Bedaquiline Resistance after Effective Treatment of Multidrug-Resistant Tuberculosis, Namibia.

Bedaquiline is currently a key drug for treating multidrug-resistant or rifampin-resistant tuberculosis. We report and discuss the unusual development of resistance to bedaquiline in a teenager in Namibia, despite an optimal background regimen and adherence. The report highlights the risk for bedaquiline resistance development and the need for rapid drug-resistance testing.

Chronic Pulmonary Aspergillosis as a Considerable Complication in Post-Tuberculosis Lung Disease.

Post-tuberculosis lung disease (PTLD) has only recently been put in the spotlight as a medical entity. Recent data suggest that up to 50% of tuberculosis (TB) patients are left with PTLD-related impairment after completion of TB treatment. The presence of residual cavities in the lung is the largest risk factor for the development of chronic pulmonary aspergillosis (CPA) globally. Diagnosis of CPA is based on four criteria including a typical radiological pattern, evidence of Aspergillus species, exclusion of alternative diagnosis, and a chronic course of disease. In this manuscript, we provide a narrative review on CPA as a serious complication for patients with PTLD.

Stereotactic body radiotherapy for recurrent hemoptysis due to chronic pulmonary aspergillosis: a case report and systematic review of the literature.

PURPOSE: Chronic pulmonary aspergillosis (CPA) can manifest as fungus balls in preexisting cavities of lung parenchyma and recurrent hemoptysis is among the most frequent complications. Radiotherapy can be considered for treatment-refractory aspergilloma and severe hemoptysis. To the best of our knowledge, we present the first application of stereotactic body radiotherapy (SBRT) for a pulmonary aspergilloma in a patient with limited functional lung capacity. The topic was further expanded on with a systematic review of the literature addressing the implementation of radiotherapy in CPA patients. CASE REPORT: A 52-year-old man presented with recurring and treatment-refractory hemoptysis caused by chronic cavitary aspergillosis localized in the left lower lobe. We applied SBRT on two consecutive days with a total dose of 16 Gy. Hemoptysis frequency decreased to a clinically insignificant level. SYSTEMATIC REVIEW: We performed a systematic search of the literature in line with the PRISMA statement. The initial PubMed search resulted in 230 articles, of which 9 were included. RESULTS: The available literature contained 35 patients with CPA who received radiotherapy. Dose fractionation usually ranged from 2 to 4 Gy per fraction, applied almost exclusively in conventional two-dimensional (2D) techniques. There is no report of SBRT usage in such a scenario. Most cases report a positive treatment response after irradiation. CONCLUSION: The presented case demonstrates long-term clinical stability after SBRT for recurrent hemoptysis due to pulmonary aspergilloma. The systematic literature search revealed that concept definition is still uncertain, and further work is necessary to establish radiotherapy in clinical practice.

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.

Drug-resistant tuberculosis: advances in diagnosis and management.

PURPOSE OF REVIEW: Diagnosis and treatment of drug-resistant tuberculosis (DR-TB) is undergoing substantial changes, owing availability of new diagnostic tools and drugs, coupled with global underdiagnosis and undertreatment. Recent developments are reviewed. RECENT FINDINGS: Molecular diagnostics, for Mycobacterium tuberculosis complex detection and prediction of drug resistance, implemented in the last decade, accelerated TB diagnosis with improved case detection. Nevertheless, access and coverage of drug-resistance testing remain insufficient. Genome sequencing-technologies, based on targeted next-generation sequencing show early potential to mitigate some of the challenges in the future. The recommendation to use an all oral, bedaquiline based regimen for treatment of multidrug-resistant/rifampicin-resistant TB is major advancement in DR-TB care. TB regimen using new and repurposed TB drugs demonstrate in recent clinical trials like, NIX-TB, ZeNIX and TB PRACTECAL considerable treatment success, shorten treatment duration and reduce toxicity. Their optimal use is threatened by the rapid occurrence and spread of strains, resistant to new drugs. Children benefit only very slowly from the progress. SUMMARY: There is notable progress in improved diagnosis and treatment of drug-resistant TB, but complicated by the COVID-19 pandemic the majority of TB patients worldwide don't have (yet) access to the advances.

Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model.

BACKGROUND: The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB. METHODS: Adult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points. RESULTS: 50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9-0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001). CONCLUSION: Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.

Defining Outcomes of Tuberculosis (Treatment): From the Past to the Future.

Untreated active tuberculosis (TB) has a very high long-term mortality. Treatment of TB reduces mortality dramatically and should maximize cure, preventing ongoing transmission and TB sequelae. However, predicting the risk of failure and relapse is crucial for the management of individual patients and for the evaluation of effectiveness of programs. Various outcome definitions for drug-sensitive and drug-resistant TB were developed, implemented, and endorsed since introduction of TB chemotherapy by the World Health Organization (WHO), mostly based on culture and smear results. They should be applicable for individual patient care, surveillance, and research. Definitions with focus on program evaluation differ from definitions to evaluate the efficacy and effectiveness of regimens. Lack of sputum production at the later stage of treatment reduces the easy applicability of current definitions. Definitions of failure and cure are sometimes difficult to apply. Alternative approaches suggest culture positivity at 6 months or more of treatment as an indicator for failure. New definitions for cure including a relapse-free period posttreatment and reduced number of culture and smear results are considered. Increasing variation and individualization of treatment and its duration urgently require new approaches using pathogen- or host-specific biomarkers, which indicate risk of failure and define cure. Such biomarkers are under evaluation but still far from translation in clinical routine practice.

[Cough - an Interdisciplinary Condition: The Pneumologist's Perspective]. / Husten ­ eine interdisziplinäre Krankheit.

Cough - an Interdisciplinary Condition: The Pneumologist's Perspective Abstract. Cough is one of the most frequent reasons for a medical consultation. Patients mostly suffer from acute cough (< 2 weeks duration) and subacute cough (2 - 8 weeks) during consultation at primary care. Chronic cough (> 8 weeks) is mostly cared for by specialists. Acute and subacute cough is most frequently caused by infections with primarily viral pathogens. Chronic cough is commonly associated with obstructive airway disease (i. e. Asthma, COPD), gastroesophageal reflux and upper airway cough syndrome. Pulmonary causes are investigated by spirometry, bodyplethysmography, blood eosinophil count, exhaled nitric oxide, methacholine challenge test, chest x-rays and computed tomography. Treatment should target underlying diseases, causing cough. Trials of inhaled corticosteroids can be considered if an asthmatic cause is suspected. Secretolytics and cough-suppressing medications should be used only to reduce patient symptoms if there is no alternative causal treatment. Clinical trials show positive results for treatment of chronic refractory (no improvement of symptoms despite adequate treatment of the underlying condition) and chronic idiopathic cough with Gefapixant, a P2X3 purinergic receptor antagonist. If recent trial results are confirmed a first specific cough modulating substance might be available soon.

Two Pandemics, One Challenge-Leveraging Molecular Test Capacity of Tuberculosis Laboratories for Rapid COVID-19 Case-Finding.

In many settings, the ongoing coronavirus disease (COVID-19) pandemic coincides with other major public health threats, in particular tuberculosis. Using tuberculosis (TB) molecular diagnostic infrastructure, which has substantially expanded worldwide in recent years, for COVID-19 case-finding might be warranted. We analyze the potential of using TB diagnostic and research infrastructures for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. We focused on quality control by adapting the 12 Quality System Essentials framework to the COVID-19 and TB context. We conclude that diagnostic infrastructures for TB can in principle be leveraged to scale-up SARS-CoV-2 testing, in particular in resource-poor settings. TB research infrastructures also can support sequencing of SARS-CoV-2 to study virus evolution and diversity globally. However, fundamental principles of quality management must be followed for both TB and SARS-CoV-2 testing to ensure valid results and to minimize biosafety hazards, and the continuity of TB diagnostic services must be guaranteed at all times.

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.

Clinical, Diagnostic, and Treatment Disparities between HIV-Infected and Non-HIV-Infected Immunocompromised Patients with Pneumocystis jirovecii Pneumonia.

The substantial decline in the Pneumocystis jirovecii pneumonia (PCP) incidence in HIV-infected patients after the introduction of antiretroviral therapy (ART) in resource-rich settings and the growing number of non-HIV-infected immunocompromised patients at risk leads to considerable epidemiologic changes with clinical, diagnostic, and treatment consequences for physicians. HIV-infected patients usually develop a subacute course of disease, while non-HIV-infected immunocompromised patients are characterized by a rapid disease progression with higher risk of respiratory failure and higher mortality. The main symptoms usually include exertional dyspnea, dry cough, and subfebrile temperature or fever. Lactate dehydrogenase may be elevated. Typical findings on computed tomography scans of the chest are bilateral ground-glass opacities with or without cystic lesions, which are usually associated with the presence of AIDS. Empiric treatment should be initiated as soon as PCP is suspected. Bronchoalveolar lavage has a higher diagnostic yield compared to induced sputum. Immunofluorescence is superior to conventional staining. A combination of different diagnostic tests such as microscopy, polymerase chain reaction, and (1,3)-ß-D-glucan is recommended. Trimeth-oprim/sulfamethoxazole for 21 days is the treatment of choice in adults and children. Alternative treatment regimens include dapsone with trimethoprim, clindamycin with primaquine, atovaquone, or pentamidine. Patients with moderate to severe disease should receive adjunctive corticosteroids. In newly diagnosed HIV-infected patients with PCP, ART should be initiated as soon as possible. In non-HIV-infected immunocompromised patients, improvement of the immune status should be discussed (e.g., temporary reduction of immunosuppressive agents). PCP prophylaxis is effective and depends on the immune status of the patient and the underlying immunocompromising disease.

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring.

INTRODUCTION: Tuberculosis (TB) remains one of the world's deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95-98 % under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes. METHODS: Therapeutic drug monitoring has been proposed in an attempt to optimize treatment outcome and reduce the development of drug resistance. Several studies have shown that maximum plasma concentrations (C max), especially of rifampicin and isoniazid, are well below the proposed target C max concentrations in a substantial fraction of patients being treated with the standard four-drug treatment schedule, even though treatment's success rate in these studies was typically at least 85 %. DISCUSSION: The proposed target C max concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of C max based on one or two sampling times may not have the necessary accuracy since absorption rate, especially for rifampicin, may be highly variable. In addition, minimum inhibitory concentration (MIC) variability should be taken into account to set clinically meaningful susceptibility breakpoints. Clearly, there is a need to better define the key target PK and pharmacodynamic (PD) parameters for therapeutic drug monitoring (TDM) of the first-line anti-TB drugs to be efficacious, C max (or area under the curve (AUC)) and C max/MIC (or AUC/MIC). CONCLUSION: Although TDM of first-line anti-TB drugs has been successfully used in a limited number of specialized centers to improve treatment outcome in slow responders, a better characterization of the target PK and/or PK/PD parameters is in our opinion necessary to make it cost-effective.

Personalized Medicine for Chronic Respiratory Infectious Diseases: Tuberculosis, Nontuberculous Mycobacterial Pulmonary Diseases, and Chronic Pulmonary Aspergillosis.

Chronic respiratory infectious diseases are causing high rates of morbidity and mortality worldwide. Tuberculosis, a major cause of chronic pulmonary infection, is currently responsible for approximately 1.5 million deaths per year. Although important advances in the fight against tuberculosis have been made, the progress towards eradication of this disease is being challenged by the dramatic increase in multidrug-resistant bacilli. Nontuberculous mycobacteria causing pulmonary disease and chronic pulmonary aspergillosis are emerging infectious diseases. In contrast to other infectious diseases, chronic respiratory infections share the trait of having highly variable treatment outcomes despite longstanding antimicrobial therapy. Recent scientific progress indicates that medicine is presently at a transition stage from programmatic to personalized management. We explain current state-of-the-art management concepts of chronic pulmonary infectious diseases as well as the underlying methods for therapeutic decisions and their implications for personalized medicine. Furthermore, we describe promising biomarkers and techniques with the potential to serve future individual treatment concepts in this field of difficult-to-treat patients. These include candidate markers to improve individual risk assessment for disease development, the design of tailor-made drug therapy regimens, and individualized biomarker-guided therapy duration to achieve relapse-free cure. In addition, the use of therapeutic drug monitoring to reach optimal drug dosing with the smallest rate of adverse events as well as candidate agents for future host-directed therapies are described. Taken together, personalized medicine will provide opportunities to substantially improve the management and treatment outcome of difficult-to-treat patients with chronic respiratory infections.

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.

Availability, price and affordability of anti-tuberculosis drugs in Europe: a TBNET survey.

Data on availability and cost of anti-tuberculosis (TB) drugs in relation to affordability at national level are scarce. We performed a cross-sectional study on availability and cost of anti-TB drugs at major TB-reference centres in 37 European countries. Costs of standardised treatment regimens used for pan-sensitive TB, multidrug-resistant (MDR) TB, pre-extensively drug-resistant (XDR) TB, and XDR-TB were compared using a purchasing power analysis. Affordability was evaluated in relation to monthly national gross domestic products per capita (GDP). At least one second-line injectable and either moxifloxacin or levofloxacin were available in all countries. Linezolid and clofazimine were available in 79% and 46% of the countries, respectively. Drug cost for XDR-TB was three-times more expensive than those for MDR-TB. The average price of treatment for pan-sensitive TB represented a maximum of 8.5% of the monthly GDP across countries, while for standard MDR-TB treatment this was <30% in only six countries and more than 100% in four countries. Treatment of XDR-TB represented more than 100% of a month's GDP in all countries where the regimen was available. High cost and limited availability of drugs for treatment of drug-resistant TB, particularly beyond resistance to first-line drugs, are a major impediment to successful TB control in Europe.

'Tree-in-bud': thinking beyond infectious causes.

High-resolution computed tomography is an important diagnostic instrument in pneumology. The 'tree-in-bud' sign is a common finding in HRCT scans. The list of the most frequent differential diagnoses for 'tree-in-bud' sign includes infections with Mycobacterium tuberculosis, nontuberculous mycobacteria, and other bacterial, fungal, or viral pathogens. Other causes could be immunological, congenital, and idiopathic disorders as well as aspiration or inhalation of toxic agents. Rare differential diagnoses are malignant conditions. We present a case with 'tree-in-bud' pulmonary infiltrates of chronic lymphatic leukemia which was only diagnosed by transbronchial biopsies, and discuss other differential diagnoses.