Alessandra Sandrini

Asbestos and the lung in the 21st century: an update

The asbestos‐related disorders (ARDs) are currently of significant occupational and public health concern. Asbestos usage has been banned in most developed countries, but asbestos is still used in many developing countries and the number of cases of ARDs worldwide is rising. Many countries are now experiencing an epidemic of ARDs that is the legacy of occupational exposure in the 1960s–1980s because of the long latency period between asbestos exposure and manifestation of disease. It is likely that asbestos‐related mortality and morbidity will continue to increase. Although the most feared complications of asbestos inhalation are the malignant conditions such as mesothelioma and lung cancer, asbestos inhalation more frequently results in benign conditions such as pleural plaques, diffuse pleural thickening, and asbestosis (pulmonary fibrosis due to asbestos exposure). Over recent years, there have been changes in the epidemiology of mesothelioma, in clinical management of ARDs and developments in new techniques for early detection of malignancy. This review provides an update on the respiratory manifestations of asbestos exposure and also considers advances in screening methods that may affect future management in the workplace.

Soluble mesothelin-related protein in an asbestos-exposed population: the dust diseases board cohort study.

RATIONALE Soluble mesothelin-related protein (SMRP) is raised in epithelial-type malignant mesothelioma (MM), but the utility of SMRP in screening for MM is unknown. OBJECTIVES We aimed to evaluate SMRP in an asbestos-exposed cohort. METHODS A total of 538 subjects were studied. Those with elevated SMRP (> or =2.5 nM) underwent further investigation including positron emission tomography/computed tomography. MEASUREMENTS AND MAIN RESULTS Mean (+/-SD) SMRP in healthy subjects exposed to asbestos (n = 223) was 0.79 (+/-0.45) nM. Fifteen subjects had elevated SMRP, of whom one had lung cancer, which was successfully resected. Another with lung cancer was undetected by SMRP. No subjects were diagnosed with MM. Mean SMRP in healthy subjects was significantly lower than in subjects with pleural plaques alone (P < 0.01). CONCLUSIONS This is the first large-scale prospective study of SMRP for screening for malignancy in asbestos-exposed individuals. A high false-positive rate was observed. SMRP seems unlikely to prove useful in screening for MM.

Fractional exhaled nitric oxide in asthma: an update

In asthma, clinical symptoms and lung function are insensitive in reflecting the underlying airway inflammation, and monitoring of this process has only recently become available. Fractional exhaled nitric oxide (FeNO) is now recognized as a reliable surrogate marker of eosinophilic airway inflammation and offers the advantage of being completely non‐invasive and very easy to obtain. This review summarizes the clinical use of FeNO in asthma. It covers the relationship between FeNO and the underlying eosinophilic inflammation, the pathophysiology and production of FeNO, technical aspects of FeNO measurement and potential confounding factors in interpreting levels. FeNO reference values and the role of FeNO in asthma assessment, diagnosis and management are also discussed.

Nitric Oxide and Exhaled Breath Nitrite/Nitrates in Chronic Obstructive Pulmonary Disease Patients

Background: Measurement of nitric oxide (NO) and nitrite/nitrates (NOx) levels in exhaled breath condensate (EBC) are non-invasive techniques, which can be used to monitor airway inflammatory diseases. Production of NO is often increased in inflammatory diseases of the airways, including exacerbations of chronic obstructive pulmonary disease (COPD). COPD-associated airway inflammation may be affected by multiple factors, including cigarette smoking and glucocorticosteroid (GCS) treatment. Objectives: To test the hypothesis that total NOx levels in EBC and exhaled NO levels would be affected by cigarette smoking or the presence of COPD. Methods: Exhaled NO levels and NOx levels in EBC were measured in 96 COPD patients and in 80 normal subjects. Results: Exhaled NO levels in COPD patients were significantly higher than those of normal subjects when comparing either the total groups (9.8 ± 0.7 vs. 5.5 ± 0.4 ppb, p < 0.0005) or 2 appropriate subgroups, ex-smokers (10.3 ± 1.0 vs. 5.4 ± 0.6 ppb, p < 0.0005) and smokers (9.2 ± 1.2 vs. 5.7 ± 0.5 ppb, p = 0.002). There was no significant difference in NOx levels in EBC, however, between COPD patients and healthy subjects when analysed either together or as subgroups. No significant difference was found in either exhaled NO levels or NOx levels in EBC between GCS-naïve subjects and those on GCS treatment in the ex-smoking or smoking COPD subgroups. Conclusions: COPD patients have higher exhaled NO levels than control subjects when either combined or analysed as non-smoking, ex-smoking and smoking subgroups. GCS treatment did not appear to affect these non-invasive markers of airway inflammation in COPD.

Clinical consequences of asbestos-related diffuse pleural thickening: A review

Asbestos-related diffuse pleural thickening (DPT), or extensive fibrosis of the visceral pleura secondary to asbestos exposure, is increasingly common due to the large number of workers previously exposed to asbestos. It may coexist with asbestos related pleural plaques but has a distinctly different pathology. The pathogenesis of this condition as distinct from pleural plaques is gradually becoming understood. Generation of reactive oxygen and nitrogen species, profibrotic cytokines and growth factors in response to asbestos is likely to play a role in the formation of a fibrinous intrapleural matrix. Benign asbestos related pleural effusions commonly antedate the development of diffuse pleural thickening. Environmental as well as occupational exposure to asbestos may also result in pleural fibrosis, particularly in geographic areas with naturally occurring asbestiform soil minerals. Pleural disorders may also occur after household exposure. High resolution computed tomography (CT) is more sensitive and specific than chest radiography for the diagnosis of diffuse pleural thickening, and several classification systems for asbestos-related disorders have been devised. Magnetic resonance imaging and fluorodeoxyglucose positron emission tomography (PET) scanning may be useful in distinguishing between DPT and malignant mesothelioma. DPT may be associated with symptoms such as dyspnoea and chest pain. It causes a restrictive defect on lung function and may rarely result in respiratory failure and death. Treatment is primarily supportive.

Anaphylaxis to Gelofusine® confirmed by in vitro basophil activation test: a case series*

The plasma expander Gelofusine® (succinylated gelatin) is a recognised cause of peri‐operative anaphylaxis. Current diagnosis of Gelofusine sensitivity is by skin testing, a procedure that itself carries a risk of allergic reaction. We evaluated the reliability of the in vitro basophil activation test as a diagnostic assay for Gelofusine sensitivity in subjects with a clinical history highly suggestive of Gelofusine allergy. Six patients with peri‐operative anaphylaxis clinically attributed to Gelofusine were skin tested to confirm sensitivity. Control subjects included three healthy subjects and five subjects allergic to a neuromuscular blocking drug, all negative on Gelofusine skin testing. Whole blood basophil activation to Gelofusine was analysed by flow cytometry for CD63 surface expression. All of the Gelofusine sensitive patients and one of the control allergic subjects showed positive basophil activation to Gelofusine. In this series of subjects, the basophil activation test for Gelofusine allergy had a sensitivity of 100% and a specificity of 87.5%. Our findings suggest that basophil activation testing is a safe and reliable in vitro assay for prediction or confirmation of Gelofusine sensitivity in patients with high clinical suspicion of Gelofusine‐induced anaphylaxis.

Exhaled breath condensate biomarkers in asbestos-related lung disorders

OBJECTIVES Asbestos induces generation of reactive oxygen and nitrogen species in laboratory studies. Several such species can be measured non-invasively in humans in exhaled breath condensate (EBC) but few have been evaluated. This study aimed to assess oxidative stress and lung inflammation in vivo. METHODS Eighty six men were studied: sixty subjects with asbestos-related disorders (asbestosis: 18, diffuse pleural thickening (DPT): 16, pleural plaques (PPs): 26) and twenty six age- and gender-matched normal individuals. RESULTS Subjects with asbestosis had raised EBC markers of oxidative stress compared with normal controls [8-isoprostane (geometric mean (95% CI) 0.51 (0.17-1.51) vs 0.07 (0.04-0.13) ng/ml, p<0.01); hydrogen peroxide (13.68 (8.63-21.68) vs 5.89 (3.99-8.69) microM, p<0.05), as well as increased EBC total protein (17.27 (10.57-28.23) vs 7.62 (5.13-11.34) microg/ml, p<0.05), and fractional exhaled nitric oxide (mean+/-SD) (9.67+/-3.26 vs 7.57+/-1.89ppb; p<0.05). EBC pH was lower in subjects with asbestosis compared with subjects with DPT (7.26+/-0.31 vs 7.53+/-0.24; p<0.05). There were no significant differences in exhaled carbon monoxide, EBC total nitrogen oxides and 3-nitrotyrosine between any of the asbestos-related disorders, or between these and controls. CONCLUSION In asbestos-related disorders, markers of inflammation and oxidative stress are significantly elevated in subjects with asbestosis compared with healthy individuals but not in pleural diseases.

Fractional exhaled nitric oxide concentration is increased in asbestosis and pleural plaques

Objective and background:  Asbestos exposure induces generation of reactive oxygen and nitrogen species. Nitric oxide is involved in asbestos‐related lung toxicity in vitro and can be measured non‐invasively in humans in exhaled breath. The authors hypothesized that fractional exhaled nitric oxide concentration (FENO) would be increased in subjects with asbestos‐related lung disorders.

Menstrual cycle variation of retroperitoneal lymphangioleiomyomas in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disease affecting women, classically involving the lungs. However, extrapulmonary manifestations also occur, including renal angiomyolipomas, retroperitoneal lymphangioleiomyomas and extrathoracic lymphadenopathy. The lung disease is hormone‐responsive, but no information exists regarding sex hormone responsiveness of abdominal LAM. Here, we report two women with LAM whose abdominal lymphangioleiomyomas increased in size with hormonal changes of the menstrual cycle. This is the first description of abdominal lymphangioleiomyomas exhibiting hormone responsiveness in LAM. We describe these cases and summarize the literature on abdominal LAM. Menstrual cycle variation should be taken into account when assessing response to therapy, both clinically and in research studies.

Regression of Pulmonary Lymphangioleiomyomatosis (PLAM)-Associated Retroperitoneal Angiomyolipoma Post–Lung Transplantation With Rapamycin Treatment

e congratulate Morton et al on their interesting report etailing the regression of an angiomyolipoma (AML) in post–lung transplant patient with lymphangioleiomyoatosis (LAM) after treatment with rapamycin. Abdomial involvement with lymphadenopathy and tumors, uch as AMLs and lymphangioleiomyomas, has been ell described. AMLs occur in almost 93% of patients ith tuberous sclerosis (TSC)-LAM and in 30% to 50% of atients with sporadic (S)-LAM. AMLs in TSC are sually more aggressive than in S-LAM and, in rare cases, ay require renal transplantation. There are rare ocurrences of LAM presenting exclusively with abdomial symptoms, often mimicking other conditions such s ovarian cancer, and we presently have several such atients under follow-up at the St Vincent’s LAM clinic s well as several with TSC. Thus, AMLs are targets for reatment independent of pulmonary LAM. The reently published proof-of-principle study from Cincinati demonstrated the efficacy of rapamycin in causing egression of AMLs with relatively few side effects, lthough this seemed to be short-lived with an increase n volume seen after cessation of therapy. Morton et al documented significant resolution of the umor at 7 months post-treatment with sirolimus and a ariety of other drugs. Sirolimus is not reimbursed for reatment of LAM under the Australian Pharmaceutical enefits Scheme (PBS), although it is available after lung