Dead space and slope indices from the expiratory carbon dioxide tension-volume curve.

The slope of phase 3 and three noninvasively determined dead space estimates derived from the expiratory carbon dioxide tension (PCO2) versus volume curve, including the Bohr dead space (VD,Bohr), the Fowler dead space (VD,Fowler) and pre-interface expirate (PIE), were investigated in 28 healthy control subjects, 12 asthma and 29 emphysema patients (20 severely obstructed and nine moderately obstructed) with the aim to establish diagnostic value. Because breath volume and frequency are closely related to CO2 elimination, the recording procedures included varying breath volumes in all subjects during self-chosen/natural breathing frequency, and fixed frequencies of 10, 15 and 20 breaths x min(-1) with varying breath volumes only in the healthy controls. From the relationships of the variables with tidal volume (VT), the values at 1 L were estimated to compare the groups. The slopes of phase 3 and VD,Bohr at 1 L VT showed the most significant difference between controls and patients with asthma or emphysema, compared to the other two dead space estimates, and were related to the degree of airways obstruction. Discrimination between no-emphysema (asthma and controls) and emphysema patients was possible on the basis of a plot of intercept and slope of the relationship between VD,Bohr and VT. A combination of both the slope of phase 3 and VD,Bohr of a breath of 1 L was equally discriminating. The influence of fixed frequencies in the controls did not change the results. The conclusion is that Bohr dead space in relation to tidal volume seems to have diagnostic properties separating patients with asthma from patients with emphysema with the same degree of airways obstruction. Equally discriminating was a combination of both phase 3 and Bohr dead space of a breath of 1 L. The different pathophysiological mechanisms in asthma and emphysema leading to airways obstruction are probably responsible for these results.

Pulmonary hypertension after transjugular intrahepatic portosystemic shunt (TIPS).

We reported the case of a patient in whom severe, and ultimately fatal, pulmonary hypertension developed 1.5 yrs after transjugular intrahepatic portosystemic shunt (TIPS). Pulmonary artery pressures were not affected by 100% oxygen, prostacyclin or nifedipine. Postmortem examinations showed pulmonary and vascular abnormalities typical of pulmonary hypertension. Pulmonary artery pressures should be measured in each patient with otherwise not readily explained dyspnoea following transjugular intrahepatic portosystemic shunt.

Does phase 2 of the expiratory PCO2 versus volume curve have diagnostic value in emphysema patients?

It has been postulated that serial inhomogeneity of ventilation in the peripheral airways in emphysema is represented by the shape of expiratory carbon dioxide tension versus volume curve. We examined the diagnostic value of this test in patients with various degrees of emphysema. The volumes between 25-50% (V25-50) and 25-75% (V25-75) of the expiratory carbon dioxide tension versus volume curve were determined in 29 emphysematous patients (20 severely obstructed and 9 moderately obstructed), 12 asthma patients in exacerbation of symptoms, and 28 healthy controls. Discriminant analysis was used to examine whether these diagnostic groups could be separated. With regard to phase 2 of the expiratory CO2 versus volume curve (mixture of anatomic deadspace and alveolar air), a plot of intercept versus slope of the relationships of (V25-50) and (V25-75) versus inspiratory volume (VI) from functional residual capacity (FRC), obtained during natural breathing frequency, proved to be most discriminating in the separation between healthy controls and severely obstructed emphysema patients. Separating healthy controls and severely obstructed emphysema patients on the basis of the discriminant line for V25-50, 9 of the 12 asthma patients in exacerbation were classified as normal, and only 5 of the 9 moderately obstructed emphysema patients as emphysematous. For V25-75 involvement of phase 3 of the curve (alveolar plateau) in asthma patients in exacerbation caused a marked overlap with the severely obstructed emphysema patients. In the healthy controls, a fixed breathing frequency of 20 breaths.min-1 led to an increase of both volumes.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential indirect anti-inflammatory effects of IL-4. Stimulation of human monocytes, macrophages, and endothelial cells by IL-4 increases aminopeptidase-N activity (CD13; EC 3.4.11.2).

IL-4 up-regulates various monocytic properties that are associated with pro-inflammatory functions. Paradoxically, IL-4 may also act as an anti-inflammatory agent by down-regulating the production of several inflammatory mediators. As the activity of some mediators has recently been shown to be regulated by peptidases, we examined whether IL-4 was able to modulate the expression of a cell membrane-associated peptidase, aminopeptidase-N (CD13). IL-4 caused a dose-dependent increase in the expression of CD13 Ag on highly purified human blood monocytes. Maximal expression was observed around 48 h of culture. This IL-4-induced increase was completely blocked by anti-IL-4 antiserum. Furthermore, the increase in surface expression was preceded by increased mRNA levels of CD13, which was maximal around 24 h of culture. We also observed that CD13-mediated leucine-aminopeptidase activity of monocytes was induced by IL-4. Other CD13-expressing cells were also sensitive to IL-4, as CD13 Ag expression and CD13 mRNA levels were up-regulated in human alveolar macrophages and endothelial cells upon IL-4 treatment. The increased expression of cell membrane aminopeptidase-N represents a potentially increased cellular ability to inactivate inflammatory mediators. Therefore, these findings represent further evidence of IL-4-mediated anti-inflammatory actions. We postulate that up-regulation of aminopeptidase-N expression may be an indirect mechanism of IL-4 to modulate the action of bioactive peptides. This mechanism may underlie, at least partially, the anti-inflammatory effects of IL-4 in vivo.

Planar cobalt-57 bleomycin scintigraphy compared with CT-scan in the diagnosis and staging of lung cancer.

OBJECTIVES: Cobalt-57 bleomycin accumulates in tumour cells and is a diagnostic aid for discriminating malignant and benign lesions. Published data indicate that planar cobalt-57 bleomycin scintigraphy (bleo-scan) is a sensitive and specific test in the diagnosis and staging of lung cancer. CT-scan was however not used in these studies. We tested the value of bleo-scan and compared the results with those of computed tomography (CT-scan). METHODS: Bleo-scan and CT-scan were obtained from patients who were consecutively investigated because of a suspicious lesion on their chest X-ray. RESULTS: In 59 patients carcinoma of the lung was diagnosed 49 times (83%). The sensitivity of bleo-scan was 90%, specificity was 30% and positive predictive value (PPV) 86%. CT-scan could not discriminate between malignant and benign lesions. Thirty-two of the 41 patients with non-small-cell lung cancer had pathological examination of mediastinal lymph nodes, revealing metastases in 47% of the patients. Bleo-scan and CT-scan, respectively, had a sensitivity of 53 and 87%, a specificity of 77 and 82%, and negative predictive values (NPV) of 65 and 87%. In the 49 lung cancer patients distant metastases were detected at 11 sites in 10 patients. Bleo-scan gave false-negative and false-positive results. CONCLUSIONS: Bleo-scan in (suspected) lung cancer adds too little to the diagnostic procedure to make it a routine procedure. CT-scan gives indispensable information about possible mediastinal involvement.

Differences in expression of monocyte/macrophage surface antigens in peripheral blood and bronchoalveolar lavage cells in interstitial lung diseases.

The surface antigens of monocytic cells in bronchoalveolar lavage (BAL) fluid were analyzed in 10 patients with sarcoidosis, 8 patients with idiopathic pulmonary fibrosis (IPF), 9 patients with extrinsic allergic alveolitis (EAA), and 10 healthy volunteers, and compared with the surface antigens of peripheral blood monocytes (PBM) of the same individuals. The absolute numbers of alveolar macrophages (AM) were increased in all disease groups as were the numbers of small monocyte-like cells, indicating an increased influx of PBM into the alveoli, which was the most prominent in EAA patients. In all groups investigated, the percentages of PBM positive for the monoclonal antibodies (mAb) CD13, CD14, CD33, U26, and Max3 were higher than the percentages of BAL macrophages positive for these markers, while the Max24 marker was equally expressed. In all groups the percentages of AM positive for RFD9 and CD68 were higher than the percentages positive for PBM. The absolute numbers of CD13+ macrophages were increased in IPF and EAA patients, probably due to the increased influx of monocytic cells. The 3 mAb in the CD68 cluster (i.e., Ki-M6, Ki-M7, and Y2/131) demonstrated marked differences in expression on PBM as well as on AM. This is probably because CD68(Ki-M6) recognizes a different epitope than CD68(Ki-M7) and CD68(Y2/131). The latter 2 become increasingly expressed by AM and this is paralleled by an increased CD68(KiM6) expression. The expression of CD68, which is associated with the generation of oxygen radicals during the respiratory burst and increased chemiluminescence, tended to be elevated on PBM and AM of IPF patients, although with a broad range.

Diffusion capacity in heart transplant recipients.

Preoperative diffusion capacity per liter alveolar volume (Kco) in cardiac transplant recipients with an intrinsic normal lung is within the normal range. In the first postoperative year, Kco showed a significant mean decrease of 12 percent (p less than 0.004). Lung function (TLC, VC, FEV1) tended to normalize after heart transplantation. Ventilation distribution remained stable before and after heart transplantation. Preoperatively, weak correlations were found between Kco and diastolic pulmonary arterial pressure (dPAP) and mean pulmonary capillary wedge pressure (PCWP). Postoperatively, correlation between Kco and PCWP was weak, and between Kco and dPAP it was not significant at all. These pressures determine the capillary blood volume before and after transplantation. Probably these weak correlations indicate that intrapulmonary factors, not cardiac factors, are of primary importance in the regulation of blood distribution. The percentage of decrease in Kco in the first postoperative year correlated with the change in dPAP and PCWP, but also with the cyclosporine level in the first posttransplant year. No correlation was found between cyclosporine level and pulmonary vascular resistance. It is suggested that higher levels of cyclosporine influence the alveolar capillary membrane, so that Kco decreases. The percentage of decrease in Kco was significantly more outspoken in patients who had rales on auscultation preoperatively. Using multiple regression analysis, we found that the factors most strongly related to the percentage of change in Kco in the first posttransplant year were the preoperative Kco, the cyclosporine level in the first postoperative year, and the change in dPAP in that year.

Cystic fibrosis in a 70 year old woman.

A 68 year old woman with a lifelong history of chronic bronchitis was diagnosed as having cystic fibrosis. The diagnosis was based on a suggestive family history, steatorrhoea, bronchiectasis with respiratory insufficiency, and very high sweat sodium content. The patient was found to be heterozygous for the delta F 508 gene defect.

Long-term multicentre trial in chronic nonspecific lung disease: methodology and baseline assessment in adult patients. Dutch CNSLD Study Group.

Airways obstruction and airways hyperresponsiveness are two dominant features in patients with chronic nonspecific lung disease (asthma and chronic obstructive pulmonary disease (COPD)). We set up a study to determine whether long-term (3 yrs) therapeutic intervention directed at airways obstruction and hyperresponsiveness is superior to one directed at airways obstruction alone. Patients were selected on functional criteria (age, baseline forced expiratory volume in one second (FEV1), and airways hyperresponsiveness) and, furthermore, extensively characterized by history, smoking habits, allergy, reversibility of airways obstruction and quality of life. The methodology and practical problems of setting up this large multicentre study are outlined, together with an analysis of baseline data. Standardization of methods and techniques and recruitment of patients required much effort, recruitment taking about twice as long as expected. A 3 month feasibility study allowed us to eliminate minor problems in the protocol. Over a 16 month period, 274 adult patients (18-60 yrs) from the out-patient clinics of six university centres entered the study; 99 met the diagnostic criteria for asthma, 51 for COPD, 88 for asthmatic bronchitis, and 36 could not be classified. Their mean (SD) FEV1% pred was 65.1 (15.2)%. Their geometric mean provoking concentration of histamine producing a 20% fall in FEV1 (PC20 histamine) was 0.28 mg.ml-1. In a multiple regression analysis, more severe airways hyperresponsiveness was associated with lower prechallenge FEV1% pred (p less than 0.0001), higher pack-years of smoking (p = 0.0099), blood eosinophil count (p = 0.0004), skin test reactivity (p = 0.0047) and with female sex (p = 0.0302). We conclude that setting up long-term multicentre trials in chronic nonspecific lung disease (CNSLD) is feasible and that these may offer valuable information on treatment and outcome of the disease.

Expression of the CD11/CD18 cell surface adhesion glycoprotein family and MHC class II antigen on blood monocytes and alveolar macrophages in interstitial lung diseases.

The expression of molecules of the CD11/CD18 cell surface adhesion glycoprotein family and HLA/DR antigen was studied on peripheral blood monocytes (PBM) and alveolar macrophages (AM) in bronchoalveolar lavage (BAL) fluid from patients with sarcoidosis, idiopathic pulmonary fibrosis (IPF), and extrinsic allergic alveolitis (EAA). Patients with these interstitial lung diseases showed increased numbers of macrophages in BAL fluid. This was probably caused by an increased influx of PBM to the alveoli since the numbers of cells with a monocytic morphology were also significantly increased in BAL samples from patients with interstitial lung disease, most prominently in IPF and EAA. The increased influx of PBM into the alveoli in patients with interstitial lung diseases was not reflected by an increased expression of the CD11/CD18 leukocyte function antigens on PBM. In healthy volunteers as well as in those with sarcoidosis, IPF, and EAA, the percentages of AM positive for CD11b (the C3bi complement receptor) and CD11c were lower than among PBM. This indicates that the expression of these cell surface adhesion molecules is downregulated during maturation and migration of PBM to the alveoli. The absolute numbers of AM positive for CD11b were increased in BAL fluid of IPF and EAA patients compared to healthy volunteers. EAA patients also showed increased absolute numbers of AM positive for CD11a and CD11c. This differentially increased expression of these leukocyte function antigens on AM suggests the influence of locally produced cytokines.

Expression of the CD11/CD18 cell surface adhesion glycoprotein family on alveolar macrophages in smokers and nonsmokers.

The CD11/CD18 leukocyte surface adhesion glycoprotein family consists of three different heterodimeric molecules that play an essential role in adhesion-related functions such as migration, chemotaxis, and phagocytosis. This suggests an important role of these molecules in inflammatory processes. The three molecules consist of a specific alpha chain (CD11a, CD11b, or CD11c) and share a common beta chain (CD18). The expression of the cell adhesion glycoprotein family on alveolar macrophages (AM) and peripheral blood monocytes (PBM) was studied in bronchoalveolar lavage (BAL) fluid samples and PB from 11 smokers and 10 nonsmoking healthy volunteers. Smokers showed increased numbers of macrophages in their BAL fluid as compared with nonsmokers. This is probably due to an increased recruitment of blood monocytes to the alveoli, since the numbers as well as percentages of cells with a monocyte-like morphology were significantly increased in BAL fluid samples from smokers. The proportion of CD11+/CD18+ AM in the BAL fluid from smokers, however, was decreased as compared with AM from nonsmokers and PBM. This suggests that tobacco smoke might play a role in the downregulation of these leukocyte adhesion glycoproteins on AM.

Choriocarcinoma with lung metastases during pregnancy with successful delivery and outcome after chemotherapy.

A patient with an intrauterine pregnancy of 27 weeks had a coexisting pulmonary metastatic choriocarcinoma. On the chest radiograph the lung metastases appeared as pulmonary infiltrates, simulating atypical pneumonia. Serum human chorionic gonadotrophin levels were normal for gestational age. Treatment with methotrexate was successful. This is the first reported case of choriocarcinoma in a woman with a pregnancy of less than 35 weeks in which both mother and child survived. The case emphasises the need to consider choriocarcinoma in any pregnant woman who presents with haemoptysis and pulmonary nodules or infiltrates.

Phenotype of blood monocytes and alveolar macrophages in interstitial lung disease.

The immunologic phenotype of the monocyte-macrophage cell populations in bronchoalveolar lavage (BAL) fluid and monocytes in peripheral blood (PB) were studied in 20 patients with sarcoidosis, 18 with idiopathic pulmonary fibrosis (IPF), seven with extrinsic allergic alveolitis (EAA), and 12 healthy volunteers. There were no significant differences in expression of the immunologic markers CD13(My7), CD14(My4), and Monocyte-2 on blood monocytes between the patient groups and healthy volunteers, but there were marked differences between groups in the expression of the three markers on BAL macrophages. The percentage of Monocyte-2+ macrophages was increased in BAL in subjects with sarcoidosis, EAA, and IPF compared with healthy volunteers, greatest in EAA. This increase is probably due to increased recruitment of blood monocytes into alveoli, since the cells had a monocytic morphology on phase contrast microscopy (in normal subjects the majority of blood monocytes, but few alveolar macrophages, express the Monocyte-2 antigen). Patients with IPF had a significantly lower percentage of CD13(My7)+ macrophages in BAL than the other three groups. Compared with IPF patients and healthy volunteers, patients with EAA had a significantly higher percentage of CD14(My4)+ macrophages, whereas in sarcoidosis patients the numbers were reduced. These observations suggest an increased influx of blood monocytes into the alveoli in interstitial lung disorders. Phenotypic differences were found between the BAL macrophage populations of the various interstitial diseases. These differences in alveolar macrophage phenotype may be due to local factors, depending on the type of inflammation.

Glucocorticoid receptors in alveolar macrophages: methodological aspects of the determination of the number of glucocorticoid receptors per cell.

Among patients with asthma or chronic obstructive pulmonary diseases the response to glucocorticoids varies considerably. To investigate the possible relationship between clinical response and number of glucocorticoid receptors in alveolar macrophages or their KD value a micro receptor assay was developed. Assay conditions were adjusted because of receptor occupancy by endogenous or therapeutically used glucocorticoids and high aspecific binding.

Bronchoalveolar lavage in extrapulmonary sarcoidosis.

Twenty-one patients presenting with extrapulmonary sarcoidosis, 20 patients with pulmonary sarcoidosis, and 12 healthy volunteers were investigated. They were evaluated for roentgenographic findings, as well as for immunologic marker expression of cells in bronchoalveolar lavage (BAL) fluid. The patients presenting with extrapulmonary sarcoidosis could be divided in two groups: nine of 21 (43 percent) presented with a stage 1 or stage 2 chest x-ray film, while 12 of 21 (57 percent) had no chest x-ray film abnormalities (stage 0). In all three groups of sarcoidosis patients, a significant increase of CD3+ T lymphocytes in the BAL fluid was found as compared to the healthy volunteers. However, the percentages of T lymphocytes in BAL fluid of patients with extrapulmonary sarcoid lesions and a normal (stage 0) chest x-ray film was significantly lower as compared to patients with extrapulmonary sarcoidosis and an abnormal (stage 1, 2) chest x-ray film, while the latter patient group did not differ from the patients with pulmonary sarcoidosis. This suggests that in patients with extrapulmonary sarcoidosis, a gradual progression of the T cell alveolitis may occur. Furthermore, these data indicate that a marked discrepancy between chest x-ray film abnormalities and the presence of an alveolitis as determined by immunologic marker analysis exists in more than 50 percent of the patients with extrapulmonary sarcoidosis.