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Background Listeria monocytogenes is an opportunistic gram-positive, facultative intracellular bacterium that causes invasive diseases mostly in pregnant women and immunosuppressed patients. Despite the predilection toward the central nervous system (CNS), it usually causes meningitis and meningoencephalitis, whereas brain abscesses are very uncommon.Case presentation We describe the case of a 69-year-old homeless patient with a brain abscess due to L. monocytogenes who was successfully treated surgically by a guided stereotactic aspiration and antibiotic therapy with ampicillin and gentamicin. Our patient was discharged after 4 weeks of therapy without neurologic deficits. Additionally, we provide a review of the literature of brain abscesses caused by L. monocytogenes.Conclusions This case highlights the need to drain cerebral abscesses and culture pus to correctly treat patients with antibiotics, especially given the high mortality rate of this infectious entity.

Item does not contain fulltext BACKGROUND: Since 2013, over 100 cases of Mycobacterium chimaera prosthetic valve endocarditis and disseminated disease were notified in Europe and the USA, linked to contaminated heater-cooler units (HCUs) used during cardiac surgery. We did a molecular epidemiological investigation to establish the source of these patients' disease. METHODS: We included 24 M chimaera isolates from 21 cardiac surgery-related patients in Switzerland, Germany, the Netherlands, and the UK, 218 M chimaera isolates from various types of HCUs in hospitals, from LivaNova (formerly Sorin; London, UK) and Maquet (Rastatt, Germany) brand HCU production sites, and unrelated environmental sources and patients, as well as eight Mycobacterium intracellulare isolates. Isolates were analysed by next-generation whole-genome sequencing using Illumina and Pacific Biosciences technologies, and compared with published M chimaera genomes. FINDINGS: Phylogenetic analysis based on whole-genome sequencing of 250 isolates revealed two major M chimaera groups. Cardiac surgery-related patient isolates were all classified into group 1, in which all, except one, formed a distinct subgroup. This subgroup also comprised isolates from 11 cardiac surgery-related patients reported from the USA, most isolates from LivaNova HCUs, and one from their production site. Isolates from other HCUs and unrelated patients were more widely distributed in the phylogenetic tree. INTERPRETATION: HCU contamination with M chimaera at the LivaNova factory seems a likely source for cardiothoracic surgery-related severe M chimaera infections diagnosed in Switzerland, Germany, the Netherlands, the UK, the USA, and Australia. Protective measures and heightened clinician awareness are essential to guarantee patient safety. FUNDING: Partly funded by the EU Horizon 2020 programme, its FP7 programme, the German Center for Infection Research (DZIF), the Swiss National Science Foundation, the Swiss Federal Office of Public Health, and National Institute of Health Research Oxford Health Protection Research Units on Healthcare Associated Infection and Antimicrobial Resistance.

Was ist neu?Steroide sollen bei der Sepsis/septischen Schock, der Tuberkulose und der Meningtitis weiterhin nur in bestimmten Fällen zum Einsatz kommen: Nämlich bei anders nicht stabilisierbarem Kreislaufversagen in der Sepsis, bei tuberkulöser Meningitis oder bei eitriger Meningitis durch Pneumokokken.Der Einsatz von Steroiden bei eher später, hyperinflammatorischer Covid-19-Erkrankung kann die Sterblichkeit wesentlich senken, wobei die Effekte vor allem für sauerstoffpflichtige und intubiert beatmete Patienten signifikant sind, während Steroide bei Patienten ohne Sauerstoffpflichtigkeit keine signifikant mortalitätssenkende Effekte haben. Untersucht sind Dexamethason, Methylprednisolon und Hydrocortison, wobei die Evidenzlage für Dexamethason am besten ist.Steroide kommen weiterhin beim Immunrekonstitutionssyndrom (IRIS) des erworbenen Immunschwächesyndroms (AIDS) durch HIV zum Einsatz.

ZusammenfassungDie neue ATS/ERS/ESCMID/IDSA-Leitlinie beantwortet 22 PICO-Fragen zur Behandlung von Erkrankungen der Lunge durch Mycobacterium avium-Komplex (MAC), M. kansasii, M. xenopi und M. abscessus. Allgemeines Insbesondere bei Patienten mit mikroskopischem Nachweis säurefester Stäbchen im Sputum oder kavernöser Verlaufsform sollte der Behandlungsbeginn nicht verzögert werden. Die Behandlung sollte auf einer speziesspezifischen Resistenztestung (entsprechend den CLSI-Guidelines) basieren. MAC-Lungenerkrankung Die Therapie erfolgt hier mit mindestens 3 Medikamenten inklusive einem Makrolid (eher Azithromycin als Clarithromycin) und Ethambutol. Für Patienten mit kavitärer, mit ausgeprägter nodulär-bronchiektatischer Erkrankung oder mit Makrolid-Resistenz wird zur täglichen oralen Therapie eine additive Gabe von parenteralem Amikacin oder Streptomycin empfohlen. Liposomal verkapseltes inhalatives Amikacin wird bei Therapieversagen empfohlen. Patienten mit nodulär-bronchiektatischer Erkrankungsmanifestation sollten eine orale Makrolid-basierte Therapie, die – je nach Ausmaß – 3 ×/Woche gegeben werden kann, erhalten. Als Dauer werden 12 Monate nach Konversion der Sputumkultur empfohlen. M. kansasii-Lungenerkrankung Empfohlen ist die Dreifachkombination aus Rifampicin, Ethambutol und Makrolid (oder Isoniazid ) für mindestens 12 Monate. Bei Rifampicin-Resistenz oder -unverträglichkeit wird Moxifloxacin als Ersatz empfohlen. M. xenopi-Lungenerkrankung Empfohlen ist die Dreifachkombination aus Rifampicin, Ethambutol und Makrolid (oder Moxifloxacin) für mindestens 12 Monate nach Konversion der Sputumkultur. Es wird empfohlen, bei Patienten mit kavernöser Verlaufsform zumindest parenterales Amikacin zu addieren und Experten zu konsultieren. M. abscessus-Lungenerkrankung Mindestens 3 Medikamente werden zur Therapie empfohlen. Die Substanzauswahl sollte auf einer In-vitro-Resistenztestung basieren. Makrolide sind die Grundlage, sollten aber bei Stämmen mit induzierbarer Makrolidresistenz nicht mitgerechnet werden. Zur Therapiedauer werden aufgrund fehlender Daten keine expliziten Empfehlungen ausgesprochen, eine Konsultation von Experten wird empfohlen.

During the Corona Virus Disease 2019 (COVID-19) pandemic, Long COVID-syndrome, which impairs patients through cognitive deficits, fatigue, and exhaustion, has become increasingly relevant. Its underlying pathophysiology, however, is unknown. In this study, we assessed cognitive profiles and regional cerebral glucose metabolism as a biomarker of neuronal function in outpatients suffering from long-term neurocognitive symptoms after COVID-19. Methods: Outpatients seeking neurological counseling with neurocognitive symptoms persisting for more than three months after polymerase chain reaction (PCR)-confirmed COVID-19 were included prospectively between June 16, 2020, and January 29, 2021. Patients (n = 31, 54±2.0 years) in the long-term phase after COVID-19 (202±58 days after positive PCR) were assessed with a neuropsychological test battery. Cerebral 18F-FDG PET imaging was performed in 14/31 patients. Results: Patients self-reported impaired attention, memory, and multitasking abilities (31/31), word-finding difficulties (27/31), and fatigue (24/31). Twelve of 31 patients could not return to the previous level of independence/employment. For all cognitive domains, average group results of the neuropsychological test-battery showed no impairment, but deficits (z-score

Cognitive impairment is a frequent complaint in coronavirus disease-19 (COVID-19) and can be related to cortical hypometabolism on 18F-FDG PET at the subacute stage. However, it is unclear if these changes are reversible. Methods: We prospectively assessed Montreal Cognitive Assessment (MoCA) and 18F-FDG PET scans in 8 COVID-19 patients at the subacute (as no longer infectious) and chronic stages (approximately six months after symptom onset). The expression of the previously established COVID-19-related covariance pattern was analyzed at both stages to examine the time course of post-COVID-19 cognitive impairment. For further validation, we also conducted a conventional group analysis. Results: Follow-up 18F-FDG PET revealed a significant reduction of initial frontoparietal and, to a lesser extent, temporal glucose hypometabolism that was accompanied by a significant improvement in cognition. The expression of the previously established COVID-19-related pattern was significantly lower at follow-up and correlated inversely with MoCA performance. However, both 18F-FDG PET and cognitive assessment suggest a residual impairment. Conclusions: Although a significant recovery of regional neuronal function and cognition can be clearly stated, residuals are still measurable in some patients six months after the manifestation of COVID-19. Given the current pandemic situation and tremendous uncertainty concerning the long-term effects of COVID-19, the present study provides novel insights of highest medical and socioeconomic relevance.

Contains fulltext : 238245.pdf (Publisher’s version ) (Open Access) Adverse events are frequent in nontuberculous mycobacteria pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus, and gastrointestinal upset. These opinions can provide assistance in individual patient management decisions.

BackgroundAcute kidney injury (AKI) is an independent risk factor for mortality, which affects about 5% of hospitalized coronavirus disease-2019 (COVID-19) patients and up to 25–29% of severely ill COVID-19 patients. Lopinavir/ritonavir and hydroxychloroquine showin vitroactivity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have been used for the treatment of COVID-19. Both, lopinavir and hydroxychloroquine are metabolized by cytochrome P450 (CYP) 3A4. The impact of a triple therapy with lopinavir/ritonavir and hydroxychloroquine (triple therapy) on kidney function in COVID-19 is currently not known.MethodsWe retrospectively analyzed both non-ICU and ICU patients with COVID-19 receiving triple therapy for the incidence of AKI. Patients receiving standard therapy served as a control group. All patients were hospitalized at the University Hospital of Freiburg, Germany, between March and April 2020. A matched-pair analysis for the National Early Warning Score (NEWS) 2 was performed to control for the severity of illness among non-intensive care unit (ICU) patients.ResultsIn non-ICU patients, the incidence of AKI was markedly increased following triple therapy (78.6% vs. 21.4% in controls, p = 0.002), while a high incidence of AKI was observed in both groups of ICU patients (triple therapy: 80.0%, control group: 90.5%). ICU patients treated with triple therapy showed a trend towards more oliguric or anuric kidney injury. We also observed a linear correlation between the duration of the triple therapy and the maximum serum creatinine level (p = 0.004, R2= 0.276, R = 0.597).ConclusionTriple therapy is associated with an increase in the incidence of AKI in non-ICU COVID-19 patients. The underlying mechanisms may comprise a CYP3A4 enzyme interaction, and may be relevant for any future therapy combining hydroxychloroquine with antiviral agents.

BackgroundReported mortality of hospitalised COVID-19 patients varies substantially, particularly in critically ill patients. So far COVID-19 in-hospital mortality and modes of death under optimised care conditions have not been systematically studied.MethodsThis retrospective observational monocenter cohort study was performed after implementation of a non-restricted, dynamic tertiary care model at the University Medical Center Freiburg, an experienced ARDS and ECMO referral center. All hospitalised patients with PCR-confirmed SARS-CoV-2 infection were included. The primary endpoint was in-hospital mortality, secondary endpoints included major complications and modes of death. A multistate analysis and a Cox regression analysis for competing risk models were performed. Modes of death were determined by two independent reviewers.ResultsBetween February 25, and May 8, 213 patients were included in the analysis. The median age was 65 years, 129 patients (61%) were male. 70 patients (33%) were admitted to the intensive care unit (ICU), of which 57 patients (81%) received mechanical ventilation and 23 patients (33%) extracorporeal membrane-oxygenation (ECMO) support. According to the multistate model the probability to die within 90 days after COVID-19 onset was 24% in the whole cohort. If the levels of care at time of study entry were accounted for, the probabilities to die were 16% if the patient was initially on a regular ward, 47% if in the ICU and 57% if mechanical ventilation was required at study entry. Age ≥65 years and male sex were predictors for in-hospital death. Predominant complications – as judged by two independent reviewers – determining modes of death were multi-organ failure, septic shock and thromboembolic and hemorrhagic complications.ConclusionIn a dynamic care model COVID-19-related in-hospital mortality remained substantial. In the absence of potent antiviral agents, strategies to alleviate or prevent the identified complications should be investigated. In this context, multistate analyses enable comparison of models-of-care and treatment strategies and allow estimation and allocation of health care resources.RegistrationGerman Clinical Trials Register (identifier DRKS00021775), retrospectively registered June 10, 2020.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

In the coronavirus disease 2019 (COVID-19) pandemic, organ transplant recipients are considered to be at high risk for an unfavorable outcome. However, in particular the role of immunosuppression in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains undetermined. Here, we present a 62-year-old male COVID-19 patient with recent heart transplantation who developed only mild symptoms, but had prolonged virus shedding, and summarize the available data on COVID-19 in cardiac allograft recipients. Initially the patient presented with a transient episode of fever and sore throat but no other symptoms, in particular no cough or dyspnea at rest. After diagnosis, immunosuppression was continued unchanged. On day 7, his temperature increased again with concurrent mild rise of C-reactive protein, IL-6, and pro-B-type natriuretic peptide levels. Hydroxychloroquine was started and continued for 7 days. While the patient no longer had clinical symptoms 20 days after initial presentation, virus culture of throat swabs on days 18 and 21 confirmed active virus replication and SARS-CoV-2 PCR remained positive on day 35 with copy numbers similar to the onset of infection. In conclusion, the immunosuppression regimen in transplant recipients with mild COVID-19-associated symptoms may be continued unchanged. However, it may contribute to delayed virus polymerase chain reaction conversion and thus possible prolonged infectivity.

Immunosuppressive therapies increase the susceptibility of patients to infections. The current pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compels clinicians to develop recommendations for successful clinical management and surveillance of immunocompromised patients at high risk for severe disease progression. With only few case studies published on SARS-CoV-2 infection in patients with rheumatic diseases, we report a 25-year-old male who developed moderate coronavirus disease 2019 (COVID-19) with fever, mild dyspnea, and no major complications despite having received high-dose prednisolone, cyclophosphamide, and rituximab for the treatment of highly active, life-threatening eosinophilic granulomatosis with polyangiitis (EGPA).

A 46-year old construction worker presented at the emergency department with two orthostatic syncopes. The patient complained of prolonged fever and coughs for 7 days which had not improved after oral treatment with sultamicillin for 5 days, prescribed by the patient's general practitioner. Physical examination showed high blood pressure due to previously known hypertension. Other vital signs without pathological findings. Pulmonary auscultation showed basal soft crackling noises of the left lung FINDINGS AND DIAGNOSIS: Laboratory examination showed increased values for LDH, pro-BNP and CRP and normal values for leucocytes and procalcitonin. Conventional X-Ray of the chest showed bipulmonal lateral atypical infiltrates. After the first PCR turned in negative another PCR-analysis for SARS-CoV-2 of a deep oral swab-sample was performed since the clinical, laboratory and radiological findings were typical for COVID-19. Again, SARS-CoV-2-RNA was not detected. A CT-scan of the chest showed bipulmonal lateral ground-glass attenuation, again typical for COVID-19 associated pneumonia. After a third attempt for a PCR-analysis of a deep oral swab-sample was negative, analysis of a sputum was performed which finally confirmed the diagnosis of COVID-19 associated pneumonia.The patient was admitted for evaluation of syncopes and suspect of COVID-19 associated pneumonia. The patient was prophylactically isolated while the result of SARS-CoV-2-PCR from a deep oral swab was pending. Suspecting a possible secondary bacterial infection at the beginning, intravenous antibiotic treatment with ampicillin/sulbactam was initiated. While further examinations showed no indication for bacterial infection, antibiotics were discontinued after 3 days. Due to clinical recovery antiviral therapy was not performed after confirming the diagnosis. The patient was discharged 17 days after onset of first symptoms without any requirements for further isolation.This casuistic describes a case of COVID-19 associated pneumonia presenting with typical clinical features, laboratory and radiological findings. Detection of viral RNA was not successful from deep oral swab-samples despite repeated attempts. Finally, PCR-analysis of sputum confirmed the diagnosis. Analysis of deeper airway samples (sputum, bronchoalveolar lavage, tracheal secretions) or stool for SARS-CoV-2 should be performed in cases of evident clinical suspicion of COVID-19 and negative PCR results from deep oral swabs.Ein 46-jähriger Bauarbeiter stellte sich bei seit ca. 7 Tagen bestehender Infektsymptomatik mit Fieber und teilweise produktivem Husten sowie 2-maliger orthotstatischer Synkope in der Notaufnahme vor. Ambulant war bereits eine orale antibiotische Therapie über 5 Tage mit Sultamicillin durch den Hausarzt eingeleitet worden, die zu keiner Beschwerdebesserung führte. In der klinischen Untersuchung zeigten sich hypertone Blutdruckwerte bei bekannter arterieller Hypertonie, ansonsten unauffällige Vitalparameter sowie pulmonal feinblasige Rasselgeräusche links basal.Laborchemisch präsentierten sich erhöhte Werte für LDH sowie pro-BNP und CRP bei normwertigen Leukozyten und normwertigem Procalcitonin. Bei Verdacht auf Pneumonie wurde zunächst ein konventionelles Röntgenbild der Lunge durchgeführt, das laterale Verschattungen in beiden Lungen zeigte, verdächtig auf eine atypische Pneumonie. Bei initial negativem Rachenabstrich trotz typischer klinischer, radiologischer und laborchemischer Konstellation erfolgte ein erneuter tiefer Rachenabstrich auf SARS-CoV-2, welcher ebenfalls negativ ausfiel. In der nachgeschalteten CT-Untersuchung des Thorax zeigten sich für COVID-19 typische bipulmonale laterale milchglasartige Infiltrate, woraufhin ein dritter Rachenabstrich durchgeführt wurde, der erneut negativ blieb. Nach Asservierung und PCR-Analyse von Sputum konnte schließlich der Nachweis von SARS-CoV-2 erbracht und die Diagnose einer COVID-19-assoziierten Pneumonie gesichert werden.Es erfolgte die stationäre Aufnahme zur Infekt- und Synkopen-Abklärung. Bei zunächst noch ausstehendem Ergebnis des Rachenabstrichs auf SARS-CoV-2 wurde der Patient prophylaktisch isoliert. Bei Verdacht auf eine mögliche bakteriell-superinfizierte Pneumonie wurde eine intravenöse antibiotische Therapie mit Ampicillin/Sulbactam eingeleitet, welche nach 3 Tagen bei fehlenden Hinweisen auf bakterielle Erreger beendet wurde. Nach Diagnosesicherung erfolgte bei bereits eingetretener klinischer Rekonvaleszenz keine antivirale Therapie. Der Patient wurde 17 Tage nach initialem Symptombeginn ohne weitere Quarantäne-Auflagen nach Hause entlassen.Die Kasuistik beschreibt einen Fall von COVID-19, bei dem trotz typischer klinischer Symptomatik sowie typischen radiologischen und laborchemischen Befunden ein Virusnachweis in mehrfach korrekt durchgeführten tiefen Rachenabstrichen nicht möglich war. Erst eine Sputum-Analyse erbrachte den Nachweis der viralen RNA und sicherte die Diagnose. Bei begründetem klinischem Verdacht auf COVID-19 sollte daher bei negativen Rachenabstrichen zum sicheren Ausschluss eine Analyse von tiefen Atemwegssekreten (Sputum, bronchoalveoläre Lavage, Trachealsekret) oder Stuhl erfolgen.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such asMycobacterium aviumcomplex,Mycobacterium kansasii, andMycobacterium xenopiamong the slowly growing NTM andMycobacterium abscessusamong the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

Background Nontuberculous mycobacterial pulmonary disease (NTM-PD) is an emerging opportunistic infection, but basic epidemiological data are lacking in most regions. We have investigated epidemiology and diagnostic and treatment practices in five EU countries (United Kingdom, Spain, Italy, France, Germany; EU5) and Japan. Study design and methods: Annual prevalence in each country was established using a 2-round Delphi method in combination with a regional prevalence-estimation model that incorporated data obtained from a blinded physician screening survey (3154 physicians) and a real-world NTM-PD treating-physician/patient-chart observational study (619 physicians – 1429 patient charts). Results The annual prevalence of NTM-PD was estimated at 6.2/100,000 in the EU5 and 24.9/100,000 in Japan. Overall prevalence between the EU5 was comparable, while differences in regional prevalence were found to be pronounced in France and The United Kingdom. Regional differences were also found in Japan, with the majority of cases in Chubu and Kanto regions. Conclusion This new methodology for obtaining often missing regional-level epidemiological data reveals dramatic variations in NTM-PD annual prevalence and helps pinpoint areas that may merit special preventative and treatment focus.

Tuberkulose ist weiterhin die Infektionskrankheit, an welcher weltweit die meisten Menschen versterben. Die aktuelle Literatur zur Assoziation von Diabetes und Tuberkulose wird beschrieben, und Fragen des klinischen Managements bei Patienten mit beiden Diagnosen werden diskutiert. Das Risiko, an einer Tuberkulose zu erkranken, ist bei Patienten mit Diabetes im Vergleich zur nicht an dieser Stoffwechselerkrankung leidenden Bevolkerung verdreifacht. Die Behandlungsergebnisse bezuglich der Tuberkulose sind bei Patienten mit vs. ohne Diabetes schlechter, und sowohl die Therapie der Tuberkulose als auch die des Diabetes werden durch Medikamenteninteraktionen erschwert.

A new name for most Mycobacterium species has been recently proposed. According to taxonomic rules novel and previous nomenclature coexist and are synonyms. The use of the latter has the advantage of avoiding confusion for healthcare and harm for patients.http://bit.ly/2XhTACc

Background Nontuberculous mycobacteria (NTM) lung disease has been increasing globally with bronchiectasis being a strong risk factor. The objective of this study was to evaluate the current screening practices of physicians for NTM disease in adult patients with non-CF bronchiectasis (NCFB). Method We conducted an online survey with 280 physicians treating adult non-CF bronchiectasis patients in Germany, UK, Italy, France and the Netherlands. Respondents had to spend at least 80% of their time in the hospital setting and manage N³10 adult NCFB patients in previous 12 months. Results 85% (range: 80%–88%) of surveyed physicians tested at least some of their NCFB patients for NTM infection. In total 51% (range: 40% [France] – 70% [Netherlands]) of NCFB patients managed by these respondents were tested for NTM infection and 17% of those (range: 8% [Netherlands] – 21% [Germany]) – were stated to have tested positive. The NTM infection was mostly suspected by physicians due to radiology exams or physical features of the lung (82%). Close to half of NCFB patients are tested for NTM on diagnosis or initial presentation. 64% of respondents (range: 52%–76%) test for NTM in at-risk patients with NCFB at least once per year. Only 38% (range: 24%–66%) of physicians test for NTM infection before initiating a macrolide monotherapy. Conclusions Physicians need to be educated to screen patients with NCFB for NTM infection before initiating macrolide monotherapy. Recommendations for NTM-screening in these patients need to be validated, and further research on risk factors associated with NTM infection is warranted.

Summary Background Several cases of Mycobacterium chimaera infection have recently been reported in cardiosurgical patients. So-called heater–cooler units (HCUs) used in cardiosurgical procedures are suspected to be the reservoir for pathogen growth and dissemination. Aim To assess the contamination status of HCUs at our facility. Methods Air sampling for mycobacteria was conducted at different distances from the machines and in the area around the operating table. Air sampling was also conducted for non-fermenters as a surrogate parameter for water-associated pathogens. Findings Mycobacterium chimaera was detected in the water tanks of the HCUs. When the devices were operating, M. chimaera was also found in their exhaust air, as well as in the area around the operating table. Non-fermenters were identified at different distances from the running HCU and the area around the operating table. Cultures remained negative when the devices were switched off. Conclusions Exhaust air from HCUs may be a pathway of pathogen transmission to patients undergoing open chest heart surgery. Although, for technical reasons, relocation of HCUs is difficult to achieve, only strict separation of the HCU from the operating room appears to enhance patient safety. Using non-fermenters as a surrogate parameter may be considered a viable option for a timely risk assessment. The design of HCUs should be modified to keep susceptibility to contamination at a minimum.

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.

Broncho-esophageal fistula formation is a rare complication of tuberculosis, most often seen in immunocompromised patients. In this paper, we report the case of a young non-immunocompromised refugee from Somalia diagnosed with open pulmonary tuberculosis complicated by extensive osseous involvement and a broncho-esophageal fistula with consecutive aspiration of gastric contents. The patient rapidly developed a severe acute respiratory distress syndrome (ARDS) requiring venovenous extracorporeal membrane oxygenation (ECMO) therapy for nearly 2 months. The fistula was initially treated by standard antituberculous combination therapy and implantation of an esophageal and a bronchial stent. Long-term antibiotic treatment was instituted for pneumonia and mediastinitis. 7 months later, discontinuity resection of the esophagus was performed and the bronchial fistula covered by an intercostal muscle flap. This case illustrates that tuberculosis should always be suspected in patients from high-incidence countries in case of lung involvement and that an interdisciplinary approach including long-term intensive care management can enable successful treatment of tuberculosis with severe, near-fatal complications.

Nontuberculous mycobacterial pulmonary diseases (NTM-PD) are increasingly recognised as opportunistic infections of humans. These chronic pulmonary infections have two main presentations. The first is a fibro-cavitary disease, that occurs in patients with pre-existing pulmonary diseases, such as chronic obstructive pulmonary disease, bronchiectasis, previous tuberculosis or other structural lung disease. The second presentation is a nodular- bronchiectatic disease of primarily the lingula and middle lobe that tends to affect a middle- aged and elderly female population [1]. Treatment of NTM-PD requires long-term administration of complex multidrug therapies that are species-specific. Currently recommended regimens are supported by a very limited evidence base [2, 3]. The increasing incidence of NTM-PD has sparked increased interest in performing prospective randomised clinical trials [4]. One of the drawbacks of the existing case series and clinical trials is that they have applied different outcome measures [5]. This hampers meta-analyses, which are important in these still understudied infectious diseases. To enhance the quality and interpretability of the results of future trials and retrospective cohort studies, we aimed to formulate clear and broadly acceptable outcome definitions for NTM-PD treatment.

Here we report on a case of primary cryptococcal skin infection in an immunocompetent 8-year-old boy. The infection first manifested itself as a subcutaneous abscess around the proximal joint of his right thumb after a minor injury from contact with a thorny shrub. After surgical incision and drainage was performed, Cryptococcus neoformans var. neoformans was the only pathogen cultured from the lesion. An agglutination test for the capsular antigen in serum displayed negative results and the immunological work-up revealed no underlying immunodeficiency. A "watch and wait" strategy - one without systemic antifungal treatment - was adopted and this resulted in uneventful healing. In summary, primary cryptococcal skin infections in immunocompetent hosts may be managed successfully by surgical treatment in combination with careful clinical follow-up. This approach may help avoid unnecessary antimicrobial treatments.

Poor adherence to diagnosis and treatment guidelines for nontuberculous mycobacterial lung disease in EU and Japan http://ow.ly/EVYl306vVcN

Vaginal bleeding may be present in up to 30% of patients presenting with signs and symptoms of a rupture of the fetal membranes (ROM). The presence of blood may lead to false positive results with biochemical markers. The data presented in this study came from a multi-centric prospective observational clinical study that, for the first time, systematically evaluated the performance of placental alpha microglobulin-1 (PAMG-1) and insulin-like growth factor binding protein-1 (IGFBP-1) detecting tests in 151 women with vaginal bleedings as well as signs and symptoms indicative of ROM. Our data showed better performance for the PAMG-1 compared with the IGFBP-1 detecting tests in all quality parameters evaluated. In detail, sensitivity (SN) was 97.8% (91.0%), specificity (SP) was 91.5% (75.0%), positive predictive value (PPV) was 94.6% (83.5%) and negative predictive value (NPV) was 96.4% (85.7%) for PAMG-1 tests (and IGFBP-1 tests, respectively). A major difference between both tests was related to the number of non-evaluable test results (e.g., hidden bands due to blood smear on the test strips). While 2% of all results were not evaluable for PAMG-1 tests, this artifact appeared in 11% of the results obtained with IGFBP-1 tests. This difference and also those in Specificity and PPV were statistically significant, demonstrating superiority of PAMG-1 over IGFBP-1 detecting tests. In conclusion, the PAMG-1 detecting test was significantly less susceptible to interference by blood than the IGFBP-1 detecting test.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking., TBNET consensus statement on the management of patients with MDR/XDR-TB has been released in the Eur Respir J http://ow.ly/uizRD

The objective of this retrospective planning study was to find a contouring definition for the rectum as an organ at risk (OAR) in curative three-dimensional external beam radiotherapy (EBRT) for prostate cancer (PCa) with a predictive correlation between the dose-volume histogram (DVH) and rectal toxicity.In a pre-study, the planning CT scans of 23 patients with PCa receiving definitive EBRT were analyzed. The rectum was contoured according to 13 different definitions, and the dose distribution was correlated with the respective rectal volumes by generating DVH curves. Three definitions were identified to represent the most distinct differences in the shapes of the DVH curves: one anatomical definition recommended by the Radiation Therapy Oncology Group (RTOG) and two functional definitions based on the target volume. In the main study, the correlation between different relative DVH parameters derived from these three contouring definitions and the occurrence of rectal toxicity during and after EBRT was studied in two consecutive collectives. The first cohort consisted of 97 patients receiving primary curative EBRT and the second cohort consisted of 66 patients treated for biochemical recurrence after prostatectomy. Rectal toxicity was investigated by clinical investigation and scored according to the Common Terminology Criteria for Adverse Events. Candidate parameters were the volume of the rectum, mean dose, maximal dose, volume receiving at least 60 Gy (VIn Cohort 1 (primary EBRT), the mean rectal volumes for definitions "RTOG", planning target volume "(PTV)-based" and "PTV-linked" were 100 cmThe RTOG anatomy-based recommendations are questionable in comparison with functional definitions, as they result in higher variances in several relative DVH parameters. Moreover, the anatomy-based definition is no better and no worse in the predictive value concerning clinical end points. Advances in knowledge: Functional definitions for the rectum as OAR are easier to apply, faster to contour, have smaller variances and do not offer less information than the anatomy-based RTOG definition.

Abdominal mesenteritis is a rare and poorly understood gastroenterological disease. Here, we report on two identical cases of Mycobacterium genavense associated retractile mesenteritis in HIV-positive patients. A literature search retrieved only few small retrospective studies, which characterize the clinical course of this seldom infection. We propose a pathogen-specific syndrome of retractile mesenteritis in HIV-positive patients linked to Mycobacterium genavense infection on the basis of our clinical observation and literature meta-analysis with duodenal wall thickening, central mesenterial mass and vascular complications.

Networking is a key feature of scientific success. The Tuberculosis Network European Trialsgroup (TBNET) was founded in 2006 as a non-profit, non-governmental peer-initiated scientific organization to collaboratively address research priorities in the area of tuberculosis in Europe. Today, TBNET is the largest tuberculosis research organization in Europe with nearly 500 members from 22 EU countries and 49 countries worldwide (www.tb-net.org). Apart from small multicenter basic research studies, a particular strength of TBNET is the performance of large collaborative projects, pan-European multicenter studies and database projects. In recent years, research from TBNET has substantially contributed to the understanding of the management, risk and prognosis of patients with multidrug (MDR) and extensively drug-resistant (XDR) tuberculosis and led to a better understanding of the clinical value of novel tests for the identification of adults and children with tuberculosis and latent infection with Mycobacterium tuberculosis. In 2009, two branches of TBNET were founded to specifically address tuberculosis in the pediatric population (ptbnet) and non-tuberculous mycobacterial diseases (NTM-NET). In addition to the research activities, TBNET is developing expert consensus documents for clinical management and provides training and capacity building especially for members from Eastern European countries, where tuberculosis is still a prevalent health problem.

Globalisation has activated a new industrial revolution, leading to a worldwide distribution of production and markets. The increasing demands for sustainability, however, have created new challenges and emerging opportunities for society and for business. In line with increasing international trade, the need to transport raw materials, energy, components, intermediate products and goods increases. The traditional transnational ways of manufacturing products and delivering services cannot be sustained in the emerging eco-sensitive business environments, where growing trade volumes and commercial operational patterns impose significant environmental challenges. This is for example evident in the greenhouse gas emission footprint related to production, logistics, transportations and other internationally operating network-related activities. Therefore, the society has to find answers how to design products and services in a more sustainable way.

The paper presents a methodology for the integrated sustainability assessment of a product-service system lifecycle, with the purpose to support continuous improvement on the side both of the manufacturer and of the user. Its eight steps are an extension of ISO 14040 life cycle assessment and consider all three sustainability dimensions – economic, environmental and social – and a service perspective, using the service unit. A set of indicators for the three dimensions, aligned to the service unit concept, is proposed based on literature suggestions.

There is a lack of data on the predictive value of tuberculosis (TB) specific interferon-gamma release assays (TIGRAs) for both immunocompetent and immunocompromised individuals. We retrospectively followed up 460 such patients after QuantiFERON®-TB Gold In-Tube (QFT-GIT) testing (mean follow-up 28 months) by reviewing patient charts. A total of 1/38 QFT-GIT-positive and no QFT-GIT-negative patients developed active TB. The incidence rate of progression to active TB assessed retrospectively in these patients after positive TIGRA was therefore low (1.2 events/100 person-years). The need for careful follow-up and prophylactic therapy after positive TIGRA in this patient group needs to be evaluated prospectively.

Pulmonale nichttuberkulose mykobakterielle (NTM) Erkrankungen sind bei Weitem die haufigsten durch NTM verursachten Krankheiten. Klinisch bedeutend sind die NTM-Lymphadenitis bei Kindern und im Rahmen eines Immunrekonstitutionssyndroms bei HIV-Patienten sowie die NTM-Hauterkrankungen, meist als Aquariumgranulom, verursacht durch Mycobacterium marinum. Im Gegensatz zu Mycobacterium tuberculosis werden NTM in der Regel nicht von Mensch zu Mensch ubertragen, und die Exposition gegenuber NTM aus der Umwelt fuhrt nicht per se zur Infektion und Erkrankung, weswegen nur wenige epidemiologische Daten und veroffentlichte Studien existieren. Neuere Studien zeigen jedoch eine zunehmende Pravalenz der NTM-Lungenerkrankungen in Nordamerika seit Mitte der 1990er-Jahre, wahrend die wenigen Daten aus Nordwesteuropa eine geringere, jedoch ebenfalls ansteigende Inzidenz sowie regionale, bisher unverstandene Unterschiede zeigen. Die Inzidenz der zervikofazialen Lymphadenitis ist am hochsten bei Kindern unter 4 Jahren, die Daten reprasentieren jedoch nur mikrobiologisch bestatigte Falle. Grunde fur die wechselnde und unterschiedliche Epidemiologie werden diskutiert. Die englische Volltextversion dieses Beitrags ist bei SpringerLink (unter „Supplemental“) verfugbar.

We conducted a systematic review and meta-analysis to compare the accuracy of the QuantiFERON-TB® Gold In-Tube (QFT-G-IT) and the T-SPOT®.TB assays with the tuberculin skin test (TST) for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI). The Medline, Embase and Cochrane databases were explored for relevant articles in November 2009. Specificities, and negative (NPV) and positive (PPV) predictive values of interferon-γ release assays (IGRAs) and the TST, and the exposure gradient influences on test results among bacille Calmette-Guérin (BCG) vaccinees were evaluated. Specificity of IGRAs varied 98-100%. In immunocompetent adults, NPV for progression to tuberculosis within 2 yrs were 97.8% for T-SPOT®.TB and 99.8% for QFT-G-IT. When test performance of an immunodiagnostic test was not restricted to prior positivity of another test, progression rates to tuberculosis among IGRA-positive individuals followed for 19-24 months varied 8-15%, exceeding those reported for the TST (2-3%). In multivariate analyses, the odd ratios for TST positivity following BCG vaccination varied 3-25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious tuberculosis cases. IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.

To the Editors: Immunocompromised patients with various causes and degrees of immunodeficiencies, such as stem cell and solid organ transplant recipients, patients with autoimmune diseases, patients with chronic renal failure or HIV-positive patients, are at increased risk of progression from latent Mycobacterium tuberculosis infection to active disease. Therefore, screening for latent tuberculosis and preventive treatment is recommended in this patient population. Tuberculosis-specific interferon (IFN)-γ release assays (TIGRAs) lacking cross-reactivity with Mycobacterium bovis bacille Calmette-Guerin have been introduced into the routine diagnosis of latent tuberculosis infection (LTBI) in the last few years as a more specific alternative to tuberculin skin test (TST). More recent results implicate that QuantiFERON®-TB Gold in tube (QFT-G-IT; Cellestis, Carnegie, Australia) may better predict progression from latent to active disease compared with TST 1, 2. TIGRAs using stimulation of T-cells with phytohemagglutinin (PHA) as a positive control for identification of false negatives and the classification of indeterminate results may be a better alternative for the prediction of LTBI in immunocompromised patients where IFN-γ release may be affected by immunosuppression. The growing list of data existing on reliability of TIGRAs in immunocompromised patients show that the prevalence of indeterminate results may vary depending on the degree of immunosuppression and the TIGRA test used 3. In addition, PHA and recall antigens use different IFN-γ secretion pathways 4, which may be differentially affected by immunosuppressive conditions. Thus, an in-depth analysis of factors influencing PHA-associated IFN-γ secretion is important for the assessment of TIGRAs in immunocompromised patients. Since disease group dependent and independent risk factors of indeterminate results in immunocompromised patients have not been evaluated prospectively using the third generation QFT-G-IT test, we tested QFT-G-IT in patients with diverse conditions of immunosuppression to determine the rate of and identify risk factors for indeterminate results. After approval of …

Summary Objectives To compare a new scoring system for multibacillary (MB) leprosy relapses, which combines time factor, risk factors and clinical presentation at relapse, to WHO criteria. Methods Data were collected on all relapses diagnosed between 1998 and 2004 at the Marie-Adelaide-Centre in Karachi, Pakistan, including case histories, clinical manifestations, follow-up, bacterial indices, treatment and contacts. For the diagnosis of MB relapses a simple scoring system was developed and validated on a data-set of mouse foot pads (MFP)-confirmed relapses (Leprosy Reviews, 76, 2005, 241). Its sensitivity was further evaluated in the Karachi relapse cohort. The P-value was calculated with McNemar’s test with continuity correction. Results The new scoring system that combines time factor, risk factors and clinical presentation at relapse had a higher sensitivity in MFP-confirmed relapses than the WHO-criteria (95%vs. 65%, P

Mycobacterium avium: complex (MAC) lung infections are associated with significant morbidity and mortality. Treatment of NTM lung infection is complicated by lengthy multidrug regimens often associated with drug toxicity and suboptimal outcomes. Liposomal amikacin for inhalation (LAI) is a novel inhaled amikacin formulation in development for the treatment of MAC lung infections. In an initial placebo-controlled study of patients with treatment-refractory NTM lung infections, which studied both MAC and M abscessus , (TR02-112), those who had LAI added to their multidrug regimen produced more negative sputum cultures at Day 84 than those on placebo (25.0% vs 6.7%; P =.01).Study INS-212 will evaluate this further by assessing culture conversion (3 consecutive negative sputum cultures) with longer-term LAI treatment added to multidrug regimens.Up to 351 adults ≥18 years with treatment-refractory MAC lung infection (≥2 positive sputum cultures while on a multidrug regimen for ≥6 months) will be stratified by smoking status and multidrug regimen use, and randomized 2:1 to LAI 590 mg QD added to a multidrug regimen or continued on a multidrug regimen alone.The primary endpoint is the proportion of subjects achieving culture conversion by Month 6. Other endpoints include the 6-minute walk test, patient-reported outcomes, and QOL scores.Converters will continue in the study for 12 months from their first negative culture used to define culture conversion. Subjects exiting study for any reason will be contacted for safety follow-up at Month 12.

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

Comparative assessment of the tuberculin skin testing (TST) and commercial IFN-γ release-assays (IGRAs) is hampered by the use of different antigens (tuberculin PPD in TST vs. ESAT-6/CFP-10 in IGRAs). Thus, PPD was used as a common stimulus to compare performance of the TST and three IGRAs in 72 controls, 101 hemodialysis patients and 100 renal transplant recipients. Results of the TST were compared with PPD-induced IFN-γ induction in vitro detected by ELISPOT, ELISA or a flow-cytometric FACS assay. Percentages of positive tests were significantly lower in TST (9.2%) compared to ELISA (55.3%), ELISPOT (45.3%) and FACS (44.9%, p < 0.0001). Agreement between TST and IGRAs was highest for controls (κ = 0.19-0.32) and poor in immunocompromised patients (κ = 0 for transplant patients, κ = 0.06-0.13 for hemodialysis patients). Discrepant results were largely TST negative and IGRA positive. Among IGRAs, agreement was highest between ELISPOT and FACS (κ = 0.61). Unlike TST, all IGRAs were associated with variables of mycobacterial exposure. Among IGRAs, the FACS assay was least affected by the level of immunosuppression. In conclusion, both the percentage of positive results and between-test-agreement were higher with IGRAs as compared to TST. This indicates superiority of IGRAs in detecting a PPD-specific immune response which may also apply for immunity toward Mycobacterium tuberculosis-specific antigens.

Aims We identified 10 patients with disseminated Mycobacterium chimaera infections subsequent to open-heart surgery at three European Hospitals. Infections originated from the heater–cooler unit of the heart–lung machine. Here we describe clinical aspects and treatment course of this novel clinical entity. Methods and results Interdisciplinary care and follow-up of all patients was documented by the study team. Patients’ characteristics, clinical manifestations, microbiological findings, and therapeutic measures including surgical reinterventions were reviewed and treatment outcomes are described. The 10 patients comprise a 1-year-old child and nine adults with a median age of 61 years (range 36–76 years). The median duration from cardiac surgery to diagnosis was 21 (range 5–40) months. All patients had prosthetic material-associated infections with either prosthetic valve endocarditis, aortic graft infection, myocarditis, or infection of the prosthetic material following banding of the pulmonary artery. Extracardiac manifestations preceded cardiovascular disease in some cases. Despite targeted antimicrobial therapy, M. chimaera infection required cardiosurgical reinterventions in eight patients. Six out of 10 patients experienced breakthrough infections, of which four were fatal. Three patients are in a post-treatment monitoring period. Conclusion Healthcare-associated infections due to M. chimaera occurred in patients subsequent to cardiac surgery with extracorporeal circulation and implantation of prosthetic material. Infections became clinically apparent after a time lag of months to years. Mycobacterium chimaera infections are easily missed by routine bacterial diagnostics and outcome is poor despite long-term antimycobacterial therapy, probably because biofilm formation hinders eradication of pathogens.

Non-tuberculous mycobacteria (NTM) are a large family of acid-fast bacteria, widespread in the environment. In children, NTM cause lymphadenitis, skin and soft tissue infections, and occasionally also lung disease and disseminated infections. These manifestations can be indistinguishable from tuberculosis on the basis of clinical and radiological findings and tuberculin skin testing. A diagnostic and therapeutic problem for respiratory physicians and other clinicians is therefore evident, particularly in settings where childhood tuberculosis is common, and bacteriological confirmation of any mycobacterial disease is difficult because of low availability of laboratory services in low-resource settings and the inherent paucibacillary nature of mycobacterial disease in childhood. The epidemiology of NTM varies by world region, and attempts to understand the burden of NTM disease and to identify risk factors in the paediatric population are hampered by inadequate mandatory NTM reporting and the overlap of clinical presentation with tuberculosis. The immune response to both NTM and Mycobacterium tuberculosis is based on cellular immunity and relies on the type-1 cytokine pathway. The disruption of this immune response by genetic or acquired mechanisms, such as mendelian susceptibility to mycobacterial disease or HIV, might result in predisposition to mycobacterial infections. Published diagnostic and management guidelines do not provide specific advice for diagnosis of NTM in children, from whom the quantity and quality of diagnostic samples are often suboptimum. Treatment of NTM infections is very different from the treatment of tuberculosis, depends on the strain and anatomical site of infection, and often involves antibiotic combinations, surgery, or both. In this Review, we summarise the epidemiological and clinical features of NTM infection in children, with a specific focus on the implications for public health in settings with a high endemic burden of childhood tuberculosis.