Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis.

In therapeutic studies in idiopathic pulmonary fibrosis (IPF), the low prevalence of significant change in pulmonary functional tests (PFTs) has been a major constraint. The prognostic value of "marginal" changes in PFTs in IPF and fibrotic non-specific interstitial pneumonia (NSIP) was evaluated. In patients with biopsy-proven IPF (n = 84) and NSIP (n = 72), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D( L,CO)) trends at 6 months were categorised as "significant" (FVC >10%; D(L,CO) >15%) or "marginal" (FVC 5-10%; D(L,CO) 7.5-15%). Proportional hazards analysis and time-dependent receiver operating characteristic methodology were used to examine PFT trends against mortality. In IPF, reductions in FVC were significant in 22 cases (26%) and marginal in 19 cases (23%). Mortality was higher in patients with a significant decline in FVC (hazard ratio (HR) 2.80, 95% CI 1.54-5.06; p<0.001) and those with a marginal decline in FVC (HR 2.31, 95% CI 1.19-4.50; p = 0.01) than in those with stable disease. Progression-free survival was lower when the decline in FVC was marginal than in stable disease (HR 2.34, 95% CI 1.19-4.60; p = 0.01). Marginal changes in D(L,CO) in IPF and marginal changes in FVC and D (L,CO) in fibrotic NSIP did not provide useful prognostic information. Marginal change in FVC in IPF denotes a poor outcome. These findings are applicable to clinical practice and to the selection of patients with more progressive disease for therapeutic studies.

Epidemiology of interstitial lung diseases in Greece.

INTRODUCTION: Few data are available on the epidemiology of interstitial lung diseases (ILDs), especially after the current classification of idiopathic interstitial pneumonias. The aim of this study is to provide data on the epidemiology of ILDs in Greece, under the ATS/ERS international consensus. METHODS: Departments of Pneumonology were contacted and asked to complete a questionnaire for every case of ILD that was alive on 2004 as well as for every new case from 1st January 2004 to 31st December 2004. Questions on the patients' demographic data, the exact diagnosis and the procedures used to establish the diagnosis were included. Centers covering about 60% of the Greek population have been analyzed. RESULTS: A total of 967 cases have been registered. The estimated prevalence of ILDs is 17.3 cases per 100,000 inhabitants. The estimated annual incidence of ILDs is 4.63 new cases per 100,000 inhabitants. The most frequent disease is sarcoidosis (34.1%), followed in decreasing order by idiopathic pulmonary fibrosis (19.5%), ILD associated with collagen vascular diseases (12.4%), cryptogenic organizing pneumonia (5.3%), histiocytosis (3.8%), and hypersensitivity pneumonitis (2.6%). Unclassified ILD or not otherwise specified accounted for the 8.5% of prevalent cases. CONCLUSIONS: These data suggest that sarcoidosis and idiopathic pulmonary fibrosis are the most frequent ILDs in our population. In comparison with the few previous reports, interesting dissimilarities have been observed.

Impaired aortic elastic properties in patients with systemic sarcoidosis.

BACKGROUND: Systemic sarcoidosis (Sar) is a granulomatous disorder involving multiple organs. Widespread vascular involvement and microangiopathy are common in patients with Sar. In addition, subclinical cardiac involvement is increasingly recognized in patients with Sar. However, data on the effect of Sar on the elastic properties of the arteries and myocardial performance are limited. In this study we looked for differences in aortic distensibility (AoD) which is an index of aortic elasticity, and myocardial performance of the ventricles, between patients with Sar and healthy subjects. In addition, we examined potential associations between AoD and clinical, respiratory and echocardiographic findings in patients with Sar. MATERIALS AND METHODS: A total of 83 consecutive patients (26 male/57 female, mean age 51.1 +/- 13.3 years) with Sar, without cardiac symptoms, were included. All patients underwent echocardiographic and respiratory evaluation including lung function tests. Additionally, 83 age- and sex-matched healthy subjects served as controls. AoD was determined non-invasively by ultrasonography. RESULTS: AoD was lower in the Sar compared to the control group (2.29 +/- 0.26 vs. 2.45 +/- 0.20 .10(-) (6) cm2 x dyn(-1), P < 0.01), while left ventricular mass (LVM) was higher in the Sar group (221.3 +/- 50.2 vs. 195.6 +/- 31.3 g, P = 0.007). Furthermore, myocardial performance of both ventricles was impaired in the Sar group. Multivariate linear regression analysis in the total sample population demonstrated a significant and independent inverse relationship between AoD and the presence of Sar (P < 0.001). The same analysis in the Sar patients showed that AoD was associated significantly and independently with the stage of Sar, age, systolic blood pressure, LVM and myocardial performance of both ventricles. No significant relationship was found between AoD and disease duration, pulmonary artery pressure or lung function tests. CONCLUSIONS: Presence and severity of Sar are associated with reduced aortic distensibility, irrespective of the disease duration, pulmonary artery pressure and lung function. In addition, patients with Sar have increased LVM and impaired myocardial performance.

Non-invasive measurement of the mean alveolar O(2) tension from the oxygen uptake versus tidal volume curve.

AIMS: The classical equations for measuring the mean and the ideal alveolar O(2) tension are based on assumptions, which are shown to be invalid. So we thought to develop a new, non-invasive method for measuring the mean alveolar P,O(2) within the volume domain (PA,O(2(Bohr))). This method is based on the oxygen uptake vs. tidal volume curve (VO(2) vs. VT) obtained during tidal breathing of room air and/or air enriched with oxygen. METHODS: PA,O(2(Bohr)) and the ideal alveolar PO(2) (PA,O(2(ideal))) were simultaneously measured in 10 healthy subjects and 34 patients suffering from chronic obstructive pulmonary disease (COPD) breathing tidally room air at rest. Additionally, 10 subjects (three healthy subjects and seven COPD patients) were studied while breathing initially room air and subsequently air enriched with oxygen. RESULTS: According to the results, PA,O(2(Bohr)) considerably differed from PA,O(2(ideal)) (P = 0.004). The cause of the difference, at the individual's R, is: (1) the difference between the arterial and Bohr's alveolar CO(2) tension, mainly in COPD patients, and (2) the inequality between Bohr's alveolar part of the tidal volume for CO(2) and O(2). Furthermore, end-tidal gas tension (PET,CO(2) and PET,O(2)) differed from Pa,CO(2) and PA,O(2(Bohr)) respectively. CONCLUSION: The deviation of PA,O(2(Bohr)) from PA,O(2(ideal)) has a definite impact on Bohr's dead space ratio for O(2) and CO(2), and on the alveolar-arterial O(2) difference. The difference (PA,O(2(Bohr)) - PA,O(2(ideal))) is not related to the pathology of the disease. So, gas exchange within the lungs should be assessed at the subject's R from PA,O(2(Bohr)) and PA,CO(2(Bohr)) but not from PA,O(2(ideal)) nor Pa,CO(2).

Long-term clinical effects of interferon gamma-1b and colchicine in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a deadly disease with no effective treatment. The purpose of this randomised prospective multicentric study was to characterise the clinical effects of interferon gamma (IFN-gamma) 1b administered subcutaneously thrice weekly versus colchicine for 2 yrs. This study had no pre-specified end-points. Fifty consecutive IPF patients were randomised. Patients with mild-to-moderate IPF were eligible for the study if they had histologically proven IPF, or, in the absence of surgical biopsy, fulfilled the European Respiratory Society/American Thoracic Society criteria. In the intent-to-treat population, five out of 32 (15.6%) IFN-gamma-1b patients and seven out of 18 (38.8%) colchicine patients died after a median follow-up period of 25 months Patients treated with IFN-gamma 1b showed a better outcome after 2 yrs of therapy, and fewer symptoms, as assessed using the St George's Respiratory Questionnaire, after 12 months of therapy. Also, the IFN-gamma-1b group exhibited a higher forced vital capacity (percentage of the predicted value) after 24 months of treatment. No significant differences were detected in resting arterial oxygen tension, total lung capacity (% pred), transfer factor of the lung for carbon monoxide (% pred) and high-resolution computed tomographic scoring between the two treatment groups. These data suggest that long-term treatment with interferon gamma 1b may improve survival and outcome in patients with mild-to-moderate idiopathic pulmonary fibrosis. Further studies are needed to verify these results.

Microscopic polyangiitis complicated by the development of prostate cancer and flutamide-induced hepatitis.

We report a case of a 65-year-old man with microscopic polyangiitis who developed prostate cancer and gastric adenocarcinoma after prolonged oral use of cyclophosphamide. Acute hepatitis with jaundice and marked increase in aminotranferases occurred after 6 months of flutamide treatment for metastatic prostate carcinoma. It is suggested that patients with vasculitis or other autoimmune disorders should avoid prolonged use of cyclophosphamide and other cytotoxic drugs in order to minimize long-term adverse effects, of which the risk of cancer is by far the most important. In patients on flutamide treatment, careful monitoring of flutamide administration with repeated liver function tests should be undertaken, and the drug must be immediately discontinued in patients with abnormal results to avoid progression of liver injury.

Tuberculous effusion: ADA activity correlates with CD4+ cell numbers in the fluid and the pleura.

BACKGROUND: Adenosine deaminase (ADA) is a commonly used marker in the diagnosis of tuberculous effusion and there is evidence that its production is linked to T cells and monocytes. Data on the correlation between ADA and T cells or macrophages in tuberculous effusions are conflicting. Furthermore, no studies have examined a possible correlation between pleural tissue infiltration and ADA. OBJECTIVES: We undertook this study to examine cell subsets in the fluid and the pleura in tuberculous effusion and their correlation to ADA. The use of cell subsets as a marker in the differential diagnosis was also examined. METHODS: Pleural fluid from 36 patients with tuberculous and 34 patients with malignant effusion as well as pleural tissue biopsies from 16 patients with tuberculous pleurisy were examined. The APAAP and the avidin-biotin complex immunocytochemical methods were used to examine CD4+ T cells and macrophages (CD68+), while ADA activity was measured by the Giusti colorimetric method. RESULTS: Our results showed that, in pleural fluid, CD4+ cells and ADA were significantly higher in tuberculous compared to malignant effusion (p<0.001 for all measurements). In pleural tissue biopsies, macrophages were the predominant cells but CD4+ T cells were also abundant. A significant correlation was found between ADA and CD4+ numbers in pleural fluid and tissue (r=0.45, p<0.01; r=0.75, p<0.001, respectively). ADA had high sensitivity and specificity for differential diagnosis while cell subsets did not. CONCLUSIONS: These results indicate that ADA activity correlates to CD4+ T cell infiltration in the pleura and the fluid. Moreover, ADA but no cell subsets may be used as markers of tuberculous effusion.

Disseminated tuberculosis complicating anti-TNF-alpha treatment.

An unusually large number of cases of tuberculosis, often of miliary or disseminated form, have been reported in patients receiving infliximab therapy for rheumatoid arthritis or Crohn's disease. We describe a patient with rheumatoid arthritis who was treated with infliximab and became systemically ill with Mycobacterium tuberculosis-disseminated infection. Patients who are candidates for treatment with tumour necrosis factor-alfa inhibitors should be evaluated for the presence of latent or active

Unevenness of ventilation assessed by the expired CO(2) gas volume versus V(T) curve in asthmatic patients.

Recently, we have shown that the expired CO2 gas volume versus tidal volume (VCO2-VT) curve is a useful tool for assessing unevenness of ventilation because it allows the separation of tidal volume into three functional compartments: (a) the CO2-free expired air (V0), (b) the transitional volume (Vtr), (c) the alveolar volume (VA) and the measurement of alveolar FCO2 during resting breathing in normal subjects and patients with COPD. In this paper, we have investigated whether changes pertaining to unevenness of ventilation taking place immediately after the administration of methacholine can be assessed using the VCO2-VT curve in asthmatic patients. The VCO2-VT curve was obtained during tidal breathing from 16 stable asthmatic patients who underwent a methacholine challenge test. It has been found that the Vtr, and hence Bohr's dead space (VD,Bohr = V0 + Vtr), over tidal volume ratios were significantly increased immediately after the methacholine administration, whilst the V0 over tidal volume ratio was not affected. The change of the above ratios was not related to the percentage decrease of FEV1.0 following methacholine administration.

BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia.

Idiopathic pulmonary fibrosis (IPF), which has the histological pattern of usual interstitial pneumonia (UIP), is a progressive interstitial lung disease with a poor prognosis. Idiopathic interstitial pneumonias with a histological pattern of nonspecific interstitial pneumonia (NSIP) have a better prognosis than UIP, and may present with a clinical picture identical to IPF. The authors hypothesised that bronchoalveolar lavage (BAL) findings may distinguish between UIP and NSIP, and have prognostic value within disease subgroups. BAL findings were studied retrospectively in 54 patients with histologically proven (surgical biopsy) idiopathic UIP (n=35) or fibrotic NSIP (n=19), all presenting clinically as IPF. These findings were also compared with the BAL profile of patients with other categories of idiopathic interstitial pneumonias. BAL total and differential cell counts did not differ between the two groups. Survival was better in NSIP. In neither group were BAL findings predictive of survival or changes in lung function at 1 yr, even after adjustment for disease severity, smoking and treatment. BAL differential counts in fibrotic NSIP differed from respiratory bronchiolitis-associated interstitial lung disease, but not from desquamative interstitial pneumonia or cellular NSIP. The authors conclude that bronchoalveolar lavage findings do not discriminate between usual interstitial pneumonia and nonspecific interstitial pneumonia in patients presenting with clinical features of idiopathic pulmonary fibrosis, and have no prognostic value, once the distinction between the two has been made histologically.

Noninvasive measurement of mean alveolar carbon dioxide tension and Bohr's dead space during tidal breathing.

The lack of methodology for measuring the alveolar carbon dioxide tension (PA,CO2) has forced investigators to make several assumptions, such as that PA,CO2 is equal to end-tidal (PET,CO2) and arterial CO2 tension (Pa,CO2). The present study measured the mean PA,CO2 and Bohr's dead space ratio (Bohr's dead space/tidal volume (VD,Bohr/VT)) during tidal breathing. The method used is a new, simple and noninvasive technique, based on the analysis of the expired CO2 volume per breath (VCO2) versus the exhaled VT. This curve was analysed in 21 normal, healthy subjects and 35 chronic obstructive pulmonary disease (COPD) patients breathing tidally through a mouthpiece apparatus in the sitting position. It is shown that: 1) PA,CO2 is similar to Pa,CO2 in normal subjects, whilst it is significantly lower than Pa,CO2 in COPD patients; 2) PA,CO2 is significantly higher than PET,CO2 in all subjects, especially in COPD patients; 3) VD,Bohr/VT is increased in COPD patients as compared to normal subjects; and 4) VD,Bohr/VT is lower than the "physiological" dead space ratio (VD,phys/VT) in COPD patients. It is concluded that the expired carbon dioxide versus tidal volume curve is a useful tool for research and clinical work, because it permits the noninvasive and accurate measurement of Bohr's dead space and mean alveolar carbon dioxide tension accurately during spontaneous breathing.

Optimal duration of chemotherapy in small cell lung cancer: a randomized study of 4 versus 6 cycles of cisplatin-etoposide.

With the purpose of investigating whether the 6-course standard dose treatment of etoposide-platinum (EP) in small cell lung cancer could be reduced to 4 courses without compromising patient's survival, 70 patients were randomized to receive either 4 or 6 cycles of etoposide 120 mg/m2 i.v. days 1-3 and cisplatin 80 mg/m2 day 1. With the intention of comparing these two durations as primary treatment policies, patients were randomized on admission and not after the fourth course. From the 69 evaluable patients 34 received EPx4 cycles and 35 EPx6 cycles. Objective response for EPx4 was achieved by 21 patients (62%, 95% CI 44%-78%) compared to 24 patients (69%, 95% CI 51%-83%) of the EPx6 group. Median times to progression were 6 mo (4-19) and 7 mo (4-40) respectively (P=0.06) in the two groups. Median survivals were 8.5 mo (4-28.5) and 9.5 mo (4-51) (p=0.04) respectively. No differences in the survival of limited-disease patients were shown with 10.5 mo (6-28.5) and 12 mo (8-51) respectively, in the two groups. Patients with extensive disease had a trend favoring prolonged chemotherapy with a median survival of 9 mo (5-16) versus 6.5 mo (4-16.5) for those in the EPx4 group (p=0.09). Toxicity was not significantly more severe in the EPx6 group. In conclusion, patients achieving complete response within 4 cycles may not need continued chemotherapy, but patients with extensive disease may benefit from 2 more cycles.

Tumour necrosis factor, interleukin-1 and adenosine deaminase in tuberculous pleural effusion.

Tumour necrosis factor (TNF) and interleukin-1 (IL-1) are powerful mediators with a key role in inflammation. This study was undertaken to study the presence of TNF and IL-1 in tuberculous effusion where there is marked inflammation and where examination of the pleural fluid may give information about the local inflammatory reaction. Adenosine deaminase activity (ADA, a marker of TB pleurisy) was also tested. Tumour necrosis factor, IL-1 and ADA levels were measured in the pleural fluid and serum of 97 patients; 33 with tuberculous effusion, 33 with malignant effusion, and 31 patients with benign non-tuberculous effusion. Pleural fluid TNF and ADA levels were higher in tuberculous (TB) patients than in patients with benign disorders or cancer (P < 0.01). Serum TNF levels were also higher in TB patients than other benign (P < 0.01) or malignant (P < 0.05) effusions. There was a positive correlation between serum and pleural fluid values (r = 0.998-0.999, P < 0.001) although pleural fluid concentration was higher (P < 0.001), possibly suggesting local production in the pleural cavity. Pleural fluid IL-1 levels were not raised in any patient group but there was a positive correlation between TNF and IL-1. In addition, a positive correlation was found between TNF and ADA levels, probably indicating some common production mechanism. Furthermore, ADA sensitivity in the diagnosis of tuberculous effusion was augmented by the combined use of TNF and ADA. The use of both these markers may prove useful in the differential diagnosis of TBC pleurisy.

Recurrent respiratory papillomatosis with malignant transformation in a young adult.

The term 'papilloma' was first used by Mackenzie 100 years ago, who claimed that this was the most benign tumour of the larynx. Today papillomas are considered to be caused by the Human Papilloma Virus group (H.P.V.). The majority of patients suffering from this disease which is also referred to as 'recurrent respiratory papillomatosis' require multiple surgical operations for tumour removal. Malignant transformation of papillomas, which is a rare condition, is considered to occur mainly to irradiated patients. The following report describes the case of a male patient, with a history of vocal cord papillomas since his first year of age, who developed bronchial and pulmonary spread of the disease. He died at the age of 26 years because of squamous cell carcinoma which was related to the malignant transformation of the pulmonary papillomas.

An immunocytochemical study of ras and myc oncoproteins and EGFr expression in pleural effusion smears.

Pleural effusion smears from 112 patients with either benign or malignant lung disease were investigated for the expression of EGFr and the oncogene proteins myc p64 and ras p21. The streptavidin-biotin peroxidase technique was used. In the studied malignant group of effusions both EGFr and ras have greater sensitivity in the detection of a malignant process than does routine cytological examination though EGFr was less specific. The combination of positive cytology and 3 positive markers is highly specific for a malignant process (90%). Myc and ras had a 100% sensitivity in squamous cell carcinomas but an overall specificity of only 67.3% and 66.6% respectively. The differences in myc and ms positivity, between squamous cell and adenocarcinoma effusion smears were highly significant (p <0.005). All effusion smears associated with undifferentiated carcinomas were ras positive and 2 of them were myc and EGFr positive.

Outcome of patients with brain metastases after combined modality therapy in small cell lung cancer (SCLC): a retrospective study.

The authors evaluated the role of whole brain radiotherapy (WBRT) on the outcome of brain metastasis and survival in 41 patients with small cell lung cancer (SCLC) treated in their department. In addition to chemotherapy, radiotherapy was given to the primary site in all responder patients. Six patients presented brain metastasis initially and 10 patients after the fourth course of chemotherapy. Brain metastases were symptomatic in 12 of 16 patients with a median time of 5 months (1-14) until symptoms developed. All patients but 2 with brain metastasis received WBRT (30 Gy in 10 fractions) in addition to chemotherapy. The median survival time of patients with brain metastasis was 8.3 months (3.5 to 16) compared to 12 months (4 to 34+) for patients without brain metastasis. In addition, the median survival time for patients with brain metastasis who responded to systemic chemotherapy was better than that of nonresponders. The authors found no improvement in survival in patients who received concomitant WBRT after chemotherapy compared to patients who received WBRT after completion of chemotherapy. In conclusion, the role of consolidating cranial irradiation in addition to chemotherapy in SCLC patients is unclear and warrants prospective randomized studies.