Pleural adverse drugs reactions and protein kinase inhibitors: Identification of suspicious targets by disproportionality analysis from VigiBase.

AIMS: To evaluate the risk of pleural disorders (PD) associated with 33 protein kinase (PK) inhibitors (PKIs) through a disproportionality analysis and to identify which PKs and pathways are involved in PKI-induced PD. METHODS: To evaluate the risk of PD, reporting odds ratios (RORs) were calculated for 33 PKIs through data registered in the World Health Organization safety report database (VigiBase). We undertook a literature review to identify PKs that were possibly involved in PD caused by PKIs. Pearson correlation coefficients (r) between RORs and affinity data of 19 PKIs were calculated to identify the cellular target most likely to be involved in PKI-induced PD. RESULTS: A total of 235 110 individual case safety reports were extracted from the database for 33 available PKIs. Among these reports, 5001 concerned PD (2.1%). Significant and positive disproportionality for PD was found for 29 of 33 PKI included in our study with top values for dasatinib [ROR = 115.3; 95% confidence interval (CI): 110.1-120.8], bosutinib (ROR = 20.4; 95% CI: 15.8-26.4) and ponatinib (ROR = 12; 95% CI: 9.2-15.6). Correlation analyses between the product of dissociation constant and ROR highlighted possibly Lyn involvement in PD with PKI (r = 0.73, P = 0.0004). CONCLUSIONS: Our study showed that 28 of the 33 tested PKIs were associated with PD. Besides, the study highlighted the role of Lyn in PD caused by PKIs through an immune-mediated process.

Radiological pleuroparenchymal fibroelastosis associated to limited cutaneous systemic sclerosis: a case report.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a very rare interstitial lung disease (ILD) characterized by progressive fibrotic lesions of the visceral pleura and the sub-pleural parenchyma, affecting predominantly the upper lobes. PPFE may occur in different contextes like bone marrow or lung transplantations, but also in the context of telomeropathy with mutations of telomerase reverse transcriptase (TERT), telomerase RNA component (TERC) or regulator of telomere elongation helicase 1 (RTEL1) genes. PPFE-like lesions have recently been described in patients with connective tissue disease (CTD)-related ILD. We report here the first detailed case of PPFE associated to systemic sclerosis (SSc) in a woman free of telomeropathy mutations. CASE PRESENTATION: A caucasian 46 year old woman was followed for SSc in a limited form with anti-centromere Ab since 1998, and seen in 2008 for a routine visit. Her SSc was stable, and she had no respiratory signs. Pulmonary function tests showed an isolated decreased cTLCO at 55.9% (of predicted value). Cardiac ultrasonography was normal. Thoracic CT-scan showed upper lobes predominant mild and focal pleural and subpleural thickenings, suggestive of PPFE, with a slight worsening at 8 years of follow-up. She remained clinically stable. Biology only found a moderate and stable peripheral thrombocytopenia, and sequencing analysis did not find any mutations in TERT and TERC genes. CONCLUSIONS: ILD is frequent in SSc but isolated PPFE has never been described so far. In our case, PPFE is not related to telomeropathy, has indolent outcome and seems to have good prognosis. PPFE might be an extremely rare form of SSc-related ILD, although a fortuitous association remains possible.

Prevalence of anti-nuclear autoantibodies in subjects exposed to natural asbestiform fibers: a cross-sectional study.

Fluoro-edenite (FE) is an asbestiform mineral fiber spotted in the lava rocks excavated from a stone quarry in Biancavilla (Italy). The derived material had been employed locally for building purposes. Previous studies found evidence that exposure to asbestos may induce autoimmunity, with frequency of anti-nuclear autoantibodies (ANA). The aim of this study was to explore the relationship between FE exposure and autoimmune responses in an exposed population. For the study, 60 subjects living in the area of Biancavilla and 60 subjects as control group were randomly invited to participate. A free medical check, including spirometry and a high-resolution computer tomography chest scan, was given to all participants. ANA were determined by indirect immunofluorescence. On medical check, no subject showed any sign and/or symptoms of illness. Prevalence for samples positive to ANA were 70% (n = 42) and 25% (n = 15), respectively, for exposed and non-exposed subjects (p < 0.05). The presence of pleural plaques (PP) was found in 21 (30%) of the exposed subjects and in 2 (3%) of the non-exposed participants. PP subjects were always ANAs positive. In conclusion, as already it was observed with exposure to asbestos fibers, levels of ANA seemed to significantly increase in subjects who had been exposed to FE. Furthermore, all subjects showing PP were also ANA-positive. This first finding in subjects exposed to FE should encourage researchers to further investigate associations between autoimmune unbalance and environmental exposure to asbestiform fibers.

Thoracic involvement in IgG4-related disease in a UK-based patient cohort.

IgG4-related disease (IgG4-RD) is a multi-system fibro-inflammatory disorder with classical histopathological findings, often in the context of elevated serum IgG4 levels. The thoracic manifestations of IgG4-RD are numerous and can mimic several common and better known conditions. The objective of this study was to outline the frequency and nature of thoracic involvement in a prospective cohort of IgG4-RD patients who met defined diagnostic criteria. Over 40% of IgG4-RD patients had clinicoradiological and/or histological evidence of thoracic involvement, predominantly mediastinal lymphadenopathy, the majority associated with multi-system disease outside the chest. Thoracic involvement was associated with a higher serum IgG4 level, potentially representing greater disease activity or spread. Our data highlight the diverse nature of thoracic IgG4-RD, and the importance of knowledge and recognition of the condition among respiratory physicians who are likely to encounter this disease entity on an increasing basis.

Libby amphibole-induced mesothelial cell autoantibodies promote collagen deposition in mice.

Libby amphibole (LA) causes a unique progressive lamellar pleural fibrosis (LPF) that is associated with pulmonary function decline. Pleural fibrosis among the LA-exposed population of Libby, MT, has been associated with the production of anti-mesothelial cell autoantibodies (MCAA), which induce collagen production from cultured human mesothelial cells. We hypothesized that the progressive nature of LPF could be at least partially attributed to an autoimmune process and sought to demonstrate that LA-induced MCAA trigger collagen deposition in vivo. C57BL/6 mice were exposed to LA for 7 mo, and serum was tested for MCAA by cell-based ELISA on primary mouse mesothelial cells. When treated in vitro with serum from mice exposed to LA, mesothelial cells upregulated collagen matrix production. This effect was lost when the serum was cleared of IgG using protein G beads, implicating IgG autoantibodies. Using the peritoneal cavity as a surrogate for the pleural cavity, groups of naïve (non-asbestos-exposed) mice were injected intraperitoneally with 1) control serum, 2) one dose of serum from LA-exposed mice (LA serum), 3) two doses of LA serum, or 4) two doses of LA serum cleared of IgG. After 1 mo, analysis of collagen in peritoneal walls using two-photon confocal microscopy (SHG analysis) and a hydroxyproline assay demonstrated significant increases in collagen by LA serum but not control or cleared serum. These data support the hypothesis that MCAA in LA-exposed mice induce fibrotic responses in vivo, demonstrating that an autoimmune component may be contributing to the progressive pleural fibrosis seen in LA-exposed patients.

Genes involved in innate immunity associated with asbestos-related fibrotic changes.

OBJECTIVES: To determine whether genetic polymorphisms in several candidate genes related to innate immunity and protease-antiprotease balance modify individual susceptibility to develop asbestos-related fibrotic pleuropulmonary changes. METHODS: Sixteen polymorphisms from nine genes (NLRP3, CARD8, TNF, TGFB1, GC, MMP1, MMP9, MMP12 and TIMP2) were genotyped from 951 Finnish asbestos-exposed workers. The genotype/haplotype data were compared to signs of fibrosis and pleural thickenings using linear and logistic regression analysis adjusted for potential confounders. RESULTS: A functional polymorphism (Q705K; rs35829419) in the NLRP3 gene was associated with interstitial lung fibrosis (p=0.013), and the TGFB1 rs2241718 SNP with visceral pleural fibrosis (VPF) (p=0.044). In stratified analysis, the carriage of at least one NLRP3 variant allele conferred a 2.5-fold increased risk for pathological interstitial lung fibrosis (OR 2.44, 95% CI 0.97 to 6.14). Conversely, the carriage of at least one TGFB1 rs2241718 variant allele protected against VPF (OR 0.62, 95% CI 0.39 to 0.98). The TIMP2 rs2277698 SNP and a haplotype consisting of the TGFB1 rs1800469 and rs1800470 SNPs were associated with the degree of pleural thickening calcification (p=0.037 and p=0.035), and the CARD8 rs2043211 SNP with the greatest thickness of pleural plaques (p=0.015). CONCLUSIONS: Our results support the hypothesis that the NLRP3 inflammasome is important in the development of fibrotic lung disease by associating the NLRP3 rs35829419 variant allele with increased risk of asbestos-related interstitial lung fibrosis, and the TGFB1 rs2241718 variant allele with decreased risk of asbestos-related VPF. Polymorphisms in CARD8 and TIMP2 are proposed to modify the development and/or calcification of pleural thickenings.

Mesothelial cell and anti-nuclear autoantibodies associated with pleural abnormalities in an asbestos exposed population of Libby MT.

Despite data linking amphibole asbestos exposure with production of autoantibodies, the role of autoantibodies in subsequent disease is unknown. Residents of Libby, Montana have experienced significant exposure to amphibole asbestos due to the mining of asbestos-contaminated vermiculite near the community over several decades. This population predominantly exhibits pleural disease, and an autoimmune-like disorder that has yet to be well defined. This study sought to determine whether autoantibodies from asbestos-exposed subjects were associated with pleural lesions. Serum samples of subjects from Libby were evaluated for anti-nuclear antibodies (ANA) and mesothelial cell autoantibodies (MCAA) using cell based ELISA. The presence of radiographic abnormalities detected during the time frame of serum collection was determined from screening records. In accord with previous studies, 61.3% (76/124) of the Libby samples were ANA positive, a frequency much higher than expected for a healthy population. The odds of having pleural or interstitial abnormalities in Libby was nearly 3.55 times greater for individuals that tested positive for ANA compared with individuals negative for ANA (p=0.004). MCAA were also detected at a strikingly high frequency (18.5%; 23/124) in samples from Libby. Individuals with MCAA had 4.9 times the risk of having pleural abnormalities compared to MCAA-negative subjects (p=0.044). In conclusion, ANA and MCAA were elevated in a study population that was known to have chronic exposure to asbestos, and these autoantibodies were associated with pleural abnormalities, the predominant finding in the asbestos-exposed population of Libby. Additional research is needed to determine the role these autoantibodies may play in pulmonary disease.

IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases.

Immunoglobulin G4 (IgG4)-related disorders can occur in the respiratory system. However, the clinicopathologic characteristics have not been well clarified. In this study, we examined clinical and pathologic features of, and follow-up data on, IgG4-related lung and pleural lesions. The patients group consisted of 17 males and 4 females with an average age of 69 years (range: 42 to 76). Pulmonary lesions in 16 patients and pleural lesions in 5 patients were examined. Histologically, all lesions showed diffuse lymphoplasmacytic infiltration. Irregular fibrosis and obliterative vascular changes were more common in solid areas. Nine cases (43%) had eosinophilic infiltration with more than 5 cells per high-power field. Immunostaining revealed numerous IgG4-positive plasma cells in inflamed areas. Sclerosing inflammation was distributed with intrapulmonary connective tissue. Pulmonary lesions showed a variety of morphologic changes according to the predominant area of inflammation. Serum IgG4 concentrations were elevated in 9 of 11 patients tested (average 6.9 g/L; range 0.3 to 18.0 g/L; normal range <1.35 g/L). Extra-pulmonary and extra-pleural IgG4-related lesions were identified in 9 patients (43%), and developed simultaneously or asynchronously during follow up. All patients treated with steroids responded, but some radiologic abnormalities remained in 3 patients. Interestingly, 1 patient was found to have a primary adenocarcinoma against a background of IgG4-related lung disease during follow up. In conclusion, IgG4-related diseases show a greater variety of pulmonary and pleural lesions than previously thought. It is important, therefore, to know the morphologic variety and clinicopathologic characteristics of this disorder.

Isolation and identification of Rhizomucor pusillus from pleural zygomycosis in an immunocompetent patient.

Zygomycosis is usually an invasive mycotic disease caused by fungi in the class Zygomycetes. It often occurs in immunocompromised patients, but sporadic cases without apparent immune impairment have been described. This report presents the first case of pleural zygomycosis caused by Rhizomucor pusillus, an uncommon pathogen of human infection. A 19-year-old man was found to have pleuritis several days after a drainage catheter was implanted to cure a pneumothorax caused by a ruptured bulla. Local pneumonectomy to resect the ruptured bulla and vacuuming of the pleural fluid was performed. Rhizomucor pusillus was cultured from the pleural fluid and irregular broad sparsely septate hyphae, consistent with zygomycetes, were histologically detected in the thickened pleura of the resected bulla. The catheter was suspected of having been contaminated with the fungus, but no evidence could be obtained. His fungal pleuritis subsided without any antifungal medical therapy and his immunocompetence seemed to contribute to limiting the infection.

Pathophysiology of the pleura.

The pleural mesothelial cell is an essential cell in maintaining the normal homeostasis of the pleural space and it is also a central component of the pathophysiologic processes affecting the pleural space. In this review, we will review the defense mechanisms of the pleural mesothelium and changes in pleural physiology as a result of inflammatory, infectious, and malignant conditions with a focus on cytokine and chemokine networks. We will also review the processes involved in the pathogenesis of pleural fibrosis.

[Effect of anti-vascular endothelial growth factor antibody on pleurodesis induced by transforming growth factor-beta or doxycycline in rabbits].

OBJECTIVE: The intrapleural injection of transforming growth factor-beta (TGF-beta) or doxycycline produces excellent pleurodesis in rabbit models. However, the intrapleural injection of these agents induces large pleural effusion which is possibly related to vascular endothelial growth factor (VEGF). This study investigated whether anti-VEGF antibody has any effect on the fluid production or the pleurodesis induced by TGF-beta or doxycycline in rabbits. METHODS: Two groups of New Zealand white rabbits (7 each) were given TGF-beta 5.0 microg intrapleurally. The TGF-beta treatment group received anti-VEGF antibody 10 mg/kg intravenously 24 h before TGF-beta injection and the TGF-beta control group received no antibody. Another two groups of New Zealand white rabbits (7 each) were given doxycycline 10 mg/kg intrapleurally after chest tube placement. The doxycycline treatment group received 10 mg/kg anti-VEGF antibody intravenously 24 h before doxycycline injection and the doxycycline control group received no Anti-VEGF antibody. The rabbits were sacrificed at 2 weeks and the pleurodesis score was graded macroscopically on a 1-8 scale. The degree of angiogenesis in pleural tissues was assessed by immunohistochemical staining for factor VIII which was assessed by computer-assisted digital analysis. RESULTS: The administration of anti-VEGF antibodies had no effect on pleural fluid volume or the characteristics of the fluid. The mean pleurodesis score of TGF-beta control group (7.7 +/- 0.8) was significantly (P < 0.05) higher than that of the antibody pre-treatment TGF-beta group (4.4 +/- 2.4). The mean pleurodesis score of the doxycycline control group (6.0 +/- 1.7) was significantly (P < 0.05) higher than that of the antibody pre-treatment doxycycline group (2.0 +/- 0.9). The administration of the anti-VEGF antibody also reduced the angiogenesis. The percentage of pleural tissue demonstrating angiogenesis in the TGF-beta control group (4.9 +/- 0.4)% was significantly (P < 0.05) higher than that of the antibody treatment TGF-beta group (2.9 +/- 0.7)%. The percentage of pleural angiogenesis in the doxycycline control group (6.9 +/- 2.2)% was significantly (P < 0.05) higher than the antibody pre-treatment doxycycline group (2.2 +/- 0.9)%. CONCLUSIONS: Anti-VEGF antibody significantly inhibits the pleurodesis induced by doxycycline or TGF-beta. This observation suggests that VEGF and angiogenesis play a pivotal role in the production of pleurodesis.

Pathogenesis of pleural infection.

The pleura responds to the presence of infecting organisms with a vigorous inflammatory response associated with an exudation of white blood cells and proteins. The development and outcome of pleural infections is a function of a balance between the virulence of the invading microorganism and the immune reaction involving professional immune cells as well as the pleural mesothelial cells. Most commonly, pleural infection occurs after invasion through the lung parenchyma and a breach in the viscera pleura resulting in the formation of a parapneumonic process. Upon infection, the microorganisms are recognized by the pleural mesothelial cell, which remains the first line of defence. Pleural responses to infection include those of innate immunity as well as adaptive or acquired immunity. Innate and acquired immune responses are closely linked. In this review, we discuss the different virulence factors that allow microorganisms to infect the pleura and the role of the pleural mesothelial cells in bridging the innate and acquired immune responses.

The pathogenetic role of immunoglobulin G from patients with systemic lupus erythematosus in the development of lupus pleuritis.

OBJECTIVE: To investigate the pathophysiological effect of immunoglobulin G (IgG) from systemic lupus erythematosus (SLE) patients on pleural mesothelial cells and related mechanisms. METHODS: Serum IgG from 28 lupus patients and 13 healthy controls was purified by protein-G affinity chromatography. The concentrations of anti-dsDNA-, anti-histone- and/or anti-nucleohistone-containing IgGs were determined by enzyme-linked immunosorbent assay (ELISA). Lupus patients were divided into an active (n = 12) and an inactive group (n = 16) on the basis of the SLE Disease Activity Index (SLEDAI). The binding of IgG to a human pleural mesothelial cell line (MeT-5A) under different conditions, including pretreatment with DNase and preincubation with exogenous histone, DNA or nucleohistone, was examined using flow cytometry and cellular ELISA. The effect of IgG on MeT-5A cell proliferation was studied using an MTT assay. Gene expression and protein synthesis for interleukin 1beta (IL-1beta), monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor beta1 (TGF-beta1) in MeT-5A cells were determined using reverse transcription-polymerase chain reaction and ELISA. RESULTS: The binding of IgG to MeT-5A cells was higher in the active lupus group than the inactive lupus group (P = 0.047) and controls (P = 0.003). The binding decreased in both lupus groups following pretreatment of MeT-5A cells with DNase. The binding of IgG to MeT-5A cells was greater by 112% in the active lupus group after preincubation with histone (P < 0.001), but not with DNA or nucleohistone. Exposure of MeT-5A cells to IgG from either lupus group induced cell proliferation when compared with IgG from healthy controls (P = 0.04). Gene expression and protein synthesis of MCP-1, TGF-beta1 and IL-1beta in MeT-5A cells were significantly increased after incubation with IgG from patients with active lupus when compared with IgG from the inactive lupus and control groups (P < 0.01). The concentration of anti-dsDNA antibodies correlated with the binding of IgG to MeT-5A cells and the synthesis of cytokines by MeT-5A cells. The serum level of anti-histone antibodies in the active lupus group was higher than that in the inactive group (P = 0.015) and the serum concentration correlated with cell binding and MCP-1 production. CONCLUSIONS: IgG from lupus patients can bind to MeT-5A cells and the binding is modulated by DNA or histone. Binding of anti-dsDNA-containing IgG to MeT-5A cells induces the synthesis of proinflammatory cytokines. Our findings suggest that the binding of anti-dsDNA antibodies, particularly the IgG isotype, to pleural mesothelium plays a direct pathogenetic role in inducing inflammatory injury in the serositis of SLE.

Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review.

We describe 18 nonimmunocompromised patients with chronic pulmonary aspergillosis. Duration of the disease ranged from several months to >12 years. All 18 patients had prior pulmonary disease. Weight loss, chronic cough (often with hemoptysis and shortness of breath), fatigue, and chest pain were the most common symptoms. All 18 patients had cavities, usually multiple and in 1 or both upper lobes of the lung, that expanded over time, with or without intraluminal fungal balls. All had detectable Aspergillus precipitins and inflammatory markers. Elevated levels of total immunoglobulin E were seen in 78% of patients and of Aspergillus-specific immunoglobulin E in 64%. Directed lung biopsies showed chronic inflammation, necrosis, or granulomas without hyphal invasion. Antifungal therapy with itraconazole resulted in 71% of patients improved or stabilized, with relapse common. Interferon-gamma treatment was useful in 3 patients. In azole nonresponders, modest responses to intravenous amphotericin B (80%) followed by itraconazole were seen. Surgery removed disease but postoperative pleural aspergillosis was inevitable. Indicators of good long-term medical outcomes were mild symptoms, thin-walled quiescent cavities, residual pleural fibrosis, and normal inflammatory markers.

Lung, pleural and colon actinomycosis in an immunocompromised patient: a rare form of presentation.

Actinomycosis is caused by gram-positive filamentous organisms of the genus Actinomyces, which may spread through trauma. Most commonly, it is a cervicofacial disease due to dental infection or a thoracic disease secondary to aspiration of foreign bodies. Primary abdominal infection usually follows some form of mucosal disruption. Any organ of the human body may be involved so that a wide range of symptoms may be present. We report a rare form of actinomycosis involving the lung, pleura and colon concomitantly in an immunocompromised patient. A fine needle aspiration from a lung lesion detected the characteristic sulfur granules, and a pleural effusion culture confirmed the diagnosis. Clinical manifestations and treatment are discussed. Actinomycetes are rarely opportunistic agents in immunocompromised patients; thus the disease deserves special attention in those patients.

Immunological mechanisms in pleural disease.

The pleural membrane consisting of pleural mesothelial cells and its underlying connective tissue layers play a critical role in immunological responses in both local and systemic diseases. The pleura, because of its intimate proximity to the lung, is positioned to respond to inflammatory changes in the lung parenchyma. Importantly, several systemic diseases have a predilection for expression on the pleural surface. Immunological responses in the pleura include the development of pleural permeability and pleural effusion formation as well as the development of pleural fibrosis and scarring. Under either circumstance, the normal functioning of the pleura is impaired and has multiple consequences leading to increased morbidity and even mortality for the patient. During infections in the pleural space, the pleural mesothelium responds by actively recruiting inflammatory phagocytic cells and allowing the movement of proteins from the vascular compartment into the pleural space. The release of chemokines by the pleural mesothelium allows for directed migration of phagocytic cells from the basilar surface of the pleura towards the apical surface. In malignant disease, the pleura may be the site of primary tumours such as mesothelioma and also the site for malignant metastatic deposits. Certain cancers such as cancers of the breast, ovary, lung, and stomach have a predilection for the pleural mesothelium. The process whereby malignant cells attach to the pleural mesothelium and develop autocrine mechanisms for survival in the pleural space are elucidated in this review. The pleura functions not only as a mechanical barrier, but also as an immunologically and metabolically responsive membrane that is involved in maintaining a dynamic homeostasis in the pleural space.

Immunological analysis of pleural fluid in post-cardiac injury syndrome.

Post-cardiac injury syndrome (PCIS) is an inflammatory process involving pleura and pericardium secondary to cardiac injury. Even though this clinical entity has been recognised for decades, diagnosis is difficult because of lack of a diagnostic test. Antimyocardial antibody titre in pleural fluid and serum has been proposed to have diagnostic value. However there are inherent difficulties in measuring and interpreting the role of antimyocardial antibody. A case of PCIS with low pleural fluid complement level is reported, which it is believed can be useful to support the diagnosis of PCIS.

Additional proteins in BAL fluid of Metsovites environmentally exposed to asbestos: more evidence of "protection" against neoplasia?

INTRODUCTION: Inhabitants of Metsovo in northwest Greece have been exposed to asbestos from use of a tremolite-containing whitewash ("luto" soil). As a result, they have increased incidence of malignant pleural mesothelioma and pleural calcifications (PCs). However, subjects with calcifications have a much lower incidence of mesothelioma than those without. A previous study of the two groups with BAL revealed higher proportional lymphocytosis among subjects with calcifications. We suggested that BAL lymphocytosis may be somehow correlated with "protection" against neoplasia. METHODS: The present report is a study of the liquid phase of BAL in the two groups. BAL specimens of 43 Metsovites (13 subjects with PCs and 30 subjects without PCs) and two control groups were examined. We measured total protein, albumin, IgG, IgA, and interleukin-6. Proteins were analyzed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis and two-dimensional electrophoresis and further characterized using an appropriate computer program. RESULTS: The most interesting finding was the presence of two additional protein spots corresponding to the electrophoretic site of Ig heavy chain and C(4) component of complement. The two proteins were present in all Metsovites with PCs but in none without PCs and also in none of the control groups. CONCLUSION: This study further separates two groups of Metsovites with different reaction to asbestos, possibly as a result of different activation of alveolar macrophages. This difference leads the first group to the formation of PCs, BAL fluid lymphocytosis, and relative "protection" against malignancy, and the second group to no calcifications, no lymphocytosis, but also no protection against malignancy.

Paraparesis induced by inflammatory contents of a pneumonectomy cavity. Case report.

The authors report on a patient who developed acute-onset paraparesis after underoing a thoracotomy 40 years earlier for a carcinoid adenoma. No infectious or neoplastic origin could be found to explain the patient's current clinical course and radiographic findings. The postoperative events in this case are discussed, as well as the literature regarding postthoracotomy complications.

Detection of the 20-kDa virulence-associated antigen of Rhodococcus equi in malakoplakia-like lesion in pleural tissue obtained from an AIDS patient.

A malakoplakia-like lesion was detected in a pleural biopsy from an AIDS patient presenting clinical and radiologic features of pneumonia. Cultures of bronchoalveolar lavage and pleural fluid evidenced Rhodococcus equi as the causative agent of pleuro-pulmonary infection. Immunochemical characterization of the R. equi isolate showed the presence of a strain similar to the ATCC 33704 reference strain presenting the capsular antigen of serotype 4, and the intermediate virulence-associated antigen of 20-kDa. Histopathology of the patient's pleural biopsy showed plaques of macrophages interspersed with lymphocytes, and intracytoplasmic cocci and bacilli in macrophages, which were variably acid-fast positive. Immunohistochemistry of cocci, bacilli and their degradation products resulted strongly positive when stained with a mouse monoclonal antibody (MAb) produced against the 20-kDa antigen. This finding could have important implications for the pathogenicity of R. equi for human beings, since we do not know yet all the factors involved in the formation of malakoplakia. Indeed, the results obtained in the present study, taken together with the results obtained for pigs inoculated with R. equi strains of intermediate virulence (Madarame et al. 1998), raise the possibility that most strains presenting the 20-kDa antigen may be capable of inducing malakoplakia. If this hypothesis is confirmed by immunohistochemical analysis of human pulmonary malakoplakia cases due to R. equi, the detection of this antigen may be extremely helpful in the diagnosis and treatment of such patients. This is the first report of R. equi infection in human beings that suggests a relationship between pleural malakoplakia and the virulence-associated antigen of 20-kDa.