family and has been identified as an agonist of ST2L. IL-33 drives the production of Th2-associated cytokines and IgE, and IL-33 administration induces eosinophilia and hypertrophy of bronchial epithelial cells, as well as mucus secretion in vivo. Such changes resemble pathological findings in bronchial asthma (BA). In this study, we investigated the relationship between IL-33 and BA by evaluating serum IL-33 levels. Serum was obtained from BA patients (n = 20), emphysema patients (n = 5) and from non-smoking healthy controls (n = 8). IL-33 levels were assayed by enzyme-linked immunosorbent assay. Then, we divided BA patients according to 5 factors; (1) IgE concentration, (2) eosinophil count, (3) current treatment, (4) classification of severity, and (5) smoking status. Atopic BA patients showed significantly higher IL-33 levels than non-atopic patients. IL-33 was significantly higher in untreated patients, and in the moderate and severely affected groups. Smoking BA and emphysema patients had lower levels than nonsmoking BA patients. Eosinophil counts were not related to IL-33 levels. The present study suggests that IL-33 is closely associated with IgE levels and the exacerbation of BA. We speculated that IL-33 elevation is responsible for the maintenance of airway inflammation and hypersensitivity. It is possible that low IL-33 levels in smokers are caused by the deterioration of the airway epithelium and endothelium.

Interstitial pneumonia with autoimmune features that met the proposed diagnostic criteria for IgG4-related respiratory disease.

We held a multidisciplinary discussion (MDD) about a 61-year-old woman who had an interstitial lung disease (ILD) without extrathoracic lesions that met the classification criteria for interstitial pneumonia with autoimmune features (IPAF) and the proposed diagnostic criteria for immunoglobulin G4 (IgG4)-related respiratory disease (IgG4-RRD). Clinically, the marked progression of lung-limited diffuse lesions was consistent with IPAF. Serum IgG4 and rheumatoid factor levels simultaneously increased and did not contribute to a diagnosis. Pathologically, the significant hyperplasia of lymphoid follicles was consistent with rheumatoid arthritis (RA)-associated ILD. Pulmonary venous occlusions by intimal fibrosis and intimal thickening were not important because these occlusions are found in IgG4-related lung disease (IgG4-RLD) and also in IPAF or ILDs related to connective tissue diseases (CTDs). Radiologically, fibrosing shadows that remained in the lung periphery after treatment were compatible with RA-associated chronic ILD. We concluded that the present case was IPAF that met the proposed diagnostic criteria for IgG4-RRD.

Pazopanib Confers a Progression-free Survival in a Patient with Ewing's Sarcoma/Primitive Neuroectodermal Tumor of the Lung.

Ewing's sarcoma (ES)/primitive neuroectodermal tumors (PNETs) are highly malignant neoplasms that usually affect the bones and soft tissues in children and young adults. ES/PNET of the lung is very rare and is associated with a poor prognosis. We herein report a case of ES/PNET of the left lung in a 45-year-old man. He was treated with neoadjuvant chemotherapy and pneumonectomy, but unfortunately his disease recurred 1.5 months after surgery. He was started on pazopanib, which resulted in a five-month progression-free survival. To our knowledge, this is the first demonstration of pazopanib efficacy in ES/PNET of the lung.

Preventive effects of edaravone, a free radical scavenger, on lipopolysaccharide-induced lung injury in mice.

BACKGROUND AND OBJECTIVE: Reactive oxygen species (ROS) play an important role in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. It was hypothesized that edaravone, a free radical scavenger, would be able to attenuate LPS-induced lung injury in mice by decreasing oxidative stress. METHODS: For the in vivo experiments, lung injury was induced in female BALB/c mice by the intranasal instillation of LPS. Edaravone was given by intraperitoneal administration 1 h before the LPS challenge. For the in vitro experiments, MH-S cells (murine alveolar macrophage cell line) were exposed to edaravone, followed by stimulation with LPS. RESULTS: In the LPS-induced ALI mouse model, the administration of edaravone attenuated cellular infiltration into and the concentrations of albumin, IL-6, tumour necrosis factor-alpha, keratinocyte-derived chemokine and macrophage inflammatory protein-2 in BAL fluid. In addition, the in vitro studies showed that the elevated IL-6 secretion from MH-S cells in response to LPS was significantly attenuated by co-incubation with edaravone. CONCLUSIONS: In an experimental murine model, a free radical scavenger may prevent ALI via repression of pro-inflammatory cytokine production by lung macrophages.

Drug-induced pneumonitis associated with imatinib mesylate in a patient with idiopathic pulmonary fibrosis.

A 74-year-old man with idiopathic pulmonary fibrosis (IPF) developed severe dyspnea on exertion after the readministration of imatinib mesylate for chronic myeloid leukemia. Chest X-ray and CT showed ground-glass opacities in both lungs in addition to preexisting honeycombing. Discontinuation of imatinib and methylprednisolone pulse therapy followed by administration of oral prednisolone resulted in improvement in both symptoms and radiographic findings. Imatinib-induced pneumonitis was diagnosed based on the clinical course and findings. Only five previous reports of imatinib-induced pneumonitis have been published in the literature, and this is the first case reported in a patient with IPF.

[A case of drug-induced pneumonia caused by propiverine: follow-up drug lymphocyte stimulation test useful for identification of the suspected drug].

A 75-year-old woman presented with general malaise and exertional dyspnea one week after the administration of propiverine, a urination-improving drug, with a diagnosis of neurogenic bladder. Her chest X-ray film and high-resolution computed tomography (HRCT) revealed bilateral, non-segmental, ground-glass opacities with partial consolidation and cord-shaped shadows. Bronchoalveolar lavage (BAL) fluid suggested an increase in the ratio of lymphocytes. A drug lymphocyte stimulation test (DLST) for propiverine showed a negative reaction 2 weeks after onset; however, a positive reaction was noted after a further 2 weeks. After the discontinuation of propiverine, the symptoms and imaging findings markedly improved. The clinical course suggested drug-induced pneumonia caused by propiverine. Considering the risk of additional administration and the necessity of subsequent prescription, drug provocation test was not performed. No study has reported propiverine-related lung injuries; however, as this agent is frequently prescribed in elderly patients, the possibility of drug-induced pneumonia must be considered.

[Our clinical experiences of amrubicin hydrochloride monotherapy in extensive-disease small cell lung cancer].

We retrospectively investigated monotherapy of amrubicin hydrochloride in patients with extensive-disease small cell lung cancer (ED-SCLC) and assessed its efficacy and safety. Twenty-two patients were enrolled. The response rate of total, previously untreated, sensitive relapsed, and refractory relapsed cases were 59%, 50%, 100% and 46%, respectively. As for the dose of amrubicin, the response rates of 30 mg/m(2), 35 mg/m(2), 40 mg/m(2), and 45 mg/m(2) were 50%, 33%, 69% and 100%, respectively. Severe myelosuppression was frequently observed as the adverse event, but significant differences among several dosages were not recognized. Median survival time was 230 days in relapsed cases. Monotherapy of amrubicin might be effective in ED-SCLC not only as first-line but also as second-line treatment in relapsed cases. The recommended dose was above 40 mg/m(2) because of its higher response rate.

[Case of minocycline-induced acute eosinophilic pneumonia accompanied by marked neutrophilia in the peripheral blood].

A 37-year-old woman presenting with high fever, dry cough and progressive dyspnea was admitted to our hospital. She took 100 mg of minocycline hydrochloride orally because of a common cold one day prior to her admission. A chest CT scan showed diffuse ground-glass opacities with interlobular septal thickening and thickening of bronchovascular bundles. An analysis of bronchoalveolar lavage fluid showed an increase in both the total cell counts and the number of eosinophils. The result of a lymphocyte stimulation test performed on peripheral blood lymphocytes was positive for minocycline. This patient had a history of pneumonia with similar clinical and radiographic findings, which had developed while receiving minocycline. As a result, we made a diagnosis of minocycline-induced acute eosinophilic pneumonia. Her symptoms and radiographic findings improved within a few days after admission. Corticosteroid therapy was effective. A marked increase of peripheral blood neutrophils were noted on admission. The serum levels of IL-8 and G-CSF increased at the early phase of the disease, but thereafter decreased in association with neutrophils, thus suggesting the contribution of these cytokines to the early phase neutrophilia in this case.

Clinical significance of changes in Torque teno virus DNA titer after chemotherapy in patients with primary lung cancer.

BACKGROUND: Several studies have reported that viral infections are related to lung cancer. We previously reported the involvement of Torque teno virus (TTV) in patients with lung cancer and idiopathic pulmonary fibrosis. However, the role of TTV in lung cancer growth, and its influence on changes in TTV DNA titers due to idiopathic pulmonary fibrosis (IPF) in lung cancer patients are poorly understood. METHODS: Serum TTV DNA titers were measured in serum samples obtained from patients with lung cancer. Forty-eight patients with primary lung cancer, including 8 patients with IPF, were enrolled. Serum TTV DNA titers were quantitated before and after chemotherapy. In addition, patients were classified into two groups according to the presence or absence of IPF, and clinical characteristics were compared between these two groups. RESULTS: Among the 33 patients with partial response to treatment or stable disease in the lung cancer, the mean TTV DNA titer in 28 patients without IPF had significantly decreased after chemotherapy. In contrast, the mean TTV DNA titer in the 5 patients with IPF tended to increase after chemotherapy. In the 15 patients with progressive lung cancer, TTV DNA titers were significantly elevated in those with and without IPF. CONCLUSION: In lung cancer patients without IPF, changes in TTV titers may be correlated with tumor growth. However, in lung cancer patients with IPF, TTV titers were not consistently associated with chemotherapy responses. Therefore, IPF may have an influence on changes in TTV DNA titers.

[Lung cancer in patients with chronic renal failure].

We evaluated the clinical characteristics of 18 patients with lung cancer complicated by chronic renal failure at our department between November 1983 and September 2004. The 18 patients consisted of 17 men and 1 woman aged 60-81 years (mean, 70 years). Fifteen patients had non-small cell lung cancer (NSCLC), and 3 had small cell lung cancer (SCLC). The stage of NSCLC was I in 7 patients, II in 2, and IV in 6. The stage of SCLC was localized disease (LD) in 2 patients and extensive disease (ED) in 1. The lung cancer was often detected due to symptoms such as cough and bloody sputum. Concerning treatment, surgery was mainly selected in patients with stage I NSCLC, but radiotherapy alone was often performed due to the wishes of patients in those with stage III or IV NSCLC. The outcome of patients who underwent chemotherapy with stage III or IV NSCLC was similar to patients with lung cancer not complicated by renal failure. In lung cancer patients with chronic renal failure, new hepatic excretion type anti-cancer drugs can be also used, but further evaluation is necessary.

[Evaluation of the drug lymphocyte stimulation test (DLST) with shosaikoto].

BACKGROUND: Our aim is to evaluate the significance of DLST by Shosaikoto. METHODS: We clinically evaluated 3 cases of drug-induced pneumonia assumed to be caused by Shosaikoto, and we performed DLST of Shosaikoto for healthy controls, and compared the data with drug-induced pneumonia cases of Shosaikoto. RESULTS: As clinical characteristics of 3 cases, 2 cases were positive for hepatitis C virus antibody, and 1 case was positive for DLST of Shosaikoto. The observed chest high-resolution CT (HRCT) findings showed hypersensitivity pneumonia (HP) pattern in all 3 cases. Prognosis was good in all 3 cases. DLST of Shosaikoto was positive in 27.5% of healthy controls. Stimulation index (S.I.) of DLST in drug-induced pneumonia cases increased depending on drug dilution density, compared to that of healthy controls. CONCLUSION: DLST of Shosaikoto showed high false-positive rate. However, we may be able to distinguish the true-positive cases with the false-positive cases by comparing the S.I. of DLST according to drug dilution density.

[Case of small cell lung cancer complicated with diabetes insipidus and Cushing syndrome due to ectopic adrenocorticotropic hormone secretion].

A 54-year-old woman had been given a diagnosis with scleroderma and interstitial pneumonia due to scleroderma when she was 45 years old. Thirst, with resulting polydipsia and polyuria (about 7 liters/day) were present since May, 2004, and bloody sputum appeared in June of 2004. The patient was admitted to our hospital. Chest CT examination showed multiple nodules in the bilateral lower lung field and multiple movable subcutaneous nodules on the abdomen. Small-cell lung cancer (metastases in the pituitary, subcutaneous tissue, and lungs) was diagnosed by transbronchial lung biopsy and subcutaneous nodule biopsy of the abdomen. The final diagnosis was diabetes insipidus and Cushing syndrome. Chemotherapy was done with CDDP and VP-16, which resulted in reduction of the tumor and improvement in endocrinological findings. Nevertheless, chemotherapy could not be continued because of infected bullae. The patient died of deteriorating illness after 91 sickness days. We concluded that this case was Cushing syndrome caused by ectopic adrenocorticotropic hormone-producing small cell lung cancer, and that it presented with diabetes insipidus because of pituitary metastasis. Therefore, when drastic endocrinological changes are found, it is important to examine for cancer, including lung cancer, as soon as possible.