Hubert Wirtz

The effects of mechanical forces on lung functions

The lung is a dynamic organ that is subjected to mechanical forces throughout development and adult life. This review article addresses the types of mechanical forces in the lung and their effects on development and normal lung functions. The effects of mechanical forces on the various different cell types of the lung are discussed, as are the mechanisms underlying mechanotransduction.

Experience with inhaled iloprost and bosentan in portopulmonary hypertension

Novel treatments, such as prostanoids or endothelin receptor antagonists, have been introduced for various forms of pulmonary arterial hypertension, but the long-term effects of these treatments on portopulmonary hypertension (PPHT) are unknown. In a retrospective analysis, the present authors assessed the safety and efficacy of inhaled iloprost, a prostacyclin analogue, and bosentan, an endothelin receptor antagonist, in patients with PPHT. In total, 31 consecutive patients with Child class A or B cirrhosis and severe PPHT were treated for up to 3 yrs with either inhaled iloprost (n = 13) or bosentan (n = 18), and the effects on exercise capacity, haemodynamics and survival were evaluated. In the iloprost group, the survival rates at 1, 2 and 3 yrs were 77, 62 and 46%, respectively. In the bosentan group, the respective survival rates were 94, 89 and 89%. Event-free survival rates, i.e. survival without transplantation, right heart failure or clinical worsening requiring the introduction of a new treatment for pulmonary hypertension, was also significantly better in the bosentan group. Bosentan had significantly better effects than inhaled iloprost on exercise capacity, as determined by the 6-min walk test, as well as on haemodynamics. Both treatments proved to be safe, especially in regards of liver function. In the present series of patients with well-preserved liver function and severe portopulmonary hypertension, treatment with both inhaled iloprost and bosentan appeared to be safe. Patients treated with bosentan had higher survival rates, but prospective controlled studies are required to confirm these findings.

Exhaled breath condensate acidification in acute lung injury

Lung injury in ventilated lungs may occur due to local or systemic disease and is usually caused by or accompanied by inflammatory processes. Recently, acidification of exhaled breath condensate pH (EBC-pH) has been suggested as marker of inflammation in airway disease. We investigated pH, ammonia, Lactate, pCO2, HCO3-, IL-6 and IL-8 in EBC of 35 ventilated patients (AECC-classification: ARDS: 15, ALI: 12, no lung injury: 8). EBC-pH was decreased in ventilated patients compared to volunteers (5.85 +/- 0.32 vs. 7.46 +/- 0.48; P < 0.0001). NH4+, lactate, HCO3-, pCO2, IL-6 and IL-8 were analyzed in EBC and correlated with EBC-pH. We observed correlations of EBC-pH with markers of local (EBC IL-6: r = -0.71, P < 0.0001, EBC IL-8: r = -0.68, P < 0.0001) but not of systemic inflammation (serum IL-6, serum IL-8) and with indices of severity of lung injury (Murrays Lung Injury Severity Score; r = -0.73, P < 0.0001, paO2/FiO2; r = 0.54, P < 0.001). Among factors potentially contributing to pH of EBC, EBC-lactate and EBC-NH4+ were found to correlate with EBC-pH. Inflammation-induced disturbances of regulatory mechanisms, such as glutaminase systems may result in EBC acidification. EBC-pH is suggested to represent a marker of acute lung injury caused by or accompanied by pulmonary inflammation.

Multiplex Analysis of Cytokines in Exhaled Breath Condensate

To improve monitoring of lung diseases, we analyzed cytokines in exhaled breath condensate (EBC). The main challenge in measurement of cytokines in EBC is the low protein content, which requires concentration steps that conflict with the need for excessive fluid required by most commonly used kits.

Effects of nasal high flow on ventilation in volunteers, COPD and idiopathic pulmonary fibrosis patients.

Background: A high flow of air applied by large bore nasal cannulae has been suggested to improve symptoms of chronic respiratory insufficiency. In pediatric patients, nasal high-flow (nHF) ventilation was similarly effective compared to noninvasive ventilation with a face mask. Objectives: The aim of this study was to describe changes in respiratory parameters. Methods: We measured pressure amplitudes during the respiratory cycle and mean pressures in patients with idiopathic pulmonary fibrosis (IPF) and COPD. In order to achieve tidal volume and minute volume measurements, we used a polysomnography device. Capillary blood was taken for blood gas analysis before and after nHF breathing (8 h). Results: nHF led to an increase in pressure amplitude and mean pressure in healthy volunteers and in patients with COPD and IPF in comparison with spontaneous breathing. In COPD, nHF increased tidal volume, while no difference in tidal volume was observed in patients with IPF. Interestingly, tidal volume decreased in healthy volunteers. Breathing rates and minute volumes were reduced in all groups. Capillary pCO2 decreased in patients with IPF and COPD. Conclusions: nHF resulted in significant effects on respiratory parameters in patients with obstructive and restrictive pulmonary diseases. The rise in pressure amplitude and mean pressure and the decrease in breathing rate and minute volume will support inspiratory efforts, helps to increase effectiveness of ventilation and will contribute to a reduction in the work of breathing. A CO2 wash-out effect in the upper airway part of the anatomical dead space may contribute to the beneficial effects of the nHF instrument.

S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose

Die idiopathische pulmonale Fibrose (IPF) ist eine schwerwiegende und in der Regel zum Tod fuhrende Erkrankung, die bisher nur unzureichend behandelt werden kann. Empfehlungen zur Diagnostik und Therapie wurden erstmals im ATS-ERS-Statement im Jahr 2000 publiziert 1 . Seither haben sich die diagnostischen Standards geandert und es liegen zahlreiche Therapiestudien zu diesem Krankheitsbild vor, die es erforderlich machten, die bestehenden Empfehlungen zu uberarbeiten und eine wissenschaftlich begrundete Leitlinie zu erstellen. Diese wurde von einer internationalen Expertengruppe in den Jahren 2006 – 2010 erarbeitet und publiziert 2 . Die folgenden Ausfuhrungen beinhalten eine Ubersetzung wesentlicher Inhalte der Originalleitlinie sowie die Interpretation und Adaptation der Empfehlungen an die speziellen Belange des deutschen Gesundheitssystems, wobei auch neue wissenschaftliche Erkenntnisse Berucksichtigung fanden. Die Deutsche Leitlinie zur Diagnostik und Therapie der IPF beruht auf einer Initiative deutscher Experten unter der Schirmherrschaft der Deutschen Gesellschaft fur Pneumologie und Beatmungsmedizin (DGP) und auf den Ergebnissen einer Konsensuskonferenz, die am 3. 12. 2011 in Bochum unter Supervision der „Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF)“ abgehalten wurde. Die Mehrzahl der Empfehlungen der internationalen Leitlinie konnten dabei ubernommen werden. Basierend auf aktuellen Studienergebnissen, die zum Zeitpunkt der Verabschiedung der internationalen Leitlinie noch nicht bzw. nicht vollstandig vorlagen wurden die schwach negativen Empfehlungen fur die Antikoagulantientherapie und die Kombinationstherapie mit Prednison, Azathioprin und N-Acteylcystein in stark negative Empfehlungen umgewandelt, wahrend fur Pirfenidon, welches inzwischen in der Europaischen Union zugelassen ist, eine schwach positive Therapieempfehlung ausgesprochen wurde.

Pulmonary hypertension due to chronic lung disease: Updated Recommendations of the Cologne Consensus Conference 2011

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. These guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the use of these drugs in patients with chronic lung disease and PH is not recommended. This recommendation, however, is not always in agreement with medical needs as physicians feel sometimes inclined to also treat other forms of pulmonary hypertension which may affect the quality of life and survival of these patients in a similar manner as in PAH. In June 2010, a consensus conference was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology (DGK, DGP and DGPK). To this end, a number of working groups were initiated, one of which was specifically dedicated to the diagnosis and treatment of PH due to chronic lung disease. This manuscript describes in detail the results and recommendations of this working group which were last updated in October 2011.

Long-Term Bosentan in Chronic Thromboembolic Pulmonary Hypertension

Background: There is no approved pharmacological treatment for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not suitable for pulmonary endarterectomy (PEA). Objective: The study investigates the effect of the dual endothelin receptor antagonist bosentan on exercise tolerance (6-min walking distance, 6MWD) and right ventricular function (Tei index) in patients with CTEPH over 24 months. Methods: Twelve consecutive patients (5 males and 7 females) with CTEPH not eligible for PEA or following partial or complete failure of PEA were included in a non-randomized, open-label prospective study. All patients were WHO class III. They were included, if progressive pulmonary hypertension was diagnosed despite best supportive treatment. Bosentan was started at 62.5 mg b.i.d. and increased to the final dose of 125 mg b.i.d. Results: 6MWD and the Tei index were assessed every 6 months. We observed a significant increase in 6MWD from 319 ± 85.0 m at baseline to 391 ± 76.9 m at 6 months and a significant decrease in the Tei index from 0.39 ± 0.10 at baseline to 0.34 ± 0.08 at 6 months. This improvement was maintained over 24 months (6 MWD: 381 ± 101 m; Tei index: 0.31 ± 0.03). Six patients exhibited an improvement in WHO class at 6, 12 and 18 months, 5 demonstrated improvement at the 24-month follow-up. The remainder were stable throughout the study period. Conclusion: This is the first study demonstrating a long-term beneficial effect of bosentan on exercise tolerance (6MWD) and right heart function (Tei index) in CTEPH.

Fatigue in patients with sarcoidosis, compared with the general population

OBJECTIVE Fatigue is a significant symptom in sarcoidosis patients. The causes for this symptom are unclear. The aims of this study were to analyze age and gender differences in fatigue, compared with the general population, and to test the psychometric properties of two questionnaires measuring fatigue in sarcoidosis. METHOD A sample of 1197 patients diagnosed with sarcoidosis was examined in Germany with the Fatigue Assessment Scale (FAS) and the Multidimensional Fatigue Inventory (MFI). RESULTS The percentages of patients exceeding the fatigue cut-offs were 70% (FAS) and 68% (MFI), respectively. While in the general population there is a nearly linear age trend (high fatigue scores with increasing age), among the patients there is only a very slight and nonlinear age trend. Female patients are more affected by fatigue than male patients, but this relationship is also true in the general population. Both questionnaires (FAS and MFI) are equally suited to test fatigue; their psychometric properties are good. They should not be replaced with a single question concerning tiredness. CONCLUSION The comparison to norm data is highly recommended for the evaluation of age and gender differences. Compared with the general population, young sarcoidosis patients are especially affected by fatigue.

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.