Best Practices for the Management of Patients with Non-Tuberculous Mycobacterial Pulmonary Disease According to a German Nationwide Analysis of Expert Centers.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic inflammatory lung disease caused by infection with non-tuberculous mycobacteria (NTM). International guidelines provide evidence-based recommendations on appropriate diagnosis and treatment strategies, but there is a need for sharing day-to-day best practice between treatment centers to optimize patient care. This is particularly valuable for rare diseases like NTM-PD. In this cross-sectional analysis of NTM-PD management in Germany, medical and administrative staff from seven treatment centers were interviewed to identify best practice in the diagnosis, treatment, and ongoing management of patients with NTM-PD, including related hospital infrastructure and administration processes. A prioritization led to a collection of best practices for the management of patients with NTM-PD in Germany, which is presented here. Selected current best practices included performance of regular sputum tests for diagnosis, use of medical reports, and regular follow-up visits as well as increased interaction between physicians across different specialties. Future best practices that may be implemented to overcome current barriers comprised disease awareness activities, patient empowerment, and new approaches to enhance physician interaction. Challenges related to their implementation are also discussed and will help to raise disease awareness. The presented best practices may guide and optimize patient management in other centers.

Risk Factors for Nontuberculous Mycobacterial Pulmonary Disease: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression. RESEARCH QUESTION: What are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis? STUDY DESIGN AND METHODS: Electronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle-Ottawa Scale. Data analysis was conducted using the R-based "meta" package. Only studies that reported association outcomes for cases with NTM-PD compared with control participants (healthy populations or participants without NTM-PD) were considered for the meta-analysis. RESULTS: Of the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95% CI, 5.90-77.82], history of TB [OR, 12.69; 95% CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95% CI, 2.65-15.37], COPD [OR, 6.63; 95% CI, 4.57-9.63], and asthma [OR, 4.15; 95% CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), solid tumors (OR, 4.66; 95% CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95% CI, 2.72-11.26). INTERPRETATION: The greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD to drive prompt testing and appropriate initiation of therapy.

Global survey of physician testing practices for nontuberculous mycobacteria.

Background: Certain patients are at greater risk of developing nontuberculous mycobacterial pulmonary disease (NTM-PD), including those with lung conditions such as bronchiectasis. Testing for nontuberculous mycobacteria (NTM) in patients at risk is necessary to identify NTM-PD and start appropriate management. The aim of this survey was to evaluate current testing practices for NTM and identify testing triggers. Methods: Physicians (n=455) who see at least one patient with NTM-PD in a typical 12-month period and test for NTM as part of practice from Europe, USA, Canada, Australia, New Zealand and Japan participated in a 10-min anonymised survey on NTM testing practices. Results: Bronchiectasis, COPD and use of immunosuppressants were the factors most likely to prompt testing among physicians in this survey (90%, 64% and 64%, respectively), with radiological findings the most common reason leading to considering NTM testing in patients with bronchiectasis and COPD (62% and 74%, respectively). Macrolide monotherapy in patients with bronchiectasis and inhaled corticosteroid use in patients with COPD were not important triggers for testing (15% and 9% of physicians, respectively). Persistent cough and weight loss triggered testing in >75% of physicians. Testing triggers were markedly different for physicians in Japan, with cystic fibrosis prompting testing in fewer physicians compared with other regions. Conclusions: Testing for NTM is influenced by underlying disease, clinical symptoms or radiological changes, but clinical practice varies considerably. Adherence to guideline recommendations for NTM testing is limited in certain patient subgroups and varies across regions. Clear recommendations on NTM testing are needed.

Eliciting Patient Insights on the Burden of Nontuberculous Mycobacterial Lung Disease (NTM-LD) and Healthcare Gaps in Germany Through Qualitative Semi-structured Interviews.

INTRODUCTION: Nontuberculous mycobacterial lung disease (NTM-LD) is a rare but growing health concern, particularly affecting vulnerable patients with chronic lung conditions. Understanding the patients' perspective on their disease and treatment expectations can help to identify healthcare gaps and improve overall patient care. Therefore, the main objective of the survey study was the evaluation of patient insights on the burden of the disease and healthcare gaps. METHODS: The study used an online survey as a pre-screener to facilitate recruitment followed by semi-structured qualitative interviews. The interviews were conducted by phone from April 2019 to February 2020 in German language. Only patients with a self-reported confirmed NTM-LD diagnosis, managed and insured in Germany were included in this study. RESULTS: In total, 20 semi-structured qualitative interviews were conducted. Most (85%) patients had at least one coexisting pulmonary condition with cystic fibrosis (CF, n = 9) being most common. Chronic cough, fatigue, and dyspnea were the most reported symptoms. Of all the symptoms reported, fatigue was perceived as the most burdensome and 85% of patients felt limited in their daily life. It took a median of 5 months for patients to receive an accurate diagnosis of NTM-LD and that time was doubled when excluding patients with CF (range 0-480 months). Ninety percent of interviewed patients (n = 18) received drug treatment for NTM-LD and most of them (n = 17) reported having experienced side effects from their treatment. Patients' expressed a particular need for more comprehensive and reliable patient-friendly information on NTM-LD and a better awareness of physicians as well. CONCLUSIONS: NTM-LD can considerably impair the lives of patients and their families and/or caregivers. A multidisciplinary approach and establishment of more widespread regional expert centers for NTM-LD management in Germany with well-structured referral and communication pathways accompanied by peer-to-peer support of patient advocacy groups are urgently needed.

Meeting the challenges of NTM-PD from the perspective of the organism and the disease process: innovations in drug development and delivery.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) poses a substantial patient, healthcare, and economic burden. Managing NTM-PD remains challenging, and factors contributing to this include morphological, species, and patient characteristics as well as the treatment itself. This narrative review focusses on the challenges of NTM-PD from the perspective of the organism and the disease process. Morphological characteristics of non-tuberculous mycobacteria (NTM), antimicrobial resistance mechanisms, and an ability to evade host defences reduce NTM susceptibility to many antibiotics. Resistance to antibiotics, particularly macrolides, is of concern, and is associated with high mortality rates in patients with NTM-PD. New therapies are desperately needed to overcome these hurdles and improve treatment outcomes in NTM-PD. Amikacin liposome inhalation suspension (ALIS) is the first therapy specifically developed to treat refractory NTM-PD caused by Mycobacterium avium complex (MAC) and is approved in the US, EU and Japan. It provides targeted delivery to the lung and effective penetration of macrophages and biofilms and has demonstrated efficacy in treating refractory MAC pulmonary disease (MAC-PD) in the Phase III CONVERT study. Several other therapies are currently being developed including vaccination, bacteriophage therapy, and optimising host defences. Newly developed antibiotics have shown potential activity against NTM-PD and include benzimidazole, delamanid, and pretomanid. Antibiotics commonly used to treat other infections have also been repurposed for NTM-PD, including clofazimine and bedaquiline. Data from larger-scale studies are needed to determine the potential of many of these therapies for treating NTM-PD.

Natural Language Processing and Graph Theory: Making Sense of Imaging Records in a Novel Representation Frame.

BACKGROUND: A concise visualization framework of related reports would increase readability and improve patient management. To this end, temporal referrals to prior comparative exams are an essential connection to previous exams in written reports. Due to unstructured narrative texts' variable structure and content, their extraction is hampered by poor computer readability. Natural language processing (NLP) permits the extraction of structured information from unstructured texts automatically and can serve as an essential input for such a novel visualization framework. OBJECTIVE: This study proposes and evaluates an NLP-based algorithm capable of extracting the temporal referrals in written radiology reports, applies it to all the radiology reports generated for 10 years, introduces a graphical representation of imaging reports, and investigates its benefits for clinical and research purposes. METHODS: In this single-center, university hospital, retrospective study, we developed a convolutional neural network capable of extracting the date of referrals from imaging reports. The model's performance was assessed by calculating precision, recall, and F1-score using an independent test set of 149 reports. Next, the algorithm was applied to our department's radiology reports generated from 2011 to 2021. Finally, the reports and their metadata were represented in a modulable graph. RESULTS: For extracting the date of referrals, the named-entity recognition (NER) model had a high precision of 0.93, a recall of 0.95, and an F1-score of 0.94. A total of 1,684,635 reports were included in the analysis. Temporal reference was mentioned in 53.3% (656,852/1,684,635), explicitly stated as not available in 21.0% (258,386/1,684,635), and omitted in 25.7% (317,059/1,684,635) of the reports. Imaging records can be visualized in a directed and modulable graph, in which the referring links represent the connecting arrows. CONCLUSIONS: Automatically extracting the date of referrals from unstructured radiology reports using deep learning NLP algorithms is feasible. Graphs refined the selection of distinct pathology pathways, facilitated the revelation of missing comparisons, and enabled the query of specific referring exam sequences. Further work is needed to evaluate its benefits in clinics, research, and resource planning.

Non-tuberculous mycobacterial pulmonary diseases in France: an 8 years nationwide study.

BACKGROUND: The objective of the study was to describe the epidemiology, management and cost of non-tuberculous mycobacteria pulmonary disease (NTM-PD) in France. METHODS: A retrospective analysis was performed using the SNDS ("Système national des données de santé") database over 2010-2017. Patients with NTM-PD were identified based on the ICD10 codes during hospitalizations and/or specific antibiotics treatment regimens. The study population was matched (age, sex and region) to a control group (1:3) without NTM-PD. RESULTS: 5628 patients with NTM-PD (men: 52.9%, mean age = 60.9 years) were identified over the study period and 1433 (25.5%) were treated with antibiotics. The proportion of patients still receiving treatment at 6 and 12 months was 40% and 22%, respectively. The prevalence of NTM-PD was estimated at 5.92 per 100,000 inhabitants and the incidence rate of NTM-PD remained stable over time between 1.025/100,000 in 2010 and 1.096/100,000 in 2017. Patients with NTM-PD had more co-morbidities compared to controls: corticoids (57.3% vs. 33.8%), chronic lower respiratory disease (34.4% vs. 2.7%), other infectious pneumonia (24.4% vs. 1.4%), malnutrition (based on hospitalization with the ICD-10 code reported during a hospital stay as a main or secondary diagnosis) (22.0% vs. 2.0%), history of tuberculosis (14.1% vs. 0.1%), HIV (8.7% vs. 0.2%), lung cancer and lung graft (5.7% vs. 0.4%), cystic fibrosis (3.2% vs. 0.0%), gastro-esophageal reflux disease (2.9% vs. 0.9%) and bone marrow transplant (1.3% vs. 0.0%) (p < 0.0001). The mean Charlson comorbidity index score was 1.6 (vs. 0.2 for controls; p < 0.0001). NTM-PD was independently associated with an increased mortality rate with a hazard ratio of 2.8 (95% CI: 2.53; 3.11). Mortality was lower for patients treated with antibiotics compared to untreated patients (HR = 0.772 (95% CI [0.628; 0.949]). Annual total expenses the year following the infection in a societal perspective were € 24,083 (SD: 29,358) in NTM-PD subjects vs. € 3402 (SD: 8575) in controls (p < 0.0001). Main driver of the total expense for NTM-PD patients was hospital expense (> 50% of the total expense). CONCLUSION: Patients with NTM-PD in France were shown to have many comorbidities, their mortality risk is high and mainly driven by NTM-PD, and their management costly. Only a minority of patients got treated with antibiotics and of those patients treated, many stopped their therapy prematurely. These results underline the high burden associated with NTM-PD and the need for improvement of NTM-PD management in France.

Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex - disease burden, unmet needs, and advances in treatment developments.

INTRODUCTION: Nontuberculous mycobacterial (NTM) lung disease (LD) is the most common clinical manifestation of NTM infection and is a growing health concern. Up to 85% of NTM-LD cases are caused by Mycobacterium avium complex (MAC). Increased awareness of NTM-LD caused by MAC is needed as patients with this disease experience substantial burden and unmet treatment needs. AREAS COVERED: This review provides clinicians and regulatory and healthcare decision makers an overview of the clinical, economic, and humanistic burden of NTM-LD and the unmet treatment needs faced by patients and clinicians. The review focuses on NTM-LD caused by MAC. A summary of the 2020 NTM guidelines specifically for MAC-LD and an overview of novel treatment options, including amikacin liposome inhalation suspension (ALIS) as the first approved therapy for refractory MAC-LD, and investigational drugs in testing phase are provided. EXPERT OPINION: Key advancements in NTM-LD management include recent updates to clinical practice guidelines, approval of ALIS for the treatment of refractory MAC-LD, and ongoing clinical trials of investigational treatments. Yet opportunities still exist to improve patient outcomes, including development of better screening tools, such as reliable and responsive biomarkers to help identify high-risk patients, and addressing unmet treatment needs.

Automated Detection of Pancreatic Cystic Lesions on CT Using Deep Learning.

Pancreatic cystic lesions (PCL) are a frequent and underreported incidental finding on CT scans and can transform into neoplasms with devastating consequences. We developed and evaluated an algorithm based on a two-step nnU-Net architecture for automated detection of PCL on CTs. A total of 543 cysts on 221 abdominal CTs were manually segmented in 3D by a radiology resident in consensus with a board-certified radiologist specialized in abdominal radiology. This information was used to train a two-step nnU-Net for detection with the performance assessed depending on lesions' volume and location in comparison to three human readers of varying experience. Mean sensitivity was 78.8 ± 0.1%. The sensitivity was highest for large lesions with 87.8% for cysts ≥220 mm3 and for lesions in the distal pancreas with up to 96.2%. The number of false-positive detections for cysts ≥220 mm3 was 0.1 per case. The algorithm's performance was comparable to human readers. To conclude, automated detection of PCL on CTs is feasible. The proposed model could serve radiologists as a second reading tool. All imaging data and code used in this study are freely available online.

Psychometric Validation of the EQ-5D-3L in Patients with Nontuberculous Mycobacterial (NTM) Lung Disease Caused by Mycobacterium avium Complex (MAC).

PURPOSE: This analysis evaluated the psychometric properties of the EQ-5D-3L among patients with Mycobacterium avium complex lung disease (MAC-LD). METHODS: Data from the Phase III CONVERT trial were analyzed. Study measures including the EQ-5D-3L, St. George's Respiratory Questionnaire (SGRQ), the 6-minute walk test (6MWT), and percent predicted forced expiratory volume in 1 second (ppFEV1) were collected at baseline, month 3 (M3), month 4 (M4; only 6MWT), and month 6 (M6). Item characteristics and validity were evaluated at baseline. Test-retest reliability was assessed using intraclass correlation coefficients (ICC) and a weighted kappa statistic among a subgroup of stable patients. Validity was tested by evaluating correlations of the EQ-5D-3L index/visual analogue scale (VAS) scores with SGRQ and 6MWT and comparing mean index/VAS scores across known groups defined using 6MWT and ppFEV1. Responsiveness of the EQ-5D-3L was assessed using 6MWT, SGRQ, ppFEV1, and culture conversion as anchors. RESULTS: The index score was subject to ceiling effects, with 32.6% of patients reporting perfect health at baseline. ICCs for the index (0.80) and VAS (0.85) scores and weighted kappas for the domains (0.5-0.72) indicated adequate test-retest reliability. Correlations between the index/VAS scores and related domains of the SGRQ and 6MWT were as hypothesized (0.31-0.62), and the mean index/VAS scores were significantly different between the 6MWT and ppFEV1 known groups (p<0.05), supporting the validity of the EQ-5D-3L. No evidence was found supporting the responsiveness of the EQ-5D-3L to changes in any of the anchors. CONCLUSION: EQ-5D-3L exhibited evidence of validity and reliability but poor responsiveness to clinically meaningful changes in patients with MAC-LD.

Predictive modeling of nontuberculous mycobacterial pulmonary disease epidemiology using German health claims data.

OBJECTIVES: Administrative claims data are prone to underestimate the burden of non-tuberculous mycobacterial pulmonary disease (NTM-PD). METHODS: We developed machine learning-based algorithms using historical claims data from cases with NTM-PD to predict patients with a high probability of having previously undiagnosed NTM-PD and to assess actual prevalence and incidence. Adults with incident NTM-PD were classified from a representative 5% sample of the German population covered by statutory health insurance during 2011-2016 by the International Classification of Diseases, 10th revision code A31.0. Pre-diagnosis characteristics (patient demographics, comorbidities, diagnostic and therapeutic procedures, and medications) were extracted and compared to that of a control group without NTM-PD to identify risk factors. RESULTS: Applying a random forest model (area under the curve 0.847; total error 19.4%) and a risk threshold of >99%, prevalence and incidence rates in 2016 increased 5-fold and 9-fold to 19 and 15 cases/100,000 population, respectively, for both coded and non-coded vs. coded cases alone. CONCLUSIONS: The use of a machine learning-based algorithm applied to German statutory health insurance claims data predicted a considerable number of previously unreported NTM-PD cases with high probabilty.

Identification of potentially undiagnosed patients with nontuberculous mycobacterial lung disease using machine learning applied to primary care data in the UK.

Nontuberculous mycobacterial lung disease (NTMLD) is a rare lung disease often missed due to a low index of suspicion and unspecific clinical presentation. This retrospective study was designed to characterise the prediagnosis features of NTMLD patients in primary care and to assess the feasibility of using machine learning to identify undiagnosed NTMLD patients.IQVIA Medical Research Data (incorporating THIN, a Cegedim Database), a UK electronic medical records primary care database was used. NTMLD patients were identified between 2003 and 2017 by diagnosis in primary or secondary care or record of NTMLD treatment regimen. Risk factors and treatments were extracted in the prediagnosis period, guided by literature and expert clinical opinion. The control population was enriched to have at least one of these features.741 NTMLD and 112 784 control patients were selected. Annual prevalence rates of NTMLD from 2006 to 2016 increased from 2.7 to 5.1 per 100 000. The most common pre-existing diagnoses and treatments for NTMLD patients were COPD and asthma and penicillin, macrolides and inhaled corticosteroids. Compared to random testing, machine learning improved detection of patients with NTMLD by almost a thousand-fold with AUC of 0.94. The total prevalence of diagnosed and undiagnosed cases of NTMLD in 2016 was estimated to range between 9 and 16 per 100 000.This study supports the feasibility of machine learning applied to primary care data to screen for undiagnosed NTMLD patients, with results indicating that there may be a substantial number of undiagnosed cases of NTMLD in the UK.

Non-tuberculous mycobacterial lung disease in patients with bronchiectasis: perceived risk, severity and guideline adherence in a European physician survey.

BACKGROUND: Patients with bronchiectasis are at increased risk of developing non-tuberculous mycobacteria lung disease (NTM-LD), and published guidelines recommend regular testing for NTM infection in this patient population. OBJECTIVE: This study aimed to survey physicians managing patients with bronchiectasis to understand the perceived risk of NTM to their patients, perceived disease severity and frequency of testing for NTM. METHODS: The study comprised an online survey of hospital-based physicians in the UK, Germany, Italy, France and the Netherlands. The target group were hospital-based physicians who had managed at least 10 adult patients with bronchiectasis over the preceding 12 months. RESULTS: In total, 280 physicians completed the survey. Most (87%) thought their patients to be at particular risk of NTM, although it was perceived as a moderate risk versus other respiratory pathogens. Most perceived NTM-LD to impact patient morbidity (84%), and 61% indicated that NTM-LD significantly impacted mortality. 68% of all respondents did not test for NTM prior to initiating macrolide monotherapy, despite guidelines recommending testing. The perceived risk of and screening for NTM varied among countries. CONCLUSIONS: The study demonstrates that physicians understand the risk of NTM-LD and associated morbidity in patients with bronchiectasis; however, a minority do not perceive that NTM-LD significantly affects mortality. Greater awareness of the need to test for NTM infection before initiating macrolide monotherapy for bronchiectasis is essential due to potential emergence of drug-resistant NTM.

A burden of illness study for neuropathic pain in Europe.

PURPOSE: Neuropathic pain (NP) is often severe and represents a major humanistic and economic burden. This study aimed at providing insight on this burden across France, Germany, Italy, Spain, and the UK, considering direct and indirect costs, productivity loss, and humanistic impact on patients and their families. METHODS: Physician questionnaires provided data on patients presenting with NP covering demographics, sick leave and retirement, number of consultations, drug treatments, and surgical procedures. Patients provided further demographic and disease-related data and completed the Work Productivity and Activity Impairment (WPAI), the EuroQol 5-Dimension (EQ-5D), and the Brief Pain Inventory (BPI) questionnaires. All health-related direct unitary costs were collected from relevant country-specific sources and adjusted to 2012 prices (€) where necessary. A subgroup analysis of costs based on diabetic peripheral neuropathy (n=894), fibromyalgia (n=300), and low back pain (n=963) was performed. FINDINGS: About 413 physicians completed a total of 3,956 patient records forms. Total annual direct health-care costs per patient ranged from €1,939 (Italy) to €3,131 (Spain). Annual professional caregiver costs ranged from €393 (France) to €1,242 (UK), but this only represented a small proportion of total care because much care is provided by family or friends. Sick leave costs ranged from €5,492 (UK) to €7,098 (France), with 10%-32% patients prevented from working at some point by NP. Total cost (including direct and indirect costs) of NP per patient was €10,313 in France (69% of the total cost), €14,446 in Germany (78%), €9,305 in Italy (69%), €10,597 in Spain (67%), and €9,685 in the UK (57%). Indirect costs (ie, sick leave) constituted the majority of costs in all five countries: €7,098 in France, €11,232 in Germany, €6,382 in Italy, €7,066 in Spain, and €5,492 in the UK. In the subgroup analysis, total annual direct costs per patient were highest for neuropathic back pain and radiculopathy, and lowest for fibromyalgia. Mean WPAI score range was 34.4-56.1; BPI interference was 4.1-4.8; and EQ-5D was 0.57-0.74. The results suggest that a significant proportion of the patient's work time in the previous week was affected by NP, and these are relatively high compared with other diseases such as diabetes, respiratory conditions, and arthritis. IMPLICATIONS: Despite differences in practice between countries, these findings suggest a high opportunity cost for society in terms of lost work and productivity due to NP. The wider costs appear significantly higher to patients, carers/families, and society as a whole than to the health system alone.

Statistical analysis of the influence of major tributaries to the eco-chemical status of the Danube River.

We have assembled and assessed the statistical procedure which is capable to objectively explore influence of the Danube's major tributaries (the Rivers Tisa, Sava, and Velika Morava) to its eco-chemical status. Procedure contains several tests for measurement of central tendencies: one-way analysis of variance (ANOVA), repeated measures ANOVA, and nonparametric Kruskal-Wallis and Mann-Whitney tests. Various nuisance factors, (outliers, departures from normality, seasonality, and heteroscedasticity) which are present in large data bases, affect the objectivity of central tendency tests; therefore, it was important not only to estimate their robustness, but also to apply proper procedures for detection of the nuisance factors (Grubbs', generalized ESD-extreme Studentized deviate, Kolmogorov-Smirnov, Shapiro-Wilk, turning point, Wald-Wolfowitz runs, Kendall rank, and Levene's tests) and to mitigate their influence (outlier exclusion, Box-Cox, and logarithmic transformations). The analysis of selected eco-chemical parameters: biological oxygen demand-5, chemical oxygen demand, UV extinction at 254 nm, dissolved oxygen, oxygen saturation, total dissolved solids, electrical conductivity, suspended matter, total phosphorus, phosphates, nitrates, ammonia, pH, total alkalinity, m-2p alkalinity, CO2, and temperature, was performed for 15 years period. The Tisa was the most polluted tributary, but its pollution load was not substantial enough to exceed the Danube self-purification potential. The City of Belgrade was also identified as serious pollution source. Assessment of assembled statistical procedure, which was based on the real environmental data, indicates that proposed tests are sufficiently robust to the observed level of nuisance factors with the exception of pronounced seasonality.

Health economic evidence of 5% lidocaine medicated plaster in post-herpetic neuralgia.

BACKGROUND: Post-herpetic neuralgia (PHN) is the most common and most debilitating complication of herpes zoster, and involves considerable associated costs. OBJECTIVE: This paper presents results from nine health economic studies undertaken in eight European countries that compared lidocaine medicated plaster with gabapentin and/or pregabalin in PHN. It aims to support the increasing need for published cost-effectiveness data for health care decision-making processes in Europe. METHODS: All studies were based on a similar core Markov model with data derived from clinical trials, local Delphi panels, and official national price and tariff lists. The main outcome measure was cost per quality-adjusted life year gained; time without pain or intolerable adverse events was also included as a secondary outcome measure. All studies focused on an elderly population of patients with PHN who had insufficient pain relief with standard analgesics and could not tolerate or had contraindications to tricyclic antidepressants. RESULTS: Despite considerable differences in many of the variables used, the results showed remarkable similarity and suggested that use of lidocaine medicated plaster offered cost-savings in many of the countries studied, where it proved a highly cost-effective alternative to both gabapentin and pregabalin. CONCLUSION: Lidocaine medicated plaster is a cost-effective alternative to gabapentin and pregabalin in the treatment of PHN. These savings are largely the result of the superior safety profile of the lidocaine medicated plaster.

Validity and responsiveness of EuroQol-5 dimension (EQ-5D) versus Short Form-6 dimension (SF-6D) questionnaire in chronic pain.

BACKGROUND: Assessments of health-related quality of life and particularly utility values are important components of health economic analyses. Several instruments have been developed to measure utilities. However no consensus has emerged regarding the most appropriate instrument within a therapeutic area such as chronic pain. The study compared two instruments - EQ-5D and SF-6D - for their performance and validity in patients with chronic pain. METHODS: Pooled data from three randomised, controlled clinical trials with two active treatment groups were used. The included patients suffered from osteoarthritis knee pain or low back pain. Differences between the utility measures were compared in terms of mean values at baseline and endpoint, Bland-Altman analysis, correlation between the dimensions, construct validity, and responsiveness. RESULTS: The analysis included 1977 patients, most with severe pain on the Numeric Rating Scale. The EQ-5D showed a greater mean change from baseline to endpoint compared with the SF-6D (0.43 to 0.58 versus 0.59 to 0.64). Bland-Altman analysis suggested the difference between two measures depended on the health status of a patient. Spearmans rank correlation showed moderate correlation between EQ-5D and SF-6D dimensions. Construct validity showed both instruments could differentiate between patient subgroups with different severities of adverse events and analgesic efficacies but larger differences were detected with the EQ-5D. Similarly, when anchoring the measures to a disease-specific questionnaire - Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) - both questionnaires could differentiate between WOMAC severity levels but the EQ-5D showed greater differences. Responsiveness was also higher with the EQ-5D and for the subgroups in which improvements in health status were expected or when WOMAC severity level was reduced the improvements with EQ-5D were higher than with SF-6D. CONCLUSIONS: This analysis showed that the mean EQ-5D scores were lower than mean SF-6D scores in patients with chronic pain. EQ-5D seemed to have higher construct validity and responsiveness in these patients.

Cost-effectiveness of tapentadol in severe chronic pain in Spain: a cost analysis of data from RCTs.

BACKGROUND: Chronic pain is known to be a significant and common health problem. Tapentadol, a recently developed centrally active, oral analgesic agent is used to treat adults with severe chronic pain that can be adequately managed only with opioid analgesics. Tapentadol has been reported to provide an improved adverse-events (AE) profile compared with other potent opioid analgesics at similar levels of analgesia. OBJECTIVES: The aim of this study was to compare the cost-effectiveness of tapentadol to that of opioids commonly used as first-line treatment of severe, chronic, nonmalignant pain from the perspective of the health care payer in Spain. METHODS: A Markov state-transition model was developed to compare the cost-effectiveness of first-line treatment with tapentadol to that of oxycodone, morphine, and transdermal fentanyl (TDF) over a 1-year time horizon. Four health states were defined: (1) treatment discontinuation due to a severe AE; (2) treatment discontinuation due to a lack of efficacy; (3) occurrence of an AE that required medical treatment; and (4) no discontinuation and no AE. If a patient discontinued a treatment, he or she was switched to an alternative, second-line opioid. Data regarding efficacy, tolerability, and utility values (EQ-5D) were derived from randomized clinical trials. Clinical experts estimated the rates of switching to other opioids and the health care resource utilization associated with the treatment of severe chronic pain. Unit costs were derived from public price lists/tariff works and were calculated from the perspective of the National Spanish Health System. The robustness of the model results was tested in extensive sensitivity analyses in which event probabilities, costs, utilities, and treatment-switching rates were altered. RESULTS: Data from 3 studies (1981 patients) were included in the model. Overall, the model predicted that initiating first-line treatment with tapentadol in patients with severe, chronic, nonmalignant pain was associated with lower costs and greater efficacy versus first-line treatment with oxycodone. Compared with morphine and TDF, tapentadol yielded incremental cost-effectiveness ratios of €2656 and €2069 per quality-adjusted life-year gained, respectively. On extensive 1-way and scenario analyses, findings on the cost-effectiveness of tapentadol were consistent. The probability that tapentadol would be cost-effective compared with each comparator at the willingness-to-pay threshold of €20,000 to €30,000/QALY gained exceeded 90%. CONCLUSIONS: Based on the findings from the present model, tapentadol is likely to be a cost-effective first-line treatment in patients with severe, chronic, nonmalignant pain in Spain according to the commonly accepted willingness-to-pay thresholds. Compared with morphine and TDF, the incremental cost-effectiveness ratios were low; compared with oxycodone, tapentadol dominated, showing better quality-of-life outcomes at lower costs.

Cost-effectiveness of tapentadol prolonged release compared with oxycodone controlled release in the UK in patients with severe non-malignant chronic pain who failed 1st line treatment with morphine.

OBJECTIVES: The aim of this analysis was to assess the cost-effectiveness of tapentadol PR (prolonged release) compared with oxycodone CR (controlled release) in severe non-malignant chronic pain patients in whom controlled release morphine was ineffective or not tolerated. METHODS: A Markov model was developed to assess costs and benefits over a 1-year time horizon from the National Health Service perspective in the UK. Patients could either continue on 2nd line therapy or switch to 3rd line opioid due to lack of efficacy or poor tolerability. Patients failing also 3rd line therapy entered the final absorbing health state (4th line). Data on tolerability, efficacy, and utilities for tapentadol and oxycodone were obtained from the three comparative phase III clinical trials. Costs of resource consumption associated with opioid treatment were derived from a retrospective database analysis of anonymized patient records. RESULTS: The model results predicted that initiating 2nd line therapy with tapentadol leads to higher effectiveness and lower costs vs oxycodone. For the overall population included in the clinical trials, mean annual costs per patient when treated with tapentadol and oxycodone were £3543 and £3656, respectively. Treatment with tapentadol, while cheaper than oxycodone, was more effective (0.6371 vs 0.6237 quality-adjusted life years (QALYs) for tapentadol and oxycodone, respectively), meaning that tapentadol dominated oxycodone. For the sub-group of opioid-experienced patients with severe pain at baseline the ranking in terms of costs and QALYs remained unchanged. Extensive sensitivity analyses showed that conclusions about the cost-effectiveness are consistent. CONCLUSIONS: The cost-effectiveness study suggested that initiating 2nd line treatment in patients with severe non-malignant chronic pain in the UK with tapentadol instead of oxycodone improves patients' quality-of-life and is less costly. Key limitations when interpreting the results are the use of different sources to populate the model and restricted generalizability due to data extrapolation.