Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The prognostic significance of serial measurements of serum KL-6 levels in patients with idiopathic pulmonary fibrosis (IPF) is unclear; hence, it was assessed in this study. METHODS: Medical records of 66 patients with IPF, who were not treated with pirfenidone prior to enrollment, were retrospectively reviewed for information on clinical progress, forced vital capacity (FVC), survival, and serum KL-6 levels. We assessed initial serum levels of KL-6, serial changes in serum KL-6 levels, yearly decline in FVC (ΔFVC), and the rate of decline (%ΔFVC). RESULTS: Patients with increased serum KL-6 levels during follow-up had a significantly steeper decline in ΔFVC than those with no KL-6 increase (-201 vs. -50.7ml/year; p=0.0001). Patients with both initial serum KL-6 ≥1000U/ml and serial increases in serum KL-6 had the steepest decline, while those with both initial serum KL-6 <1000ml and no serial increases in KL-6 had the least decline in ΔFVC and %ΔFVC. Relative to the non-increased KL-6 group, survival in the increased KL-6 group tended to be poorer (p=0.0530). Patients with both initial serum KL-6 values <1000U/ml and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000U/ml (p<0.0044). Prognosis was significantly poorer in patients with serial KL-6 changes >51.8U/ml/year than in those with serial KL-6 changes <51.8U/ml/year (p=0.0009). CONCLUSION: Thus, serial serum KL-6 measurements can be useful for assessing prognosis in patients with IPF.

Opsonic and Antibody Responses to Pneumococcal Polysaccharide in Rheumatoid Arthritis Patients Receiving Golimumab Plus Methotrexate.

Vaccination against Streptococcus pneumoniae is recommended for rheumatoid arthritis (RA) patients receiving immunosuppressive treatments. The objective of this study was to evaluate the humoral response to 23-valent pneumococcal polysaccharide vaccination (PPSV23) in RA patients receiving methotrexate (MTX) alone or in combination with a tumor necrosis factor inhibitor, golimumab (GOM).PPSV23 was given to 114 RA patients, who were classified into three groups: RA control (n = 35), MTX alone (n = 55), and GOM + MTX (n = 24). Before and 4 to 6 weeks after vaccination, concentrations of antibodies against pneumococcal serotypes 6B and 23F were measured using an enzyme-linked immunosorbent assay and antibody functionality was determined using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI).The IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the GOM + MTX group, the IgG responses were lower than those in the MTX alone or control groups, whereas the OI responses were similar to those in the other 2 groups. Furthermore, discrepancies between the IgG and OI responses were found in GOM + MTX group. No severe adverse effect was observed in any treatment groups.OI responses indicate that antibody functionality rather than antibody quantity is important. The similarity of these measurements between all 3 groups suggests that RA patients receiving MTX + GOM still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. These results can help clinicians to better schedule and evaluate pneumococcal vaccination for RA patients.

[A case of myocarditis associated with polymyositis preceded by interstitial pneumonia].

A 33-year old man was admitted to our hospital because of an abnormal shadow on the chest radiograph, dry cough, and exertional dyspnea. Chest radiograph and high-resolution computed tomography (HRCT) on admission showed ground-glass opacities and bronchiectasis with volume loss in the bilateral dorsal areas. Thoracoscopic lung biopsy specimens showed mainly a pattern of NSIP (nonspecific interstitial pneumonia). We considered this case as hypersensitivity pneumonia or interstitial pneumonia (IP) associated with collagen disease. Oral prednisolone (PSL) was initiated at 55 mg/day (1 mg/kg). However he complained of proximal muscle weakness and pain and difficulty of breathing. He had heart failure due to the myocarditis. We established a diagnosis of IP associated with polymyositis and it was confirmed by his symptoms, muscle biopsy findings and elevation of serum CPK. We considered this case as the myocarditis due to polymyositis.

[A case of pulmonary tuberculous initially diagnosed as sarcoidosis because of necrotizing granuloma].

A 75-year-old man with diabetes mellitus visited our hospital because of a chest radiograph abnormality. He was asymptomatic, and no abnormality was detected by blood tests including QuantiFERON-TB Gold (QFT-2 G); hence we conducted a follow-up examination. In 8 months, his chest radiography and CT findings worsened despite remaining asymptomatic. He was admitted for further tests. Analysis of bronchoalveolar lavage fluid (BALF) showed normal results for total cell counts and lymphocytes, but the CD4/8 ratio increased, and bacterial examination yielded negative results. Surgical lung biopsy showed an epithelioid cell granuloma with fibrinoid necrosis and Langhans giant cells, and some bacilli were positive for acid-fast stain. At this point, we suspected sarcoidosis, necrotizing granulomatosis, and mycobacterosis. However, the mycobacterial culture from the lung tissue was positive, and it was identified as Mycobacterium tuberculosis. We diagnosed pulmonary tuberculosis. Even if QuantiFERON-TB Gold In-Tube (QFT-3 G) for active tuberculosis is negative, it may yield false negative results in individuals in an immunosuppressed state and low CD4 count. When we suspect pulmonary tuberculosis from radiographic and pathological findings, we should consider the results of QFT-2 G and QFT-3 G carefully as an adjunct to the diagnosis of tuberculosis.

Prognostic value of immunohistochemical surfactant protein A expression in regenerative/hyperplastic alveolar epithelial cells in idiopathic interstitial pneumonias.

BACKGROUND: It is difficult to predict survival in patients with idiopathic pulmonary fibrosis. Recently, several proteins, such as surfactant protein (SP) and KL-6, have been reported to be useful biologic markers for prediction of prognosis for interstitial pneumonias. It is not clear whether there is any relationship between expression of these proteins in regenerative/hyperplastic alveolar epithelial cells and prognosis of idiopathic interstitial pneumonias (IIPs). OBJECTIVES: This study aimed to elucidate the clinical significance of the expression of such lung secretory proteins as SP-A and KL-6 in lung tissues of patients with IIPs. METHODS: We retrospectively investigated the immunohistochemical expression of SP-A, KL-6, cytokeratin (CK), and epithelial membrane antigen (EMA) in alveolar epithelial cells in lung tissues obtained from surgical lung biopsy in 43 patients with IIPs, and analyzed the correlation between expression of these markers and the prognosis of each IIP patient. CK and EMA were used as general markers for epithelial cells. RESULTS: In patients with usual interstitial pneumonia (UIP), the ratio of SP-A positive epithelial cells to all alveolar epithelial cells (SP-A positive ratio) in the collapsed and mural fibrosis areas varied, ranging from cases where almost all alveolar epithelial cells expressed SP-A to cases where only a few did. On the other hand, in many patients with nonspecific interstitial pneumonia (NSIP), many of the alveolar epithelial cells in the diseased areas expressed SP-A. The SP-A positive ratio was significantly lower in patients who died from progression of UIP than in patients with UIP who remained stable or deteriorated but did not die. In NSIP patients, a similar tendency was noted between the SP-A positive ratio and prognosis. CONCLUSIONS: The results suggest that the paucity of immunohistochemical SP-A expression in alveolar epithelial cells in diseased areas (i.e. regenerative/hyperplastic alveolar epithelial cells) may predict a worse prognosis for patients with IIPs, especially patients with UIP. A prospective study is needed to confirm these results.

[A possible case of drug-induced pneumonia due to L-carbocisteine].

A 70-year-old man presented with a deteriorating fever and productive cough after the administration of drugs including L-carbocisteine against the common cold. Since chest radiograph revealed pulmonary infiltrates in the right lower lung field, he was admitted to our hospital, then L-carbocisteine was continued and antibiotics started. However, his symptoms, laboratory findings, and hypoxia worsened. Pulmonary infiltrates on his chest radiograph increased and chest CT demonstrated pulmonary consolidation with traction bronchiectasis and ground glass opacity with thickened of interlobular septae in the right lung field. Analysis of bronchoalveolar lavage fluid showed elevated numbers of total cells, neutrophils and eosinophils, and the CD4/CD8 ratio was 5.65. Under a suspected diagnosis of drug-induced pneumonia, we halted L-carbocisteine administration stopped and began corticosteroid therapy. Subsequently his symptoms and findings markedly improved. The drug lymphocyte stimulation test for L-carbocisteine using peripheral blood lymphocytes showed positive results. On the basis of the clinical course, laboratory and radiographic findings, we considered this case to possibly be drug-induced pneumonia due to L-carbocisteine. To our knowledge, this is possibly the first case of L-carbocisteine-induced pneumonia to be reported.

Pleural cryptococcosis with idiopathic CD4 positive T-lymphocytopenia.

A 19-year-old man was admitted to our hospital because of chest pain. He was diagnosed as having pleural cryptococcosis by pleural biopsy. His CD4 positive T-lymphocyte count was low (< 300 microl) and there was no evidence of human immunodeficiency virus infection. He was successfully treated with fluconazole. However, his CD4 positive lymphocyte counts remained low after the recovery and he was diagnosed as idiopathic CD4 positive T-lymphocytopenia. Pleural cryptococcosis is rare and its predisposing condition is still controversial. To our knowledge, this is the first case of pleural cryptococcosis associated with idiopathic CD4 positive T lymphocytopenia.

TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus.

Neutropenia is a common laboratory finding in systemic lupus erythematosus (SLE). However, the molecular mechanism of SLE neutropenia has not been fully explained. In this study, we examined whether TNF-related apoptosis-inducing ligand (TRAIL) is involved in the pathogenesis of SLE neutropenia using samples from SLE patients. Serum TRAIL levels in SLE patients with neutropenia were significantly higher than those of SLE patients without neutropenia and healthy volunteers. Serum TRAIL levels showed a significant negative correlation with neutrophil counts in SLE patients. The expression of TRAIL receptor 3 was significantly lower in SLE patients with neutropenia than in patients without neutropenia or in healthy volunteers. Treatment with glucocorticoids negated the decrease of TRAIL receptor 3 expression on neutrophils of SLE patients. TRAIL may accelerate neutrophil apoptosis of neutrophils from SLE patients, and autologous T cells of SLE patients, which express TRAIL on surface, may kill autologous neutrophils. Interferon gamma and glucocorticoid modulated the expression of TRAIL on T cells of SLE patients and also modulated the expression of cellular Fas-associating protein with death domain-like interleukin-1 beta-converting enzyme (FLICE)-inhibitory protein (cFLIP), an inhibitor of death receptor signaling, in neutrophils. Thus, our results provide a novel insight into the molecular pathogenesis of SLE neutropenia.

Stromal-derived factor-1alpha/CXCL12-CXCR 4 axis is involved in the dissemination of NSCLC cells into pleural space.

Malignant pleural effusion (PE) is one of the poor prognostic factors in non-small cell lung cancer (NSCLC), and the detailed mechanism of the malignant PE formation is not fully elucidated. Recently, CXCR4, a receptor for chemokine stromal-derived factor-1alpha (SDF-1alpha) that can induce chemotaxis of cells, was reported to be expressed on NSCLC. In this study, we hypothesized that the SDF-1alpha/CXCR4 axis may be involved in the dissemination of malignant cells into pleural space, and investigated its expression, function, and signaling pathway using NSCLC cell lines and clinical samples from 43 patients with NSCLC with malignant PE. We found functional expression of CXCR4 on NSCLC cell lines, and also found that SDF-1alpha could induce migration via phosphatidylinositol 3 (PI-3) kinase- and p44/42 mitogen-activated protein kinase-dependent manner. The SDF-1alpha levels in malignant PE were significantly higher than those in transudate PE and showed a significant positive correlation with PE volumes. The sensitivity and specificity for prediction of recurrence of malignant PE was 61.5% and 83.3%, respectively (cutoff SDF-1alpha = 2,500 ng/ml), and better than those using pH of PE. Cancer cells in malignant PE expressed CXCR4, and mesothelial cells of the pleura stained positive for SDF-1alpha. The SDF-1alpha/CXCR4 axis is involved in the dissemination of NSCLC cells into pleural space.

Vascular endothelial growth factor and proinflammatory cytokines in pleural effusions.

To evaluate the predictive value of vascular endothelial growth factor (VEGF) in the differential diagnosis of pleuritis and its association with other proinflammatory cytokines in pleural effusion, we measured VEGF together with interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1) in pleural effusions. We investigated 127 patients with pleural effusion (congestive heart failure: 21; parapneumonic: 27; tuberculous: 41; malignant: 38). We examined standard parameters of pleural effusion and measured pleural effusion VEGF, IL-1beta, TNF-alpha and sICAM-1 using enzyme-linked immunosorbent assay. VEGF level was significantly higher in malignant effusion than in other groups. TNF-alpha level was significantly higher in tuberculous pleurisy than in other groups. In tuberculous pleurisy VEGF level showed significant positive correlations with mononuclear cell counts and all investigated cytokines. The sensitivity and specificity of VEGF in the diagnosis of malignancy was 100 and 84%, respectively (cutoff = 2000 pg/ml). The sensitivity and specificity of VEGF and TNF-alpha in the diagnosis of tuberculous pleurisy (VEGF titer <2000 pg/ml and TNF-alpha titer > 55 pg/ml) was 88.9 and 77.1%, respectively. We propose that measurement of VEGF together with TNF-alpha is helpful in differentiating between tuberculous pleurisy and malignant pleural effusion and that VEGF correlates with proinflammatory cytokines especially in tuberculous pleurisy. We also propose that measurement of pleural VEGF is helpful for the diagnosis of malignant pleural effusion.

[A long-term surviving patient with invasive thymoma who underwent radiotherapy and/or resection for chest wall, intrathoracic and intrapelvic recurrent tumors].

A 49-year-old woman with myasthenia gravis who underwent left panpleuropneumonectomy for an invasive thymoma that disseminated through the left thoracic cavity. After six year, radiotherapy was conducted on the recurrent tumor in the left anterior chest wall. Two years later, the recurrent tumors in the intrapelvic and intrathoracic cavities were resected. It was thought that long-term survival was obtained by combining radiotherapy and surgical treatment in view of the patient's general condition, and of the recurrent invasive thymoma present in this case.

Purified protein derivative of tuberculin upregulates the expression of vascular endothelial growth factor in T lymphocytes in vitro.

The purpose of this study was to investigate the cellular source and significance of vascular endothelial growth factor (VEGF) which, as reported previously, is elevated in the sera of pulmonary tuberculous patients. We obtained peripheral blood mononuclear cells (PBMCs) from 28 patients with active pulmonary tuberculosis, from 11 healthy controls who were positive for purified protein derivative of tuberculin (PPD), and from eight healthy individuals who were negative for PPD. We incubated the PBMCs with PPD in the presence or absence of major histocompatibility (MHC) class I or class II antibody in vitro, and measured the VEGF levels of culture supernatants. We also analysed the source of cells that secrete VEGF by using flow cytometry with intracellular staining. The T lymphocytes of active tuberculous patients secreted a higher level of VEGF than those of healthy controls. This production of VEGF was inhibited by adding MHC class II antibody. The addition of MHC class I antibody, however, did not inhibit. We propose that CD4+ T lymphocytes are almost certainly the cells that produce VEGF in response to PPD. VEGF production might be associated with an antigen-specific immune reaction via CD4+ T lymphocytes in tuberculosis.