Gerhard Hoheisel

Proinflammatory Cytokine Levels in Patients with Lung Cancer and Carcinomatous Pleurisy

Increased levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) have been reported in various diseases, including lung cancer. The role of the soluble form of the IL-6 receptor (sIL-6R) remains to be explored. We therefore measured IL-6, IL-8 and sIL-6R in effusion fluid and blood serum of 10 lung cancer patients with carcinomatous pleurisy (5 men, 5 women, age 64.3 ± 4.4 years) by enzyme-linked immunosorbent assays. Serum levels of healthy individuals served as control. Concentrations of sIL-6R were much higher in serum compared to pleural effusion fluids of tumor patients (25,698 ± 1,993 vs. 9,438 ± 1,407 pg/ml; p < 0.0001). In contrast, IL-6 and IL-8 were found at high concentrations in carcinomatous pleural effusions in comparison to serum (IL-6: 964 ± 176 vs. 10.2 ± 1.3 pg/ml, p < 0.0001; IL-8: 319 ± 85 vs. 9.6 ± 9.6 pg/ml, p < 0.0001). The serum concentrations of IL-6 were not significantly increased in lung cancer patients (10.2 ± 1.3 pg/ml) in comparison to controls (7.3 ± 1.0 pg/ml). IL-8 was detected in the serum of only 1 patient and in low levels in the serum of controls (8.0 ± 1.5 pg/ml; all values are mean ± SEM). We conclude from this study that decreased levels of sIL-6R, but increased levels of IL-6 and IL-8, are found in pleural effusion fluid of patients with lung cancer and carcinomatous pleurisy. The low sIL-6R levels in the presence of high IL-6 levels in pleural effusions and the high sIL-6R levels in the presence of low IL-6 levels in serum may suggest a downregulation of sIL-6R expression or sIL-6R shedding in the presence of excessive amounts of IL-6.

Compartmentalization of pro-inflammatory cytokines in tuberculous pleurisy

Increased levels of interleukin-6 (IL-6) and IL-8 are found in various immunologically mediated inflammatory disorders. Concentrations of IL-6, IL-8 and the soluble form of the IL-6 receptor (sIL-6R) were determined in serum and effusion fluid of 25 patients with tuberculous pleurisy utilizing enzyme linked immunosorbent assays (EIA). Serum IL-6 levels were only slightly increased in patients with tuberculous pleurisy in comparison to controls (11.1 +/- 2.1 vs 7.3 +/- 1.0 pg ml-1). IL-8 could not be detected in the serum of tuberculosis patients, but it was detected in the serum of healthy controls (8.0 +/- 1.5 pg ml-1). In comparison to serum, IL-6 and IL-8 were found in high concentrations in pleural effusions (IL-6: 932 +/- 70 vs 11.1 +/- 2.1 pg ml-1, P < 0.0001; IL-8: 450 +/- 85 vs 0 +/- 0 pg ml-1). In contrast, sIL-6R concentrations were much higher in serum compared to pleural effusion levels [30,477 +/- 1905 vs 9881 +/- 1177 pg ml-1, P < 0.0001 (mean +/- SEM)]. The authors conclude that elevated levels of IL-6 and IL-8 in pleural effusions are compartmentalized at the site of active disease. The low levels of sIL-6R in the presence of high levels of IL-6 in pleural effusions, and the high levels of sIL-6R in the presence of low levels of IL-6 in serum suggest that the expression or shedding of sIL-6R may be downregulated in the presence of excessive amounts of IL-6.

Angiogenic markers in breath condensate identify non-small cell lung cancer

Early recognition of lung cancer is a prerequisite for any strategy to improve lung cancer treatment outcome. Here we report a cross-sectional study intended as a proof of principle investigation using breath based detection (exhaled breath condensate, EBC) of angiogenic markers (VEGF, bFGF, angiogenin), TNF-alpha and IL-8 to discriminate 74 individuals, with confirmed presence or absence (X-ray, CT) of non-small lung cancer (NSCLC). Levels of angiogenic markers bFGF, angiogenin and VEGF in EBC significantly discriminated between 17 individuals with newly detected NSCLC versus stable and exacerbated chronic obstructive pulmonary disease (COPD) patients as well as healthy volunteers. Levels of IL-8 and TNF-alpha in EBC indicated acute inflammation, e.g. in acute exacerbated COPD (AECOPD) and were not indicative of lung cancer. In a different group of patients that were already treated with two cycles of chemotherapy and who responded with at least a 25% reduction in primary tumor diameter, levels of angiogenic markers were lower compared to patients with newly diagnosed NSCLC. We suggest that breath based detection of angiogenic markers may help in the early detection of lung cancer.

Procoagulant activity of purified protein derivative-stimulated pleural effusion mononuclear cells in tuberculous pleurisy.

Mononuclear cells (MNC) generate cell-bound procoagulant activity (PCA) which shortens recalcification time after incubation with an antigen to which the donor has been sensitized. PCA has been demonstrated in various lung diseases, including exudative pleural effusions. To determine the value of measuring cell-bound PCA in the diagnosis of tuberculous pleural effusions we examined pleural effusion MNC of patients with tuberculosis (n = 19), congestive heart failure (n = 7), and carcinoma (n = 7). MNC were isolated, incubated in 0 or 10 micrograms/ml purified protein derivative (PPD) for 15 min and for 20 h, and recalcification time determined. Incubation with thromboplastin was used as control. The recalcification times in serum incubated for 15 min varied within a wide range, the mean values were longest for tuberculous effusion MNC, incubation for 20 h increased variation. Incubation of cells for 15 min with thromboplastin led to a decrease of mean recalcification time in tuberculous (p < 0.001) and heart failure (p < 0.05), and with no significance in carcinomatous effusions. Incubation with PPD led to decrease of recalcification time which was not significant. Comparisons of the mean relative recalcification times after PPD incubation showed that tuberculosis differed from lung cancer (p < 0.001), lung cancer from heart failure (p < 0.05), but not heart failure from tuberculosis. We conclude from our study that pleural effusion MNC express spontaneous PCA in vitro which is strongest in carcinomatous pleural effusions. Incubation of MNC with thromboplastin and less discernable with PPD leads to an increase in PCA which is more pronounced in tuberculous pleural effusions. However, due to substantial intersubject variability and overlap between the study groups, this test does not allow reliable differentiation of tuberculous from other MNC rich pleural effusions.

Treatment of Invasive Pulmonary Aspergillosis in Neutropenic Patients by Additional Bronchoscopic Amphotericin B Instillation

Background: Invasive pulmonary aspergillosis (IPA) remains a life-threatening condition despite systemic antifungal therapy. Objectives: This retrospective analysis investigated whether additional bronchoscopic instillation of amphotericin B (amB) would improve efficacy of antifungal treatment in patients with haematological malignancies suffering from IPA. Methods: Twenty patients (40.6 ± 14.2 years, 14 male) with preceding chemotherapy, bone marrow or stem cell transplantation complicated by severe IPA who did not respond sufficiently to systemic antifungal therapy were additionally treated by repeated bronchoscopic instillations of amB solution (91 instillations, on average 4.6 ± 2.2 instillations per patient over a period of 24.1 ± 21.0 days). Therapeutic response to this combined treatment regimen was monitored by chest X-ray and CT scan. Results: The mean infiltration sizes during systemic antifungal therapy alone (mean duration 11.9 ± 9.9 days) did not change significantly. However, after additional bronchoscopic instillation of amB solution infiltration sizes were reduced significantly (p < 0.05). A total resolution of infiltrates was seen in 3 and a partial reduction in 13 of 20 patients. Mean duration of total antifungal treatment was 50.1 ± 24.0 days. The mean follow-up period was 34.1 ± 31.2 months. The IPA-related mortality rate was 18.8% (3 of 16 patients). Conclusions: Additional bronchoscopic instillation of amB may improve the efficacy of systemic antifungal therapy in patients with haematological malignancies complicated by severe IPA. Bronchoscopic instillation of amB should be considered as an additional treatment option in cases with IPA unresponsive to systemic therapy.

Spektrum tuberkulöser Erkrankungen in der pneumologischen Praxis

ZusammenfassungHintergrund:Obgleich in Deutschland im Jahre 2006 die Inzidenz mit 6,6 Neuerkrankungen an Tuberkulose (TB) pro 100 000 Einwohner weiterhin rückläufig ist, bleibt die TB eine Erkrankung von erheblicher epidemiologischer Bedeutung.Patienten und Methodik:Von 04/2001 bis 07/2008 waren 75 Patienten einer internistisch-pneumologischen Praxis wegen einer TB (0,5% aller Patienten) behandelt worden. Die Kriterien einer aktiven TB erfüllten 58 (77,3%), die einer latenten Tuberkuloseinfektion (LTBI) 17 Patienten (22,7%). Der Anteil männlicher Patienten betrug 68,0% (Durchschnittsalter Männer 39,3 ± 16,9 Jahre [Mittelwert ± Standardabweichung], Frauen 46,8 ± 21,5 Jahre; p = nicht signifikant). In Deutschland waren 69,3% der Patienten geboren, 30,7% im Ausland. Einen ausschließlichen Lungenbefall hatten 84,5% Patienten, 8,6% wiesen zusätzliche Organbeteiligungen und 6,9% eine extrapulmonale TB auf. Mikrobiologisch gesichert wurden 62,1% der aktiven TB (51,7% mikroskopisch, 43,1% zusätzlich kulturell, 6,9% ausschließlich kulturell, 19,0% durch Polymerase-Kettenreaktion [PCR]).Ergebnisse:Von 23 Testungen zeigten 52,2% eine volle Sensibilität gegenüber den wichtigsten Erstrangmedikamenten Ethambutol (M), Isoniazid (H), Rifampicin (R), Pyrazinamid (Z) und Streptomycin (S). 13,0% hatten eine Monoresistenz gegen H (4,4%) oder S (8,6%), 4,4% eine Multiresistenz (MDR) gegen R und H, 30,4% eine Polyresistenz (S und H). Die Symptomatik war oft unspezifisch, wurde nicht beachtet oder fehlgedeutet.Schlussfolgerung:Die Diagnosefindung und Therapie einer aktiven oder latenten TB-Erkrankung bleiben weiterhin eine wichtige Aufgabe und Herausforderung, die der effektiven Zusammenarbeit ambulanter, klinischer und behördlicher Gesundheitseinrichtungen bedürfen.AbstractBackground:Although the incidence of 6.6 newly diagnosed tuberculosis (TB) cases per 100,000 inhabitants is in decline in Germany, TB remains a disease of significant epidemiologic importance.Patients and Methods:From 04/2001 to 07/2008, a total of 75 TB patients of an internal-pulmonary outpatient clinic had been treated (0.5% of all patients). 58 (77.3%) patients fulfilled the criteria of an active TB, 17 (22.7%) of latent tuberculous infection (LTBI). 68.0% were male (average age men 39.3 ± 16.9 years [mean ± standard deviation], women 46.8 ± 21.5 years; p = not significant). 69.3% of the patients were born in Germany, 30.7% abroad. 84.5% patients had isolated pulmonary, 8.6% additional organ involvement, and 6.9% isolated extrapulmonary TB. 62.1% of active TB cases were microbiologically proven (51.7% microscopically, 43.1% in addition culturally, 6.9% exclusively culturally, 19.0% by polymerase chain reaction [PCR]).Results:Of 23 tests, 52.2% were fully sensitive against the most important first-line drugs ethambutol (M), isoniazid (H), rifampicin (R), pyrazinamide (Z), und streptomycin (S). 13.0% had an isolated resistance against H (4.4%) or S (8.6%), 4.4% a multiple drug resistance (MDR) against R und H, 30.4% a polyresistance (S and H). Symptoms were quite often unspecific, not taken care of, or misinterpreted.Conclusion:Diagnosis and therapy of an active or latent TB illness remains, an important task and challenge, necessitating an effective cooperation of outpatient, hospital, and health authority institutions.BACKGROUND Although the incidence of 6.6 newly diagnosed tuberculosis (TB) cases per 100,000 inhabitants is in decline in Germany, TB remains a disease of significant epidemiologic importance. PATIENTS AND METHODS From 04/2001 to 07/2008, a total of 75 TB patients of an internal-pulmonary outpatient clinic had been treated (0.5% of all patients). 58 (77.3%) patients fulfilled the criteria of an active TB, 17 (22.7%) of latent tuberculous infection (LTBI). 68.0% were male (average age men 39.3 +/- 16.9 years [mean +/- standard deviation], women 46.8 +/- 21.5 years; p = not significant). 69.3% of the patients were born in Germany, 30.7% abroad. 84.5% patients had isolated pulmonary, 8.6% additional organ involvement, and 6.9% isolated extrapulmonary TB. 62.1% of active TB cases were microbiologically proven (51.7% microscopically, 43.1% in addition culturally, 6.9% exclusively culturally, 19.0% by polymerase chain reaction [PCR]). RESULTS Of 23 tests, 52.2% were fully sensitive against the most important first-line drugs ethambutol (M), isoniazid (H), rifampicin (R), pyrazinamide (Z), und streptomycin (S). 13.0% had an isolated resistance against H (4.4%) or S (8.6%), 4.4% a multiple drug resistance (MDR) against R und H, 30.4% a polyresistance (S and H). Symptoms were quite often unspecific, not taken care of, or misinterpreted. CONCLUSION Diagnosis and therapy of an active or latent TB illness remains, an important task and challenge, necessitating an effective cooperation of outpatient, hospital, and health authority institutions.

Diagnostics and therapy of idiopathic pulmonary hemosiderosis

ZusammenfassungDie idiopathische pulmonale Hämosiderose (IPH) ist eine seltene Erkrankung, die durch eine alveoläre Blutung charakterisiert ist. Die diesen meist häufig sich wiederholenden Blutungen zugrundeliegende Ätiologie ist unbekannt. Somit handelt es sich bei der auch als Morbus Ceelen bezeichneten Erkrankung um eine Ausschlussdiagnose. Sie verläuft häufig in Schüben, wobei sich wahrscheinlich im Rahmen einer immunologischen oder sogar toxischen zellulären Entzündung in Spätstadien eine Lungenfibrose ausbilden kann. Neben den von den Patienten typischerweise geklagten Hämoptysen fällt in der radiologischen Bildgebung der Lunge ein alveoläres Verschattungsmuster auf. Die Therapie besteht aus einer initial hochdosierten und später empirisch anzupassenden Prednisolontherapie mit einer ggf. zusätzlichen Immunsuppression. Es wird ergänzend eine Kasuistik eines Patienten mit einem Morbus Ceelen vorgestellt, der nach einem komplikationsreichen klinischen Verlauf erst mit einer Kombinationstherapie, die aus einer Prednisolon und Azathioprin bestand, zu stabilisieren war.AbstractIdiopathic pulmonary hemosiderosis (IPH) is a rare clinical entity characterized by recurrent episodes of diffuse alveolar hemorrhage. The disease – also called Ceelens syndrome – was subsequently defined as a clinical entity comprising the triade of hemoptysis, opacities in X-ray, and anemia, in which the etiology is still unknown. Intensive search for a specific etiology ends up negative, and there are no features, which are specifically pathognomonic for IPH. Therefore, the diagnosis relies solely on the exclusion of other disorders in which diffuse alveolar hemorrhage is a cardinal sign. Acute episodes may occur frequently, eventually leading to lung fibrosis in the chronic stage. Usually, the therapy consists of high doses of corticosteroids, which can be combined with immunosuppressive drugs. In addition to this review, a case having Ceelens syndrome is presented. After a complicated clinical course, the patient could finally be stabilized with a combination therapy of prednisolone and azathioprine.

Die idiopathische pulmonale Hämosiderose

ZusammenfassungDie idiopathische pulmonale Hämosiderose (IPH) ist eine seltene Erkrankung, die durch eine alveoläre Blutung charakterisiert ist. Die diesen meist häufig sich wiederholenden Blutungen zugrundeliegende Ätiologie ist unbekannt. Somit handelt es sich bei der auch als Morbus Ceelen bezeichneten Erkrankung um eine Ausschlussdiagnose. Sie verläuft häufig in Schüben, wobei sich wahrscheinlich im Rahmen einer immunologischen oder sogar toxischen zellulären Entzündung in Spätstadien eine Lungenfibrose ausbilden kann. Neben den von den Patienten typischerweise geklagten Hämoptysen fällt in der radiologischen Bildgebung der Lunge ein alveoläres Verschattungsmuster auf. Die Therapie besteht aus einer initial hochdosierten und später empirisch anzupassenden Prednisolontherapie mit einer ggf. zusätzlichen Immunsuppression. Es wird ergänzend eine Kasuistik eines Patienten mit einem Morbus Ceelen vorgestellt, der nach einem komplikationsreichen klinischen Verlauf erst mit einer Kombinationstherapie, die aus einer Prednisolon und Azathioprin bestand, zu stabilisieren war.AbstractIdiopathic pulmonary hemosiderosis (IPH) is a rare clinical entity characterized by recurrent episodes of diffuse alveolar hemorrhage. The disease – also called Ceelens syndrome – was subsequently defined as a clinical entity comprising the triade of hemoptysis, opacities in X-ray, and anemia, in which the etiology is still unknown. Intensive search for a specific etiology ends up negative, and there are no features, which are specifically pathognomonic for IPH. Therefore, the diagnosis relies solely on the exclusion of other disorders in which diffuse alveolar hemorrhage is a cardinal sign. Acute episodes may occur frequently, eventually leading to lung fibrosis in the chronic stage. Usually, the therapy consists of high doses of corticosteroids, which can be combined with immunosuppressive drugs. In addition to this review, a case having Ceelens syndrome is presented. After a complicated clinical course, the patient could finally be stabilized with a combination therapy of prednisolone and azathioprine.

Analyses of exhaled breath condensate cytokines for identification of lung cancer

Abstract Early non-invasive detection of lung cancer is a precondition for enabling better prognosis supported by new innovative therapy regimes. The aim of our study was to evaluate angiogenic and inflammatory proteins in exhaled breath condensate (EBC) as markers for lung cancer. Our report presents a diagnostic study of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and tumor necrosis factor-α (TNF-α) in EBC of 300 individuals, 84 patients with lung cancer, 111 patients with stable chronic obstructive pulmonary disease (COPD), and in 105 healthy controls. Detection of VEGF and bFGF in EBC was applicable to discriminate cancer patients from COPD patients as well as from healthy volunteers. Especially VEGF seems to be suitable to discriminate between non-small cell lung cancer (NSCLC) patients and control groups with highest VEGF values in EBC of patients with progressive NSCLC. The concentration of angiogenic factors correlated with disease progression as well as higher tumor stage. This study supports cytokine analysis in EBC as a suitable noninvasive diagnostic screening method for lung cancer detection and monitoring.

Mediators in pleural effusions of different origin: a two-step diagnostic study

Abstract Background: Many mediators in pleural effusions give diagnostic information. This study therefore aimed to find out whether the repeated determination of interleukin (IL)-6, IL-15, vascular endothelial growth factor (VEGF), and tissue inhibitors of metalloproteinase (TIMP)-2 would confirm previous results and, furthermore, whether a combination of these parameters could achieve a higher diagnostic yield. Methods: Two consecutive groups of patients with pleural effusions were included. The underlying disease entities in series I vs. series II were: 12 vs. 0 tuberculosis (TB), 19 vs. 30 primary lung cancer, 7 vs. 14 secondaries to the lung, 5 vs. 13 congestive heart failure, and 2 vs. 7 parapneumonic effusion. Results: VEGF could not differentiate values of series I to the same degree as in series II. For IL-15, totally deviating levels were obtained in series II. IL-6, however, showed comparable results in both series. Values of TIMP-2 were generally higher in series II. The diagnostic accuracies of VEGF and IL-6 were comparable. With logistic regression, the data of VEGF and IL-6 could be used as a classifying tool when TB cases were excluded. The classifying tool based on the data of series I showed a high degree of diagnostic accuracy (area under the curve, AUC=0.94) in contrast to the calculation based on the data of series II (AUC=0.56). Combining both series, VEGF was superior. Conclusions: VEGF was confirmed as a valid marker for malignant diseases. VEGF in combination with IL-6 could serve as a classifying tool. TB cases, however, should be excluded. The previously proposed relevance of TIMP-2 as a diagnostic parameter could, similarly to IL-15, not be confirmed.