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Purpose Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) has spread around the world. Differentiation between pure viral COVID-19 pneumonia and secondary infection can be challenging. In patients with elevated C-reactive protein (CRP) on admission physicians often decide to prescribe antibiotic therapy. However, overuse of anti-infective therapy in the pandemic should be avoided to prevent increasing antimicrobial resistance. Procalcitonin (PCT) and CRP have proven useful in other lower respiratory tract infections and might help to differentiate between pure viral or secondary infection. Methods We performed a retrospective study of patients admitted with COVID-19 between 6th March and 30th October 2020. Patient background, clinical course, laboratory findings with focus on PCT and CRP levels and microbiology results were evaluated. Patients with and without secondary bacterial infection in relation to PCT and CRP were compared. Using receiver operating characteristic (ROC) analysis, the best discriminating cut-off value of PCT and CRP with the corresponding sensitivity and specificity was calculated. Results Out of 99 inpatients (52 ICU, 47 Non-ICU) with COVID-19, 32 (32%) presented with secondary bacterial infection during hospitalization. Patients with secondary bacterial infection had higher PCT (0.4 versus 0.1 ng/mL; p = 0.016) and CRP (131 versus 73 mg/L; p = 0.001) levels at admission and during the hospital stay (2.9 versus 0.1 ng/mL; p p p p Conclusion PCT and CRP measurement on admission and during the course of the disease in patients with COVID-19 may be helpful in identifying secondary bacterial infections and guiding the use of antibiotic therapy.

Background and aims Bacterial infections are common in patients with decompensated liver cirrhosis and a leading cause of death. Reliable data on antibiotic resistance are required to initiate effective empiric therapy. We here aim to assess the antimicrobial resistance profile of bacteria among patients with liver cirrhosis and infection. Methods Overall, 666 cirrhotic patients admitted to Hannover Medical School between January 2012 and April 2018 with ascites were assessed for bacterial infection. In case of infection, bacteria cultured from microbiological specimens of ascites, blood or urine were identified and analyzed for resistances against common antibiotic agents. Furthermore, analyses compared two periods of time and community-acquired vs. nosocomial infections. Results In 281 patients with infection, microbiological sampling was performed and culture-positive results were obtained in 56.9%. Multidrug-resistant (MDR)-bacteria were found in 54 patients (19.2%). Gram-positive organisms were more common (n = 141/261, 54.0%) and detected in 116/192 culture-positive infections (60.4%). Comparing infections before and after 2015, a numerical decline for MDR-bacteria (23.8% vs. 15.6%, p = 0.08) was observed with a significant decline in meropenem resistance (34.9% vs. 19.5%, p = 0.03). MDR-bacteria were more frequent in the case of nosocomial infections. Of note, in ascites the majority of the tested bacteria were resistant against ceftriaxone (73.8%) whereas significantly less were resistant against meropenem (27.0%) and vancomycin (25.9%). Conclusions In our tertiary center, distinct ratios of gram-positive infection with overall low ratios of MDR-bacteria were found. Adequate gram-positive coverage in the empiric therapy should be considered. Carbapenem treatment may be omitted even in nosocomial infection. In contrast, 3rd generation cephalosporins cannot be recommended even in community-acquired infection in our cirrhotic population.

Among patients with bronchiectasis, nontuberculous mycobacterial pulmonary disease (NTM-PD) ranged between 1 and 6% and it is suspected that its prevalence is underestimated. Our aim was to evaluate differences in computed tomography (CT) features in patients with bronchiectasis, with and without NTM-PD, in order to facilitate earlier diagnosis in the future. In addition, we evaluated longitudinal changes after successful NTM-PD treatment. One hundred and twenty-eight CTs performed in adults with bronchiectasis were scored for the involvement, type, and lobar distribution of bronchiectasis, bronchial dilatation, and bronchial wall thickening according to Reiff. In addition, associated findings, such as mucus plugging, tree-in-bud, consolidations, ground-glass opacities, interlobular thickening, intralobular lines, cavities, and atelectasis, were registered. Patients with NTM-PD (n = 36), as defined by ATS/IDSA diagnostic criteria, were compared to bronchiectasis patients without NTM-PD (n = 92). In twelve patients with an available consecutive CT scan after microbiological cure of NTM-PD imaging findings were also scored according to Kim and compared in the course. In patients with NTM-PD, there was a higher prevalence of bronchiectasis in the middle lobes (p &lt, 0.001), extended bronchiolitis (p = 0.032) and more small and large nodules (p &lt, 0.001). Furthermore, cavities turned out to be larger (p = 0.038), and walls thickened (p = 0.019) and extended (p = 0.016). Patients without NTM more often showed peripheral ground-glass opacities (0.003) and interstitial changes (p = 0.001). CT findings decreased after successful NTM-PD treatment in the follow-up CT, however, without statistical significance for most features (p = 0.056), but bronchiolitis was the only significantly reduced score item (p = 0.043). CT patterns in patients with bronchiectasis and NTM-PD differ from those of patients with bronchiectasis without NTM-PD, although the findings are non-specific radiological features. Follow-up CT findings after microbiological cure differed interindividual regarding the decline in imaging features. Our findings may help practitioners to identify NTM-PD in patients with bronchiectasis. Further research is needed regarding the use of CT as a potential imaging biomarker for the evaluation of treatment response.

Anti-infective treatment of pulmonary exacerbations is a major issue in people with cystic fibrosis (CF). Individualized dosing strategies and adaptation of infusion times are important concepts to optimize anti-infective therapy. In this prospective non-randomized controlled open-label trial, we compared pharmacokinetics of meropenem in 12 people with CF experiencing a pulmonary exacerbation, of whom six received parenteral meropenem 2 g tid as short infusion over 30 min and six extended infusion over 120 min. We measured blood concentrations of meropenem at five predetermined time points over 240 min and calculated differences in the percentages of the time above the minimal inhibitory concentration (fT > MIC) for meropenem concentrations >16 and >32 mg/L, respectively. Mean percentages of fT > 16 and fT > 32 mg/L were higher in the extended compared to the short infusion group (83 and 56% vs. 59% and 34%), with a statistically significant prolongation of the fT > 32 mg/L (mean 134 vs. 82 min; p = 0.037). Our results demonstrate that, in people with CF, longer fT > MIC can be achieved with a simple modification of meropenem dosing. Further studies are needed to clarify if this may translate into improved microbiological and clinical outcomes, in particular in adults with difficult-to-treat chronic infection by carbapenem-resistant Pseudomonas aeruginosa.

Introduction: Immunodeficiency is a recognised cause of bronchiectasis but individual cohorts are typically too small to describe the demographics and severity of disease in this group. The EMBARC Registry represents a large dataset to address this. Methods: Data submitted from centres to EMBARC from Jan 2015 to June 2019 was studied. Severity of disease was evaluated using the Bronchiectasis severity index (BSI) and quality of life using the QOL-B. Results: Of the 13512 patients included, 491 (3.6%) patients were reported as having bronchiectasis due to immunodeficiency. The most commonly reported cause entered was common variable immunodeficiency (35.8%). Patients with immunodeficiency had a mean age of 56.5 years (sd 17.3), with moderate severity (median BSI 6, IQR 3-10) and symptomatic impairment (QOL-B 63.5, sd 20.6). During follow-up (mean 3 years) patients with immunodeficiency as the reported aetiology did not have a higher exacerbation frequency compared to idiopathic bronchiectasis – rate ratio 0.90 95% CI 0.78-1.04,p=0.15. Interestingly, patients with immunodeficiency had significantly less severe respiratory symptoms using the QOL-B (difference 3.5 points 95% CI 1.61-5.37,p Conclusion: Immunodeficiency accounts for 3.6% of bronchiectasis cases. Patients have a wide spectrum of severity but on average less severe symptoms compared to patients with other aetiologies.

Introduction: Alpha-1 antitrypsin deficiency is a recognised cause of bronchiectasis. There are few large cohorts, however, describing the frequency, clinical characteristics and severity of disease in this population. Methods: The European Bronchiectasis Registry (EMBARC) was studied from Jan 2015 to June 2019. Severity of disease was evaluated using the Bronchiectasis severity index (BSI) and quality of life using the QOL-B questionnaire. Results: Of 13512 patients included in the analysis, 3390 patients were tested for alpha-1 antitrypsin deficiency. Rates of testing by country varied from 0% in several countries to 67.5% in Portugal (UK 12.8%, Germany 40.2%, Italy 28.3%, Spain 43.8%) . Alpha-1 deficiency was identified in 77 patients (2.3%). Mean age was 61 years (SD 12), 47 females (61.0%). The mean bronchiectasis severity index was 7.8 points (SD 5.2). 26, 20 and 31 patients were classified as mild, moderate and severe respectively. The median exacerbation rate was 2 per year (range 0-13). Mean FEV1 was 70.2% (SD 32). Patients had moderate symptomatic impairment (mean QOL-B symptom score 58.7 SD 23). The most common organisms were Pseudomonas aeruginosa (23.4%), Enterobacteriales (9.1%), Staphylococcus aureus (9.1%), Haemophilus influenzae (6.5%) and NTM (5.2%). During follow-up (mean 3 years) patients with alpha-1 antitrypsin deficiency had a similar rate of exacerbations as patients with idiopathic bronchiectasis- rate ratio 1.12 95% CI 0.80-1.58,p=0.51. Conclusions: Alpha-1 antitrypsin deficiency is an uncommon cause of bronchiectasis in the EMBARC registry, but estimates are limited by infrequent testing. A study to determine the true prevalence of alpha-1 antitrypsin deficiency through systematic testing is needed.

Background: Randomized Trials in bronchiectasis may have been underpowered due to unexpectedly large “placebo effects”. We used a combination of meta-analysis and analysis of the European Bronchiectasis Registry (EMBARC) to quantify “placebo effects” in randomized trials in bronchiectasis Method: We searched electronic databases from 1990-2019, to identify double blind, randomized, placebo-controlled trials of drug treatment in bronchiectasis. We defined the “placebo effects” by comparing the outcomes at the end of placebo treatment and at baseline prior to treatment. EMBARC registry data were employed to model changes in exacerbation rate and quality of life (QoL) Result: 27 trials were included for meta-analysis (N=1739 placebo-treated patients). Placebo treatment was associated with significantly reduced exacerbation rate (mean difference [MD] -1.79, -2.03 to -1.56; p Conclusion: Placebo treatment was associated with improved QoL and reduced exacerbation in bronchiectasis. Enrolling patients with 1 or more exacerbation may be an optimal inclusion criteria

Bronchiectasis is a chronic disease with a variety of aetiologies that influence the clinical presentation and management of the disease. One of these aetiologies is allergic bronchopulmonary aspergillosis (ABPA). Methods: 27 of 1000 patients (2.7%) included in PROGNOSIS had ABPA as aetiology of bronchiectasis (per investigator judgment). ABPA testing was the most common aetiological test performed in 58% of subjects. Comparison was made to 973 adults with bronchiectasis caused by any other aetiology. Results: Mean age was 63 years in ABPA compared to 61 years (p=0.410), 37% were male (vs 41%; p=0.694). Median annual exacerbation rate was 2 (each; p=0.47). Although mean ppFEV1 differed from 59.7% (95% CI: 52.5-77.0) to 70.6% (95% CI: 66.9-71.3), there was no significant difference (p=0.842). Radiological features showed predominant involvement of upper lobes (left 70.4% vs. 35.5%, p Method: Adults with ABPA as aetiology of bronchiectasis show mainly upper lobe involvement and cystic bronchiectasis with no differences in frequency of positive fungal cultures. The majority is treated with OCS, only two-thirds received ICS, antimycotics were infrequently used. Further research is warranted, especially as ABPA is considered a treatable trait in bronchiectasis.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disorder which requires a complex diagnostic workup. Thus, an easy and widely available screening method would be helpful to identify patients who need a further diagnostic workup for PCD. Objectives: The aim of the study was to develop and validate a computed tomography (CT) score for PCD to facilitate etiological diagnosis in adults with bronchiectasis. Method: Chest CTs from 121 adults with bronchiectasis were scored for bronchiectasis morphology, distribution, and associated findings. Patients with and without the etiological diagnosis of PCD (46 and 75, respectively) were compared. Significantly, different imaging findings (p < 0.05) in univariate analysis were considered for multivariate analysis. Distinct findings were used to build the score. Based on this score, receiver operating characteristic (ROC) curve analysis was performed. The score was validated with 2 independent cohorts, another cohort from the same institution with 56 patients (28 with PCD) and an external cohort from another referral center with 172 patients (86 with PCD). Results: The following parameters predicted PCD in adults with bronchiectasis and were included in the score with weighting according to their regression coefficients: 2 points were given for predominance in the middle/lower lobe, 2 points for tree-in-bud pattern, 2 points for atelectasis or prior resection of a middle/lower lobe, and 3 points for absence of emphysema and fibrosis. Situs inversus was only observed in subjects with PCD (Kartagener syndrome) and, thus, was not used in the primary ciliary dyskinesia computed tomography (PCD-CT) score as group comparisons could not be performed. ROC curve analysis revealed an area under the curve (AUC) of 0.90 (95% CI 0.85–0.96). Youden index was the highest at a threshold of >6 with a sensitivity of 83% and a specificity of 83%. In the validation cohorts, ROC curve analysis confirmed the performance of the score with an AUC of 0.83 (95% CI 0.72–0.94) in the first validation cohort and 0.79 (95% CI 0.73–0.86) in the external validation cohort. Conclusions: The PCD-CT score provides the first validated CT score for PCD and helps physicians in identifying adult bronchiectasis patients who require further diagnostic workup. Key message: The PCD-CT score provides the first validated CT score to assist physicians in identifying adult bronchiectasis patients who require a further diagnostic workup for PCD. It potentially improves earlier recognition of this rare and underdiagnosed disease.

Background: YNS is an orphan disease, the prevalence is estimated to be Objective: To describe the phenotype of patients with YNS and bronchiectasis to identify targets for future research regarding the pathogenesis, diagnosis and specific treatment. Methods: Data from the German and European bronchiectasis registries PROGNOSIS and EMBARC was analyzed descriptively. Differences between subjects with YNS (pooled data from PROGNOSIS and EMBARC) and other etiologies of bronchiectasis (data from PROGNOSIS) were assessed by Fisher´s exact, Chi2 and Mann-Whitney-U test. Results: Overall, 31 patients in PROGNOSIS and EMBARC had YNS as aetiology. Median age was 67 yrs; 58% were female, the median (IQR) FEV1% predicted was 68% (59-83) and 32% grew Pseudomonas aeruginosa in sputum cultures. Bronchiectasis were seen predominantly in lower lobes. Compared to 994 subjects without YNS from PROGNOSIS registry significant differences were observed with regard to the proportion with chronic rhinosinusitis (CRS) (52% in YNS vs. 30%; p=0.016) and the median [IQR] exacerbation frequency (2 [1-6] vs. 1 [0-3]; p=0.009). Conclusion: Our data suggest that YNS is a rare cause of bronchiectasis, which may be associated with frequent exacerbations and rhinosinusitis. Further multicenter research is warranted.

Purpose: Aim of this multicenter study was to evaluate specific features of Primary Ciliary Dyskinesia (PCD) in computed tomography and to develop and validate a CT score for PCD to facilitate diagnosis. Methods: 121 CT in adult patients with bronchiectasis were scored. In univariate analysis imaging findings with p Results: In multivariate analysis, Situs inversus (p Conclusions: PCD-CT provides the first validated CT score for PCD to help practitioners in identifying bronchiectasis patients who require a further diagnostic workup for PCD.

Background: The relevance of nontuberculous mycobacteria (NTM) among subjects with bronchiectasis in Germany is unknown. In this regard, the German Bronchiectasis Registry PROGNOSIS is an excellent opportunity to provide further insights. Methods: We analyzed the first consecutively recruited and validated 1000 baseline datasets of PROGNOSIS and compared subjects with a history of NTM and/or a positive respiratory culture at baseline (NTM group) to subjects without such history and no isolation (non-NTM group). Differences between groups were assessed by univariate analysis. Results: Overall, only 56% received AFB cultures at baseline. Among 49 subjects with a positive culture MAC (76%), M. kansasii (14%) and M. gordonae (12%) were the most frequent NTM species. Using the above definition we identified 73 NTM patients (7.3%). Those were older (mean age 63 vs. 59 years; P=0.041), more often female (69 vs. 59%, P=0.11) and had a lower median BMI (23.1 vs. 24.2 kg/m²; P=0.046). Upper airway involvement, PCD as an etiology and ICS use was less frequent (18 vs. 34%, P=0.004; 3 vs. 9%, P=0.055; and 3 vs. 19%, P Conclusion: Patients with bronchiectasis and NTM exhibit distinct clinical features. Comparing our findings to those of the US Bronchiectasis Research Registry we found similarities and differences, which warrant further investigation by multivariate analysis.

Patients with clinically significant bronchiectasis featuring an eosinophilic inflammatory endotype who were treated with add-on mepolizumab or benralizumab showed a significant improvement of FEV1, symptom burden and quality of lifehttp://bit.ly/2AZvBLm

This study sought to investigate the prognostic importance of a low diffusion capacity of the lung for carbon monoxide (DLCO) in patients with a catheter-based diagnosis of pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF).In patients with pulmonary arterial hypertension, a low DLCO is associated with poor outcome. It is unclear whether the same is true in patients with PH-HFpEF.This study retrospectively analyzed clinical characteristics, smoking history, lung function measurements, chest computed tomography, hemodynamics, and survival in 108 patients with PH-HFpEF. The presence of post-capillary PH was determined by right heart catheterization. Patients with moderate or severe lung function abnormalities were excluded.On the basis of previous studies and receiver-operating characteristic curve analysis, the study cohort was divided into patients with a DLCO 45% of the predicted value (DLCO45%, low DLCO; n = 52) and patients with a DLCO ≥45% of the predicted value (DLCO≥45%; n = 56). DLCO45% was associated with male sex (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.05 to 6.99; p = 0.039) and smoking history (OR: 5.01; 95% CI: 1.91 to 13.10; p 0.001). There were no correlations between DLCO and other lung function parameters and hemodynamics. Compared with patients with DLCO≥45%, patients with DLCO45% had a significantly worse outcome (survival rate at 3 years 36.5% vs. 87.8%, p 0.001 by log-rank analysis). Cox proportional hazard analysis identified DLCO45% as an independent predictor of death (hazard ratio: 6.6; 95% CI: 2.6 to 16.9; p 0.001).In patients with PH-HFpEF, a low DLCO is strongly associated with mortality.

Background Lung transplantation (LTx) is a well-established treatment for end-stage pulmonary disease. However, data regarding microbiology and outcome of patients with non-cystic fibrosis bronchiectasis (NCFB) after lung transplantation are limited. Methods A retrospective analysis between August 1992 and September 2014 of all patients undergoing lung transplantation at our program of all recipients with a primary diagnosis of bronchiectasis was performed. Microbiology of sputum and bronchoalveolar lavage specimens, lung function and clinical parameters pre- and post-LTx were assessed retrospectively. Overall survival was compared to the total cohort of lung transplant recipients at institution. The survival and development of chronic lung allograft dysfunction (CLAD) was compared in patients with and without chronic Pseudomonas aeruginosa (PSA) infection after LTx. Results 34 patients were transplanted. Median age at transplantation was 40 (IQR 33–52) years. The most common etiologies of bronchiectasis were idiopathic (41%), chronic obstructive pulmonary disease (COPD) (21%) and post-infectious (15%). The most common organism of pre- and posttransplant chronic airway infection was PSA. One-year Kaplan-Meier survival for patients with bronchiectasis was 85% and 5-year survival was 73% and similar to the entire cohort. All three patients with an associated diagnosis of immunodeficiency died due to infection and sepsis within the first year. Patients with persistent colonization with Pseudomonas aeruginosa after transplantation had worse long-term survival by trend and developed chronic lung allograft dysfunction more frequently. Conclusions Overall survival of patients with bronchiectasis after LTx is comparable to other underlying diseases. A reduced survival was observed in patients with the underlying diagnosis of immunodeficiency.

We analyzed routine statutory health insurance claim data to determine prevalence of nontuberculous mycobacterial pulmonary disease in Germany. Documented prevalence rates of this nonnotifiable disease increased from 2.3 to 3.3 cases/100,000 population from 2009 to 2014. Prevalence showed a strong association with advanced age and chronic obstructive pulmonary disease.

Background Incidence and prevalence of patients with non-cystic fibrosis bronchiectasis (NCFB) appear to be increasing worldwide but supporting epidemiological data are scarce. This study assesses the incidence of NCFB patients in Germany in 2013 and analyzes comorbidities and basic patterns of resource use. Methods A representative sample of 3.988.648 anonymized persons covered by German public statutory health insurances was used to identify incident patients with NCFB in 2013. Results After extrapolation to the general population of the 728 patients found in the reference insurance database, we estimate that a total of 17,095 NCFB patients were newly diagnosed across the country in 2013 as having NCFB. This corresponds to an incidence of 21.23 per 100.000 inhabitants. The majority of NCFB patients (98.4%) was at least 18 years old, and 52.7% of the NCFB patients were male. Trend analysis shows a rise of NCFB incidence in Germany from 2011 through 2013. COPD (41.4%), asthma (32.8%) and gastroesophageal reflux (18.3%) were the most frequent predisposing conditions. Coronary heart disease was observed in more than one quarter of NCFB patients (28.2%). 58.4% of the NCFB outpatients received antiobstructive inhalative medication. Of the adult NCFB patients, 51.6% were prescribed antibiotics to treat NCFB by settled doctors (outpatient treatment); 51.5% of those patients were males. The peak of antibiotic treatment was observed in the 75–79 age group for males and 70–74 and 75–79 years for females. The majority of diagnosed patients (54.1%) received at least two prescriptions during 2013. Bacterial pathogens were coded for a total of 10.7% of NCFB patients, while Pseudomonas aeruginosa was only documented in 2.3%. Among those diagnosed in 2013, 8.0% of the adult NCFB patients who received antibiotic treatment had to be hospitalized. Conclusions Although hospital admissions due to exacerbation in the first year of diagnosing NCFB are not rare, outpatient burden and costs must also be considered a major part of care. Given the increasing recognition of NCFB, a better understanding of the economic burden of the disease is required, with a view towards improving patient management. For this, more detailed, prospective studies are needed.

Bronchiectasis is a chronic and progressive disease, which frequently is associated with a significant symptom burden and which may require intensive treatment. To date there is no data how many patients with bronchiectasis suffer from eosinophilia and how monoclonal anti-allergic antibodies work in these patients. The aim of this case series study was to describe the effect of mepolizumab in patients with bronchiectasis and underlying eosinophilic conditions. 300 patients are in regular follow up in the adult bronchiectasis clinic of the Hannover Medical School and 7% of patients had an eosinophilic blood count of more than 300 per cubic millimeter. In 15 patients of this cohort we decided to treat the disease with the Anti- IL5 antibody mepolizumab due to high exacerbation rate, low quality of life and high corticosteroid use. Overall, twelve patients of the cohort receiving mepolizumab had follow up data after 3 and 6 months of therapy. After six months of therapy the median (IQR) eosinophilic cell count decreased significantly from 1000 (500-1900) to 100 (0-200) per cubic millimeter (p=0.001). The median (IQR) annual rate of exacerbations improved with 1 (0-3) per year after 6 months of therapy, as compared with 3 (1-5) per year at baseline. Similar results showed the median (IQR) mMRC dyspnoe scale, which decreased from 2 (1-3) to 0 (0-1) (p=0.004). In the patient-reported outcomes the median (IQR) quality of life measured in a visual analog scale (1-10) improved significantly from 4 (3-6) to 6.5 (5-7) (p=0.01). In conclusion, patients with bronchiectasis and eosinophilia had significantly less dyspnea; a higher quality of life score and lower eosinophilic cell count under the therapy of mepolizumab.

We investigated associations between the Quality of Life Questionnaire-Bronchiectasis (QoL-B) scales and symptom burden as well as markers of disease severity within the German Bronchiectasis Registry PROGNOSIS. The German translation of the QoL-B V.3.0, which uses 8 scales (Respiratory Symptoms [RS], Physical Functioning [PF], Vitality [V], Role Functioning [RF], Health Perceptions [HP], Emotional Functioning [EF], Social Functioning [SF] and Treatment Burden [TB]), is routinely applied at baseline. Between Jun 2015 and Feb 2018, 1043 subjects were recruited from 38 centers (median age 61 years, 59% female). At baseline, up to 95% of subjects completed the QoL-B. All scales were significantly associated with higher MRC dyspnea scores (p Our analysis confirms that the QoL-B is a feasible tool to determine quality of life in this representative cohort of German patients with bronchiectasis.

Bronchiectasis represents the final pathway of several infectious, genetic, immunologic or allergic disorders. Accurate and prompt identification of the underlying cause is a key recommendation of several international guidelines, in order to tailor treatment appropriately. Primary ciliary dyskinesia (PCD) is a genetic cause of bronchiectasis in which failure of motile cilia leads to poor mucociliary clearance. Due to poor ciliary function in other organs, individuals can suffer from chronic rhinosinusitis, otitis media and infertility. This paper explores the current literature describing why, when and how to investigate PCD in adult patients with bronchiectasis. We describe the main PCD diagnostic tests and compare the two international PCD diagnostic guidelines. The expensive multi-test diagnostic approach requiring a high level of expertise and specialist equipment, make the multifaceted PCD diagnostic pathway complex. Therefore, the risk of late or missed diagnosis is high and has clinical and research implications. Defining the number of patients with bronchiectasis due to PCD is complex. To date, few studies outlining the aetiology of adult patients with bronchiectasis conduct screening tests for PCD, but they do differ in their diagnostic approach. Comparison of these studies reveals an estimated PCD prevalence of 1–13% in adults with bronchiectasis and describe patients as younger than their counterparts with moderate impairment of lung function and higher rates of chronic infection with Pseudomonas aeruginosa. Diagnosing PCD has clinical, socioeconomic and psychological implications, which affect patients’ life, including the possibility to have a specific and multidisciplinary team approach in a PCD referral centre, as well as a genetic and fertility counselling and special legal aspects in some countries. To date no specific treatments for PCD have been approved, standardized diagnostic protocols for PCD and recent diagnostic guidelines will be helpful to accurately define a population on which planning RCT studies to evaluate efficacy, safety and accuracy of PCD specific treatments.

The rationale behind surgical treatment of localized form of disease is to break the circulus vitiosus starting from bronchiectasis, through consecutive inflammation and toxin release with impaired mucociliary clearance, to subsequent destruction as a final consequence. Apart from interrupting this harmful course, operation removes the segments that are no longer functional, in the same time preventing the infectious contamination of adjacent lung zones and leading to significant symptom relief.

Background: PROGNOSIS (www.bronchiektasen-register.de) is a representative registry, to adress important epidemiologic questions and to provide real-life data of current bronchiectasis management in Germany. Methods: Prospective, observational and longitudinal register study with baseline and follow—up data collection every year; recruitment across all levels of of healthcare. Results: Recruitment (8 Feb 2017, first 18 months): 706 subjects, 36 centers. Data from the first 505 validated datasets (50% academic centers, AC) will be presented. 250 validated datasets (66% AC) showed: average age 57±15 yrs (60% female; 54% never-smokers); median annual exacerbation 2 (0-3) and hospitalisation 0 (0-1) rate; ppFEV1 67±27%; FEV1/FVC ratio 0.67±0.16; BMI 24±5 kg/m2; 46% duration of bronchiectasis >10 years; radiological mainly basal distribution. Most common etiologies: 35% idiopathic, 11% COPD, 11% Primary Ciliary Dyskinesia, 10% postinfectious, 7% primary immunodeficiency, 7% asthma. Relevant pathogens if clinically stable: 37% P. aeruginosa (PA), 18% S. aureus , 13% A. fumigatus , 8% H. influenzae , 7% nontuberculous mycobacteria. 71% of PA positive subjects received at least one eradication attempt. Regular bronchiectasis therapy 90%: 78% physiotherapy, 64% mucoactive physio adjuncts, 33% azithromycin maintenance therapy, 26% inhaled antibiotics, 12% prior thoracic surgery. Vaccination coverage: pneumococcal PPSV23 50% and PCV13 38%, influenza 79%. Pulmonary rehab 44%. Conclusions: Data structure is likely to change due to more non-academic centers. Basic treatments (e.g. vaccination) are underused. Interventional clinical trials are needed. Support: CAPNETZ STIFTUNG, BREATH/DZL, Bayer, Grifols, Insmed, IMI (EU/EFPIA).

The risk of transmission of infections in partnerships between 2 transplant recipients is unknown. The aim of this study was to evaluate transmission in such couples. In this single-center study, lung transplant (LTx) couples were identified among outpatients between 1988 and 2016. Infection rates per year and survival were compared to matched LTx-recipients not living in a transplant partnership. Twelve transplant couples were analyzed with cumulative 65 years of relationship. Overall infections were similar between LTx-couples and matched LTx-patients. No significant differences were noted in bacterial infections (.12 vs .27 per year), community-acquired viral (CARV) infections (.26 vs .22 per year), rejection treatments (.22 vs .12 per year), or hospitalizations (.26 vs .46 per year) in transplant couples and matched controls, respectively. There was no transmission of any microbial colonization from 1 partner to the other. Five cases of simultaneously detected CARV infections occurred (metapneumovirus [3], H1N1 [1], and respiratory syncytial virus [RSV; 1]). Three couples exhibited cytomegalovirus (CMV) reactivation in both partners at the same time with confirmed seronegativity before transplantation. In this case series of 12 lung transplant couples, the partnerships between 2 transplant recipients have no greater risk of bacterial infection and colonization transmission in comparison with recipients not living in a transplant relationship. However, transplant couples should be informed about the risk for transmission of viral infections, which could impact the development of chronic lung allograft dysfunction (CLAD).

Background: Pathogenic organisms in sputum of COPD patients are associated with increased risk of exacerbations and with a higher prevalence of bronchiectasis. This study evaluates the rate of colonization in patients with advanced COPD, along with severity of bronchiectasis. Methods: A retrospective single-center evaluation of 378 patients with advanced COPD was performed in our pretransplant outpatient clinic between October 2008 and June 2011. Lung function, exacerbation rate in the preceding 12 months and lung and sputum microbiology were analyzed. CT scans were assessed for bronchiectasis by blinded radiologists. Results: Sputum expectoration was reported in 196 patients (52%). Potential pathogens were identified in 77 cases (20%), Pseudomonas aeruginosa (20%) and Staphylococcus aureus (21%) were the dominant bacterials. Patients with positive sputum cultures were more likely to be hospitalized due to exacerbation (p=0.01) and demonstrated more severe bronchiectasis in standardized qualitative CT examination (p=0.002). Ninety-four patients (25%) underwent lungtransplantation during the observation period. In the explanted lungs, evidence of potential pathogen was found in 21 patients (22%). Conclusions: Within our cohort of advanced COPD patients, almost 1 of 5 patients exhibited a positive respiratory culture. Pathogenic bacterial colonisation correlated with more severe bronchiectasis and significantly increased hospitalization due to exacerbations.

Robust evidence for the prevalence of bronchiectasis in Germany and its association with chronic airflow obstruction http://ow.ly/QvSBo

Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality in lung transplant recipients after the first year. Treatment remains limited and unpredictable. Existing data suggests extracorporeal photopheresis (ECP) may be beneficial. This study aimed to identify factors predicting treatment response and the prognostic implications. A single center retrospective analysis of all patients commencing ECP for CLAD between November 1, 2007 and September 1, 2011 was performed. In total 65 patients were included, 64 of whom had deteriorated under azithromycin. Median follow-up after commencing ECP was 503 days. Upon commencing ECP, all patients were classified using proposed criteria for emerging clinical phenotypes, including "restrictive allograft syndrome (RAS)", "neutrophilic CLAD (nCLAD)" and "rapid decliners". At follow-up, 8 patients demonstrated ≥10% improvement in FEV1 , 27 patients had stabilized and 30 patients exhibited ≥10% decline in FEV1 . Patients fulfilling criteria for "rapid decliners" (n=21, p=0.005), RAS (n=22, p=0.002) and those not exhibiting neutrophilia in bronchoalveolar lavage (n=44, p=0.01) exhibited poorer outcomes. ECP appears an effective second line treatment in CLAD patients progressing under azithromycin. ECP responders demonstrated improved progression-free survival (median 401 vs. 133 days). Proposed CLAD phenotypes require refinement, but appear to predict the likelihood of ECP response.

Background: A low diffusion capacity of the lung for carbon monoxide (DLCO) is associated with poor outcome in patients with pulmonary arterial hypertension. It is unclear if the same is true in patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). Objective: To elucidate the impact of a low DLCO on survival in patients with PH-HFpEF. Methods: Retrospective analysis of clinical characteristics, smoking history, lung function tests (LFT), chest computed tomography (CT), hemodynamics and survival in 108 patients with PH-HFpEF. Post-capillary PH was determined by right heart catheterization. Patients with moderate or severe lung function abnormalities were excluded. Results: According to ROC-analysis, the study cohort was divided into patients with a DLCO

Several reports indicated an association among inherited A1ATD, pulmonary infections and bronchiectasis. Most reported A1ATD cases with bronchiectasis are elderly homozygous PiZZ (Glu342Lys) smokers with emphysema. Whether there is an increased risk for bronchiectasis in heterozygous PiMZ A1ATD carriers is not clear. We describe a non-smoking 18 years old male with bronchiectasis. Pulmonary function testing showed a moderate airflow obstruction and hyperinflation. Capillary blood gas analysis showed moderate respiratory failure and hyperventilation. A high-resolution CT scan of the chest revealed bronchiectasis in both lower lobes with thickening of bronchial walls and additional tree-in-bud sign, indicating bronchiolitis and mucus plugging, but no emphysema. Analysis of the serum A1AT and phenotyping revealed that this patient had reduced A1AT levels of 0.78 g/L (normal is 0.9-2.0g/L) associated with an intermediate PiMZ A1ATD. Although microscopic examination of Giemsa-stained cytospins revealed normal appearance of PiMZ neutrophils, they had significantly lower A1AT (SERPINA1) but higher elastase (ELANE) expression when compared to PiMM neutrophils. Affinity purified MZ A1AT protein contained a mixture of polymeric forms and lower ability to inhibit endotoxin-induced TNFα and IL-1β expression than MM A1AT. Our findings highlight the quantitative and qualitative deficiency of MZ A1AT and increased expression of neutrophil elastase, which may explain the early-age onset of bronchiectasis. Our data suggest that patients with bronchiectasis, even in the absence of emphysema, need to be tested for A1ATD.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure and leads to bronchiectasis. The disease is probably underrecognized in the cohort of bronchiectasis due to extensive diagnostic testing and low recognition of PCD. To find a reliable screening method for PCD in the cohort of non-cystic fibrosis bronchiectasis. All patients who presented to our outpatient clinic were analysed. Nasal NO and a symptom score of key clinical features of PCD (neonatal respiratory symptoms, chronic cough since childhood, otitis media, rhinosinusitis, recurrent pneumonia) were measured post-hoc and compared in the two groups of PCD-bronchiectasis and non-PCD-bronchiectasis. 118 patients (42 male, 76 females) had a sufficient nasal NO and were eligible for analysis. The median (IQR) in nNO levels in parts per billion (ppb) in the PCD and non- PCD groups were 35 (IQR 22-70) and 525 (IQR 367-690), respectively. The median nasal NO levels were significantly lower in the PCD- group than in the other group (p Low nasal NO and a clinical scoring of typical PCD signs and symptoms is a suitable and cheap screening test for PCD in the cohort of non-cystic fibrosis bronchiectasis.

Recurrent infections of the upper airways in early life may be a warning sign of inherited α 1 -antitrypsin deficiency http://ow.ly/iJsF300kbyV

BACKGROUND An obstructive pattern in pulmonary function test is common after lung transplantation (LTx) and may be caused by multiple disorders. In this study, the impact and outcome of an obstructive spirometric pattern identified in transplant recipients early posttransplantation were investigated. METHODS Analyzing all patients undergoing double LTx between September 1, 2007, and October 1, 2009, we separated patients with an obstructive (forced expiratory volume in 1 sec [FEV(1)]: vital capacity [VC]

Bortezomib is highly effective in multiple myeloma and is widely used in this disease. Recently, an increased incidence of varicella zoster virus (VZV) reactivation was reported in patients with myeloma undergoing bortezomib treatment.We investigated the influence of bortezomib on T-cell subpopulations in 53 patients with myeloma before initiation of bortezomib and during therapy.A decrease of CD4+ T cells was seen in 41 of 53 patients (77%). The median CD3+/CD4+ lymphocyte counts declined from 494/microL (range, 130-2187/microL) to 274/microL (range, 41-1404/microL) during bortezomib treatment (P.001). In the majority of patients (40 of 53 patients, 75%), CD4+ lymphocytes dropped to400/microL during bortezomib treatment, and in 18 of 53 patients (33.9%) the CD4+ T cells fell below 200/microL. The minimum CD4S+ cell count was observed at a median of 6 weeks (range, 2-22 weeks) after initiation of treatment. The incidence of herpes zoster reactivation was 5.7% in the whole population of patients with myeloma receiving bortezomib. Nineteen of 53 patients received acyclovir at a dose of 400 mg daily as prophylaxis against VZV reactivation. In this group, none of the patients developed herpes zoster. The incidence of VZV reactivation in patients not receiving acyclovir was 3 of 34 (8.8%). Importantly, occurrence of herpes zoster was associated with reduced CD4+ T-cell subpopulation: all patients who developed herpes zoster had CD4+ lymphocytes400/microL.Our results show that bortezomib leads to a transient decrease in CD4+ lymphocytes, accompanied by an increased incidence of VZV infections. The antiviral prophylaxis with acyclovir is effective in patients with myeloma treated with bortezomib.

Objectives Among patients with non-cystic fibrosis bronchiectasis, 1–18% have an underlying diagnosis of primary ciliary dyskinesia (PCD) and it is suspected that there is under-recognition of this disease. Our intention was to evaluate the specific features of PCD seen on computed tomography (CT) in the cohort of bronchiectasis in order to facilitate the diagnosis. Materials and methods One hundred and twenty-one CTs performed in patients with bronchiectasis were scored for the involvement, type, and lobar distribution of bronchiectasis, bronchial dilatation, and bronchial wall thickening. Later, associated findings such as mucus plugging, tree in bud, consolidations, ground glass opacities, interlobular thickening, intralobular lines, situs inversus, emphysema, mosaic attenuation, and atelectasis were registered. Patients with PCD (n = 46) were compared to patients with other underlying diseases (n = 75). Results In patients with PCD, the extent and severity of the bronchiectasis and bronchial wall thickness were significantly lower in the upper lung lobes (p

Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. So far, there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. Methods: DKK-1 serum levels were quantified in 184 untreated MM patients and 33 monoclonal gammopathy of undetermined significance (MGUS) patients by ELISA, using a monoclonal anti-DKK-1 antibody. Results: Serum DKK-1 was elevated in MM as compared with MGUS (mean 11 963 pg/mL vs. 1993 pg/mL; P 3 lesions: 3114 pg/mL vs. 3559 pg/mL vs. 24 068 pg/mL; P = 0.002). Conclusion: Using a large series of myeloma patients, we could show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, indicating that DKK-1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

Background: Lung transplantation is a well-established treatment for end- stage pulmonary disease. Data concerning the outcome of patients with Non-CF-Bronchiectasis (NCFB) and lung transplantation are limited. Methods: Between August 1992 and Sept. 2014, 34 patients underwent lung transplantation in the medical school of Hannover due to non- cystic fibrosis bronchiectasis. Microbiology, lung function and clinical parameters were recorded. The results with respect to survival and lung function were compared to a matched control group of patients with chronic obstructive lung disease (COPD) without bronchiectasis after lung transplantation. Results: Procedures were one single and 33 double-lung transplants (3 re-do transplants). Mean age of transplantation was 44.2 years (range 21-65). The most common organism identified pre- and post- transplantion was pseudomonas aeruginosa, followed by Staphylococcus aureus and Stenotrophomonas maltophiliae. Chronic colonization was seen in 60.6% pre- and 44% post- transplantation. Forced expiratory volume in 1 second improved from 1.2ltr (29% predicted) to 2.8ltr (66% predicted) post transplantation. One year survival for all patients was 76%, and 5-year survival was 45.7%. Survival rates were similar to the control group of COPD patients without bronchiectasis. The CLAD- free survival was 56.2% in compare to COPD with 52.5% after 5 years. Conclusions: Overall- and CLAD-free survival after lung transplantation for non- cystic fibrosis was similar to that after transplantation for COPD without bronchiectasis. Pseudomonas aeruginosa is the most common pathogen in pre- and post-transplantation and leads to worse survival.

The disease caused by nontuberculous mycobacteria (NTM) forms a broad clinical spectrum from asymptomatic infection to fatal disseminated disease in humans. While many NTM patients have underlying pulmonary diseases, NTM symptoms are undifferentiated from symptoms of patients with chronic pulmonary structural diseases [1]. Not all CF patients with MAC detected in respiratory samples require anti-mycobacterial treatment

ENaC polymorphism p.W493R is associated with bronchiectasis but does not necessarily lead to aberrant ion conductance http://ow.ly/S5Mwj

To the Editor: Respiratory tract infections due to viral, bacterial or even fungal pathogens are common after lung transplantation [1]. Previous studies demonstrated increased hospitalisation rates and a greater risk of chronic lung allograft dysfunction in colonised patients with cystic fibrosis (CF) [2]. Positive effects of inhaled antibiotics have been demonstrated for pneumonia in non-transplant patients with improvements of lung function, hospitalisation rates and need for i.v. antibiotics [3, 4]. Inhaled colistin is known to provide high drug concentrations in sputum while low systemic concentrations occur and treatment is well tolerated [5]. Here, the impact of inhaled colistin, both in reducing bacterial load in previously colonised patients and as a preventive therapy in non-colonised CF patients, after lung transplantation, was studied in a retrospective single-centre study (Hanover Medical School, Hanover, Germany). CF patients who underwent lung transplantation between January 1, 2005 and May 1, 2011 were included and follow-up continued until June 6, 2011. Perioperative antibiotics were continued for 2 weeks after lung transplantation, consisting of combination therapy based on previous microbiological findings. A routine surveillance programme at 1, 3, 6, 9 and 12 months after transplantation included pulmonary function testing, blood gas analysis and bronchoscopy with bronchoalveolar …

Background Bronchoscopy represents an important diagnostic and therapeutic tool in the management of lung transplant (LTx) recipients. Outpatient bronchoscopy reduces health costs and may improve quality of life amongst these patients. This retrospective study assessed the safety and efficacy of outpatient bronchoscopy including trans-bronchial biopsy. Methods All outpatient bronchoscopies performed on lung transplant recipients between 1 August 2008 and 31 January 2011 were reviewed. Sample quality, duration and complications were recorded. Cost analysis was performed from local trust financial data. Results A total of 3,197 bronchoscopies were performed on 571 LTx recipients under topical anaesthesia. Fourteen percent of examinations required intravenous sedation. In 79.8% of examinations no complications were observed. Most complications were minor (17.9%) including cough (5.3%) and minimal bleeding after trans-bronchial biopsy (7.8%). Major complications (2.3%) were pneumothorax, severe bleeding and severe desaturation. No attributable deaths were recorded during the observation period. Quality of examination based on bronchoalveolar lavage recovery median (>50%) and biopsy results was adequate at 75% and 77.4%, respectively. Independent risk factors associated with complication were long-term oxygen therapy, sedation before examination, balloon dilatation and transbronchial biopsy. After excluding high-risk procedures annual savings per patient (2.2 bronchoscopies per year) were 2140€. Conclusions Outpatient bronchoscopy after LTx is safe. The low complication rate could be attributed to withholding of intravenous sedation. Furthermore, it reduces health community costs.

Background Accurate immunosuppression is of critical importance in preventing rejection, while avoiding toxicity following lung transplantation. The mainstay immunosuppressants are calcineurin inhibitors, which require regular monitoring due to interactions with other medications and diet. Adherence to immunosuppression and patient knowledge is vital and can be improved through patient education. Education using tablet-computers was investigated. Objective To compare tablet-PC education and conventional education in improving immunosuppression trough levels in target range 6 months after a single education. Secondary parameters were ratio of immunosuppression level measurements divided by per protocol recommended measurements, time and patient satisfaction regarding education. Design Single-centre, open labelled randomised controlled trial. Participants Patients >6 months after lung-transplantation with

Background Representative population-based data on the epidemiology of pulmonary non-tuberculous mycobacterial (PNTM) infections in Europe are limited. However, these data are needed in order to optimise patient care and to facilitate the allocation of healthcare resources. The aim of the present study was to investigate the current burden and the trends of PNTM infection-associated hospitalisations in Germany. Methods International Classification of Diseases, 10th revision (ICD-10) discharge diagnosis codes were extracted from the official nationwide diagnosis-related groups (DRG) hospital statistics in order to identify PNTM infection-associated hospitalisations (ICD-10 code A31.0) between 2005 and 2011. Poisson log-linear regression analysis was used to assess the significance of trends. Results Overall, 5,959 records with PNTM infection as any hospital discharge diagnosis were extracted from more than 125 million hospitalisations. The average annual age-adjusted rate was 0.91 hospitalisations per 100,000 population. Hospitalisation rates increased during the study period for both males and females, with the highest rate of 3.0 hospitalisations per 100,000 population among elderly men, but the most pronounced average increase of 6.4%/year among females, particularly those of young and middle age, and hospitalisations associated with cystic fibrosis. Overall, chronic obstructive pulmonary disease (COPD) was the most frequent PNTM infection-associated condition in 28.9% of hospitalisations and also showed a significant average annual increase of 4.8%. Conclusions The prevalence of PNTM infection-associated hospitalisations is steadily increasing in Germany. COPD is currently the most important associated condition. Our population-based study provides evidence of a changing epidemiology of PNTM infections and highlights emerging clinical implications.

BACKGROUND Advanced chronic lung allograft dysfunction limits survival after lung transplantation. We hypothesize that patients with chronic lung allograft dysfunction can be subdivided by exercise tolerance in two groups, and quality of life (QOL) and survival differ between the groups. METHODS A single-center, cross-sectional, partly prospective, study was performed in our outpatient clinic between July and November 2011, including all patients with a forced expiratory volume in 1 s

Lytic bone destruction is a hallmark of multiple myeloma (MM) and is because of an uncoupling of bone remodeling. Secretion of Dickkopf (DKK)-1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. In this study, the effect of different treatment regimens for MM on serum DKK-1 was evaluated and correlated with the response to treatment in 101 myeloma patients receiving bortezomib, thalidomide, lenalidomide, adriamycin and dexamethasone (AD) or high-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT). At baseline, myeloma patients had increased serum DKK-1 as compared with patients with MGUS (mean 3786 pg/mL vs. 1993 pg/mL). There was no difference between previously untreated MM patients and patients at relapse. A significant decrease of DKK-1 after therapy was seen in the following groups: Bortezomib (4059 pg/mL vs. 1862 pg/mL, P = 0.016), lenalidomide (11837 pg/mL vs. 4374 pg/mL, P = 0.039), AD (1668 pg/mL vs. 1241 pg/mL, P = 0.016), and AD + HDCT + ASCT (2446 pg/mL vs. 1082 pg/mL, P = 0.001). Thalidomide led to a non-significant decrease in DKK-1 (1705 pg/mL vs. 1269 pg/mL, P = 0.081). Within all groups, a significant decrease of DKK-1 was only seen in responders (i.e. patients achieving complete remission or partial remission), but not in non-responders. We show for the first time that serum DKK-1 levels decrease in myeloma patients responding to treatment, irrespective of the regimen chosen. These data suggest that myeloma cells are the main source of circulating DKK-1 protein and provide a framework for clinical trials on anti-DKK-1 treatment in MM.

Several prognostic markers, including parameters of tumor burden and cytogenetics, were adopted to identify high-risk patients in multiple myeloma (MM). Recently, the International Staging System (ISS), including beta2-microglobulin (beta2M) and albumin, was introduced for patients with symptomatic MM. As bone disease is a hallmark of MM, we investigated the prognostic impact of the bone resorption marker carboxy-terminal telopeptide of type-1 collagen (ICTP) in combination with ISS, beta2M, albumin, deletion of chromosome 13 and high-dose therapy (HDT) in 100 patients with newly diagnosed symptomatic MM. beta2M alone, albumin alone, ISS, HDT, del(13q14) and ICTP were significant prognostic factors for overall survival (OS). In a multivariate analysis, ICTP was the most powerful prognostic factor (log-rank P0.001, hazard ratio: ninefold increase). ICTP clearly separated two subgroups with a good and a worse prognosis within each of the three ISS stages (ISS I: P=0.027, ISS II: P=0.022, ISS III: P=0.013). Incorporation of ICTP in a combined ICTP-ISS score significantly (P0.001) separated four risk groups with a 5-year OS rate of 95, 64, 46 and 22%, [corrected] respectively. These data demonstrate for the first time that the inclusion of the collagen-I degradation product ICTP, as a biomarker of bone resorption, adds to the prognostic value of ISS.