Decreased diffusion capacity on lung function testing in asymptomatic patients with systemic lupus erythematosus does not predict future lung disease.

BACKGROUND: In a previous study performed 9 ± 3.6 years ago, 74 asymptomatic patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) underwent lung function testing. A significantly low diffusion capacity (DLCO) ranging from 45% to 70% was recorded in 28 of the 74 (37.8%) patients who were all free of respiratory symptoms. AIM: The aim of this report is to assess the clinical importance and the predictive value of a low DLCO in asymptomatic patients with SLE or APS. METHODS: Asymptomatic patients with SLE and/or APS who were found to have a low DLCO in the previous study were contacted. Of the 28 patients, 15 were recruited and reevaluated in the current study (SLE with APS (n = 7), SLE without APS (n = 7); primary APS (n = 1)). A full history, physical examination, nail bed capillaroscopy, current laboratory tests and full lung function tests including DLCO were performed. RESULTS: During a surveillance period of 9 ± 3.6 years, none of the patients developed lung disease. Diffusion capacity corrected for alveolar volume (DLCO/VA) improved in the study group during this period from 60.4% ± 7.0 to 76.1% ± 11.2 (p < 0.0001). Lung function tests including total lung capacity (TLC) and forced expiratory volume in one second (FEV1) remained within normal limits. Capillaroscopy studies did not reveal changes compatible with scleroderma in any of the patients. CONCLUSION: Low DLCO findings on lung function testing does not have a positive predictive value for the development of future lung disease in patients with SLE, with or without APS, who are free of respiratory symptoms. Our results suggest that a finding of low DLCO in asymptomatic patients with SLE, with or without APS, does not necessarily require further evaluation and imaging and may improve spontaneously over time. Further studies in a larger group of patients are needed to validate these findings.

Outbreak of autoimmune disease in silicosis linked to artificial stone.

BACKGROUND: There is a well-established association between inhalational exposure to silica and autoimmune disease. We recently observed an outbreak of silica-related autoimmune disease among synthetic stone construction workers with silicosis referred for lung transplantation assessment. AIMS: To characterize the rheumatologic complications in silicosis within these highly exposed, clinically well-characterized patients. METHODS: We systematically reviewed data from all cases of silicosis due to synthetic stone dust referred to our pulmonary institute for lung transplant assessment, which represents the national centre for all such referrals. In addition to silicosis-specific data, we extracted data relevant to the clinical and serological manifestations of autoimmune diseases present in these patients. RESULTS: Of 40 patients in our advanced silicosis national data, we identified nine (23%) with findings consistent with various autoimmune diseases. Among these nine, three also had findings consistent with pulmonary alveolar proteinosis. Based on an expected autoimmune disease prevalence of 3% (based on the upper-end estimate for this group of diseases in European international data), the proportion of disease in our group represents a >7-fold excess (prevalence ratio 7.5; 99% confidence interval 2.6-16.7). CONCLUSIONS: These cases underscore the strong link between silicosis and multiple distinct syndromes of autoimmune diseases. Vigilance is warranted for the recognition of autoimmune complications in persons with known silicosis; so too is consideration of the occupational exposure history in persons presenting with manifestations of autoimmune disease.

Chest wall shrapnel-induced beryllium-sensitization and associated pulmonary disease.

Chronic beryllium disease (CBD) is an exposure-related granulomatous disease mimicking sarcoidosis. Beryllium exposure-associated disease occurs mainly via inhalation, but skin may also be a source of sensitization. A 65-year-old male with a history of war-related shrapnel wounds was initially diagnosed with pulmonary sarcoidosis. Twenty years later, the possibility of a metal-related etiology for the lung disease was raised. A beryllium lymphocyte proliferation test, elemental analysis of removed shrapnel, and genetic studies were consistent with a diagnosis of CBD. This case demonstrates that retained beryllium-containing foreign bodies can be linked to a pathophysiologic response in the lung consistent with CBD.

Non-invasive diagnosis of chronic beryllium disease in workers exposed to hazardous dust in Israel.

OBJECTIVES: Chronic beryllium disease (CBD) is caused by prolonged occupational exposure to beryllium and is characterised by various clinical presentations, mostly pulmonary. The inflammatory process involves non-caseous granulomas and proliferation of CD4+ cells. CBD is diagnosed by lung biopsy showing tissue granuloma formation, and by the beryllium lymphocyte proliferation test (BeLPT) for past exposure and sensitisation to beryllium. The induced sputum (IS) technique was developed for diagnosing asthma, chronic obstructive pulmonary disease and interstitial lung diseases. A CD4/CD8 ratio >2.5 in T cells from IS is a positive result for granulomatous lung diseases. We previously revealed that dental technicians are exposed to excessive levels of beryllium. The efficacy of IS (CD4/CD8 >2.5) and BeLPT in diagnosing CBD in 17 workplaces where beryllium was present was evaluated. METHODS: All consecutive patients with a clinical suspicion of CBD referred to our institution for diagnosis and management were enrolled. Results of the gold standard lung biopsy with BeLPT were compared to the non-invasive IS+BeLPT. Kappa and McNemar tests evaluated agreement levels. Correlations between demographic and clinical parameters and a confirmed diagnosis of CBD were analysed. RESULTS: The two approaches were compared in 57 of 98 subjects. There was a high level of agreement (kappa 0.920) between IS+BeLPT and biopsy+BeLPT. IS+BeLPT had a specificity of 97.3% and sensitivity of 87.5%. 21 of 87 exposed workers (24%) had CBD, of whom 12 were dental technicians (p=0.044 dental technicians versus all other occupations). CONCLUSIONS: This study demonstrated that the CD4/CD8 ratio in IS together with positive/negative BeLPT findings can be used in diagnosing CBD.

HO-1 and VEGF gene expressions are time dependant during exposure to welding fumes.

Hemeoxygenase-1 (HO-1) is a defensive enzyme against oxidative stress. Vascular epithelial growth factor (VEGF) is a potent cytokine which promotes angiogenesis. We used induced sputum (IS) technology to study HO-1 and VEGF expressions in neutrophilic inflammation in asymptomatic welders. Aircraft plant employees were divided into three groups: Welders 1 (n=30) had short-term exposure to aluminum/iron, Welders 2 (n=16) had long-term exposure to cadmium/chromium/iron/nickel, and controls (n=27 non-exposed individuals). Participants underwent pulmonary function tests (PFTs), IS, differential cell counts, and determination of particle size distribution in IS samples. HO-1 and VEGF gene expressions were analyzed by real-time polymerase chain reaction, and protein levels were measured by bilirubin reductase-dependant reaction and ELISA, respectively. All subjects had normal PFTs. Welders 2 had neutrophilic inflammation and higher percentages of particles between 2-5 micron than the other groups. HO-1 inversely correlated with VEGF gene expression: HO-1 was significantly higher and VEGF was significantly lower in the Welders 1 group than in the other groups. There was a correlation between HO-1 expression and protein activity (r=0.33, P=0.05). Particulate matters significantly influenced HO-1 and VEGF gene expressions, caused neutrophilic inflammation and promoted oxidative stress in welders with long-term exposure.

High extracellular induced sputum haem oxygenase-1 in sarcoidosis and chronic beryllium disease.

BACKGROUND: Sarcoidosis and chronic beryllium disease (CBD) are inflammatory conditions in which oxidative stress state may be crucial for disease outcome. This study compares haem oxygenase-1 (HO-1) extracellular activity for the first time in patients with sarcoidosis or CBD and in healthy controls. MATERIALS AND METHODS: Induced sputum was recovered using a standard protocol. Pulmonary function tests (PFT) were performed by conventional methods. T lymphocyte subsets (CD4 and CD8) were measured by flow activated cell shorter (FACS). The HO-1 and nitrite levels were measured by a bilirubin-biliverdin reductase-dependent reaction and Greiss reaction respectively. Ferritin and iron levels were measured by enzymatic reaction and chemiluminometric immunoassay respectively. RESULTS: The mean percentage of lymphocytes was significantly higher in the 36 sarcoid patients compared with that in the 17 controls (P=0.001). The mean CD4/CD8 ratio was significantly higher in the sarcoid and the 10 CBD patients compared to that in controls (P=0.000 and 0.002 respectively), as was the mean HO-1 activity (P=0.045 and 0.041 respectively). The HO-1 activity did not differ with the sarcoidosis stage. The HO-1 level and PFT parameters were negatively correlated. The differences in mean nitrite, ferritin and iron levels were non-significant between the three groups. The HO-1 and ferritin levels were correlated (P=0.008). CONCLUSIONS: We succeeded in non-invasively measuring the activity of HO-1 from cells of airways in spite of its being an intracellular enzyme. The HO-1 levels in sarcoidosis and CBD were abnormally elevated.

Terrestrial ages of four allan hills meteorites: consequences for antarctic ice.

The terrestrial ages of three Allan Hills meteorites are between 3 x 10(4) and 3 x 10(5) years and one is (1.54(-0.28)(+0.14)) x 10(6) years old. The Antarctic ice sheet is therefore older than (1.54(-0.28)(+0.14)) x 10(6) years and the meteorite accumulation process at Allan Hills probably began between 3 x 10(4) and 3 x 10(5)years ago.

Aluminum-26 and beryllium-10 in greenland ice.

Activities of beryllium-10 and aluminum-26 dissolved in 200-year-old Greenland ice were found to be 18.4 (+ 8.4, - 4.8) x 10(-6) and 3.2 +/- 0.9 x 10(-7) disintegration per minute per liter, respectively. From these values and the precipitation rate (30 milliliters of water per square centimeter per year), the production rates of these isotopes are calculated to be 3.6 (+ 1.6, - 0.9) x 10(-2) and 1.7 +/- 0.5 x 10(-4) atom per second * square centimeter. These rates agree with the rates calculated for the production of these isotopes by cosmic rays in the atmosphere. Probably all the Al(26) in the ice is accounted for by such atmospheric production; however, an upper limit for the influx of cosmic dust bearing aluminum-26 is calculated at 3.2 x 10(5) tons per year for Earth. Only upper limits could be found for Al(26) and Be(10) in the undissolved particulate matter in the ice; their addition to the activities in the dissolved material leaves our conclusions unchanged.

Tritium and argon radioactivties in lunar material.

Tritium and argon radioactivities, attributable to galactic and solar cosmic-ray interactions, were measured in lunar soil and in three lunar rocks. The tritium in the soil, 325 +/- 17 disintegrations per minute per kilogram, is slightly higher than that in the rocks, 212 to 250 dpm/kg. For two rocks, the tritium was combined with the helium-3 in order to calculate exposure ages of 375 +/- 40 and 205 +/- 25 million years. The argon-37 radioactivities, 21.0 to 27.2 dpm/kg, and the argon-39 radioactivities, 12.1 to 16.4 dpm/kg, are slightly higher than those in stony meteorites. Higher exposure ages were obtained from the argon isotopes than from tritium and helium-3. On the basis of the known galactic cosmic-ray flux and the known cross section, at least half of the observed radioactivities are produced by solar cosmic rays.

The effect of exercise on basophil histamine release in patients with bronchial asthma.

There is increasing evidence for the role of basophils in allergic bronchial asthma. We studied the potential role of basophils in the pathogenesis of post-exercise-induced bronchoconstriction by measuring the histamine release from basophils both spontaneously and following ConA, FMLP, anti-IgE and TPA treatment. Two groups of patients with allergic asthma were studied: group I consisted of 8 patients with an exercise-induced fall in FEV1 of 20% or more, and group II had 7 patients with bronchial asthma who had less than a 5% fall in FEV1 following exercise. The mean spontaneous histamine release (SHR%) from basophils for group I was significantly larger than that of group II both before as well as at 5-10 and 60 min following exercise. The SHR% at baseline was 25 +/- 10 in group I (mean +/- SD) and 15 +/- 5 in group II (mean +/- SD). At 5-10 min following exercise it was 24 +/- 6 in group I and 11 +/- 2 in group II, while at 60 min following exercise it was 24 +/- 6 in group I and 17 +/- 2 in group II. There was no significant difference between the two groups in the effect of ConA, FMLP, anti-IgE or TPA treatment on basophil histamine release. The enhanced bronchoconstriction by exercise did not affect histamine release either spontaneously or following those 4 stimuli. It was concluded that, although patients with exercise-induced asthma have a greater degree of spontaneous histamine release, this is not affected by induced bronchoconstriction, a finding which does not support a role for basophils in exercise-induced asthma.

A comparison of the inhibitory effect of cromoline and nedocromil Na on histamine release from airway metachromatic cells and from peripheral basophils.

Metachromatic cells are increased in the airways of asthmatic patients. We obtained metachromatic cells from asthmatic airways using an induced sputum technique. The histamine release following ConA, anti-IgE and anti-IgE + IL3 from those cells were evaluated before and following the addition of cromoline Na and nedocromil Na. Metachromatic cells had a higher rate of spontaneous histamine release when compared to peripheral basophils. Cromoline Na and nedocromil Na inhibited histamine release from triggered metachromatic cells but not from peripheral basophils. It is concluded that airway metachromatic cells from asthmatics behave differently than peripheral basophils.

Secretion of stem cell factor by alveolar fibroblasts in interstitial lung diseases.

Sarcoidosis (SA) and diffuse interstitial fibrosis (DIF) are characterized by alveolitis, mast cell hyperplasia and increased fibroblast proliferation. Stem cell factor (SCF) stimulates proliferation of hematopoietic progenitor cells involved in mast and stromal cell interaction. We assessed the role of SCF secreted by alveolar fibroblasts (AFb) in the development of fibrosis of DIF and SA in six patients with SA and six patients with DIF. Bronchoalveolar lavage (BAL) was performed by conventional methods. A total of 500 cells were differentially counted from Giemsa-stained cytopreps. AFb and supernatants were recovered from long-term cultures of BAL cells and from 24 h cultures of confluent AFb. Levels of SCF were measured by ELISA. Alpha actin content of AFb was characterized by immunohistochemistry. The expression of AFb mRNA for IL1-alpha and beta, TGF-beta, IFN-gamma, IL-2, IL-4, IL-5 and IL-6 was determined by RT-PCR. There was a lymphocytic predominance in the SA patients and an increase in neutrophils and eosinophils in DIF. SCF secreted by AFb from DIF was significantly higher than in SA. TNF + IL-1 significantly decreased the secretion of SCF by AFb. There was a positive correlation between SCF levels and the percentage eosinophils but not for metachromatic cells. Alpha-actin expression of AFb in DIF was significantly higher than in SA. Cytokine mRNA was extracted from AFb of two SA and two DIF patients. The profile showed that only in stimulated AFb isolated from the DIF patients can IL-5 transcripts be visualized. In conclusion, AFb can contribute to the onset of fibrosis by secreting SCF and IL-5 which, in turn, may recruit eosinophils.

Correlation between PGE2 production and suppressor activity of alveolar macrophages from patients with interstitial lung diseases.

The suppressive activity of alveolar macrophages (AM) obtained from bronchoalveolar lavage (BAL), on PHA stimulation of autologous peripheral blood lymphocytes (APL) was evaluated. The effect on lymphocyte stimulation was evaluated by coculturing the AM and APL cells at a ratio of 1:1. PGE2 released by AM during the culture period was measured by a radioimmune assay. The patients included in the study were 11 cases with interstitial lung disease (ILD), 8 cases of lung cancer (CA), and 5 controls (CO). Addition of AM of patients from the CA group resulted in slight suppression of lymphocyte stimulation in 4 cases, slight enhancement in 3 cases and no effect in one case. AM from the CO group induced slight suppression in 4 out of 5 cases. AM from all 11 ILD cases exerted a significant high suppressive activity (65.6% +/- 18.2 - P less than 0.001 by comparison with the CO and CA groups). In ILD cases, a dichotomous pattern was found in regard to relation between high suppressive activity of AM and release of PGE2: in idiopathic pulmonary fibrosis (IPF) patients, high suppressive activity of AM (70.4% +/- 15.4) correlated well with elevated secretion of PGE2: 3.58 +/- 0.26 ng/ml/10(5) cells (P less than 0.02 compared to CO). AM from sarcoidosis patients suppressed PHA stimulation by 61.6% +/- 19.3 but secreted only 0.357 +/- 0.26 ng/ml/10(5) cells of PGE2 (P less than 0.02 compared with the idiopathic pulmonary fibrosis group). Therefore, it seems that other factors, in addition to PGE2, might be involved in the suppressive activity of AM from interstitial lung diseases.

Assessment of hazardous dust exposure by BAL and induced sputum.

OBJECTIVES: BAL, an important tool in assessing occupational lung diseases, is unsuitable for screening programs, exposure evaluation, or monitoring hazardous dust because it is an invasive technique. The results of induced sputum (IS) analysis were compared with BAL and evaluated as a possible alternative. METHODS: We compared BAL with IS analysis of 5 workers exposed to asbestos and 14 exposed to silica and hard metals. Pulmonary function tests and BAL were performed by conventional methods. IS induction was performed after a 20-min inhalation of 3.5% saline solution with an ultrasonic nebulizer. Giemsa-stained cytopreparations were differentially counted. T-lymphocyte subsets were analyzed by flow-activated cell sorter, and messenger RNA (mRNA) was transcribed by reverse transcriptase-polymerase chain reaction. Mineralogic particles were analyzed by scanning electron microscopy and polarizing light microscopy and quantified by an analyzer. RESULTS: The percentage of neutrophils was significantly lower in BAL fluid than in IS specimens, whereas no differences were found in the percentage of lymphocytes and subsets profile. Asbestos fibers were found in BAL but not in IS samples from workers exposed to asbestos. Polarizing particles were found in both samples. Similar mineral elements were found in qualitative analysis by scanning electron microscopy. Quantitative studies showed similar size distribution with a small shift toward larger particles in sputum; mRNA showed the same cytokine profile. CONCLUSIONS: A comparison of BAL and IS specimens in the evaluation of the study population yielded similar quantitative and qualitative results. Further research is needed to evaluate the hypothesis that IS, being a noninvasive technique, may be useful in monitoring exposed workers.

Eosinophilic lung reaction to aluminium and hard metal.

A nonsmoker drill polisher with interstitial lung disease is presented. The environmental exposure was mainly to aluminum oxide, aluminum silicate, and hard metals. Bronchoalveolar lavage revealed high eosinophilia, and transbronchial biopsy specimen disclosed interstitial pneumonia with giant cell infiltrates and peribronchiolar accumulation of macrophages laden with opaque dust. Mineralogic studies done from the tissue revealed a high concentration of exogenous particles that were identified as hard metals and aluminum silicate. These findings are compatible with hard metal pneumoconiosis.

Induced sputum: opening a new window to the lung.

The interest in sputum assessment as a non-invasive technique to retrieve cells and soluble material from the lung has increased and gained momentum during the last decade. As a marker of inflammation in airway diseases, induced sputum (IS) is a particularly promising procedure since it provides specific information on both the cellular and molecular constituents in inflammation. From 1950-1970, sputum cells had been examined on stained smears, with the procedure having been applied in both research and clinical settings. After having been recovered by spontaneous coughing, the cells were used to study lung cancer and respiratory infections and, later on, to diagnose Pneumocystis carinii pneumonia in patients infected with human immuno-deficiency virus (HIV). The method was widely improved upon by the induction of sputum with aerosol of hypertonic saline and then extended to become part of the assessment of airway inflammation in bronchial asthma and chronic obstructive pulmonary disease (COPD). It was recently shown that IS can be used to study interstitial lung diseases (ILD) and, more specifically, pneumoconiosis, sarcoidosis, non-granulomatous ILD and occupational lung diseases. In light of the fact that immunologic and functional bronchopulmonary abnormalities may be present in up to two-thirds of patients with Crohn's disease, we studied the use of IS in this condition as well. This review analyzes the value of IS and its present applications in pulmonary medicine.

Eosinophil influx into the airways in patients with exercise-induced asthma.

Exercise-induced asthma is a common phenomenon, the mechanism of which is undetermined. Eosinophils have been suggested as playing a role in its occurrence. We studied the effect of exercise-induced asthma on the cellular and mediator composition of spontaneously obtained sputum. Twenty-five patients with bronchial asthma were investigated by studying sputum spontaneously obtained before and following challenge. One group with (n=9) and one without (n=9) exercise-induced asthma performed exercise challenge. A third group (n=7) performed methacholine challenge. The sputum was analysed using Giemsa staining for differential cell count, measuring eosinophil cationic proteins and mixtures of leukotrienes (D4, E4 and C4) in the liquid phase using ELISA. The group with exercise-induced asthma had a mean drop of 23.7+/-7.4% in FEV1, significantly (P=0.001) higher than the group without it. Following challenges, there were significant increases in sputum eosinophils only in the group with exercise-induced asthma (from 8.1+/-13.9% to 18.3+/-20.2%, P=0.0017) and not in control groups (from 0.9+/-0.9% to 1.5+/-15%) or in those who had methacholine challenge (from 23.6+/-27.2% to 22.3+/-23.8%). Eosinophil cationic proteins did not change significantly in any group. In the liquid phase of the sputum, the amount of leukotrienes increased following exercise in six of the seven patients with exercise-induced asthma in whom it was measured. The influx of eosinophils to the airway in patients who develop exercise-induced asthma can be partially explained by the leukotrienes in the airways of those patients.

Induced sputum compared to bronchoalveolar lavage for evaluating patients with sarcoidosis and non-granulomatous interstitial lung disease.

Bronchoalveolar lavage (BAL), an important tool for evaluating interstitial lung diseases (ILDs), has limited utility due to its invasiveness and the difficulty of performing it in clinically contraindicated patients. We compared BAL with the induced sputum (IS) technique to analyse cells and T lymphocytes in patients with sarcoidosis (SA) and non-granulomatous ILD (NG-ILD). Pulmonary function tests and BAL were performed by conventional methods. IS induction was done 20 sec after inhalation of 3.5% saline with an ultrasonic nebulizer. Giemsa-stained cytopreps were differentially counted. T lymphocyte subsets were analysed by flow activated cell sorter (FACS). Patients with NG-ILD had impaired total lung capacity (TLC). Transbronchial biopsy demonstrated lung fibrosis in NG-ILD and non-caseating granuloma in SA. The differential cell count in both groups demonstrated a significantly lower percentage of neutrophils and a significantly higher percentage of macrophages in BAL than in IS. The IS samples of patients with SA were significantly richer in metachromatic cells and eosinophils, but had a lower percentage of lymphocytes, compared to the BAL samples. The profiles of T cell subsets showed the same pattern, in both samples, in both groups. A CD4/CD8 ratio of 2.5 or greater had a sensitivity of 100% and a specificity of 81.2%, with a positive predictive value of 81.2% to distinguish SA from NG-ILD. IS is an effective non-invasive technique to identify CD4+ inflammation which distinguishes sarcoidosis from other NG-ILDs.

Accelerated silicosis with mixed-dust pneumoconiosis in a hard-metal grinder.

We describe a fatal case of accelerated silicosis with a component of mixed-dust pneumoconiosis in a young hard-metal grinder that we believe is the first case of its kind in Israel and one of the rare cases reported worldwide. The patient's diagnosis was based on typical features: restrictive lung function, abnormal chest roentgenogram suggesting lung fibrosis, a history of exposure to silica and hard metals, bronchoalveolar lavage (BAL) fluid findings, and mineralogical studies. BAL cells showed an abundance of giant multinucleated macrophages. The CD4/CD8 ratio of T lymphocytes was 1.1, with a high percentage of CD8 and CD8/38 positive cells (37% suppressor/cytotoxic and 12% cytotoxic T lymphocytes, respectively). mRNA transcripts isolated from BAL cells were positive for interleukin-1 (IL-1) and transforming growth factor (TGF) Il-5, IL-2, and IL-10 but not for IL-6, IL-4, and interferon. Polarizing light microscopic studies of BAL and induced sputum cells showed polarizing particles, which are typical for silica. Mineralogical studies of electron microscopy performed on BAL fluid and on dust collected at the patient's workstation revealed silica particles as well as aluminum-titanium and other particles. The latter might have contributed to the patient's lung disease.