Heterogeneity of perception of symptoms in patients with asthma.

BACKGROUND: Cough-dominant or cough-variant asthma is common in Japan. However, it is unclear whether cough and dyspnea, the cardinal symptoms of bronchial asthma, are similarly perceived, and whether these symptoms are linked to pulmonary function tests. METHODS: The subjects were 548 physician-diagnosed naive patients with asthma. Visual analogue scale (VAS) scores were determined and spirometry was performed before and after 1-month inhaled corticosteroid/long-acting beta2 agonist therapy. RESULTS: The patients were divided into those with a significant bronchodilating response and an increase in FEV1 (>12% and >200 mL) after treatment (n=146); and nonresponders without this response (n=402). Cough was more dominant than dyspnea in both groups at the initial evaluation. Both symptoms were diminished after treatment, but scores for cough remained significantly higher than those for dyspnea in nonresponders. VAS scores for dyspnea at both time points differed in responders and nonresponders, and changes of cough and dyspnea scores were larger in responders. In responders, peak expiratory flow (PEF) (absolute, %predicted) for cough and FEV1 (%predicted), VC (%predicted) and PEF (absolute) for dyspnea were correlated at both time points, but in nonresponders, neither cough nor dyspnea was related to a common spirometric parameter at both time points. Changes in cough and dyspnea scores were correlated with changes of FEV1 (absolute, %predicted) and FEF25-75 (absolute) for responders, while only PEF (%predicted) was correlated with these changes in nonresponders. Calculated slopes (ΔVAS score/ΔFEV1) suggested that responders were more sensitive to dyspnea than nonresponders. CONCLUSIONS: Perception of cough and dyspnea were similar, but not identical, for bronchodilating responders and nonresponders among patients with bronchial asthma. Linkage of pulmonary function parameters with perceptions of cough and dyspnea also differed between the responders and nonresponders.

Concave pattern of a maximal expiratory flow-volume curve: a sign of airflow limitation in adult bronchial asthma.

Background. In patients with bronchial asthma, spirometry could identify the airflow limitation of small airways by evaluating the concave shape of the maximal expiratory flow-volume (MEFV) curve. As the concave shape of the MEFV curve is not well documented, we reevaluated the importance of this curve in adult asthmatic patients. Methods. We evaluated spirometric parameters, the MEFV curve, and its concave shape (scoop between the peak and endpoint of expiration) in 27 nonsmoking asthmatic patients with physician-confirmed wheeze and positive bronchial reversibility after a short-acting ß2-agonist inhalation. We also calculated angle ß and shape factors (SF(25%) and SF(50%)) to quantitate the curvilinearity of the MEFV curve. Results. The MEFV curve was concave in all patients. Along with improvements in standard spirometric parameters, curvilinear parameters, angle ß, SF(25%), and SF(50%) were significantly improved after bronchodilator inhalation. There were significant correlations between improvements in angle ß, and FEF(50%), and FEF(25-75%), and between improvements in SF(25%), and SF(50%), and FEF(75%). Conclusions. The bronchodilator greatly affected the concave shape of the MEFV curve, correlating with spirometric parameters of small airway obstructions (FEF(50%), FEF(75%), and FEF(25-75%)). Thus, the concave shape of the MEFV curve is an important indicator of airflow limitation in adult asthmatic patients.

Bronchial reversibility with a short-acting ß2-agonist predicts the FEV1 response to administration of a long-acting ß2-agonist with inhaled corticosteroids in patients with bronchial asthma.

A long-acting ß2-agonist (LABA) combined with an inhaled corticosteroid (ICS) is frequently prescribed as initial therapy in steroid-naïve asthma patients because of its effective control of symptoms and improvement of pulmonary function. However, it is unclear which patients will be responsive to LABAs and whether bronchial responsiveness to LABAs is similar to that to short-acting ß2-agonists (SABAs) in a clinical setting. Therefore, the goal of the present study was to compare the changes in spirometric parameters after SABA (salbutamol) inhalation to those after 1-month LABA/ICS (salmeterol/fluticasone propionate) therapy. Spirometric changes were evaluated as absolute values, as the percentage of predicted normal values and as the percentage of baseline values after salbutamol inhalation or 1-month LABA/ICS therapy in 45 patients with asthma. Compared to SABA inhalation, LABA/ICS therapy produced significant improvements in forced expiratory volume in 1 sec (FEV1), peak expiratory flow (PEF), forced expiratory flow at 50% of vital capacity expired (FEF50%) from baseline (expressed as the percentage predicted) in all patients. FEV1 and the FEV1/forced vital capacity (FVC) ratio after SABA or LABA/ICS therapy were inversely related to the corresponding baseline values. Analysis of spirometric changes after SABA inhalation showed that FEV1 was the best among spirometric parameters, such as PEF, correlated with responsiveness to LABA/ICS therapy. Reversibility of FEV1 with SABA inhalation predicts the spirometric response to LABA/ICS as initial therapy in patients with bronchial asthma. LABA/ICS therapy had a greater effect on bronchial reversibility in asthmatic patients, compared to SABA inhalation. This suggested that evaluation of bronchial reversibility after LABA/ICS therapy would be superior to that after SABA inhalation.

[Evaluation of clinical effectiveness of Pazufloxacin Mesilate in acute exacerbation of chronic respiratory diseases].

Patients with chronic respiratory disease have increased susceptibility to infection, because of impairment of the local immunologic defense mechanism in the airway system, which often results in acute exacerbation. Acute exacerbation of chronic respiratory disease is one of the most important predictors of increased morbidity and mortality, and thus the management in the acute phase is essential for better prognosis. Although the clinical guidelines for the management of respiratory tract infections published by the Japanese Respiratory Society recommend administering fluoroquinolones intravenously in case of hospitalized patients, the clinical evidence is still limited. In this study, we evaluated the efficacy of Pazufloxacin Mesilate (PZFX). an intravenous fluoroquinolone. in patients with chronic respiratory diseases complicated with acute exacerbation caused by acute respiratory infections. As a result, 16 out of 18 cases were successfully treated with PZFX. No adverse event was observed during this study. These results may support the validity of administering intravenous fluoroquinolone in hospitalized patients with acute exacerbation caused by infections, as recommended by the Japanese Respiratory Society.

Pulmonary paragonimiasis with coincidental malignant mesothelioma.

A 72-year-old man patient was referred to our institution for evaluation and treatment of right pleural effusion. Eosinophilic pleural effusion and peripheral eosinophilia were identified during the course of hospitalization. Pulmonary paragonimiasis was confirmed by the presence of paragonimus-specific IgG antibodies for Paragonimus (P.) westermani and P. miyazakii in his serum. Although Praziquantel, a highly effective agent for the treatment of lung flukes was repeatedly administered, the pleural effusion did not subside and the patient's condition gradually deteriorated until his death due to circulatory insufficiency. Postmortem examination revealed malignant mesothelioma of the sarcomatous type encasing the right lung and heart. Cardiac involvement accompanied with old and recent-onset myocardial ischemic changes resulted in death of this patient. Here, we report a very rare case of malignant mesothelioma with a concomitant infection of parasitic lung fluke.

Ultrasonographic evaluation of the diaphragm in patients with amyotrophic lateral sclerosis.

Real-time diaphragmatic movement was evaluated with ultrasonography in three patients with amyotrophic lateral sclerosis (ALS). The initial complaint of two patients was weakness of the extremities followed by dyspnoea later in the disease course, while the third patient had dyspnoea as the initial symptom. Ultrasonographic analyses revealed that the contractile function of the diaphragm was not maintained during maximum inspiratory effort, with unsatisfactory diaphragmatic excursion and no change in diaphragmatic thickness during respiration, indicating diaphragmatic paralysis. Ultrasonography may be useful for the diagnosis and follow up of diaphragmatic involvement with amyotrophic lateral sclerosis and other motor-neuron diseases.

Immune responses against a single CD8+-T-cell epitope induced by virus vector vaccination can successfully control Trypanosoma cruzi infection.

In order to develop CD8+-T-cell-mediated immunotherapy against intracellular infectious agents, vaccination using recombinant virus vectors has become a promising strategy. In this study, we generated recombinant adenoviral and vaccinia virus vectors expressing a single CD8+-T-cell epitope, ANYNFTLV, which is derived from a Trypanosoma cruzi antigen. Immunogenicity of these two recombinant virus vectors was confirmed by the detection of ANYNFTLV-specific CD8+ T cells in the spleens of immunized mice. Priming/boosting immunization using combinations of these two recombinant virus vectors revealed that the adenovirus vector was efficient for priming and the vaccinia virus vector was effective for boosting the CD8+-T-cell responses. Moreover, we also demonstrated that the ANYNFTLV-specific CD8+-T-cell responses were further augmented by coadministration of recombinant vaccinia virus vector expressing the receptor activator of NFkappaB (RANK) ligand as an adjuvant. By priming with the adenovirus vector expressing ANYNFTLV and boosting with the vaccinia virus vectors expressing ANYNFTLV and RANK ligand, the immunized mice were efficiently protected from subsequent challenge with lethal doses of T. cruzi. These results indicated, for the first time, that the induction of immune responses against a single CD8+-T-cell epitope derived from an intrinsic T. cruzi antigen was sufficient to control lethal T. cruzi infection.

[A patient with pleural thickening of sarcoidosis].

We report a 51-year-old woman with characteristic pleural involvement of sarcoidosis. Video-assisted thoracoscopic examination identified diffuse pleural thickening in the right lung, which coincided in distribution with parenchymal reticular shadows demonstrated with high-resolution thoracic CT scan. Biopsied specimens revealed epithelioid cell granuloma with noncaseating necrosis and multi-nucleated giant cells in the parenchymal lung tissue. Infiltration of inflammatory cells was demonstrated in the thickened pleural tissue, but no typical sarcoid lesion. This pleural lesion was considered as pleural involvement of sarcoidosis, since deterioration of the pleural thickening was accompanied with progression of a parenchymal sarcoid lesion during the period of two months after biopsy. Video-assisted thoracoscopy and high-resolution CT scan both supported the diagnosis of sarcoidosis with pleural involvement.

[Clinical evaluation of meningeal carcinomatosis associated with primary lung cancer].

We evaluated diagnosis and treatment of four cases of meningeal carcinomatosis associated with primary lung cancer: case 1; small cell carcinoma (64 years old), case 2; small cell carcinoma (50 years old), case 3; adenocarcinoma (53 years old), and case 4; adenocarcinoma (55 years old). Determination of tumor markers in cerebrospinal fluid (CSF) together with the MRI findings that Gd-DTPA-enhanced T1-weighted image showing high intensity signal along the spinal cord was clinically useful in the diagnosis of meningeal carcinomatosis. Two of four patients received intrathecal chemotherapy and/or CSF drainage through Ommaya-Reservoir, resulting in dramatic improvement of various symptoms such as motor weakness and vesicorectal disorder. Intrathecal chemotherapy and placement of an Ommaya-Reservoir for CSF drainage should be considered to provide better Quality of Life (QOL) when patient can tolerate it.

Visible male nipple shadows in chest radiographs.

OBJECTIVE: Annual company employee physical examinations are performed in Japan and include a chest X-ray. Among nodular shadows observed in the lower lung field, nipple shadow is a normal structure to be differentiated, and understanding its characteristics in chest X-rays aids in the interpretation of solitary nodular shadows. METHODOLOGY: Chest X-rays from male employees over 35 years of age at two different companies were analysed for anatomical location, morphology, and size of nipple shadows. If unilateral or bilateral solitary nodular shadows in the lower lung field coincided with the lead nipple marker, we defined it as 'definitive' nipple shadow. If the nodular shadow was observed to be stable for at least 2 years at the typical nipple position, we defined it as 'possible' nipple shadow without confirmation with nipple marking. RESULTS: Typical nipple position, from the analyses of definitive nipple shadows (n = 15), was between the ninth and tenth posterior ribs and within 60 mm from the inner margin of the rib. The nipple was oval or round and did not exceed 15 mm in size. Incidence of definitive and possible (n = 25) nipple shadows was estimated as 3.5% of examined males (n = 1150). Thoracic computed tomography scanning was conducted in four cases, of which three cases involved solitary nodular shadows that did not coincide with the nipple marker, and one was for a newly formed nodular lesion not detected in previous chest X-rays. CONCLUSION: Visible male nipple shadows are not rare and need to be differentiated among the solitary nodular shadows in the lower lung field.

Inhalation of tobramycin in a patient with aspiration pneumonia as a result of medullary stroke.

A 78-year-old man suffered from refractory aspiration pneumonia as a result of a minor medullary stroke. The only neurological symptom observed in this patient was difficulty in swallowing. He was managed with i.v. hyperalimentation with termination of oral intake, including water. However, he still experienced several episodes of aspiration pneumonia. As he was considered to have a bacterial infection because of silent aspiration of colonized oropharyngeal material, inhalation of tobramycin was introduced and successful control of airway infection was attained.

Immunohistochemistry for the differentiation of peritoneal disseminated carcinoma of unknown origin.

We report a woman with ascites, hydrothorax, pancreatic tumor, left cystic ovarian tumor, and an elevated serum cancer antigen 125 level. Exploratory laparotomy was performed to determine peritoneal disseminated carcinoma of unknown origin. Immunohistochemical analysis demonstrated positive staining for carcinoembryonic antigen, trypsin, and progesterone receptor and nonspecific or negative reaction for calretinin, estrogen receptor, amylase, lipase, Wilms tumor gene 1 protein, and inhibin or chromogranin A. These results together with the morphology of tubular structure suggested the pathological diagnosis of adenocarcinoma with pancreatic characteristics and contradicted ovarian cancer or mesothelioma. Immunohistochemistry is an adjunct tool to differentiate the primary site of carcinomatous peritonitis.

Pancoast's syndrome in a patient with B-cell lymphoma diagnosed and confirmed with immunoglobulin gene rearrangement.

Pancoast's syndrome due to malignant lymphoma is extremely rare. A case of diffuse large B-cell lymphoma presenting as Pancoast's syndrome is described. A 66-year-old man complained of pain and weakness of the right arm, and CXR revealed a right apical lung tumour. Histological findings were consistent with it being a diffuse large cell type lymphoma and Southern blot analysis revealed clonal rearrangement of the immunoglobulin heavy-chain JH. Thus, the tumour in this patient was diagnosed to be diffuse large B-cell lymphoma. Malignant lymphoma is an extremely rare cause of Pancoast's syndrome and only five cases have been described. This is the first reported case of Pancoast's syndrome caused by B-cell lymphoma, which was accurately diagnosed by analysis of gene rearrangement.

Acid exposure potentiates intercellular adhesion molecule-1 and e-cadherin expression on A549 alveolar lining epithelial cells.

Recruitment of neutrophils into the alveoli plays a major role in the pathogenesis of acid-induced pneumonitis. Preliminary data suggest that alteration in the expression of cellular adhesion molecules on the airway epithelial cells may play an important role in the recruitment of neutrophils following acid-induced lung injury. The aim of this study was to evaluate the change in the surface expression of intercellular adhesion molecule-1 (ICAM-1), E-cadherin, and vascular cell adhesion molecule -1 (VCAM-1) on acid-exposed A549 alveolar lining epithelial cells by flow cytometry and confocal laser microscopy. Acid exposure changed cell morphology, increased cell adhesion after trypsin-EDTA treatment, and up-regulated the expression of ICAM-1 and E-cadherin but not of VCAM-1. The up-regulation of ICAM-1 expression will induce the dysfunction of epithelial cells with or without accumulation of neutrophils in air spaces. Because the distribution of E-cadherin in acid-exposed A549 cells was at the sites where the cells attached to culture dish but not at the intercellular junctions between adjoining cells, up-regulated expression of E-cadherin will rather result in alterations of epithelial morphology and function of epithelial barrier. In addition, pentoxifylline suppressed the up-regulation of ICAM-1 and E-cadherin expression and may therefore attenuated the airway inflammation in acid-induced pneumonitis.

CD4+ T cells in lung tissue predict responsiveness to cyclosporin A in interstitial pneumonia.

OBJECTIVE: A limited number of case studies have demonstrated the steroid-sparing and disease stabilization effects of cyclosporin A (CsA) combined with corticosteroid in patients with chronic interstitial pneumonia (IP). Although CsA is known to inhibit the proliferation and function of CD4+ T cells, it is not clear what type of IP is responsive to CsA administration. METHODOLOGY: In order to evaluate whether any lymphocyte subsets in alveolar tissue predict the responsiveness to CsA, morphometric analysis was performed on lung tissue obtained from six IP patients who were treated with a combination of CsA and steroid because the therapeutic effect of steroid alone had been limited. RESULTS: Cell densities of CD4+ T cells were significantly decreased in the alveolar tissues obtained from CsA responders (n = 3) compared to non-responders (n = 3) (120 +/- 86/mm2 vs 503 +/- 172/mm2, P=0.0495). CD4/CD8 ratios of CsA responders were also significantly lower than those of non-responders (0.315 +/- 0.070 vs 1.975 +/- 0.965, P=0.0463). However, cell densities of CD8+ T cell and areas of B cells aggregates were similar in both groups. CONCLUSIONS: The present observations, contrary to expectation, reveal that lower cell densities of CD4+ T cells and lower CD4/CD8 ratios are associated with responsiveness to CsA in combination therapy, suggesting that pharmacological actions other than suppression of CD4+ T cells explain the efficacy of CsA in patients with chronic IP.

Increased circulating CD16+ CD14dim monocytes in a patient with pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is characterized by filling of the alveoli with a periodic acid-Schiff-positive proteinaceous material. Although the pathogenesis of primary or idiopathic PAP remains unknown, it has been proposed that a deficiency or loss of responsiveness of the monocyte/macrophage lineage to granulocyte-macrophage colony stimulating factor (GM-CSF) is involved in PAP. Secondary PAP is associated with haematological malignancies, especially in myeloid disorders. Herein, we report on an adult with PAP associated with myelodysplastic syndrome (MDS). The CD16+ CD14dim monocytes comprise 5-10% of circulating monocytes in healthy volunteers. Flow cytometric analysis of the patient in the present study revealed increased CD16+ CD14dim monocytes in the peripheral blood. It has been demonstrated that the expression of CD16 and CD14 is regulated by macrophage colony stimulating factor (M-CSF) and GM-CSF. Hence, serum cytokines were analysed in our patient and the concentration of serum GM-CSF was found to be less than the lower limit of the assay. In addition, serum M-CSF and granulocyte colony stimulating factor levels were only slightly increased above the normal range. These results suggest that the increase in the CD16+ CD14dim subpopulation in the circulation of our patient indicates another pathogenetic mechanism for secondary PAP, such as hyperresponsiveness of the monocyte/macrophage lineage to these cytokines.

Coadministration of an interleukin-12 gene and a Trypanosoma cruzi gene improves vaccine efficacy.

We tested the immunogenicity of two Trypanosoma cruzi antigens injected into mice in the form of DNA vaccine. Immunization with DNA encoding dihydroorotate dehydrogenase did not confer protective immunity in all mouse strains tested. Immunization with DNA encoding trans-sialidase surface antigen (TSSA) protected C57BL/6 (H-2(b)) mice but not BALB/c (H-2(d)) or C3H/Hej (H-2(k)) mice against lethal T. cruzi infection. In vivo depletion of CD4(+) or CD8(+) T cells abolished the protective immunity elicited by TSSA gene in C57BL/6 mice. Enzyme-linked immunospot assay with splenocytes from T. cruzi-infected mice or TSSA gene-vaccinated mice identified an H-2K(b)-restricted antigenic peptide, ANYNFTLV. The CD8(+)-T-cell line specific for this peptide could recognize T. cruzi-infected cells in vitro and could protect naive mice from lethal infection when adoptively transferred. Coadministration of the interleukin-12 (IL-12) gene with the TSSA gene facilitated the induction of ANYNFTLV-specific CD8(+) T cells and improved the vaccine efficacy against lethal T. cruzi infection. These results reinforced the utility of immunomodulatory adjuvants such as IL-12 gene for eliciting protective immunity against intracellular parasites by DNA vaccination.

Exogenous lipoid pneumonia following ingestion of liquid paraffin.

An asymptomatic patient with exogenous lipoid pneumonia (ELP) due to silent aspiration of liquid paraffin ingested as a lubricant was diagnosed by bronchoalveolar lavage (BAL). BAL fluid separated into oily upper phase and lower aqueous phase spontaneously. Microscopic analysis of BAL cells revealed the presence of lipid-laden alveolar macrophages. Classic histochemical staining and electron microscope examination indicated that neutral lipid was dominant but phospholipid was also present in the lipid-laden macrophages. Together with the history of ingestion of liquid paraffin, we identified that the ingested liquid paraffin was the origin of the neutral lipid in the lipid-laden macrophages observed in the BAL fluid.

Adenovirus vector-mediated transfer of 9 kDa granulysin induces DNA fragmentation in HuD antigen-expressing small cell lung cancer murine model cells.

OBJECTIVE: Granulysin is a tumoricidal molecule secreted by cytotoxic T cells (CTL) and natural killer (NK) cells, that induces apoptotic cell death in tumour cells. It has been demonstrated that small cell lung cancer (SCLC) cell lines are susceptible to NK cells and lymphokine activated killer (LAK) cells, and HuD antigen is assumed to be a target molecule on SCLC cells for host cellular immunity. METHODOLOGY: In order to understand the mechanism of sensitivity of SCLC to cellular immunity, we evaluated granulysin-induced apoptosis using mouse adenocarcinoma Colon 26 (Colon 26/HuD) cells transfected with the 9 kDa active form of granulysin using an adenovirus vector as a murine model of SCLC cells. RESULTS: Adenovirus vector-mediated transfer of 9 kDa granulysin increased DNA fragmentation in Colon 26/HuD cells 2.5-fold and suppressed Colon 26/HuD proliferation by 21% on day 3 (P < 0.05 for each value) compared with the control adenovirus vector transfer. In contrast, adenovirus vector-mediated transfer of 9 kDa granulysin did not increase DNA fragmentation nor suppress the proliferation of Colon 26 parent cells. CONCLUSIONS: The sensitivity of HuD-expressing tumour cells to granulysin is likely to partially explain the susceptibility of SCLC to cell-mediated immunity.