Mortality risk factors and fulminant sub-phenotype in anaerobic bacteremia: a 10-year retrospective, multicenter, observational cohort study.

PURPOSE: During the last decade, the incidence of anaerobic bacteremia (AB) has been increasing. Patients with AB may develop complex underlying diseases, which can occasionally be accompanied by fatal or fulminant outcomes. However, the risk factors for AB-related mortality remain unclear. Herein, we sought to elucidate the risk factors for AB-related mortality. METHODS: In this multicenter, retrospective, observational study, we enrolled patients with culture-proven AB from six tertiary hospitals in Japan, between January 2012 and December 2021. Data on patient and infection characteristics, laboratory findings, treatment, and outcome were collected, and their associations with mortality were analyzed. RESULTS: A total of 520 participants were included. The 30-day mortality in the study cohort was 14.0% (73 patients), and malignant tumors were frequently observed comorbidities in 48% of the entire cohort. Multivariable logistic regression analysis showed a Charlson comorbidity score of > 6, serum creatinine level of > 1.17 mg/dL, and hypotension to be independent risk factors for 30-day mortality in AB (odds ratios [ORs] 2.12, 2.25, and 5.12, respectively; p < 0.05), whereas drainage significantly reduced this risk (OR, 0.28; p < 0.0001). Twelve patients (2.3% of the whole cohort and 16.4% of the deceased patients) presented with extremely rapid progression leading to fatal outcome, consistent with "fulminant AB." CONCLUSIONS: This study identified acute circulatory dysfunction and performance of drainage as independent predictive factors for 30-day AB-related mortality and revealed the existence of a fulminant AB sub-phenotype. Our findings could serve as a practical guide to predict the clinical outcomes of AB.

First clinical evaluation of the QIAreachTM QuantiFERON-TB for tuberculosis infection and active pulmonary disease.

OBJECTIVE: 1) to compare the QIAreachTM QuantiFERON-TB (QIAreach QFT) vs. QuantiFERON®-TB Gold Plus assay (QFT-Plus) to detect tuberculosis (TB) infection; 2) to evaluate diagnostic sensitivity of QIAreach QFT using active TB as surrogate for TB infection; 3) to preliminarily evaluate QIAreach QFT in immunocompromised individuals. METHODS: QIAreach QFT measures the level of interferon-γ (IFN-γ) in plasma specimens from blood stimulated by ESAT-6 and CFP-10 peptides in one blood collection tube (equivalent to the TB2 tube of the QFT-Plus). QIAreach QFT was applied to plasma samples from 41 patients with pulmonary TB and from 42 healthy or low-TB-risk individuals. RESULTS: Sensitivity and specificity of QIAreach QFT vs. QFT-Plus were 100% (41/41) and 97.6% (41/42), respectively; overall concordance was 98.8% (82/83). All samples were measured within 20 min. The time to result of each sample was significantly correlated with IFN-γ level with a natural logarithmic scale (r = -0.913, p < 0.001). Seven cases in the active TB group were immunocompromised (CD4 <200/µL) and tested positive by QIAreach QFT. CONCLUSIONS: QIAreach QFT provides an objective readout with a minimum blood sample volume (1 mL/subject), potentially being a useful point-of-care screening test for TB infection in high-TB-burden, low-resource countries and for immunocompromised patients.

IL-15 is a biomarker involved in the development of rapidly progressive interstitial lung disease complicated with polymyositis/dermatomyositis.

BACKGROUND: Polymyositis/dermatomyositis (PM/DM) is an autoimmune disease that is sometimes complicated with rapidly progressive interstitial lung disease (RPILD). However, serum and lung biomarkers that can predict RPILD development remain unclear. OBJECTIVES: To determine potential serum and lung biomarkers that can predict RPILD development in patients with PM/DM-ILD. METHODS: In total, 49 patients with PM/DM-ILD were enrolled. We measured the serum levels of 41 cytokines/chemokines, ferritin and anti-MDA5 antibody, compared them between the RPILD (n = 23) and non-RPILD (n = 26) groups, and ranked them by their importance through random forest analysis. To distinguish the two groups, we determined biomarker combinations by logistic regression analysis. We also measured the bronchoalveolar lavage fluid (BALF) levels of 41 cytokines/chemokines. Using immunohistochemistry, we examined IL-15 expression in lung tissues. The IL-15 production was also investigated using A549 and BEAS-2B cells. RESULTS: The RPILD group had significantly higher IL-15, IL-1RA, IL-6, CXCL10, VCAM-1, anti-MDA5 antibody and ferritin serum levels than the non-RPILD group, but it had a significantly low CCL22 level. Meanwhile, anti-MDA5 antibody, IL-15, CXCL8, CCL22, IL-1RA and ferritin were the best combination to distinguish the two groups. IL-15 and CCL22 were also predictive marker for RPILD development in anti-MDA5 antibody-positive patients. Additionally, the RPILD group had significantly high IL-15 levels in BALF. The lung tissues expressed IL-15, which increased after cytokine stimulation in the A549 cells. CONCLUSION: This study identified a combination of biomarkers predicting PM/DM-RPILD progression, and IL-15 is an important cytokine for predicting RPILD development and reflecting ILD severity.

Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker that can predict the efficacy of direct-acting anti-viral-based triple therapy for chronic hepatitis C.

BACKGROUND: The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+) -M2BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA(+) -M2BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve. AIM: To evaluate the diagnostic ability of WFA(+) -M2BP for liver fibrosis in the clinical setting and the clinical utility of WFA(+) -M2BP for predicting the efficacy of direct-acting anti-viral (DAA) treatment for chronic hepatitis C patients. METHODS: The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir-based triple treatment). The relation between baseline serum WFA(+) -M2BP and treatment efficacy was evaluated. RESULTS: The serum WFA(+) -M2BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index (COI) for WFA(+) -M2BP for diagnosing advanced fibrosis. The sustained virological response (SVR) rate was significantly, negatively correlated with the serum WFA(+) -M2BP level. Multiple logistic regression analysis found a low serum WFA(+) -M2BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA(+) -M2BP level. CONCLUSION: Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients.

Association of distinct clinical subsets with myositis-specific autoantibodies towards anti-155/140-kDa polypeptides, anti-140-kDa polypeptides, and anti-aminoacyl tRNA synthetases in Japanese patients with dermatomyositis: a single-centre, cross-sectional study.

OBJECTIVE: To determine the association of distinct clinical subsets with myositis-specific autoantibodies (MSAs) towards anti-155/140-kDa polypeptides [anti-155/140 antibodies (Abs)], anti-140-kDa polypeptides (anti-140 Abs), and anti-aminoacyl tRNA synthetases (ARS Abs) in Japanese patients with dermatomyositis (DM). METHODS: We compared the clinical features and short-term prognoses of 30 DM patients whose serological status included these MSAs. The MSAs were determined by immunoprecipitation. RESULTS: Anti-155/140 Abs (n = 5), anti-140 Abs (n = 8), and anti-ARS Abs (n = 7) did not overlap each other. All of the anti-155/140 Ab-positive patients (n = 5) were complicated by malignancies, as were all of the anti-140 Ab-positive patients (n = 8), who showed rapidly progressive interstitial lung disease (ILD). The survival rate at 6 months from the diagnosis of DM was significantly lower in the anti-140 Ab-positive patients than in the other patients. CONCLUSION: This is the first study to report, in a single cohort of DM patients, that distinct clinical subsets are distributed in an anti-155/140 Ab-positive group, an anti-140 Ab-positive group, or an anti-ARS Ab-positive group. Our data also confirm previous evidence that anti-155/140 Abs are involved in malignancies and that anti-140 Abs are involved in rapidly progressive ILD.

Concentrations of alpha- and beta-defensins in plasma of patients with inflammatory bowel disease.

BACKGROUND: Impaired production/release of defensins, representative endogenous antimicrobial peptides, is associated with the pathogenesis of inflammatory bowel disease (IBD). MATERIAL AND METHODS: Employing in house radioimmunoassay, we examined concentrations of the major forms alpha-defensins, human neutrophil peptides (HNP) 1-3 and human beta-defensin (HBD)-2 in plasma of 55 IBD patients consisting of 29 patients with ulcerative colitis (UC) and 26 with Crohn's disease (CD) and 57 controls. RESULTS: The circulating HNP 1-3, but not HBD-2, levels in IBD patients were significantly higher than those in controls. Plasma HNP 1-3 concentrations in CD patients significantly correlated with Crohn's disease activity index, peripheral white blood cell counts, serum CRP values and TNF-alpha levels. CONCLUSIONS: Elevation of circulating alpha-defensins levels is suggestive of their physiopathological roles in IBD. Plasma HNP 1-3 concentrations may be an indicator for CD activity and their association with CRP and TNF-alpha supports a possible association with the inflammatory process.

Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells.

Summary The macrolide antibiotics are now well known to have anti-inflammatory effects. Because dendritic cells (DCs) orchestrate immune responses, we examined the in vitro effects of clarithromycin (CAM), azithromycin (AZM) and midecamycin (MDM) on the expression of co-stimulatory molecules and production of cytokines [interleukin (IL)-10, IL-6, interferon (IFN)-gamma, IL-12p40, tumour necrosis factor (TNF)-alpha] of murine bone marrow-derived DCs by lipopolysaccharide (LPS) stimulation. A 15-membered macrolide, AZM, and a 14-membered macrolide, CAM, significantly enhanced the intensity of a co-stimulatory molecule, CD80, on DCs but not CD86 and CD40. AZM significantly increased the production of IL-10 and CAM significantly inhibited the production of IL-6 by DCs. However, a 16-membered macrolide, MDM, did not have any significant effect on these surface markers and cytokine productions. Moreover, AZM increased IL-10 and CAM decreased IL-2 productions significantly, when naive T cells derived from spleen were co-cultured with DCs treated in advance with LPS and these macrolides. These findings suggest that 14-membered and 15-membered, but not 16-membered macrolides play as anti-inflammatory agents, at least in part, through modulating the functions of DCs. However, each macrolide affects them in different ways.

Identification of hBD-3 in respiratory tract and serum: the increase in pneumonia.

Human beta-defensin (hBD)-3, a 45 amino acid antimicrobial peptide, was originally isolated from human skin. hBD-3 mRNA has also been detected in the airways by RT-PCR. While hBD-3 may be involved in antimicrobial defences within the respiratory tract, the presence of hBD-3 peptide in the respiratory system has not yet been confirmed. The antimicrobial activity of the synthesised hBD-3 peptide was measured by a radial diffusion assay and a colony count assay. The present authors confirmed the presence of hBD-3 peptide in homogenates of human lung and serum using reverse-phase HPLC coupled with a highly sensitive RIA. The localisation of the hBD-3 peptide was investigated by immunohistochemistry. In addition, the serum concentrations of hBD-3 were measured by RIA. hBD-3 exhibited a strong antimicrobial activity, which was unaffected by increasing salt concentrations. Immunohistochemically, the current authors observed the expression of hBD-3 in bronchial and bronchiolar epithelial cells. The mean+/-sd serum concentration of hBD-3 in patients with bacterial pneumonia was 239.4+/-17.8 pg x mL(-1) in the acute phase and, decreased to 159.3+/-20.1 pg x mL(-1) after the completion of therapy. In conclusion, these findings will help elucidate the role of human beta-defensin-3 in host immune responses and identify the pathophysiological significance of this molecule in respiratory infections.

Effects of macrolides on pneumolysin of macrolide-resistant Streptococcus pneumoniae.

To clarify the discrepancy between increasing resistance and conservative clinical effects of macrolides on macrolide-resistant Streptococcus pneumoniae, the authors evaluated the effects of sub-minimum inhibitory concentrations of macrolides on pneumolysin. In vitro, S. pneumoniae was incubated with 1, 2 and 4 microg.mL(-1) of clarithromycin (CLR) and azithromycin (AZM) for 8 h. Western blot analysis and haemolytic assay were performed to examine the production and activities of pneumolysin. In vivo, mice were infected with S. pneumoniae intra-nasally and treated with CLR (40 or 200 mg.kg(-1) twice daily) or AZM (40 or 200 mg.kg(-1) once daily) orally for 7 days. After 72 h post-infection, western blot analysis was performed to examine pneumolysin production in lungs. Survival rates were observed for 10 days. In vitro, every concentration of macrolide inhibited pneumolysin production more than the control. CLR (2 and 4 microg.mL(-1)) and AZM (4 microg.mL(-1)) reduced the pneumolysin activities more than the control. In vivo, macrolides (200 mg.kg(-1)) reduced pneumolysin in murine lungs more than the control. CLR (40 and 200 mg.kg(-1)) and AZM (200 mg.kg(-1)) improved the survival rates more than the control. The study results show that sub-minimum inhibitory concentrations of macrolides reduced pneumolysin. This might be related to the effectiveness of macrolides against pneumonia caused by high-level macrolide-resistant Streptococcus pneumoniae. Further investigations are necessary to evaluate the effects of macrolides on macrolide-resistant Streptococcus pneumoniae.

High plasma concentrations of osteopontin in patients with interstitial pneumonia.

Osteopontin (OPN) produced by alveolar macrophages functions as a fibrogenic cytokine in the development of bleomycin (BLM)-induced murine pulmonary fibrosis, and OPN mRNA is expressed on lung tissues from patients with idiopathic pulmonary fibrosis (IPF). The present study investigates plasma OPN levels in human interstitial pneumonia (IP) and their relationships with disease severity by analyzing the correlation between plasma OPN concentrations and pulmonary functions. The concentrations of OPN in plasma were measured in 17 patients with IP, in 9 with sarcoidosis and in 20 healthy controls using an antigen-capture enzyme-linked immunosorbent assay. The concentrations of OPN in plasma were significantly higher in IP patients than in those with sarcoidosis or in controls. Based on a Receiver Operating Characteristic curve analysis, cut-off points between 300 and 380 ng/ml discriminated between IP and control subjects with 100% sensitivity and 100% specificity. In such case, the sensitivity for sarcoidosis decreased (55.5-33.3%) in cut-offs with 100% specificity. Plasma OPN levels inversely and closely correlated with arterial oxygen tension (PaO2) in patients with IP. Immunohistochemically, OPN was localized predominantly in macrophages and airway epithelium. These findings suggest that plasma OPN levels were found to be associated with the presence of IP, and that OPN play an important role in the development of IP.

Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis.

Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. The present study was undertaken to investigate whether treatment with the antifibrotic drug pirfenidone attenuates the bleomycin (BL)-induced overexpression of HSP47 in the lungs. Male ICR mice were intravenously injected with BL or saline (SA). Pirfenidone or control drug (CD) was administered 14 days after commencement of BL or SA, and continued throughout the course of the experiment. The mice were randomly divided into three experimental groups: 1) SA-treated with CD (SA group); 2) BL-treated with CD (BL group); and 3) BL-treated with pirfenidone (pirfenidone group). Lungs of the pirfenidone group showed a marked reduction of fibrotic lesions compared with the corresponding BL group. Immunohistochemical studies showed that BL treatment significantly increased the number of macrophages, myofibroblasts, HSP47-positive type II pneumocytes and HSP47-positive interstitial spindle-shaped cells. Treatment with pirfenidone significantly reduced the number of these cells compared with the corresponding BL group. Furthermore, treatment with pirfenidone significantly suppressed the BL-induced increase of the positive ratio of HSP47 and alpha-smooth muscle actin to interstitial spindle-shaped cells. The present study results showed that pirfenidone inhibited heat shock protein 47-positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis.

Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis.

Diffuse panbronchiolitis (DPB) can now be cured with long-term erythromycin treatment. Our group conducted a prospective open trial of long-term treatment with a macrolide antibiotic, clarithromycin. We studied ten patients who were treated for 4 years with oral clarithromycin (200 mg once a day). Pulmonary function test, blood gas analysis, comprehensive improvement score, and bacterial culture of sputum were examined at 3, 6, 12 months, and at 2, 3, 4 years after the initiation of the therapy. Pulmonary function improved in most of the patients within 6 months: the forced expiratory volume in one second showed a maximal increase from a mean (SE) value of 1.74 (0.12) l at baseline to 2.31 (0.22) l at 6 months (P < 0.01) and the volume (l) of forced vital capacity also showed a maximal increase within 6 months. The partial pressure of arterial oxygen at rest significantly increased at 3-6 months. The comprehensive improvement score also reached maximum within 6 months in nine of the patients. The majority of patients have developed sputum culture in which bacteria were negative within 6 months after the therapy. All of the patients maintained a stable condition with continued therapy, and no side effects of clarithromycin were observed during the study. This prospective study demonstrated that 6-month treatment with clarithromycin might be necessary to improve the clinical conditions of patients with DPB and the drug could be safely used for a long term.

Increased concentrations of human beta-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis.

BACKGROUND: Human beta-defensin (HBD)-1 and -2 are antimicrobial peptides present in the respiratory tract. Recent reports have indicated reduced activity of beta-defensins in cystic fibrosis, suggesting that beta-defensins may play an important role in the pathological process of chronic respiratory tract infection. Diffuse panbronchiolitis (DPB) is a progressive disease characterised by frequent episodes of superimposed infection, typically caused by Pseudomonas aeruginosa. The aim of this study was to elucidate the role of these antimicrobial peptides in this disease. METHODS: The concentrations of HBD-1 and HBD-2 in plasma and bronchoalveolar lavage (BAL) fluid from 33 patients with DPB and 30 normal adults were measured by radioimmunoassay. Localisation of HBD-2 was investigated immunohistochemically in an open lung biopsy specimen obtained from a patient with DPB. RESULTS: High concentrations of HBD-1 and HBD-2 were noted in BAL fluid from DPB patients. Increased plasma concentrations of HBD-2, but not HBD-1, were found in patients with DPB compared with control subjects. In patients with DPB the HBD-2 concentration in BAL fluid correlated significantly with the numbers of cells recovered from the BAL fluid (total cells, neutrophils, and lymphocytes) and with the BAL fluid concentration of IL-1beta. Synthetic HBD-2, but not HBD-1, had dose dependent bactericidal activity against P aeruginosa. Treatment of 14 patients with macrolides significantly reduced BAL fluid concentrations of HBD-2 but not HBD-1 or plasma concentrations of HBD-1 and HBD-2. Immunohistochemistry of lung tissue showed localisation of HBD-2 in the epithelia of the distal bronchioles. CONCLUSIONS: These results indicate that beta-defensins, particularly HBD-2, participate in antimicrobial defence in the respiratory tract in DPB, and that the BAL fluid concentration of HBD-2 may be a useful marker of airway inflammation in patients with DPB.

High serum concentrations of surfactant protein A in usual interstitial pneumonia compared with non-specific interstitial pneumonia.

BACKGROUND: The pathological diagnosis of interstitial lung diseases (ILD) by surgical lung biopsy is important for clinical decision making. There is a need, however, to use serum markers for differentiating usual interstitial pneumonia (UIP) from other ILD. Surfactant protein (SP)-A, SP-D, KL-6, sialyl SSEA-1 (SLX), and sialyl Lewis(a) (CA19-9) are useful markers for the diagnosis and evaluation of activity of ILD. We have investigated the usefulness of these proteins as markers of UIP. METHODS: Serum and bronchoalveolar lavage (BAL) fluid levels of the above five markers were measured in 57 patients with various forms of ILD (19 with UIP, 12 with non-specific interstitial pneumonia (NSIP), eight with bronchiolitis obliterans organising pneumonia (BOOP), and 10 with sarcoidosis), eight patients with the control disease (diffuse panbronchiolitis (DPB)), and nine healthy volunteers. RESULTS: Serum levels of SP-A, SP-D, and KL-6 in patients with UIP and NSIP were significantly higher than in healthy volunteers. In particular, the serum levels of SP-A in patients with UIP were significantly higher than in patients with NSIP (p<0.0001, mean difference -58.3 ng/ml, 95% confidence interval -81.6 to -35.0), and BAL fluid levels of SP-D in patients with UIP were significantly lower than in patients with NSIP (p=0.01, mean difference 322.4 ng/ml, 95% confidence interval 79.3 to 565.5). CONCLUSION: Serum SP-A levels may be clinically useful as a biomarker to differentiate between UIP and NSIP.

Elevated levels of thymus and activation-regulated chemokine (TARC) in pleural effusion samples from patients infested with Paragonimus westermani.

To investigate the pathogenic mechanisms of eosinophilic pleural effusion in patients with paragonimiasis, we measured the levels of various chemokines including thymus and activation-regulated chemokine (TARC), eotaxin, RANTES and IL-8 in pleural effusion samples. Samples were obtained from 11 patients with Paragonimus westermani infection, six patients with pleural transudate, eight with tuberculous pleurisy and five with empyema. High percentages of eosinophils were detected in pleural fluid (range 9-100%, median 81%) of patients with paragonimiasis. TARC concentrations in pleural effusions of paragonimiasis were markedly higher than those of other groups. Eotaxin levels were also higher in pleural effusions of paragonimiasis patients, although significant difference was noted only against transudate samples. There was a significant correlation between TARC concentrations and percentages of eosinophils, and between TARC and eotaxin concentrations in pleural effusion. There were also significant correlations between TARC concentration and the titre of anti-P. westermani IgG and between eotaxin concentration and the titre of anti-P. westermani IgG. Our findings suggest that TARC contributes to the pathogenesis of eosinophilic pleural effusion in paragonimiasis.

Raised plasma concentrations of alpha-defensins in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Neutrophils are thought to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Human neutrophils contain antimicrobial and cytotoxic peptides in the azurophil granules which belong to a family of mammalian neutrophil peptides named alpha-defensins. A study was undertaken to investigate the role of alpha-defensins in the pathogenesis of IPF. METHODS: The concentrations of alpha-defensins (human neutrophil peptides (HNPs) 1, 2, and 3) in plasma and bronchoalveolar lavage (BAL) fluid of 30 patients with IPF and 15 healthy subjects were measured by radioimmunoassay. RESULTS: The concentrations of alpha-defensins in plasma, but not in BAL fluid, were significantly higher in IPF patients than in controls. BAL fluid concentrations of interleukin (IL)-8 in patients with IPF, which were significantly higher than in controls, correlated with those of alpha-defensins. An inverse relationship was seen between plasma alpha-defensin levels and the arterial oxygen tension (PaO(2)) and pulmonary function (vital capacity (%VC), forced expiratory volume in 1 second (FEV(1)), and carbon monoxide transfer factor (%TLCO)) in patients with IPF. Plasma levels of alpha-defensins also correlated with the clinical course in IPF patients with an acute exacerbation. Immunohistochemically, positive staining was observed inside and outside neutrophils in the alveolar septa, especially in dense fibrotic areas. CONCLUSION: These findings suggest that alpha-defensins play an important role in the pathogenesis of IPF, and that the plasma alpha-defensin level may be a useful marker of disease severity and activity.

Characterization of CD44 expressed on alveolar macrophages in patients with diffuse panbronchiolitis.

Interleukin (IL)-8 may play an important role in neutrophil infiltration in the airways of patients with diffuse panbronchiolitis (DPB). Furthermore, alveolar macrophages could produce IL-8 subsequent to CD44-hyaluronic acid (HA) interaction. The purpose of this study was to evaluate the contribution of CD44 expressed on alveolar macrophages to the pathogenesis of DPB. We examined the concentration of soluble CD44 (sCD44) in bronchoalveolar lavage fluid (BALF) and CD44 expression on macrophages in BALF from patients with DPB before and after low-dose, long-term macrolide therapy. We also assessed the HA-binding ability of alveolar macrophages as a functional analysis of the CD44 molecule. The sCD44 concentration in BALF was significantly lower in patients with DPB than in healthy volunteers. Percentages of alveolar macrophages expressing low CD44 (CD44 low(+)) and HA-nonbinding alveolar macrophages were higher in patients with DPB compared with healthy volunteers. Furthermore, macrolide therapy normalized CD44 expression and HA-binding ability of macrophages in BALF from DPB patients. Our findings suggest that alveolar macrophage dysfunction could result from abnormalities of CD44 expression in patients with DPB and that these events could contribute to the pathogenesis of DPB.

[Two cases of visceral larva migrans due to Ascaris suum showing a migratory nodular shadow].

The number of cases of visceral larva migrans caused by the pig ascarid, Ascaris suum has recently been increasing. We have encountered two cases of visceral larva migrans due to A. suum with a nodular shadow on the chest radiograph and eosinophilia in the peripheral blood. Patient 1 was a 26-year-old man who had been admitted to our hospital for an elective minor operation. His chest radiology and chest computed tomography revealed a nodule in the left lung field. Peripheral blood eosinophil counts and serum IgE values were elevated. Radiological abnormality disappeared without treatment. Patient 2 was a 57-year-old man who had been admitted to our hospital because of a migratory nodule on chest radiography and eosinophilia in the peripheral blood. The diagnosis of visceral larva migrans caused by A. suum was made because the serum of both patients was positive for an antibody against A. suum. Patient 1 and patient 2 were accustomed to eating the raw flesh of wild boar and deer, and of chicken and turkey, respectively. Treatment with albentazole was effective in these patients.

Cytokines involved in the systemic inflammatory response induced by exposure to particulate matter air pollutants (PM(10)).

Elevated levels of ambient particulate matter (PM(10)) have been associated with increased cardiopulmonary morbidity and mortality. We previously showed that the deposition of particles in the lung induces a systemic inflammatory response that includes stimulation of the bone marrow. This marrow response is related to mediators released by alveolar macrophages (AM) and in this study we measured cytokines produced by human AM exposed to ambient particles of different composition and size. Identified cytokines were also measured in the circulation of healthy young subjects exposed to air pollutants during the 1997 Southeast Asian forest fires. Human AM were incubated with particle suspensions of residual oil fly ash (ROFA), ambient urban particles (EHC 93), inert carbon particles, and latex particles of different sizes (0.1, 1, and 10 microm) and concentrations for 24 h. Tumor necrosis factor-alpha (TNF-alpha) increases in a dose-dependent manner when AM were exposed to EHC 93 particles (p < 0.02). The TNF response of AM exposed to different sizes of latex particles was similar. The latex (158 +/- 31%), inert carbon (179 +/- 32%), and ROFA (216 +/- 34%) particles all show a similar maximum TNF response (percent change from baseline) whereas EHC 93 (1,020 +/- 212%, p < 0.05) showed a greater maximum response that was similar to lipopolysaccharide (LPS) 1 microg/ml (812 +/- 320%). Macrophages incubated with an optimal dose of EHC 93 particles (0.1 mg/ml) also produce a broad spectrum of other proinflammatory cytokines, particularly interleukin (IL)-6 (p < 0.01), IL-1 beta (p < 0.05), macrophage inflammatory protein-1 alpha (MIP-1 alpha) (p < 0.05), and granulocyte macrophage colony-stimulating factor (GM-CSF) (p < 0.01) with no difference in concentrations of the anti-inflammatory cytokine IL-10 (p = NS). Circulating levels of IL-1 beta, IL-6, and GM-CSF were elevated in subjects exposed to high levels of PM(10) during an episode of acute air pollution. These results show that a range of different particles stimulate AM to produce proinflammatory cytokines and these cytokines are also present in the blood of subjects during an episode of acute atmospheric air pollution. We postulate that these cytokines induced a systemic response that has an important role in the pathogenesis of the cardiopulmonary adverse health effects associated with atmospheric pollution.