Value of adding an IGRA to the TST to screen for latent tuberculous infection in Greek health care workers.

SETTING: Ioannina University Hospital, Ioannina, Greece. OBJECTIVE: To evaluate the value of adding an interferon-gamma release assay (IGRA) to the tuberculin skin test (TST) for detecting latent tuberculous infection (LTBI) in a Greek university hospital among health care workers (HCWs) predominantly vaccinated with bacille Calmette-Guérin (BCG). DESIGN: Of 788 HCWs enrolled, 68.1% were BCG-vaccinated. A TST ⩾ 10 mm was considered positive and was followed by the QuantiFERON-TB(®) Gold In-Tube assay (QFT-GIT) in a two-step strategy. RESULTS: Of the enrolled HCWs, 36.4% were TST-positive, of whom only 14.4% were IGRA-positive. Agreement between the tests was poor (κ = 0.019; 95%CI -0.014-0.05, P = 0.355). Both TST and IGRA positivity increased with TST diameter, from 5.7% in TST 10-14 mm to 48.8% in TST ⩾20 mm. TST-positive, IGRA-negative results were most likely in younger, recently BCG-vaccinated HCWs (84.6% in those aged 20-29 years) and less likely in older HCWs (45% in those aged 50-59 years). The two-step strategy would have been more cost saving compared to the TST-only approach if adherence to LTBI treatment in our cohort had been ⩾24%. CONCLUSIONS: Poor overall agreement between TST and QFT-GIT was found. Use of IGRA as a second step in TST-positive cases offers an appropriate tool for LTBI detection among BCG-vaccinated HCWs in low-TB-incidence settings.

Interferon-gamma release assay clarifies the effect of bacille Calmette-Guérin vaccination in Greek army recruits.

OBJECTIVE: To compare the most recent commercial interferon-gamma release assay (IGRA), the QuantiFERON-TB Gold In-Tube (QFT-GIT), with the tuberculin skin test (TST) in Greek army recruits who were bacille Calmette-Guérin (BCG) vaccinated during childhood and had no history of tuberculosis (TB) exposure. METHOD: We conducted a cross-sectional comparison study of 1750 young army recruits. TST was performed on all participants, while QFT-GIT was performed in all subjects with TST > 0 mm and in 18 TST-negative controls (TST = 0 mm). RESULTS: Among the study subjects, 5.4% (96/1750) had TST indurations of >or=10 mm, and 3.4% (59/1750) had indurations of >or=15 mm. Among subjects with a positive TST, 11.4% (11/96) tested positive on QFT-GIT. All those with QFT-GIT positivity had TST indurations of >or=15 mm, and none of those with TST indurations of 10-14 mm were positive by QFT-GIT. The overall agreement between TST and QFT-GIT was poor (kappa = 0.02). CONCLUSION: We found a significant discordance between TST and QFT-GIT in BCG-vaccinated Greek army recruits consistent with previous studies showing that BCG received after infancy produces false-positive TST reactions. Our findings underline the need for a two-step approach in diagnosing latent TB infection in all BCG-vaccinated individuals: initial TST screening, followed by an IGRA to confirm TST positivity.

Lymphocytic alveolitis: A surprising index of poor prognosis in patients with primary Sjogren's syndrome.

Twelve years ago we reported that lymphocytic alveolitis [or bronchoalveolar lavage (BAL) lymphocytosis] correlates with clinical pulmonary involvement in primary Sjogren's syndrome (pSS). Our thesis was based on subtle clinical and functional evidence of interstitial lung disease (ILD) in pSS patients with "high lymphocytic alveolitis" (>15% lymphocytes in BAL). This report is a follow-up study of these patients. Basic clinical and functional re-evaluation of the 22 patients with pSS, studied in 1991, emphasized the differences between those with alveolitis and those without alveolitis. There was no significant functional decline. There were, however, two statistically significant differences between the two groups: (1) only patients with BAL lymphocytosis had to be treated with steroids (5/12 vs. 0/10, P < 0.05) and (2) only patients with BAL lymphocytosis had died in the mean time (6/12 vs. 0/10, P < 0.01). The causes of death were various. On only two occasions were they related to respiratory infections while there were no deaths from respiratory failure secondary to ILD. BAL lymphocytosis appears to be a surprisingly serious index of dismal prognosis in patients with pSS. We offer no unifying pathophysiologic mechanism for it and, therefore, all we propose is that BAL is performed early, in as many patients with pSS as possible. These patients should then be followed up systematically, in order to evaluate if BAL lymphocytosis has any pathophysiologic importance in the development of clinically serious pSS, which is serious enough to lead to death.

Cadherin superfamily of adhesion molecules in primary lung cancer.

Cadherins are Ca(2+-)dependent cell-cell adhesion molecules which interact with intracellular proteins called catenins. Cadherins are the most interesting adhesion molecules and among them most important is epithelial E-cadherin. Loss of the function or/and the expression of any of the elements of E-cadherin/catenins complex make the cell incapable to adhere resulting to a loss of the normal architecture of tissues. Reduced, absent or disorganised expression of E-cadherin has been found in several carcinomas, including lung cancer. Soluble E-cadherin found in serum from patients with lung cancer could be a tumor marker, while alterations observed in non-small cell lung cancer probably play a role in manifestation of a malignant phenotype. Reduced expression of E-cadherin is a key event in tumorgenicity and metastasis and possible therapeutic strategies are based on that conclusion. In addition, E-cadherin has a role as a marker of differential diagnosis between bronchioloalveolar carcinoma and conventional pulmonary carcinoma as well as between mesothelioma and metastatic pulmonary adenocarcinoma. Small cell lung cancer cells express several types of cadherins too. In conclusion, many studies are in process and it is very possible that soon some cadherins will be used as useful biomarkers and theraupeutic targets in cases of primary lung cancer.

Primary angiosarcoma of the lung and pleura.

A 46 year old male smoker was admitted for severe continuing hemoptysis. Chest-X-rays and chest computed tomography revealed nodular infiltrates and bilateral hemothorax. Fiberoptic bronchoscopy resulted to non-diagnostic cytological and microbiological findings. Open lung and pleural biopsies after right thoracotomy revealed epithelioid angiosarcoma and further staging assessment showed secondary brain and liver foci. The patient received several courses of chemotherapy but he died one month later. The clinical, radiological, pathological, histochemical and therapeutic aspects of the disease are discussed. Angiosarcoma, a rare tumour with poor prognosis should be taken into consideration in the differential diagnosis of hemoptysis.

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.

Evaluation of the end-expiratory pressure by multiple linear regression and Fourier analysis in humans.

This study was designed to compare the end-expiratory pressure (EEP) during mechanical ventilation (MV) measured dynamically (EEPdyn), by multiple linear regression (MLR) of the airway pressure (Pao) vs volume (V) and flow (V') and after Fourier analysis (FA) of the Pao and V'. Pao and V' were recorded from 32 ICU patients (II without respiratory disease, 10 COPD, II ARDS) under MV, at three levels of PEEPe (0, 5 and 10 hPa). Volume was calculated by numerical integration of V'. Data were analysed by MLR and FA, while the actual value of EEPdyn was recognised on the Pao signal at zero V' and V. EEPdyn, EEPMLR and EEPFA were compared for all patients, for each group of patients and for every level of applied PEEPe. Despite the different evaluation of respiratory mechanics between MLR and FA, the EEP values were always not significantly different between the three applied methods (P > 0.05). A high degree of correlation was found between them, taken two at a time (r > 0.99, P < 0.001). Two non-invasive analytical methods for the evaluation of respiratory mechanics during MV, MLR and FA offer a reliable and clinically useful estimation of EEP during MV.

Endobronchial metastases secondary to solid tumors: report of eight cases and review of the literature.

Endobronchial metastases (EBM) secondaries to extrapulmonary solid malignant tumors are rare. Breast, colon and renal adenocarcinomas are the most frequent tumors associated with EBM. Since 1990 we have treated eight patients with EBM secondary to renal adenocarcinoma (three cases), colon adenocarcinoma (two cases), gastric adenocarcinoma (one case), bladder carcinoma (one case) and basal cell carcinoma (one case). Endobronchial lesions were detected by bronchoscopy and their metastatic nature was confirmed histopathologically in all eight cases. We also conducted a review of EBM reporting studies published in English language. The median interval from the diagnosis of the primary tumour was 41 months. Symptoms and radiological findings were indistinguishable from those of primary lung cancer. Five patients were treated with external radiotherapy with symptomatic improvement while two patients had chemotherapy and one patient underwent surgical resection of the metastasis. Systemic treatment was used in six cases with no significant effect on EBM. Median survival after EBM diagnosis was 9 months with one patient surviving 3.5 years and two patients still alive at 1 year. In conclusion, EBM usually represent a late manifestation requiring differential diagnosis from a primary lung cancer. Local treatment may result in symptomatic improvement but prognosis is generally poor averaging 1-2 years in most series.

Lung involvement in primary Sjögren's syndrome is mainly related to the small airway disease.

OBJECTIVE: To evaluate lung involvement in patients with primary Sjögren's syndrome. METHODS: Sixty one consecutive, non-smoking patients, 58 women and three men, were evaluated clinically, physiologically, and radiologically. A bronchial and/or transbronchial biopsy was performed on 13 of the patients. Physiological data were compared with that of a control group of 53 healthy non-smoking subjects matched for age and sex. RESULTS: In 41% of the patients the main symptom was dry cough. Physiological studies revealed that the patients presented significantly lower expiratory flow values (% pred) when compared with those of the control group: the forced expiratory volume in one second (FEV1) (mean (SD)) was 96% (16) v 111% (13) (p < 0.0001), the maximal expiratory flow at the 50% of the vital capacity (MEF50) was 72% (24) v 103% (17) (p < 0.0001), and the maximal expiratory flow at the 25% of the vital capacity (MEF25) was 49% (25) v 98% (20) (p < 0.0001). No significant difference was noted for the carbon monoxide diffusion value (% pred), between patients and controls. Blood gases were evaluated in 44 patients: mild hypoxemia was observed, and the alveolo-arterial oxygen difference (P(A-a)O2) correlated significantly with MEF50 (r = 0.35, p < 0.01) and MEF25 (r = 0.33, p < 0.01) values. Chest radiography showed mild, interstitial-like changes in 27 patients while slightly increased markings were present in 21. High resolution computed tomography of the lungs was performed in 32 patients (four with a normal chest radiograph, six with suspected interstitial pattern, 19 with apparent interstitial pattern, and three with hyperinflation) and revealed predominantly wall thickening at the segmental bronchi. All positive findings by computed tomography derived from the patients with abnormal chest radiographs. Transbronchial and/or endobronchial biopsy specimens in 10 of the 11 sufficient tissue samples revealed peribronchial and/or peribronchiolar mononuclear inflammation, while interstitial inflammation coexisted in two patients. CONCLUSION: The airway epithelia seem to be the main target of the inflammatory lesion of the lung in patients with primary Sjögren's syndrome. It seems to be common, subclinically leading to obstructive small airway physiological abnormalities.

Is pyrazinamide really the third drug of choice in the treatment of tuberculosis?

SETTING: University Hospital in a rural area of Greece. OBJECTIVE: Pyrazinamide (PZA) is recommended as the third drug in the 6-month regimens for tuberculosis. This has replaced previously satisfactory 9-month regimens with ethambutol (EMB). Several cases of severe hyperuricemia and at least one episode of acute arthritis in patients receiving PZA prompted us to study PZA prospectively with regard to these side effects. DESIGN AND SUBJECTS: Prospective study of 20 patients receiving PZA for tuberculosis compared to control patients with tuberculosis not receiving PZA. RESULTS: The study was discontinued with the twentieth patient when it became obvious that uric acid was elevated in all patients while on PZA and the last patient developed acute arthritis. This occurred in none of the control patients. CONCLUSION: Hyperuricemia should either be considered a significant side effect and make us reconsider PZA as the third drug of choice in tuberculosis, or it should be officially declared trivial by a major health organization. If so, it should be suggested to all health providers involved that there is no need to monitor uric acid in tuberculosis patients receiving PZA.

Pneumothorax as a first manifestation of sarcoidosis.

Pneumothorax is a rare manifestation of sarcoidosis, occurring usually late in the course of the disease. We report five cases of pneumothorax as a presenting manifestation of sarcoidosis. In two patients, thoracotomy showed extensive pleural infiltration by noncaseating granulomas. High-resolution CT scans showed cavitated subpleural nodules and subpleural bullae in one case. These findings support that necrosis of subpleural granulomas or rupture of a subpleural bullae, or both, are the mechanisms of pneumothorax in sarcoidosis. Three patients with a lung function impairment were treated with oral corticosteroids. One nontreated patient died due to progression of the disease.

Idiopathic pulmonary fibrosis and pulmonary fibrosis in diffuse systemic sclerosis: two fibroses with different prognoses.

Idiopathic pulmonary fibrosis and diffuse cutaneous systemic sclerosis (dSSc) involve the lung by a fibrotic process. In recent years, there has been increasing awareness that the natural history of these two types of pulmonary fibrosis might be different. The purpose of this study was to compare lung involvement in these two diseases in a prospective fashion in order to address differences in their clinical course. Forty-three consecutive patients, 18 with lone interstitial pulmonary fibrosis (lone IPF) and 25 with dSSc-IPF were evaluated clinically, radiologically and physiologically at the entry into the study and the evolution of their disease was contrasted by survival analysis. Patients with lone IPF compared with dSSc-IPF were characterized by male predominance (p < 0.001), older age at disease onset (p < 0.001), shorter disease duration (p < 0.001), more frequent crackles on auscultation and clubbing (p < 0.001 and p < 0.0001, respectively), more severe dyspnea (p < 0.0001) and more advanced radiological involvement (p < 0.0001). Functional indices presented comparable values and did not reach statistically significant differences except for the values of single breath CO diffusing capacity (p < 0.0001) and the PaO2 (p < 0.01) which was worse in patients with lone IPF. Finally 12 of the 18 patients with lone IPF died in 2.66 +/- 1.18 years from the onset of respiratory symptoms, while none of the dSSc-IPF patients had died 5.6 +/- 4.25 years from the first ever appearance of respiratory involvement (p < 0.001). In conclusion, although the two groups of patients were not at an absolutely comparable stage of their disease, a worse prognosis for patients with lone IPF seems to emerge from this study.

Malignant pleural mesothelioma from nonoccupational asbestos exposure in Metsovo (north-west Greece): slow end of an epidemic?

Inhabitants of the Metsovo area, north-west Greece have been exposed since childhood to inhalation of asbestos, from a material containing tremolite, used for whitewashing ("luto soil"). This has resulted in endemic pleural calcifications (47% of adult population) and increased incidence of malignant pleural mesothelioma (MPM). In 1987, we reported that the incidence of MPM between 1981-1985 was around 300 times higher than expected in a nonasbestos exposed population (seven cases in 5 yrs in a population of 4,000-5,000). The present study is an updated report regarding this "mesothelioma epidemic", in conjunction with the diminished use and final abandonment of "luto soil" in the early 1980s. It appears that the incidence of MPM in Metsovo has dropped considerably since our first report. Between 1985-1994, we diagnosed six such cases (incidence rate = 1.4 cases per 10,000 person-years), whilst between 1980-1984 eight cases had been diagnosed (incidence rate = 3.7 cases per 10,000 person-years). Although, because of the small number of cases, this did not reach statistical significance (p = 0.08), we note that the incidence is now considerably lower than before. Had it remained unchanged, we would have expected 17 cases of MPM instead of six. This drop follows the diminished use of "luto" whitewash (by 92% of the population in 1950 and only 18% in 1980). If we take into account a 30-40 year latency period for mesothelioma, we expect that the "Metsovo mesothelioma epidemic" will fade away by the year 2020-2030, since the material has not been used since 1985.

Acquired nasopharyngeal obstruction and "Metsovo lung".

Acquired nasopharyngeal obstruction is a rare lesion today. Formerly it was the result of infections, but today it is more commonly seen as an unusual complication of surgical trauma. This article reports the first case, as we know it from the international literature, of nasopharyngeal obstruction which cannot be attributed to the already known causes and which occurred in a woman with "Metsovo lung" (i.e., occupational exposure to the asbestos-containing mineral tremolite). The ascertainment in the future of other cases like this will confirm the correlation between nasopharyngeal stenosis and Metsovo lung for which we have not any doubts.

Chronic eosinophilic pneumonia in rheumatoid arthritis.

We report the case of a 47 year old woman with rheumatoid arthritis and infiltrates on chest radiogram. Typical features of eosinophilic pneumonia were detected upon open lung biopsy, probably unrelated to hydroxychloroquine, the only drug administered to the patient. Good response to steroids was obtained. This case brings to light one more example of the rare association between chronic eosinophilic pneumonia and rheumatoid arthritis.

Wide geographic variations of sensitivity to MOTT sensitins in Greece.

Several studies have suggested that large bodies of water are a main source of infection with mycobacteria other than tuberculosis (MOTT). If this is correct, there should be a gradient in the infection rate with MOTT between mountainous and seaside areas. To test this hypothesis, we performed skin testing with tuberculin and sensitins in 19,470 Greek Armed Forces recruits. Initially, several MOTT sensitins were used, but when it became clear that the Mycobacterium scrofulaceum sensitin was the most appropriate, the study was continued with it alone in 17,403 recruits. Finally, in order to evaluate the geographical distribution of sensitivity to sensitins, we studied the results of 8,507 of these recruits living in or near their birthplace. They were divided into three geophysical areas: seaside 3,389 recruits; mountains 2,692 recruits; and inland plains 2,426 recruits. MOTT sensitivity rates were 4.1% in mountainous areas and 7.1% in seaside areas. All small Aegean islands had high MOTT rates (above 8%). In inland plains, high MOTT rates (above 8%) were observed among those living near big rivers. This geographical distribution of MOTT sensitivity supports the theory that large bodies of water are a main source of infection with MOTT.

Pulmonary damage due to paraquat poisoning through skin absorption.

A case of recovery from acute respiratory insufficiency due to paraquat is described. A 57-year-old farmer developed breathlessness, high fever and interstitial infiltrates in the upper and middle lung fields few days after percutaneous paraquat poisoning with rapid evolution to pulmonary fibrosis. Anti-inflammatory drugs and antioxidants, were administered to the patient, though with a delay, with some improvement; the patient survived despite residual lung fibrosis. Paraquat lung, as confirmed by this paper, is not invariably fatal.