Lymphatic manifestations of lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a slowly progressive, low grade, metastasizing neoplasm, associated with cellular invasion and cystic destruction of the pulmonary parenchyma. Although the source of LAM cells that infiltrate the lung is unknown, available evidence indicates that the disease spreads primarily through lymphatic channels, often involving abdominal, axial, and retroperitoneal nodes, suggestive of an origin in the pelvis. LAM cells harbor mutations in tuberous sclerosis genes and produce lymphangiogenic growth factors, which facilitate access to and movement through the lymphatic system and likely play an important role in destructive tissue remodeling in the lung. Lymphatic manifestations of LAM include thoracic duct wall invasion, lymphangioleiomyoma formation, chylous fluid collections in the peritoneal, pleural, and pericardial spaces, chyloptysis, chylocolporrheal chylometrorrhea, chyle leak from the umbilicus, chylous pulmonary congestion, and lower extremity lymphedema. LAM lesions express lymphangiogenic growth factors VEGF-C and VEGF-D; growth factor receptors, VEGFR-2 and VEGFR-3; and markers LYVE-1 and podoplanin, and are laced with chaotic lymphatic channels. Serum VEGF-D is elevated in 70% of patients with LAM and is a clinically useful diagnostic and prognostic biomarker. Molecular targeted therapy with sirolimus stabilizes lung function, is anti-lymphangiogenic, and is highly effective for the lymphatic and chylous complications of LAM. Future trials in patients with LAM who have lymphatic manifestations or elevated serum VEGF-D will likely focus on the VEGF-C/VEGF-D/VEGFR-3 axis.

Polymyxin-B hemoperfusion for acute exacerbation of idiopathic pulmonary fibrosis: serum IL-7 as a prognostic marker.

BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) has an extremely poor prognosis. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) has been used to improve oxygenation for acute respiratory distress syndrome. The study aim was to retrospectively determine the predictive factors affecting the prognosis of AE of IPF treated with PMX-DHP. METHODS: We studied patients suffering from AE of IPF, treated with PMX-DHP combined with high-dose corticosteroid therapy. Stored serum taken before and after PMX-DHP therapy was analyzed for 27 cytokines and chemokines. RESULTS: Nineteen patients with AE of IPF were studied. The median survival time after diagnosis of AE was 22 days. Survival rates after diagnosis of AE were 47.4% at 30 days, 31.6% at 60 days, and 26.3% at 90 days. Serum levels of Interleukin (IL)-7, an anti-fibrotic cytokine, in survivors at day 30 following PMX-DHP therapy ('Survivors') significantly increased after the treatment, compared to serum levels of non-survivors at day 30 after the therapy ('Nonsurvivors'), which did not demonstrate a significant change. Serum levels of IL-1beta, interferon-y and chemokine ligand (CCL) 2 levels were not significantly altered in 'Survivors', but were significantly changed in 'Nonsurvivors.' Multivariate Cox proportional-hazards analysis showed that an increase in IL-7 levels after PMX-DHP therapy and treatment without intubation (other than invasive positive-pressure ventilation) were significantly better prognostic factors. CONCLUSION: The results suggest that serum IL-7 may be a useful prognostic factor for patients with AE of IPF treated with PMX-DHP, possibly reflecting underlying anti-fibrotic mechanisms.

Risk factors of acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a well known clinical condition, predicting risk factors remain unknown. We evaluated the frequency, risk factors and impact on survival of AE-IPF. METHODS: We retrospectively studied patients diagnosed with IPF based on the criteria of the ATS/ERS consensus statement and followed them for periods of more than 3 years except in dead cases. Initial characteristics including the level of dyspnoea, which was assessed with the modified Medical Research Council (MRC) scale, and decline of forced vital capacity (FVC) defined by at least 10% decline at 6 months, were evaluated as possible risk factors for AE. RESULTS: Seventy-four patients with IPF were studied. One-year, two-year, and three-year incidence of AE were 8.6%, 12.6%, and 23.9%, respectively. Multivariate analysis revealed that higher body mass index (BMI) [hazard ratio (HR), 1.20; 95% confidence interval (CI), 1.03-1.40], higher modified MRC scale [HR, 2.93; 95% CI, 1.46-5.85], and a decline in FVC at 6 mounths [HR, 0.97-2.60 (per mo); 95% CI, 1.01-7.45] were independent risk factors for AE-IPF. The causes of death were assessed to be AE in 20 of 57 expired patients. A stepwise multivariate Cox regression model evaluating AE-IPF, adjusted for %FVC and decline in FVC, demonstrated a statistically significant impact on overall survival [HR, 2.79; 95% CI, 1.59-4.88; p < 0.001]. CONCLUSION: These data suggest that initial high modified MRC scale, high BMI, and decline in FVC at 6 months were significant independent risk factors for AE-IPF. AE was an independent prognostic factor in IPF.

Long-term complications and prognosis of chronic beryllium disease.

BACKGROUND: Chronic beryllium disease (CBD) is a rare disease, and there are no previous reports that have followed CBD patients over several decades. Thus, the long-term complications and prognosis of this illness still remain unclear. OBJECTIVE: The aim of this study was to investigate long-term complications and prognosis of CBD patients. STUDY DESIGN AND METHODS: This was a retrospective study based on the medical records of all CBD patients diagnosed at Kyoto University Hospital between the period 1973 to the present day. Ultimately, ten patients whose diagnoses had been made during the period 1973 to 1977 were included. Long-term physiological and radiological change, complications and prognosis of these patients were investigated. RESULTS: Three patients completely remitted, and one died of cor-pulmonale. Among the remaining six patients, four have been followed up for more than thirty years in our institute. The majority developed mixed patterns of lung function impairment, cavity lesions of the lung, pneumothorax, and respiratory infections. CONCLUSIONS: Long-term prognosis of CBD was poor with several complications due to chronic parenchymal and airway lesions.

Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia.

Most studies of idiopathic nonspecific interstitial pneumonia (NSIP) have primarily studied mortality. In order to clarify the detailed outcome and prognostic markers in idiopathic NSIP, the clinical course with initial radiological and clinical features was analysed. The clinical course of 83 patients who were classified with idiopathic NSIP (72 fibrotic, 11 cellular; 27 males and 56 females; mean+/-sd age 54.4+/-10.1 yrs) was retrospectively analysed. In fibrotic NSIP, 16 (22%) patients died of NSIP-related causes with a median (range) follow-up of 53 (0.3-181) months. Despite the favourable survival (5-yr 74%), patients with fibrotic NSIP were frequently hospitalised with recurrence rate of 36%. Reduced forced vital capacity at 12 months was a predictor of mortality. On follow-up, lung function was improved or stable in approximately 80% of the patients. The extent of consolidation and ground-glass opacity on initial high-resolution computed tomography correlated significantly with serial changes of lung function, and the presence of honeycombing was a predictor of poor prognosis. During follow-up, eight (10%) patients developed collagen vascular disease. In conclusion, the overall prognosis of fibrotic nonspecific interstitial pneumonia was good; however, there were significant recurrences despite initial improvement and a subset of the patients did not respond to therapy. Some patients developed collagen vascular diseases at a later date.

Acute exacerbation of idiopathic pulmonary fibrosis as the initial presentation of the disease.

The clinical course of patients with idiopathic pulmonary fibrosis (IPF) is generally marked by a decline in pulmonary function over time, although recently there is increasing recognition that fatal deterioration from acute exacerbation can occur at any stage. The patient described in the present case study was a 65-yr-old male who presented with exertional dyspnoea and fever of 2 weeks' duration. He had no history of chronic lung disease or physiological or radiological hallmarks of pre-existing disease. He underwent surgical lung biopsy and the histological examination showed a background pattern of usual interstitial pneumonia (UIP) with a pattern of focal acute diffuse alveolar damage (DAD) in the area where normal lung architecture was preserved. It is notable that the pathological diagnosis of this rapidly progressive interstitial pneumonia was DAD on UIP, which is typically seen in acute exacerbations of IPF. Unusual findings on high-resolution computed tomography scan were also noted. We presume that in this case acute exacerbation developed in the very early course of IPF. Given the possibility that similar cases may have arisen among patients diagnosed with acute interstitial pneumonia or acute respiratory distress syndrome, the histopathology of rapidly progressive interstitial pneumonia may need to be revisited.

Changes in HRCT findings in patients with respiratory bronchiolitis-associated interstitial lung disease after smoking cessation.

High-resolution computed tomography (HRCT) findings in patients with respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) are varied and nonspecific. There is no known report of changes in HRCT findings and respiratory function test results for RB-ILD patients following the cessation of smoking. Five patients with RB-ILD, confirmed by surgical lung biopsy, were retrospectively studied. Each stopped cigarette smoking and did not receive corticosteroid therapy after diagnosis. The clinical symptoms, respiratory function test results and HRCT findings obtained at the final observation were compared with those from the time of diagnosis. Ground-glass opacity and centrilobular nodules corresponding to pathological respiratory bronchiolitis, as well as intralobular fine linear-reticular opacity corresponding to fibrosis involving the subpleural alveolar septa, showed computed tomography-pathological correlations. Both clinical symptoms and the diffusing capacity of the lungs for carbon monoxide improved significantly following smoking cessation, as did ground-glass opacity and centrilobular nodules seen during the initial HRCT examination. Centrilobular nodules and ground-glass opacity, which are the main features of high-resolution computed tomography of respiratory bronchiolitis-associated interstitial lung disease patients and represent pathological respiratory bronchiolitis, can be improved by smoking cessation. The diffusing capacity of the lung for carbon monoxide in respiratory function tests can be also improved.

Chronic bird fancier's lung: histopathological and clinical correlation. An application of the 2002 ATS/ERS consensus classification of the idiopathic interstitial pneumonias.

BACKGROUND: Chronic bird fancier's lung (BFL) has often been misdiagnosed as one of the idiopathic interstitial pneumonias (IIPs). METHODS: To define the clinical and pathological characteristics of chronic BFL, 26 patients with chronic BFL from whom a surgical lung biopsy specimen was taken between October 1992 and June 2001 were evaluated. The histopathological characteristics of the surgical lung biopsy specimens were examined and correlations between the histopathology and clinical characteristics were analysed. The quality of chronic inflammatory and fibrotic changes was expressed according to the 2002 ATS/ERS consensus classification of IIPs. RESULTS: Two patients were diagnosed as having bronchiolitis obliterans organising pneumonia (BOOP)-like lesions, five as having cellular non-specific interstitial pneumonia (NSIP)-like lesions, and eight as having fibrotic NSIP-like lesions. The other 11 patients were considered to have usual interstitial pneumonia (UIP)-like lesions because of the temporal heterogeneous appearances of the fibrotic changes. However, fibrosis in these patients had developed in centrilobular as well as perilobular areas, suggestive of hypersensitivity pneumonitis. Nineteen patients (73.1%) had multinucleated giant cells, often with cholesterol clefts, while only five patients (19.2%) had granulomas. Patients with BOOP-like or cellular NSIP-like lesions tended to have recurrent acute episodes, whereas patients with UIP-like lesions had an insidious onset. Patients with BOOP-like or cellular NSIP-like lesions had a more favourable outcome than those with fibrotic NSIP-like and UIP-like lesions. CONCLUSIONS: The qualities of chronic inflammatory and fibrotic lesions vary significantly among patients with chronic BFL but correlate with clinical features and prognosis.

Fluence to effective dose conversion coefficients calculated for monoenergetic electrons up to 200 MeV in partial exposure geometries.

Organ doses and effective doses were calculated for monoenergetic electrons from 0.1 to 200 MeV using the EGS4 Monte Carlo simulation code and the MIRD-5 human phantom in various non-uniform exposure geometries: anterior-posterior (AP) and posterior-anterior (PA). Below 1 MeV, the skin is the main contributor to the effective dose conversion coefficients for each exposure geometry; however, above 1 MeV the calculations showed that the effective doses of partial exposures depended on the incident electron energy, the place and the size of the exposure on the body.

Effective doses and organ doses in the MIRD-5 phantom exposed to monoenergetic 0.1 MeV to 200 MeV electrons in the LAT direction.

Organ doses and effective doses were calculated using the EGS-4 Monte Carlo simulation code and a MIRD-5 mathematical human phantom placed in a vacuum. For broad right and left lateral beams of monoenergetic (0.1-200 MeV) electrons, conversion coefficients from the incident fluence to organ dose, to effective dose, and to effective dose equivalent were obtained. There were no clear differences between the conversion coefficients in the case of left-lateral (LLAT) and right-lateral (RLAT) irradiation. Therefore, when investigating lateral geometries for electron exposure, it is not necessary to evaluate both directions independently. In general, conversion coefficients for lateral irradiation (LAT) were smaller than those for AP and PA. The difference between the AP and PA conversion coefficients and LAT became smaller with increasing incident energy; at 200 MeV the conversion coefficients were almost independent of the irradiation geometry. The agreement between the results of the present study and those of other studies was acceptable within the statistical uncertainties.

[A patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma].

We here reported a 54-year-old female patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. She was found to have scattered tumor in 1990. Although the tumor had slowly grown for the last 10 years, she showed no clinical symptoms. Numbness and weakness of lower extremities began in June 1999, and she was referred to Kyoto University Hospital on Oct. 21 1999 for evaluation of progressive symptoms. She had skin pigmentation, edema of the lower extremities, lymphadenopathy, muscle weakness and sensory disturbance in a glove-and-stocking distribution. Serological examination showed monoclonal IgG-lambda gammopathy. Serum vascular endothelial growth factor (VEGF) was markedly elevated. Microscopic studies on biopsied sural nerve demonstrated mild decrease of myelinated fibers. Immunohistochemically, the pulmonary tumor was defined as an IgG (lambda type) plasmacytoma. After treatment with melphalan-prednisolone therapy, the neurological symptoms improved along with decrease of serum VEGF levels as well as the size of pulmonary plasmacytoma. This is the first report of a patient with Crow-Fukase syndrome associated with pulmonary plasmacytoma. This case suggests that growth of pulmonary plasmacytoma might have played an important role in the overproduction of VEGF and thus development of Crow-Fukase syndrome.

Sarcoidosis with granulomatous interstitial nephritis: report of three cases.

Three cases of sarcoidosis with granulomatous interstitial nephritis are reported. Patients were all male and over 50 years of age. They simultaneously had evidence of multiorgan involvement of sarcoidosis including lung and skin and/or eye. In addition, distinct features were found in each case: a granulomatous infiltration mimicking unilateral renal tumor (case 1); renal insufficiency solely due to granulomatous interstitial nephritis (case 2); and renal insufficiency with calcemic nephropathy and granulomatous interstitial nephritis (case 3). Prednisolone therapy resulted in disappearance of the pseudotumor in case 1 and partial improvement of renal function in cases 2 and 3. In cases 2 and 3, however, plasma creatinine did not return to normal values and a second renal biopsy in case 2 demonstrated residual interstitial fibrosis and few granulomas, suggesting that steroid therapy did not achieve complete reversal of changes.

Usual interstitial pneumonia: idiopathic pulmonary fibrosis versus collagen vascular diseases.

BACKGROUND: Bronchoalveolar lavage fluid (BALF) lymphocytosis was found in patients with usual interstitial pneumonia (UIP) associated with collagen vascular diseases (CVD) other than diffuse systemic sclerosis (SSc), but it was not found in patients with idiopathic pulmonary fibrosis (IPF), a disease histologically diagnosed as UIP. This difference could be partly due to variations of UIP spectrums between IPF and interstitial pneumonia associated with CVD. METHODS: We scored histopathological findings of lung specimens obtained from 31 cases (16 IPF, 9 CVD other than SSc and 6 SSc) using a semiquantitative scoring method. All cases were diagnosed as UIP by surgical lung biopsy. None of the patients were current smokers. RESULTS: Compared with IPF and SSc cases, CVD patients without SSc presented decreased scores of fibrosis (p < 0.01) and alveolar space cellularity (severity, p < 0.05). Lymphocytes were mainly localized in the alveolar walls and the majority of cells in the alveolar spaces were macrophages. On the other hand, other scores such as cellularity and alveolar wall cell infiltrate did not vary among these three groups. CONCLUSION: Fewer macrophages in the alveolar spaces and a decrease in the degree of fibrosis may contribute to BALF lymphocytosis more in patients with UIP/CVD non-SSc than in patients with IPF/UIP and UIP-SSc.

Leiomyosarcoma of the pulmonary vein.

A case of a 74-year-old man with leiomyosarcoma of the pulmonary vein is reported. The patient felt transient chest oppression while playing golf 1 week before he visited a clinic with a common cold. He underwent an ultrasonographic examination of the heart, which showed a mass lesion in the left atrium. The preoperative clinical diagnosis was myxoma of the left atrium. Cardiac surgery revealed the mass to be a leiomyosarcoma, probably extending from the left inferior pulmonary vein. The patient underwent a left lower lobectomy of the lung, and the tumor was confirmed to have originated from the wall of the left inferior pulmonary vein. Although the patient had a metastatic lesion in the right axillary lymph node 11 months later, which was excised, he remained free of disease 14 months after the initial operation. Histologically, the tumors were composed of pleomorphic cells with bizarre nuclei and spindle cells with blunt-ended nuclei with 1-4 mitotic figures in 10 high power fields. Immunohistologically, the tumor cells were positive for alpha-smooth muscle actin and desmin. We reviewed 17 cases of leiomyosarcoma of the pulmonary vein (six males and 11 females with a mean age of 50 years in each group). The present case was the oldest in age and to our knowledge was the first reported case with metastasis in a distant lymph node.

Fibroblast contractility: usual interstitial pneumonia and nonspecific interstitial pneumonia.

The aim of this study was to compare the function of lung fibroblasts obtained from surgically biopsied specimens of patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP; n = 5), nonspecific interstitial pneumonia (NSIP; n = 5), and normal parts of surgically resected lungs (control; n = 5). The results showed that (1) fibroblasts obtained from UIP showed increased contractility compared with those obtained from NSIP or controls (UIP, 72.7 +/- 6.21%; NSIP, 32.8 +/- 5.46; controls, 28.5 +/- 3.51, p < 0.01 in UIP versus NSIP or control); (2) this increase in contractility was consistent with enhanced F-actin content in fibroblasts; (3) conditioned media from UIP fibroblast cultures enhanced control fibroblast contractility, whereas those obtained from NSIP or controls did not; (4) the 180 and 25 kD products representing the contractility in conditioned media were identified as fibronectin (ED-A domain) and TGF-beta1 by immunoblots, respectively; (5) the UIP-conditioned media contained higher amounts of fibronectin or TGF-beta 1 (fibronectin: UIP 289 +/- 47.1 ng/ml, NSIP 121 +/- 23.0, control 118 +/- 16.0; TGF-beta1: UIP 798 +/- 119 pg/ml, NSIP 246 +/- 69.1, control 247 +/- 53.6, p < 0.01 in UIP versus NSIP or control); () the contractility positively correlated with the amount of either fibronectin (r = 0.867, p < 0.001, n = 15) or TGF-beta 1 (r = 0.939, p < 0.001, n = 15), respectively. Thus, UIP fibroblasts showed greater contractility than did NSIP fibroblasts and up-regulated control fibroblasts.

Recurrent spontaneous pneumothoraces associated with juvenile polymyositis.

A 17-year-old man, who had received a diagnosis of juvenile polymyositis (PM) at the age of 1 year, developed recurrent spontaneous pneumothoraces and underwent surgical treatment by means of video-assisted thoracic surgery. Intraoperative observation and microscopic studies demonstrated numerous bleb-like lesions below the visceral pleura. To our knowledge, this is the first article that describes a case of spontaneous pneumothorax associated with PM. Our observation should lead to broadening of the spectrum of pleuropulmonary manifestations of PM.

Facts and controversies in the classification of idiopathic interstitial pneumonias.

Idiopathic interstitial pneumonias are defined from the pathological point of view as non granulomatous intralobular inflammatory and fibrotic processes involving the alveolar walls. More than thirty years ago Liebow and Carrington pioneered the notion that morphological characteristics could be used with benefit in separating the different entities found in this group, which present with typical, but not pathognomonic clinical features. In the mid-1980s some entities, including giant cell interstitial pneumonia (GIP) and lymphocytic interstitial pneumonia (LIP), were removed from this group and considered as peculiar forms. In the early 90s the concept of cellular or nonspecific interstitial pneumonia was reconsidered, leading to an in depth revision of various types of interstitial pneumonia of unknown etiology. The histological pattern observed in patients with idiopathic pulmonary fibrosis is now referred to as usual interstitial pneumonia (UIP). Other entities that have been revised during the last ten years are desquamative interstitial pneumonia/alveolar macrophage pneumonia (DIP/AMP), respiratory bronchiolitis-interstitial lung disease (RB-ILD), acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP) and nonspecific interstitial pneumonia (NSIP). This paper provides a detailed description of pulmonary disorders which have been included in the new classification systems of idiopathic interstitial pneumonias. In the second part of the paper we will discuss several doubts and controversies that this new classification schemes leave unresolved.

Increased levels of interleukin-6 are associated with lymphocytosis in bronchoalveolar lavage fluids of idiopathic nonspecific interstitial pneumonia.

Local overexpression of interleukin-6 (IL-6) experimentally induces lymphocytic infiltration in the bronchial tree of rat. Among idiopathic interstitial pneumonia (IIP), nonspecific interstitial pneumonia/fibrosis (NSIP) has an increased number of lymphocytes in bronchoalveolar lavage (BAL) fluid when compared with usual interstitial pneumonia (UIP). To reveal a relation of IL-6 with the lymphocyte infiltration of NSIP, IL-6 was measured in BAL fluids of idiopathic NSIP (n = 7), idiopathic UIP (n = 16), and normal control subjects (n = 45). IL-6-producing sites were assessed by IL-6 protein stain on biopsy specimens of NSIP, UIP, and normal lung of mediastinal tumors. Lymphocyte numbers and IL-6 levels in BAL fluids were higher in NSIP than those in UIP (p < 0.01, respectively), which were also higher when compared with those of normal control subjects (p < 0.01, respectively). In NSIP, the levels of IL-6 correlated with the number of lymphocytes (r = 0.93, p < 0.01). UIP cases were divided into two groups: high-UIP (n = 7) or low-UIP (n = 9) according to IL-6 levels greater than or within the 95 percentile of normal control subjects, respectively. The high-UIP group had BAL lymphocytosis when compared with the low-UIP group (p < 0.05). IL-6 stained on epithelial cells of the bronchial tree and on alveolar macrophages of NSIP and UIP. In conclusion, the lymphocytosis in BAL fluid of patients with NSIP and a subgroup of UIP is associated with the high levels of IL-6 and its sources are the epithelial cells of the small airway and the alveolar macrophages.

Airway remodelling in cough-variant asthma.

Subepithelial-layer thickening, a pathological feature of airway remodelling, is present in cough-variant asthma. In bronchial biopsy samples we found mean subepithelial-layer thickness was 7.1 (SE 0.4) microm in patients with cough-variant asthma, 8.6 (0.4) microm in patients with classic asthma with wheezing, and 5.0 (0.2) microm in healthy controls. Thickness was significantly higher in patients with asthma than in controls, and was significantly greater in those with classic asthma than in those with cough-variant asthma. Early anti-inflammatory treatment might, therefore, be beneficial in cough-variant asthma, as recommended in classic asthma.