Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023. RESULTS: 24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries. CONCLUSION: Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe.

Tuberculosis incidence in foreign-born people residing in European countries in 2020.

BackgroundEuropean-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.AimWe aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.MethodsThe Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.ResultsData on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.ConclusionsCountry of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

Health Outcomes with Curative and Palliative Therapies in Real World: Role of the Quality of Life Summary Score in Thoracic Oncology Patients.

BACKGROUND: For patients receiving therapy with curative or palliative intent for a thoracic malignancy, prediction of quality of life (QOL), once therapy starts, remains challenging. The role of health assessments by the patient instead of the doctor herein remains ill-defined. AIMS: To assess the evolution of QOL in patients with thoracic malignancies treated with curative and palliative intent, respectively. To identify factors that determine QOL one year after the start of cancer therapy. To identify factors that affect survival. METHODS: We prospectively included consecutive patients with a thoracic malignancy who were starting anti-cancer therapy and measured QOL with QLQ-C30 before the start of therapy, and thereafter at regular intervals for up to 12 months. A multivariate regression analysis of the global health score (GHS) and QOL summary scores (QSS) one year after the start of therapy was conducted. A proportional hazards Cox regression was conducted to investigate the effects of case-mix variables on survival. RESULTS: Of 587 new patients, 375 started different forms of therapy. Most had non-small cell lung cancer (n = 298), 35 had small cell lung cancer, and 42 had other thoracic malignancies or were diagnosed on imaging alone. There were 203 who went for a curative intent and 172 for a palliative intent strategy. The WHO score of 0-1 was more prevalent in the former group (p = 0.02), and comorbidities were equally distributed. At baseline, all QOL indices were better in the curative group (p < 0.05). The curative group was characterized by a significant worsening of GHS and QSS (p < 0.05). The palliative group was characterized by an improvement in GHS and emotional health (p < 0.05), while other dimensions of functioning remained stable. GHS at 12 months was estimated in a multivariate linear regression model (R2 = 0.23-p < 0.001) based on baseline GHS, QSS, and comorbidity burden. QSS at 12 months was estimated (R2 = 0.31-p < 0.001) by baseline QSS and therapeutic intent strategy (curative vs. palliative). The prognostic factors for overall survival were the type of therapy (curative vs. palliative intent, p < 0.001) and occurrence of early toxicity-related hospitalization (grade ≥ 3, p = 0.001). CONCLUSION: Patients with thoracic malignancies treated with curative intent experience a worsening of their QOL in the first year, whereas those receiving palliative anti-cancer therapy do not. QOL one year after the start of therapy depends on the baseline health scores as determined by the patient, comorbidity burden, and therapeutic strategy. Survival depends on therapeutic strategy and early hospitalization due to toxicity.

Differential expression of maturation and activation markers on NK cells in patients with active and latent tuberculosis.

NK cells were recently suggested to be important for the initial control of M. tuberculosis infection. The phenotypes of the 3 main NK blood subsets, CD56bright , CD56dim , and CD56neg cells, were characterized by flow cytometry in a cohort of 81 prospectively enrolled subjects (21 untreated patients with active tuberculosis -aTB-, 35 latently TB infected -LTBI- subjects, and 25 non-infected controls), using 9 different mAbs added to whole blood. Compared to LTBI subjects, patients with aTB had lower proportions of total NK cells, lower proportions and numbers of CD56neg cells expressing early maturation markers (CD161, NKp30, NKp46), but higher density of NKp30 and NKp46 expression on both CD56neg and CD56dim subsets, associated with higher expression of granzymes A/B. They also had higher proportions of activated CD69pos cells within all 3 NK cell subsets and, the percentage of CD69pos CD56dim cells among CD69pos and/or NKG2Cpos NK cells was identified as a potential biomarker to discriminate aTB from LTBI. LTBI subjects were in contrast characterized by higher expression of late maturation markers (CD57, KIR molecules) on the CD56neg subset, by higher proportions of NKG2Cpos KIRpos CD56dim NK cells, and by higher in vitro IFN-γ production than patients with aTB. Thus, the in-depth phenotypic characterization of blood NK cell subsets provides new insights on possible functional modifications and the potential role of NK cells in the control of M. tuberculosis infection in humans.

Severe pulmonary infections complicating nivolumab treatment for lung cancer: a report of two cases.

BACKGROUND: Immunotherapy represents a recent milestone in the treatment of lung cancer, particularly with the rapidly expanding development of monoclonal antibodies targeting checkpoint inhibitors in the programmed cell death-1 (PD-1) pathway, such as nivolumab and pembrolizumab. Classical auto-immune side effects of these treatments, often called immune-related adverse events (irAEs), can affect multiple organs, including the lungs in which potentially life-threatening pneumonitis may require rapid treatment with high doses of corticosteroids. Nevertheless, the occurrence of severe infections in cancer patients treated with nivolumab, outside the context of immunosuppressive therapy, is a complication that has rarely been reported in the literature. CLINICAL CASES: We report two cases of severe pulmonary infection with unusual microbes, Mycobacterium tuberculosis and Aspergillus fumigatus, in patients treated with nivolumab for non-small cell lung cancer. CONCLUSION: Ruling out pulmonary infections may require extensive investigation, as these may have an atypical presentation due to immunomodulation. Furthermore, treating the patient with corticosteroids for immune-related pneumonia could lead to a fatal outcome in this context. This report highlights the importance of excluding the presence of opportunistic infections and tuberculosis before considering immune-related pulmonary toxicity with or without a history of prior corticosteroid use. These cases also emphasize the potential value of tuberculosis screening in patients treated with PD-1 checkpoint inhibitors.

Clinical Management of Multidrug-Resistant Tuberculosis in 16 European Countries.

RATIONALE: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less, and cure rates are even lower. OBJECTIVES: To document the management and treatment outcome in patients with MDR-TB in Europe. METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by World Health Organization and alternative simplified definitions by the Tuberculosis Network European Trialsgroup (TBNET). MEASUREMENTS AND MAIN RESULTS: A total of 380 patients with MDR-TB were recruited and followed up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median, 111 vs. 28 d), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying World Health Organization outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include 1 year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%), and high-incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6%). CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared with individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by World Health Organization outcome definitions.

Pregnancy in patients with tuberculosis: a TBNET cross-sectional survey.

BACKGROUND: Objectives: To determine whether the incidence of tuberculosis with pregnancy is more common than would be expected from the crude birth rate; to see whether there is significant delay in the diagnosis of tuberculosis during pregnancy. METHOD: Design: A cross-sectional survey. SETTING: 13 tuberculosis clinics within different European countries and the USA. POPULATION/SAMPLE: All patients with tuberculosis seen at these clinics for a period > 1 year. INSTRUMENT: Questionnaire survey based on continuous data collection. MAIN OUTCOME MEASURES: number and proportion of women with tuberculosis who were pregnant; timing of diagnosis in relation to pregnancy, including those who were pregnant or delivered in the 3 months prior to the diagnosis of TB and those who developed TB within 3 months after delivery. RESULTS: Pregnancy occurred in 224 (1.5 %) of 15,217 TB patients and followed the expected rate predicted from the crude birth rate for the clinic populations. TB was diagnosed more commonly in the 3 months after delivery (n = 103) than during pregnancy (n = 68; χ 2 = 25.1, P < 0.001). CONCLUSIONS: TB is diagnosed more frequently after delivery, despite variations in local TB incidence and healthcare systems.

The Feasibility of Tracheal Oxygen Supplementation during Flexible Bronchoscopy.

BACKGROUND: Hypoxemia is a frequent adverse event occurring during flexible bronchoscopy and is usually prevented by close monitoring and, if needed, oxygen supplementation by nasal cannula. OBJECTIVE: We aim to demonstrate that tracheal oxygen supplementation during flexible bronchoscopy is a feasible, safe and effective method to restore oxygen saturation levels after oxygen desaturation. METHODS: In a first phase, we compare oxygen supplementation by the tracheal or nasal route in a single blinded cross-over design in healthy volunteers. In a second phase, we study patients referred for diagnostic flexible bronchoscopy, who desaturate despite oxygen supplementation by nasal cannula, in order to assess the ability to correct hypoxemia through tracheal oxygen supplementation. RESULTS: In the first phase, the mean capillary partial pressure of oxygen was 181 mm Hg when oxygen at a flow rate of 4 liters/min was administered by the tracheal route, compared to 125 mm Hg by the nasal route (p < 0.001). The capillary partial pressure of carbon dioxide was not significantly different. During 950 bronchoscopic procedures in the second phase of the trial, 30 patients desaturated below 90% despite oxygen supplementation by nasal cannula. In 22 out of these 30 patients, switching to the tracheal route resulted in a correction of the saturation within 120 s. In the remaining 8 patients, saturation levels were corrected after increasing the oxygen flow rate to 4 liters/min. After restoring saturation levels, the bronchoscopy could be completed in 25 of 30 patients. CONCLUSIONS: Tracheal oxygen supplementation is safe, feasible and an effective way to restore oxygen saturation levels during flexible bronchoscopy.

Driver oncogenes in Sub-Saharan African patients with non-small cell lung cancer.

Non-small cell lung cancer can exhibit driver oncogenes, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), that are possible targets for therapy. The prevalence of these rearranged driver oncogenes is influenced by race, smoking habits, and gender. Most data come from Caucasian and Asian populations. To our knowledge, there is no literature available about the prevalence of driver oncogenes in Sub-Saharan Africa, where the tobacco epidemic is still in the early stage. In this small case series, 6 patients of Sub-Saharan African ethnicity with stage IV lung adenocarcinoma are described. EGFR mutation was present in 3/6 patients and ALK rearrangement in 1/6 patients. This incidence seems high but interestingly, all patients were non-smokers or light smokers. In this series, the high prevalence of driver oncogene was probably related to low smoking habits and these initial data in Sub-Saharan Africans suggest high prevalence of driver mutations for this reason.

Multidrug-resistant tuberculosis in Europe, 2010-2011.

Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non-MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010-2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ≥1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe.

Asthma control measurement using five different questionnaires: a prospective study.

UNLABELLED: Questionnaires play a key place in the assessment of asthma control. Different questionnaires have been developed. However, it remains largely unknown whether they can be used interchangeably. We wondered whether the panel of frequently used scores would give similar measurement of asthma control. The present study aimed to assess the agreement between five specific questionnaires. METHODS: In this prospective study, ninety-nine patients completed five commonly used asthma control scores: the GINA, the Asthma Control Test™, the Royal College of Physician score, the Asthma Therapy Assessment Questionnaire (ATAQ), and the Asthma Control Questionnaire(©) (ACQ). The kappa coefficient was used to assess the agreement between questionnaires. RESULTS: The agreement between the GINA and other scores was only moderate (kappa coefficients amounted from 0.41 to 0.60). With respect to the "controlled" level, all the other scores gave higher results than GINA. All other scores also tended to underestimate GINA "uncontrolled level". For the "partly controlled level" defined by 3 of the 5 questionnaires, ACQ identified the same percentage of patients than GINA while ATAQ overestimated this percentage. CONCLUSION: This study shows only moderate agreement between five commonly used asthma control scores. The GINA score showed the lowest percentage of controlled and the highest percentage of uncontrolled asthma. As a consequence, all these scores do not seem to evaluate the same symptoms. TRIAL REGISTRATION NUMBER: NCT01350661.

Endobronchial ultrasound in the management of nonsmall cell lung cancer.

Flexible bronchoscopy plays a major role in the diagnosis and staging of lung cancer. One of the most important advances in this field is the development of endobronchial ultrasound (EBUS), which has extended the view of the bronchoscopist. These techniques are safe and allow assessment of the depth of tumour invasion in the central airways, detection of peripheral tumours before sampling, localisation of the central tumour in the lung parenchyma close to the central airways for real-time guided sampling, and staging of lymph nodes within the mediastinum. Progress in handling and analyses of the small samples obtained during EBUS procedures also allow modern pathological and molecular studies to be performed. This article reviews the data currently available in the field of convex and radial probe EBUS for the diagnosis and staging of nonsmall cell lung cancer and highlights the strengths but also the weaknesses of these new techniques.

Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis.

The combination of meropenem with clavulanate has high antimycobacterial activity in vitro against extensively drug-resistant Mycobacterium tuberculosis strains. We report the successful use of this combination in association with linezolid in the management of an advanced extensively drug-resistant tuberculosis disease with complex second-line drug resistance in a 14-year-old teenager.