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Die Cytomegalievirus(CMV)-Pneumonie ist eine schwere Erkrankung des immunsupprimierten Patienten. Insbesondere in der Transplantationsmedizin muss das CMV als Verursacher ernster Komplikationen berucksichtigt werden. Die Diagnostik ist nicht trivial, weil Symptomatik und Erstbefunde unspezifisch und wenig suggestiv sind. Differenzialdiagnosen, wie beispielsweise die bakterielle Pneumonie, interstitielle Lungenerkrankungen oder Abstosungsreaktionen, mussen erwogen werden und konnen parallel mit einer relevanten CMV-Infektion auftreten. Aufgrund der speziellen antiviralen Therapieoptionen hat die sorgfaltige Diagnostik erhebliche Relevanz. Nur wenn der Arzt die CMV-Pneumonie bedenkt, wird er sie erkennen und behandeln konnen.

The involvement of the IL-23/IL23R pathway is well known in the disease pathogenesis of sarcoidosis and other inflammatory diseases. To date, the pathogenic mechanism of IL-23 is most notably described on CD4+ Th17 lymphocytes. However, the function of the IL23R on myeloid cells in sarcoidosis is poorly understood. Thus, the aim of the study is to investigate the role of the IL23R on myeloid cell in pulmonary granuloma formation. Methods: We generated IL23RLysMCre mice lacking the IL23R gene in myeloid cells. The importance of IL23R in myeloid cells for the development of sarcoidosis was studied in a mouse model of inflammatory lung granuloma formation through embolization of PPD from Mycobacterium bovis-coated Sepharose beads into previously PPD-immunized mice. In addition the function of IL23R on myeloid cells was studied in LPS or IFNγ stimulated BMDMs and BMDCs. The mRNA and protein expression levels of relevant cytokines were analyzed by RT-PCR (TaqMan) and ELISA. The composition of immune cells in BALF was quantified by flow cytometry and alteration in granuloma sizes were observed by H&E stained lung sections. Results: Mycobacterium Ag-elicted pulmonary granulomas tend to be smaller in IL23RLysMCre mice and NF-κB dependent Th1 cytokines in the murine lungs are reduced compared to wildtype mice. In line, we observed that IL23R-deficient bone marrow-derived macrophages show a reduced production of Th1 cytokines after LPS stimulation. Conclusion: We here for the first time demonstrate a role for IL23R on myeloid cells in pulmonary inflammation and granuloma formation. Our findings provide essential insights in the pathogenesis of inflammatory lung diseases like sarcoidosis, which might be useful for the development of novel therapeutics targeting distinct immunological pathways like IL-23/IL23R.

(1) Background: Acute kidney injury (AKI) is a common but under-investigated complication in patients receiving extracorporeal membrane oxygenation (ECMO). We aimed to define the incidence and clinical course, as well as the predictors of AKI in adults receiving ECMO support. (2) Materials and Methods: This is a retrospective analysis of all patients undergoing veno-venous ECMO treatment in a tertiary care center between December 2008 and December 2017. The primary endpoint was the new occurrence of an AKI of stage 2 or 3 according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification after ECMO implantation. (3) Results: During the observation period, 103 patients underwent veno-venous ECMO implantation. In total, 59 patients (57.3%) met the primary endpoint with an AKI of stage 2 or 3 and 55 patients (53.4%) required renal replacement therapy. Patients with an AKI of 2 or 3 suffered from more bleeding and infectious complications. Whereas weaning failure from ECMO (30/59 (50.8%) vs. 15/44 (34.1%), p = 0.08) and 30-day mortality (35/59 (59.3%) vs. 17/44 (38.6%), p = 0.06) only tended to be higher in the group with an AKI of stage 2 or 3, long-term survival of up to five years was significantly lower in the group with an AKI of stage 2 or 3 (p = 0.015). High lactate, serum creatinine, and ECMO pump-speed levels, and low platelets, a low base excess, and a low hematocrit level before ECMO were independent predictors of moderate to severe AKI. Primary hypercapnic acidosis was more common in AKI non-survivors (12 (32.4%) vs. 0 (0.0%), p < 0.01). Accordingly, pCO2-levels prior to ECMO implantation tended to be higher in AKI non-survivors (76.12 ± 27.90 mmHg vs. 64.44 ± 44.31 mmHg, p = 0.08). In addition, the duration of mechanical ventilation prior to ECMO-implantation tended to be longer (91.14 ± 108.16 h vs. 75.90 ± 86.81 h, p = 0.078), while serum creatinine (180.92 ± 115.72 mmol/L vs. 124.95 ± 77.77 mmol/L, p = 0.03) and bicarbonate levels were significantly higher in non-survivors (28.22 ± 8.44 mmol/L vs. 23.36 ± 4.19 mmol/L, p = 0.04). (4) Conclusion: Two-thirds of adult patients receiving ECMO suffered from moderate to severe AKI, with a significantly increased morbidity and long-term mortality.

Background: Guidelines for chronic obstructive pulmonary disease (COPD) recommend supplementing pharmacotherapy with non-pharmacological interventions. Little is known about the use of such interventions by patients. We analyzed the utilization of a number of non-pharmacological interventions and identified potential determinants of use.Methods: Based on self-reports, use of interventions (smoking cessation, influenza vaccination, physiotherapy, sports program, patient education, pulmonary rehabilitation) and recommendation to use were assessed in 1410 patients with COPD. The utilization was analyzed according to sex and severity of disease. Potential determinants of utilization included demographic variables and disease characteristics and were analyzed using logistic regression models.Results: Influenza vaccination in the previous autumn/winter was reported by 73% of patients. About 19% were currently participating in a reimbursed sports program, 10% received physiotherapy, 38% were ever enrolled in an educational program, and 34% had ever participated in an outpatient or inpatient pulmonary rehabilitation program. Out of 553 current or former smokers, 24% had participated in a smoking cessation program. While reports of having received a recommendation to use mainly did not differ according to sex, women showed significantly (p < 0.05) higher utilization rates than men for all interventions except influenza vaccination. Smoking was a predictor for not having received a recommendation for utilization and also significantly associated with a reduced odds of utilization. We found a correlation between recommendation to use and utilization.Conclusions: Utilization of non-pharmacological interventions was lower in men and smokers. A recommendation or offer to use by the physician could help to increase uptake.

The COPD Assessment Test (CAT) is in widespread use for the evaluation of patients with chronic obstructive pulmonary disease (COPD). We assessed whether the CAT items carry additional information beyond the sum score regarding COPD characteristics including emphysema. Patients of GOLD grades 1 to 4 from the COPD cohort COSYCONET (German COPD and Systemic Consequences - Comorbidities Network) with complete CAT data were included (n = 2270), of whom 493 had chest CT evaluated for the presence of emphysema. Comorbidities and lung function were assessed following standardised procedures. Cross-sectional data analysis was based on multiple regression analysis of the single CAT items against a panel of comorbidities, lung function, or CT characteristics (qualitative score, 15th percentile of mean lung density), with age, BMI and gender as covariates. This was supported by exploratory factor analysis. Regarding the relationship to comorbidities and emphysema, there were marked differences between CAT items, especially items 1 and 2 versus 3 to 8. This grouping was basically confirmed by factor analysis. Items 4 and 5, and to a lower degree 1, 2 and 6, appeared to be informative regarding the presence of emphysema, whereas the total score was not or less informative. Regarding comorbidities, similar findings as for the total CAT score were obtained for the modified Medical Research Council scale (mMRC) which was also informative regarding emphysema. Our findings suggest that the usefulness of the CAT can be increased if evaluated on the basis of single items which may be indicating the presence of comorbidities and emphysema.

Limbic encephalitis is commonly regarded as an autoimmune-mediated disease. However, after the recent detection of zoonotic variegated squirrel bornavirus 1 in a Prevost's squirrel (Callosciurus prevostii) in a zoo in northern Germany, we retrospectively investigated a fatal case in an autoantibody-seronegative animal caretaker who had worked at that zoo. The virus had been discovered in 2015 as the cause of a cluster of cases of fatal encephalitis among breeders of variegated squirrels (Sciurus variegatoides) in eastern Germany. Molecular assays and immunohistochemistry detected a limbic distribution of the virus in brain tissue of the animal caretaker. Phylogenetic analyses demonstrated a spillover infection from the Prevost's squirrel. Antibodies against bornaviruses were detected in the patient's cerebrospinal fluid by immunofluorescence and newly developed ELISAs and immunoblot. The putative antigenic epitope was identified on the viral nucleoprotein. Other zoo workers were not infected; however, avoidance of direct contact with exotic squirrels and screening of squirrels are recommended.

BackgroundChronic pulmonary infections by Pseudomonas aeruginosa require frequent intravenous antibiotic treatment in cystic fibrosis (CF) patients. Emergence of antimicrobial resistance is common in these patients, which to date has been investigated at long-term intervals only.ObjectivesTo investigate under close to real-time conditions the dynamics of the response by P. aeruginosa to a single course of antibiotic therapy and the potentially associated rapid spread of antimicrobial resistance, as well as the impact on the airway microbiome.MethodsWe investigated a cohort of adult CF patients that were treated with a single course of antimicrobial combination therapy. Using daily sampling during treatment, we quantified the expression of resistance by P. aeruginosa (median of six isolates per daily sample, 347 isolates in total), measured bacterial load by P. aeruginosa-specific quantitative PCR and characterized the airway microbiome with a 16S rRNA-based approach. WGS was performed to reconstruct intrapatient strain phylogenies.ResultsIn two patients, we found rapid and large increases in resistance to meropenem and ceftazidime. Phylogenetic reconstruction of strain relationships revealed that resistance shifts are probably due to de novo evolution and/or the selection of resistant subpopulations. We observed high interindividual variation in the reduction of bacterial load, microbiome composition and antibiotic resistance.ConclusionsWe show that CF-associated P. aeruginosa populations can quickly respond to antibiotic therapy and that responses are patient specific. Thus, resistance evolution can be a direct consequence of treatment, and drug efficacy can be lost much faster than usually assumed. The consideration of these patient-specific rapid resistance shifts can help to improve treatment of CF-associated infections, for example by deeper sampling of bacteria for diagnostics, repeated monitoring of pathogen susceptibility and switching between drugs.

PURPOSE The primary contact for German physicians with national quality assurance in community-acquired pneumonia (CAP) is frequently experienced as time-consuming obligatory documentation. Since the regular feedback loop stretches up to 18 months, the immediate impact on quality is perceived as rather low. Ultimately, a method leading to increase in the quality of data collection, clarification on expected clinical treatment standards, and improvement in the acceptance and feedback mechanism is needed. METHODS We developed a form merging data collection for quality indicators with a standard operating procedure (SOP) in CAP and implemented it in the daily routine of a university's department for internal medicine. Fulfillment of quality indicators before and after the implementation of the new form was measured. RESULTS Critical parameters such as the documentation of breathing rate and clinical parameters at discharge strongly improved after implementation of the intervention. Uncritical parameters showed slight improvement or stable results at a high level. CONCLUSION The combination of collection of quality data with a clinical SOP and context information may improve the impact of quality measures by increasing acceptance, quality of data capture, short-loop feedback, and possibly quality of care.

Background Shortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. Methods Eligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results The study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, −4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. Conclusions Cyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function. ClinicalTrials.gov Identifier: NCT01315678

Real-world studies include a broader patient population for a longer duration than randomised controlled trials (RCTs) and can provide relevant insights for clinical practice. PASSPORT was a multicentre, prospective, post-authorisation study of patients who were newly prescribed pirfenidone and followed for 2 years after initiating treatment. Physicians collected data on adverse drug reactions (ADRs), serious ADRs (SADRs) and ADRs of special interest (ADRSI) at baseline and then every 3 months. Post hoc stepwise logistic regression models were used to identify baseline characteristics associated with discontinuing treatment due to an ADR. Patients (n=1009, 99.7% with idiopathic pulmonary fibrosis) had a median pirfenidone exposure of 442.0 days. Overall, 741 (73.4%) patients experienced ADRs, most commonly nausea (20.6%) and fatigue (18.5%). ADRs led to treatment discontinuation in 290 (28.7%) patients after a median of 99.5 days. Overall, 55 (5.5%) patients experienced SADRs, with a fatal outcome in six patients. ADRSI were reported in 693 patients, most commonly gastrointestinal symptoms (38.3%) and photosensitivity reactions/skin rashes (29.0%). Older age and female sex were associated with early treatment discontinuation due to an ADR. Findings were consistent with the known safety profile of pirfenidone, based on RCT data and other post-marketing experience, with no new safety signals observed., Real-world safety results from 1009 patients in PASSPORT were consistent with the known pirfenidone safety profile http://ow.ly/oXjv30lrzAf

To assess the parenting experience of mothers with cystic fibrosis (CF) and to compare with normative data.Cross-sectional study with a validated generic parental stress questionnaire (PSQ). This PSQ differentiates four components of parental stress: main factor "parental stress", compounding factor "role restrictions", protective factors "support from spouse", and "social support". Cut-off scores categorise results as "normal", "borderline" or "concerning".Seventy-three women were informed by their local CF centre. Of these, 36 enrolled and had a first-born child aged 1-12 years (consistent with reference values of the PSQ). Of these, 31 (86%) returned the PSQ. Mean age of mothers was 32.6 years ± 6.9 years, mean age of first-born child was 5.2 years ± 3.4 years. Most of the mothers had one biological child, five women had two children and one had three children.Parental stress scores were normally distributed, the same applies for contributing factors and for the two protective factors. Favourable scores were twice as frequent as concerning scores. Mothers of younger children scored slightly better than mothers of school-aged children.In line with the only comparable study, mothers with CF seem to be a remarkably resilient group who mostly cope well with parental stress even in the face of a progressive, chronic disease requiring time-consuming treatment.Today, motherhood is increasingly becoming an option in fertile women with cystic fibrosis. The additional burden of parenting seems to be rewarded by fulfilling essential personal goals. CF clinics should routinely address a possible wish for a child and to discuss it, openly.

Hintergrund: Von Muttern mit Zystischer Fibrose (CF) gibt es bislang keine Daten uber Schwangerschaft und Mutterschaft aus Patientinnensicht. Methode: Befragung der Mutter mit eigens zusammengestelltem Fragebogen, unter anderem zu: Schwangerschaft und Geburt (Reaktionen im personlichen Umfeld der Frauen, ihr Vorwissen, Sorgen, Gesamturteil) sowie dem ersten Jahr nach der Geburt (Gesamturteil). Stichprobe: 38 von 73 angefragten Muttern beteiligten sich (Durchschnittsalter 33,8 ± 7,1 Jahre, Alter erstgeborenes Kind 6,9 ± 5,7 Jahre). Neun Frauen hatten mehr als ein Kind. Aktuell berufstatig waren 18 der Mutter (47 %), davon 12 Frauen mindestens halbtags (19 – 30 Std./Woche). Die durchschnittliche Lungenfunktion (FEV1) lag zum Zeitpunkt der Befragung bei 66 ± 19 % des Solls. Ergebnisse: Bei 28 /38 Frauen waren die Schwangerschaften – wie man es bei CF anstrebt – geplant, in 10 Fallen ungeplant. Die Reaktionen im Umfeld auf Kinderwunsch bzw. Schwangerschaft fielen bei ungeplanter Schwangerschaft negativer aus. Unabhangig davon reagierten die Eltern der Frauen durchweg weniger positiv als andere wichtige Personen im Umfeld. Die Reaktionen der CF-Behandler waren abhangig von der Lungenfunktion der Frau. Vorkenntnisse der Frauen uber „Schwangerschaft und CF“ waren eher gering. Ihre Befurchtungen richteten sich primar auf eine mogliche Schadigung des Foten durch CF-Medikamente. Schlussfolgerungen: Mutterschaft trotz CF ist fur junge Frauen zunehmend ein Thema und CF-Teams sollten dazu Gesprachsangebote in der Sprechstunde unterbreiten. Anzustreben ist auch ein besseres Verstandnis der Zusammenhange von Schwangerschaft und CF.

Although a profound barrier dysfunction has been reported, little is known about the pathophysiological mechanism evoking gastrointestinal graft-vs.-host disease (GI-GvHD) and apparent therapeutic options. The aim of this study was to evaluate the influence of oral glutamine on the course of GI-GvHD in an acute semiallogenic graft-vs.-host disease (GvHD) in irradiated B6D2F1 mice. An acute semiallogenic GvHD was induced by intraperitoneal injection of lymphocytes from C57BL/6 mice to irradiated B6D2F1 mice. Half of the GvHD animals received oral glutamine supplementation for 6 days started at the time of lymphocyte transfer. Six days after induction of the semiallogenic GvHD, jejunum specimens were prepared. The expression of the proinflammatory cytokine TNF-α and the tight junction protein occludin was investigated by PCR. Histological changes along with the apoptotic response were evaluated and intestinal permeability was assessed. Animals with GvHD showed a strong increase in paracellular permeability as a sign of the disturbed barrier function. TNF-α expression was significantly increased and the expression of the tight junction protein occludin decreased. GvHD led to mucosal atrophy, crypt hyperplasia, crypt apoptosis, and a disintegration of the tight junctions. Glutamine-treated mice showed reduced expression of TNF-α, increased occludin expression, fewer histological changes in the jejunum, smaller number of apoptotic cells in the crypt, and reduced gastrointestinal permeability. In conclusion, oral glutamine seems to have beneficial effects on the severity of inflammatory changes in the course of GvHD and might be a therapeutic option.

A 43-year-old woman experienced increasing dyspnea over a period of 1 year. She was examined first at an outside hospital. Diagnostic workup revealed an elevated precapillary mean pulmonary arterial pressure of >44 mm Hg. Left ventricular function was nearly normal (cardiac index, 2.1 L/min·m2; pulmonary wedge pressure, 15 mm Hg). Computed tomography of the lung demonstrated regional ground glass opacities and pleural effusions but no signs of pulmonary embolism. Perfusion and ventilation scintigraphy showed perfusion defects typical for peripheral lung embolism (Figure 1). The diagnosis of chronic thromboembolic pulmonary hypertension was made. There was no correlate in pulmonary angiography …

Background and aims: Intestinal barrier function in Crohn's disease patients and their first degree healthy relatives is impaired. The increased intestinal permeability may result in an enhanced mucosal immune response and thereby aggravate intestinal inflammation. Humanised anti-TNF-α antibodies have been shown to be effective in the treatment of active Crohn's disease and in the treatment of entero-cutaneous fistula. The aim of the present study was to investigate the influence of anti-TNF-α antibody (infliximab) treatment on the intestinal barrier function of patients with active Crohn's disease. Methods: The differential intestinal uptake of lactulose and mannitol was measured to quantify intestinal permeability in patients with long standing active Crohn's disease (n = 17) directly before and seven days after treatment with infliximab (5 mg/kg bodyweight). In parallel, intestinal permeability was studied in a healthy control group (n = 20). Serum samples were analysed with pulsed amperometric detection after separation on an anion exchange column. Results: Intestinal permeability was significantly increased in all patients with Crohn's disease (L/M ratio 0.24 ± 0.17) prior to infliximab treatment compared to the control group (L/M ratio 0.01 ± 0.02; p-value < 1 × 10− 7). Treatment of patients with infliximab resulted in a marked decrease of intestinal permeability as measured by L/M ratio from 0.24 ± 0.17 before to 0.02 ± 0.02 (p-value < 1 × 10− 7) seven days after infliximab application. Conclusions: Treatment with anti-TNF-α antibodies improved impaired intestinal barrier function in patients with Crohn's disease. This effect may correlate to the well documented anti-inflammatory effect of TNF-α blockade in this intestinal disease.

Immunosuppression with subsequent opportunistic infections is a well-recognized complication of severe hypercortisolism. We report a case of fatal pneumocystis jirovecii pneumonia (formerly pneumocystis carinii pneumonia) in a case of ectopic Cushing's syndrome caused by a neuroendocrine carcinoma of the kidney. The 36-year old male patient had consulted a physician because of weight gain. Further endocrine diagnostic work-up revealed ACTH-dependent hypercortisolism of non-pituitary origin. Because of rapid clinical deterioration therapy with metyrapone was initiated. A neuroendocrine carcinoma of the right kidney with regional lymph node infiltration was identified and was suspected to be the source of the ACTH excess. Before any causal therapy could be initiated, the patient developed severe pneumocystis jirovecii pneumonia and died shortly thereafter from multiorgan failure one month after he first consulted a physician. Pneumocystosis has been reported in only a few cases of Cushing's syndrome. There seems to be a relationship between the degree of hypercortisolism and the susceptibility to opportunistic infections. Since ACTH concentrations may be excessively high in ectopic Cushing's syndrome and pneumocystosis may deteriorate as a consequence of decreasing circulating cortisol levels under adrenolytic therapy, prophylaxis against pneumocystis jirovecii infection should be considered.

Immunosenescence is characterized by a quantitative decline of adequate immune responses, which renders the elderly individual particularly susceptible to bacterial, viral and fungal pathogens. Whereas changes of the aging adaptive immune system (for example, reduced immunoglobulin secretion) have been extensively characterized, alterations of the innate immune system are still poorly understood. The aim of the present study was to systematically examine mRNA expression levels of innate immune genes and proinflammatory cytokines in peripheral and intestinal leukocytes of subjects of different ages. In both, whole blood samples and in colonic biopsies most of the Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain-like receptors (NLRs) transcript levels were significantly downregulated in elderly subjects (90-99 years). Older individuals, when compared to the younger, exhibited an increased expression and/or secretion of proinflammatory cytokines by peripheral and intestinal leukocytes as well as an increased level of nuclear factor-kappaB activation in colonic biopsies. The observed downregulation of TLRs and NLRs during the aging process may contribute to the lack of effective recognition of invading pathogens or the commensal flora. This effect results in aberrant secondary immune cell activation and could significantly contribute to morbidity and mortality at advanced age.

Aim: To explore the stress related to motherhood and its perceived impact on adherence to therapy in women with cystic fibrosis (CF). Methods: Cross-sectional study with a purpose-designed questionnaire. Sample: 46/73 eligible women were enrolled and 38 returned the questionnaire. Mean age of mothers was 33.8 y ± 7.1 y, mean age of firstborn child was 6.9 y ± 5.7 y. Nine women had more than one biological child. 18 mothers (47 %) were currently employed, 12 of whom worked 19 to 30 hours per week and none full-time. Results: There were mothers who reported a detrimental effect on adherence (time constraints 38 %; intentional nonadherence 42 %), and mothers who reported that adherence had actually improved (29 %). Both of these effects were related to daily CF therapy at home. By contrast, i. v. antibiotic therapy was less impaired by role strains, mainly due to home i. v. therapy being an alternative and/or due to intensive social support (husband, parents). Participants clearly addressed the importance of adherence and the need for adequate self-management in narrative comments. Conclusion: Motherhood may improve adherence to CF therapy as well as it may affect it negatively. Health caregivers are well-advised to address a possible detrimental effect, proactively.

Bronchiolitis obliterans syndrome (BOS) is a severe complication after lung transplantation (LTX). In a retrospective cohort study 12 stable healthy recipients (non-BOS) and eight patients with BOS were enrolled after LTX and matrix metalloproteinases (MMP)-9, TIMP-1 and cell characteristics in bronchoalveolar lavage (BAL) samples (n = 145) were analysed. BALs from patients with BOS were further divided according to whether they were obtained before (pre-BOS) or after manifestation of BOS (BOS group). The MMP-9/TIMP-1 ratio was significantly increased in the BOS group compared with non-BOS or pre-BOS; furthermore, the ratio was negatively correlated with forced expiratory volume in one second. In zymography, the active form of MMP-9 was detected predominantly in the BOS group. In addition, zymography showed the banding pattern of neutrophil-derived MMP-9, indicating that polymorphonuclear neutrophils (PMNs) were the main source of MMP-9. According to that, MMP-9 was significantly correlated with the number of PMN. In immunocytochemistry, MMP-9 was also associated predominantly with PMN. This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 over time during manifestation of a fibroproliferative lung disease in patients. It demonstrates development of bronchiolitis obliterans syndrome after lung transplantation is associated with an imbalance of matrix metalloproteinases-9/tissue inhibitors of metalloproteinase-1 ratio.

Objectives: To evaluate clinical and laboratory effects of the administration of recombinant human activated protein C (rhAPC) in the treatment of a 25-year-old patient with septic shock and multiple organ failure secondary to perinephritic abscesses. Interventions: Intravenous administration of rhAPC—or drotrecogin alfa (activated)—(24 mcg/kg/h) for a total of 80 h as an adjunct to antimicrobial therapy, mechanical ventilation, hemodynamic support, hemodiafiltration and surgical intervention. Measurements and Main Results: The administration of rhAPC was associated with a rapid recovery of the patient's clinical condition reflected by decreasing Sepsis-related Organ Failure Assessment (SOFA) scores. Laboratory parameters monitoring inflammation and coagulopathy improved during the treatment. No drug-related adverse events were noted. Conclusions: RhAPC has been observed to have anticoagulant, anti-inflammatory and profibrinolytic properties in vitro and in vivo. This report describes the effects of rhAPC administration on standard laboratory parameters indicating that no single laboratory parameter exists that is capable of monitoring the effects of rhAPC on the coagulation cascade and the clinical course of sepsis. This description of a patient suffering from sepsis-induced multiple organ failure may illustrate a possible beneficial effect of rhAPC on the course of coagulopathy and systemic inflammatory response and provides evidence for rhAPC complementing standard intensive care therapy in severe sepsis.

Colonization or infection with various pathogens is frequently found in patients listed for lung transplantation. We describe a case of a 50-year-old woman with α-1-antitrypsin deficiency, which was listed for double-lung transplantation, with multidrug-resistant gram-negative Acinetobacter baumannii (MRGN4-Ab) skin colonization. Transplantation was successfully performed. Colistin (Polymyxine E) was administered intravenously and through inhalation in the first month. MRGN4-Ab was still detectable in skin swabs without evidence of infection. After good recovery and clinical inapparence, the patient was discharged 2 months after transplantation.

A pumpless interventional arteriovenous lung assist device (iLA) facilitates the removal of carbon dioxide from the blood and is used as part of the lung-protective ventilation strategy in patients with acute respiratory distress syndrome (ARDS). In case of bacterial infection, delayed antimicrobial therapy increases the mortality in this group of high-risk critically ill patients, whereas overtreatment promotes bacterial resistance and leads to increased drug toxicity and costs. Besides clinical signs and symptoms, antimicrobial treatment is based on the kinetics of biomarkers such as procalcitonin (PCT). We hereby report an up to 10-fold increase in PCT serum concentrations in four mechanically ventilated patients with ARDS detected within 12-20 hours after iLA implantation in the absence of any infection. Procalcitonin concentrations returned to nearly baseline values in all patients on the fourth day after iLA implantation. We discuss the possible mechanisms of PCT induction in this specific patient population and recommend the onset of antibiotics administration after iLA implantation to be carefully considered in the context of other clinical findings and not solely based on the PCT kinetics. Repeated PCT measurements in short time intervals should be performed in these patients.

Secretory immunoglobulin A (sIgA) is the most important Ig on mucosal surfaces. In bronchoalveolar lavage (BAL) fluid, sIgA is mainly produced by bronchus-associated lymphoid tissue (BALT). The presence of pre-formed antibodies against donor tissue in kidney transplantation is associated with hyperacute rejection, indicating a humoral (antibody-mediated) reaction. In heart and liver transplantation, humoral rejection has also been documented. The goal of this study was to evaluate the role of IgA in patients after lung transplantation. An enzyme-linked immunosorbent assay was established to determine the levels of sIgA, IgA, and total protein in the lavage. IgA and sIgA were both detectable in BAL from transplanted lungs. IgA and sIgA levels were both higher during episodes of infection than during episodes of rejection or during the control episodes. The level of IgA during episodes of rejection equaled the level of IgA during the control episodes. The level of sIgA was significantly decreased during episodes of acute rejection (1.8 +/- 1.0 microg/mL) when compared with the control (7.2 +/- 1.0 microg/mL; p = 0.013). This study demonstrates that BALT retains the ability to produce Ig even after lung transplantation. The levels of IgA and sIgA and their ratio do not contribute to the differentiation between rejection and infection in lung-transplanted patients.

Ulcerative tracheobronchial aspergillosis after lung transplantation (ltx) may lead to bronchial-pulmonary artery fistula that results in fatal bleeding. We report our early experience with combined systemic, aerolized and topical application of amphotericin B in 3 cases of bronchial aspergillosis after ltx. Two patients are still alive, but 1 died of bleeding from a fistula between the left upper lobe bronchus and the pulmonary artery. Aspergillosis in the second patient resolved with minimal stenosis of the left main and the left upper lobe bronchus, and the third patient developed an anastomotic stenosis that was successfully dilated.

Leukocyte adhesion molecules, such as intercellular adhesion molecule (ICAM)-1 and its ligands, are involved in inflammatory processes of the lung. For ICAM-1, differential expression during different kinds of complications after transplantation has been proposed. We analyzed the role of ICAM-1, CD18, CD11a, CD11b, and CD11c during episodes of rejection or infection in patients after lung transplantation and compared the results to episodes without apparent complication. A total of 98 bronchoalveolar lavage (BAL) samples and 90 serum samples were analyzed. ICAM-1, CD18, CD11a, CD11b, and CD11c expressions were detected immunocytochemically on alveolar macrophages. Soluble ICAM-1 was quantified in serum and BAL. In the control group, 49.8±18% of macrophages stained positive for CD11b. During rejection, the mean of cells showing CD11b on the surface was significantly higher (64.6±11.4%), with no difference compared to episodes of infection (59.7±22.7). All other epitopes were not expressed differently with regard to a normal clinical course or episodes of infection and rejections. In summary, assessment of ICAM-1 and corresponding ligands did not allow for a reliable discrimination between episodes of rejection or infection in lung transplantation.

Abstract To evaluate the concept that localized delivery of angiogenic factors via virus-mediated gene transfer may be useful in the treatment of ischemic disorders, the replication-deficient adenovirus (Ad) vector AdCMV.VEGF 165 (where CMV is cytomegalovirus and VEGF is vascular endothelial growth factor) containing the cDNA for human VEGF 165 , a secreted endothelial cell–specific angiogenic growth factor, was constructed. Human umbilical vein endothelial cells (HUVECs) and rat aorta smooth muscle cells (RASMCs) infected with AdCMV.VEGF 165 (5 and 20 plaque-forming units [pfu] per cell) demonstrated VEGF mRNA expression and protein secretion into the supernatant. Furthermore, the conditioned medium from these cells enhanced vascular permeability in vivo. In contrast, neither VEGF mRNA nor secreted protein was found in uninfected HUVECs or RASMCs or in cells infected with the control vector AdCMV.βgal (where βgal is β-galactosidase). Assessment of starved HUVECs at 14 days demonstrated sixfold more cells for AdCMV.VEGF 165 -infected HUVECs (20 pfu per cell) than for either infected or uninfected control cells. RASMC proliferation was unaffected by infection with AdCMV.VEGF 165 . When plated in 2% serum on dishes precoated with reconstituted basement membrane (Matrigel), HUVECs infected with AdCMV.VEGF 165 (20 pfu per cell) differentiated into capillary-like structures. Under similar conditions, both uninfected HUVECs and HUVECs infected with AdCMV.βgal did not differentiate. To evaluate the ability of AdCMV.VEGF 165 to function in vivo, either AdCMV. VEGF 165 or AdCMV.βgal (2×10 10 pfu) was resuspended in 0.5 mL Matrigel and injected subcutaneously into mice. Immunohistochemical staining demonstrated VEGF in the tissues surrounding the Matrigel plugs containing AdCMV.VEGF 165 up to 3 weeks after injection, whereas no VEGF was found in the control plugs with AdCMV.βgal. Two weeks after injection, there was histological evidence of neovascularization in the tissues surrounding the Matrigel containing AdCMV.VEGF 165 , whereas no significant angiogenesis was observed in response to AdCMV.βgal. Furthermore, the Matrigel plugs with AdCMV.VEGF 165 demonstrated hemoglobin content fourfold higher than the plugs with AdCMV.βgal. Together, these in vitro and in vivo studies are consistent with the concept that Ad vectors may provide a useful strategy for efficient local delivery of VEGF 165 in the treatment of ischemic diseases.

Congenital pulmonary alveolar proteinosis (CPAP) is a fatal disease of full-term infants that is unresponsive to current medical therapy. It is now recognized that at least some forms of this disorder are associated with a deficiency of SP-B, one of the surfactant-associated proteins, as well as probable aberrations in the surfactant-associated proteins SP-A and SP-C. Given these developments, it is logical to hypothesize that CPAP may be amenable to gene therapy, in which the human SP-B cDNA, and possibly the cDNAs of the other surfactant associated proteins, are transferred to the epithelium of the lower respiratory tract. We constructed replication-deficient, recombinant adenovirus vectors in which a constitutive viral promoter drives the expression of the DNAs for the surfactant-associated proteins, SP-B (AdCMV.SP-B) and SP-A (AdCMV.SP-A). Following infection of the human lung A549 epithelial cell line with these vectors in vitro, the appropriately sized mRNAs for these cDNAs were detected, whereas cells infected with a control virus or uninfected cells produced none. Western blots demonstrated expression of these proteins, including appropriate processing of the hydrophobic protein, SP-B. Following in vivo intratracheal infection of rats with these vectors, Northern analysis of the lungs revealed appropriately sized mRNAs for these cDNAs whereas rats infected with control virus or uninfected rats show no hybridization with the human surfactant-associated protein probes. In the AdCM-V.SP-A-infected rats, Western blots confirmed the overproduction of the human SP-A protein in both the bronchoalveolar lavage and lung homogenates compared to controls. Thus, it is feasible to utilize adenovirus vectors to transfer and express the human surfactant associated protein cDNAs in vitro and in vivo, presenting a possible mode of therapy for CPAP, as well as other surfactant deficiency states such as the neonatal respiratory distress syndrome and possibly the adult respiratory distress syndrome.

Purpose: To assess ultrasonographic (US) examination results of the cervical part of the thoracic duct, to provide standard diameters, and to evaluate the diameter of the cervical thoracic duct in certain diseases suspected to involve an abnormal load of chyle (liver, heart, and inflammatory bowel diseases).Materials and Methods: The study was approved by the institutional review committee, and written informed consent was obtained from all subjects. Diameter and variations of the cervical thoracic duct were assessed by using US in 265 healthy volunteers (age range, 21-82 years) from a population-based study, in 196 subjects with documented liver cirrhosis (age range, 19-87 years), in 68 subjects with chronic hepatitis (age range, 17-73 years), in 39 subjects with congestive heart failure (age range, 46-85 years), and in 17 subjects with inflammatory bowel disease (age range, 18-66 years). US examinations were performed with high-resolution linear probes (7-12 MHz). Results: A standard imaging approach guided by anatomic structures was established. Dynamic imaging of the chyle flow and valve function was possible. The thoracic duct was visualized in 564 (96%) of 585 examinations. The average thoracic duct diameter in healthy volunteers was 2.5 mm, which was independent of the subjects' age. The diameter was significantly higher in subjects with congestive heart failure (6.3 mm, P < .0001) and liver cirrhosis (5.6 mm, P < .0001). Anatomic variations were present in 27% of subjects. Conclusion: High-resolution US with linear probes allows assessment of the cervical thoracic duct with high detection rates. Recognition of local anatomy, diameter, and chyle flow may aid functional assessment.

Granulomatous disorders like sarcoidosis or Crohn’s disease are commonly associated with extrapulmonary or extraintestinal manifestations which occasionally may represent the only symptoms. We describe a 28-year-old female patient suffering from atypical erythema nodosum and arthritis. Although the chest x-ray was unremarkable bronchoalveolar lavage revealed lymphocytic alveolitis with an elevated CD4/CD8 ratio of 8 and 11.4 at repeated examinations suggesting a diagnosis of sarcoidosis. Further diagnostic workup included endoscopy of the bowel. The macroscopic aspect and histology of the terminal small bowel and colon ascendens indicated Crohn’s disease. The patient recovered on steroids and sulfasalazine. Six months later she developed a perianal abscess for which she needed surgery supporting the diagnosis of Crohn’s disease. This is the first case of a significantly (>6) elevated CD4/CD8 ratio in Crohn’s disease previously regarded as highly specific for sarcoidosis.

The Ashcroft scale for the evaluation of bleomycin-induced lung fibrosis is the analysis of stained histological samples by visual assessment. Based on the knowledge that this procedure is not standardized in animals and results are highly variable, we hypothesized that modification of this method may improve quantification of lung fibrosis in small animals. To prove our hypothesis, we evaluated pulmonary fibrosis in Lewis rats induced by a single intratracheal injection of 0.3 mg/kg body weight bleomycin (n = 13) compared with the same amount of saline in a control group (n = 4). We modified the Ashcroft scale by precisely defining the assignment of grades from 0 to 8 for the increasing extent of fibrosis in lung histological samples. Thirty-two observers were randomly assigned to evaluate 108 photographs of slides using either the Ashcroft scale or the modified scale. Consistent with our hypothesis, there was a significant reduction in the variability of standard deviations with the modified scale compared with the Ashcroft scale (mean of variability 0.25 versus 0.62, P < 0.0001). Applying the κ index, the Ashcroft scale showed only a fair to moderate agreement (0.23–0.59) between the observers and a low intra-observer agreement (0.51–0.74) in contrast to the modified scale, which demonstrated a moderate to good agreement between the observers (0.65–0.93, P < 0.0001) and a high intra-observer agreement (0.87–0.91, P < 0.05). To test the modified scale in vivo, we compared both scales with the results of computed tomography (CT) of the lungs obtained from the same mice. In agreement, the modified scale demonstrated a better correlation to CT scans (R = 0.58) compared with the Ashcroft scale (R = 0.33). In summary, quantification of lung fibrosis in histological lung sections using the modified scale is reliable and reproducible.

A prospective study to evaluate the diagnostic potential and limitations of three fast MRI sequences in patients with bronchial carcinoma based on the comparison with spiral CT.Three fast chest MRI sequences from 20 patients with central or peripheral bronchial carcinoma were evaluated by two observers for relation of tumour to adjacent structures, lymph node enlargement, additional pulmonary lesions and artefacts. The information from MR-imaging was compared with the results from spiral CT. MRI comprised a T1-3D-GRE breath-hold examination ("VIBE", TR/TE 4.5/1.9 ms, flip-angle 12 degrees , matrix 502 x 512, 2.5 mm coronal slices), a breath-hold, T2-HASTE sequence (TR/TE 2000/43 ms, matrix 192 x 256, 10 mm coronal slices) and a respiration-triggered T2-TSE sequence (TR/TE 3000-6000/120 ms, matrix 270 x 512, 6 mm transverse slices). The FOV was adapted individually (380-480 mm).The presence of the primary bronchial carcinoma and infiltration of thoracic structures by tumour tissue could be demonstrated by all sequences. VIBE sequence was more suitable for detecting small pulmonary nodules than the other MRI examinations, but compared to CT still 20% of these lesions were missed. Contrary to VIBE and T2-weighted TSE scans, HASTE sequence was limited in imaging mediastinal lymph nodes due to missing relevant findings in 2/20 patients. HASTE images significantly provided the lowest rate of artefacts in imaging lung parenchyma (P0.001 in peripheral parenchyma), but spatial resolution was limited in this sequence. Concerning the differentiation between tumour and adjacent atelectasis (n = 8), T2-weighted TSE imaging was superior to CT and VIBE in all cases and to HASTE sequence in 4/8 patients.The combination of VIBE and HASTE sequence allows for an adaequate imaging of thoracic processes in patients with bronchial carcinoma, limited only in visualizing small pulmonary nodules. To obtain more detail resolution and to differentiate tumour tissue from adjacent atelectasis, T2-TSE examination may be added in selected cases.

To investigate the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) and GM-CSF/IL-3/IL-5 receptor common beta chain (beta c receptor) in an adult patient with idiopathic pulmonary alveolar proteinosis (PAP), so as to demonstrate the possible association of the GM-CSF and beta c receptor with the pathogenesis of human PAP.The GM-CSF levels were measured with a commercial ELISA kit (sensitivity 5 pg/ml) and the beta c receptor expression on the cell surface was detected by flow cytometry analysis. Reverse transcription polymerase chain reaction (RT-PCR) analysis was employed to detect the expression of the GM-CSF mRNA and the beta c receptor mRNA in peripheral blood mononuclear cells and alveolar macrophages. The entire coding regions of the GM-CSF cDNA and the beta c receptor cDNA were sequenced by the Sanger dideoxy-mediated chain termination method to detect possible mutations.The patient with PAP failed to release the GM-CSF protein either from circulating mononuclear cells or from alveolar macrophages. The expression of the GM-CSF mRNA was normal after the stimulation of lipopolysaccharide, whereas a point mutation at position 382 of the GM-CSF cDNA from "T" to "C" was revealed by cDNA sequencing, which caused a change in amino acid 117 of the protein from isoleucine to threonine. The beta c receptor expression on the cell surface was normal, and the beta c receptor mRNA expression and the sequence of the entire coding region of the beta c receptor were also normal.The decreased GM-CSF production is associated with the pathogenesis of human PAP. A point mutation of the GM-CSF cDNA may contribute to the decreased GM-CSF production in our adult PAP patient. The mutation of the beta c receptor in some of paediatric patients with PAP may not be a common problem in adult patients.

Background: Cytomegalovirus (CMV) is known as a common pathogen causing infections after lung transplantation. Rapid diagnosis of CMV infection is important for the initiation of a specific treatment. Objective: Evaluation of methods for the rapid diagnosis of CMV pneumonitis. Methods: The detection rates of CMV DNA in bronchoalveolar lavage (BAL) and bronchial brushes by polymerase chain reaction (PCR), of viral antigens (p52 and IE1) in BAL and of pp65 antigen in peripheral blood leukocytes were compared to the clinical status after lung transplantation. In 28 patients, 105 BAL, 96 blood samples and 14 brushes were analyzed. Results: In 6 patients, a total of eight episodes of CMV pneumonitis occurred. Five of the 6 with positive CMV antigens in BAL (p52 or IE1) showed signs of CMV pneumonitis. All episodes of CMV pneumonitis were detected by the PCR of BAL cells. Fourteen samples positive for CMV pp65 antigen in blood were negative in BAL PCR. In these cases, no clinical signs of pulmonary CMV infection occurred. Overall sensitivity, specificity, and positive and negative predictive values for the detection of CMV pneumonitis by PCR of BAL cells were 100, 98.9, 88.9 and 100%, respectively. In brush samples, PCR did not provide additional information to the results of the PCR of BAL cells. Conclusions: PCR of DNA from BAL cells is suitable for reliable and rapid detection of CMV pneumonitis.

Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) has become a crucial tool in the management of lung transplant recipients. Detection of pulmonary infectious pathogens by culture, cytology, and histology of BAL, protected brush specimens, and transbronchial biopsies (TBB) is highly effective. Morphologic and phenotypological analyses of BAL cells may be suggestive for certain complications after lung transplantation. For interpretation of BAL findings, the natural course of BAL cell morphology and phenotypology after lung transplantation must be considered. During the first 3 months after pulmonary transplantation, elevated total cell count in BAL and neutrophilic alveolitis are common, representing the cellular response to graft injury and interaction of immunocompetent cells of donor and recipient origin. With increasing time after transplantation the CD4/CD8 ratio decreases due to lowered percentages of CD4 cells in BAL. During bacterial pneumonias, the cellular profile of BAL is characterized by a marked granulocytic alveolitis. Lymphocytic alveolitis with a decreased CD4/CD8 ratio is suggestive of acute rejection, but is also found in viral pneumonias and obliterative bronchiolitis. In the case of a combined lymphocytosis and neutrophilia without any evidence of infection, obliterative bronchiolitis should be considered. Functional analyses of BAL cells can give additional information about the immunologic status of the graft, even before histologic changes become evident but have not been established in routine transplant monitoring. However, functional studies suggest an important role of activated, alloreactive and donor-specific T lymphocytes in the pathogenesis of acute and chronic lung rejection. Investigations of soluble components in BAL have given further insight into the immunologic processes after lung transplantation. In this overview, the characteristics of BAL after lung transplantation will be summarized, and its relevance for the detection of pulmonary complications will be discussed.

Background Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models. Methods To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice. Results By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated. Conclusions This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.

A 47-year-old woman presented with swelling, pain, and reddish discoloration of the right arm and hand after strenuous effort. Ultrasonography with a microconvex probe revealed a subtotal occlusion in the subclavian vein close to the clavicle, caused by a small thrombus fixed on a venous valve.

Recent advances in ultrasound imaging allow visualization of the cervical part of the thoracic duct. The movements of chyle and blood are identified with the use of a method of digital subtraction that separates static tissue from the flow in the vessels without the need for an enhancing contrast agent.