MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era.

BACKGROUND: Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini. METHODS: We investigate the evolution and spread of MDR strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole-genome sequencing in two collections ((1) national drug resistance survey, 2009-2010; (2) MDR strains from the Nhlangano region, 2014-2017). RESULTS: MDR strains in collection 1 had a high cluster rate (95%, 117/123 MDR strains) with 55% grouped into the two largest clusters (gCL3, n = 28; gCL10, n = 40). All gCL10 isolates, which likely emerged around 1993 (95% highest posterior density 1987-1998), carried the mutation RpoB I491F that is missed by commercial mDST assays. In addition, 21 (53%) gCL10 isolates shared a Rv0678 M146T mutation that correlated with elevated minimum inhibitory concentrations (MICs) to BDQ and CFZ compared to wild type isolates. gCL10 isolates with the Rv0678 M146T mutation were also detected in collection 2. CONCLUSION: The high clustering rate suggests that transmission has been driving the MDR-TB epidemic in Eswatini for three decades. The presence of MDR strains in Eswatini that are not detected by commercial mDST assays and have elevated MICs to BDQ and CFZ potentially jeopardizes the successful implementation of new MDR-TB treatment guidelines. Measures to limit the spread of these outbreak isolates need to be implemented urgently.

Systematic, Point-of-Care Urine Lipoarabinomannan (Alere TB-LAM) Assay for Diagnosing Tuberculosis in Severely Immunocompromised HIV-Positive Ambulatory Patients.

Point-of-care urine-lipoarabinomannan (LAM) Alere Determine TB-LAM assay has shown utility diagnosing tuberculosis (TB) in HIV-positive, severely immunocompromised, TB-symptomatic patients. We assessed LAM results in severely immunocompromised patients, who had LAM systematically performed at new or follow-up HIV consultations. This was a prospective, observational study on consecutive ambulatory, > 15-year-old HIV-positive patients with CD4 < 100 cells/µL in Mozambique. Clinical assessments and LAM were performed for all and microscopy, Xpert, sputum culture, and chest X-ray for LAM-positive participants. Patients were followed up for 6 months. Of 360 patients, half were ART-naive. Lipoarabinomannan positivity was 11.9% (43/360), higher among symptomatic patients compared with asymptomatic: 18.5% (30/162), and 6.6% (13/198), respectively, P = 0.001. Tuberculosis was bacteriologically confirmed in 6/35 LAM-positive patients (2 of them asymptomatic). Lipoarabinomannan positivity was associated with higher risk of mortality (adjusted odds ratio [aOR]: 4.6, 95% CI: 1.3-15.6, P = 0.015). Systematic urine-LAM allows for rapid TB treatment initiation in severely immunocompromised HIV ambulatory patients and identifies patients at a higher risk of death.

Diagnostic value of the urine lipoarabinomannan assay in HIV-positive, ambulatory patients with CD4 below 200 cells/µl in 2 low-resource settings: A prospective observational study.

BACKGROUND: Current guidelines recommend the use of the lateral flow urine lipoarabinomannan assay (LAM) in HIV-positive, ambulatory patients with signs and symptoms of tuberculosis (TB) only if they are seriously ill or have CD4 count ≤ 100 cells/µl. We assessed the diagnostic yield of including LAM in TB diagnostic algorithms in HIV-positive, ambulatory patients with CD4 < 200 cells/µl, as well as the risk of mortality in LAM-positive patients who were not diagnosed using other diagnostic tools and not treated for TB. METHODS AND FINDINGS: We conducted a prospective observational study including HIV-positive adult patients with signs and symptoms of TB and CD4 < 200 cells/µl attending 6 health facilities in Malawi and Mozambique. Patients were included consecutively from 18 September 2015 to 27 October 2016 in Malawi and from 3 December 2014 to 22 August 2016 in Mozambique. All patients had a clinical exam and LAM, chest X-ray, sputum microscopy, and Xpert MTB/RIF assay (Xpert) requested. Culture in sputum was done for a subset of patients. The diagnostic yield was defined as the proportion of patients with a positive assay result among those with laboratory-confirmed TB. For the 456 patients included in the study, the median age was 36 years (IQR 31-43) and the median CD4 count was 50 cells/µl (IQR 21-108). Forty-five percent (205/456) of the patients had laboratory-confirmed TB. The diagnostic yields of LAM, microscopy, and Xpert were 82.4% (169/205), 33.7% (69/205), and 40.0% (84/205), respectively. In total, 50.2% (103/205) of the patients with laboratory-confirmed TB were diagnosed only through LAM. Overall, the use of LAM in diagnostic algorithms increased the yield of algorithms with microscopy and with Xpert by 38.0% (78/205) and 34.6% (71/205), respectively, and, specifically among patients with CD4 100-199 cells/µl, by 27.5% (14/51) and 29.4% (15/51), respectively. LAM-positive patients not diagnosed through other tools and not treated for TB had a significantly higher risk of mortality than LAM-positive patients who received treatment (adjusted risk ratio 2.57, 95% CI 1.27-5.19, p = 0.009). Although the TB diagnostic conditions in the study sites were similar to those in other resource-limited settings, the added value of LAM may depend on the availability of microscopy or Xpert results. CONCLUSIONS: LAM has diagnostic value for identifying TB in HIV-positive patients with signs and symptoms of TB and advanced immunodeficiency, including those with a CD4 count of 100-199 cells/µl. In this study, the use of LAM enabled the diagnosis of TB in half of the patients with confirmed TB disease; without LAM, these patients would have been missed. The rapid identification and treatment of TB enabled by LAM may decrease overall mortality risk for these patients.

High prevalence of infection and low incidence of disease in child contacts of patients with drug-resistant tuberculosis: a prospective cohort study.

OBJECTIVE: We aimed to measure the prevalence and incidence of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease in children in close contact with patients with drug-resistant TB (DR-TB) in a country with high DR-TB prevalence. DESIGN AND SETTING: This is a prospective cohort study of paediatric contacts of adult patients with pulmonary DR-TB in Armenia. Children were screened using tuberculin skin test, interferon-gamma release assay and chest X-ray at the initial consultation, and were reassessed every 3-6 months for a period of 24 months. Children did not receive preventive treatment. MAIN OUTCOME MEASURES: Prevalence and incidence of LTBI and TB disease; factors associated with prevalent LTBI. RESULTS: At initial evaluation, 3 of the 150 children included were diagnosed with TB disease (2.0%). The prevalence of LTBI was 58.7%. The incidence of LTBI was 19.9 per 100 children per year, and was especially high during the first 6 months of follow-up (33.3 per 100 children per year). No additional cases with incident disease were diagnosed during follow-up. After adjustment, prevalent LTBI was significantly associated with the child's age, sleeping in the same house, higher household density, the index case's age, positive smear result and presence of lung cavities. CONCLUSIONS: Children in close contact with patients with DR-TB or in contact with very contagious patients had an increased risk of prevalent LTBI. Although none of the children developed TB disease during a 2-year follow-up period, screening for symptoms of TB disease, based on the prevalence of disease at recruitment, together with follow-up and repeated testing of non-infected contacts, is highly recommended in paediatric contacts of patients with DR-TB.

Outcomes of HIV-infected versus HIV-non-infected patients treated for drug-resistance tuberculosis: Multicenter cohort study.

BACKGROUND: The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance. METHODS: We retrospectively reported and compared the DR-TB treatment outcomes of HIV-positive and HIV-negative patients treated with an individualized regimen based on WHO guidelines in seven countries: Abkhazia, Armenia, Colombia, Kenya, Kyrgyzstan, Swaziland and Uzbekistan. RESULTS: Of the 1,369 patients started DRTB treatment, 809 (59.1%) were multi-drug resistant (MDR-TB) and 418 (30.5%) were HIV-positive. HIV-positive patients were mainly from African countries (90.1%) while HIV-negative originated from Former Soviet Union (FSU) countries. Despite a higher case fatality rate (19.0% vs 9.4%), HIV-positive MDR-TB patients had a 10% higher success rate than HIV-negative patients (64.0% vs 53.2%, p = 0.007). No difference in treatment success was found among polydrug-resistant (PDR-TB) patients. Overall, lost to follow-up rate was much higher among HIV-negative (22.0% vs. 8.4%). Older age and not receiving ART were the only factors associated with unfavorable treatment outcome among HIV-positive patients. CONCLUSIONS: As already known for HIV-negative patients, success rate of DR-TB HIV-positive patients remains low and requires more effective DR-TB regimen using new drugs also suitable to HIV-infected patients on ART. The study also confirms the need of ART introduction in HIV co-infected patients.

Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages.

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.

Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage.

Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.

Effects of treatment interruption patterns on treatment success among patients with multidrug-resistant tuberculosis in Armenia and Abkhazia.

BACKGROUND: The success of the current treatment regimen for multidrug-resistant (MDR) tuberculosis is poor partly owing to a high default rate. Many studies have explored predictors of poor outcomes, but very few have assessed the effects of treatment interruptions on treatment outcomes for MDR tuberculosis. METHODS: We conducted a retrospective analysis among patients with MDR tuberculosis enrolled in 2 MDR tuberculosis programs using regimens recommended by the World Health Organization under directly observed therapy. Treatment outcomes were defined as successful if the patient was cured or completed treatment and unsuccessful if the patient died or defaulted from treatment or if treatment failed. The effect of patterns of interruptions on treatment outcomes was assessed through multivariate logistic regression. RESULTS: A total of 393 patients with MDR tuberculosis were included in the study; 171 (43.5%) had a successful outcome, and 222 (56.5%) an unsuccessful outcome: 39 (9.9%) died, 56 (14.3%) had failed treatment, and 127 (32.3%) defaulted from treatment. In multivariate analysis, long interruptions (≥3 days) (adjusted odds ratio, 3.87; 95% confidence interval, 1.66-8.98) and short gaps (<10 days) between interruptions (3.94; 1.76-8.81) were independently associated with an unsuccessful treatment outcome. DISCUSSION: This study shows that in a directly observed therapy-based MDR tuberculosis program, treatment interruptions at short intervals of ≥3 days directly affect treatment outcome.

High prevalence of multidrug-resistant tuberculosis, Swaziland, 2009-2010.

In Africa, although emergence of multidrug-resistant (MDR) tuberculosis (TB) represents a serious threat in countries severely affected by the HIV epidemic, most countries lack drug-resistant TB data. This finding was particularly true in the Kingdom of Swaziland, which has the world's highest HIV and TB prevalences. Therefore, we conducted a national survey in 2009-2010 to measure prevalence of drug-resistant TB. Of 988 patients screened, 420 new case-patients and 420 previously treated case-patients met the study criteria. Among culture-positive patients, 15.3% new case-patients and 49.5% previously treated case-patients harbored drug-resistant strains. MDR TB prevalence was 7.7% and 33.8% among new case-patients and previously treated case-patients, respectively. HIV infection and past TB treatment were independently associated with MDR TB. The findings assert the need for wide-scale intervention in resource-limited contexts such as Swaziland, where diagnostic and treatment facilities and health personnel are lacking.

The Colombian conflict: a description of a mental health program in the Department of Tolima.

Colombia has been seriously affected by an internal armed conflict for more than 40 years affecting mainly the civilian population, who is forced to displace, suffers kidnapping, extortion, threats and assassinations. Between 2005 and 2008, Médecins Sans Frontières-France provided psychological care and treatment in the region of Tolima, a strategic place in the armed conflict. The mental health program was based on a short-term multi-faceted treatment developed according to the psychological and psychosomatic needs of the population. Here we describe the population attending during 2005-2008, in both urban and rural settings, as well as the psychological treatment provided during this period and its outcomes.We observed differences between the urban and rural settings in the traumatic events reported, the clinical expression of the disorders, the disorders diagnosed, and their severity. Although the duration of the treatment was limited due to security reasons and access difficulties, patient condition at last visit improved in most of the patients. These descriptive results suggest that further studies should be conducted to examine the role of short-term psychotherapy, adapted specifically to the context, can be a useful tool to provide psychological care to population affected by an armed conflict.

Burden of disease and circulating serotypes of rotavirus infection in sub-Saharan Africa: systematic review and meta-analysis.

Two new rotavirus vaccines have recently been licensed in many countries. However, their efficacy has only been shown against certain serotypes commonly circulating in Europe, North America, and Latin America, but thought to be globally important. To assess the potential impact of these vaccines in sub-Saharan Africa, where rotavirus mortality is high, knowledge of prevalent types is essential because an effective rotavirus vaccine is needed to protect against prevailing serotypes in the community. We did two systematic reviews and two meta-analyses of the most recent published data on the burden of rotavirus disease in children aged under 5 years and rotavirus serotypes circulating in countries in sub-Saharan Africa. Eligible studies were selected from PubMed/Medline, Cochrane Library, EmBase, LILACS, Academic Search Premier, Biological Abstracts, ISI Web of Science, and the African Index Medicus. Depending on the heterogeneity, DerSimonian-Laird random-effects or fixed-effects models were used for meta-analyses. Geographical variability in rotavirus burden within countries in sub-Saharan Africa is substantial, and most countries lack information on rotavirus epidemiology. We estimated that annual mortality for this region was 243.3 (95% CI 187.6-301.7) deaths per 100,000 under 5 years (ie, a total of 300,000 children die of rotavirus infection in this region each year). The most common G type detected was G1 (34.9%), followed by G2 (9.1%), and G3 (8.6%). The most common P types detected were P[8] (35.5%) and P[6] (27.5%). Accurate information should be collected from surveillance based on standardised methods in these countries to obtain comparable data on the burden of disease and the circulating strains to assess the potential impact of vaccine introduction.

[Profile of paediatric admissions and emergencies during an epidemic period of rotavirus in Valladolid [Spain]. Utility of a predictive model]. / Perfil de ingresos y urgencias pediátricas en período epidémico de rotavirus en Valladolid. Utilidad de un modelo predictivo.

INTRODUCTION: The aim of this study was to determine the weeks of high rotavirus circulation in Valladolid (Spain) and to compare the characteristics of hospitalizations and emergencies in epidemic and nonepidemic periods. METHODS: The information sources consisted of the weekly notifications to the Microbiological Information System, the Minimum Data Set, and the Emergency Registry. Expected cases for 2006 were calculated using a previously developed model. Weeks with observed cases over the upper limit of the 95% confidence interval for expected cases were considered epidemic periods. Hospitalization and emergencies in epidemic and nonepidemic periods were compared. RESULTS: The number of cases in 2006 was 42% less than the expected number. The mean number of daily admissions was higher in epidemic periods (d=1.49; p=0.01) and the length of admissions was longer. CONCLUSION: The activity of the paediatric service increased during the epidemic period. Consequently, implementation of surveillance activities and prevention and control programs for rotavirus in hospitals would seem advisable.

Perfil de ingresos y urgencias pediátricas en período epidémico de rotavirus en Valladolid. Utilidad de un modelo predictivo / Profile of paediatric admissions and emergencies during an epidemic period of rotavirus in Valladolid [Spain]. Utility of a predictive model

Introducción: Este estudio pretende determinar las semanas de alta circulación de rotavirus en valladolid, y comparar las características de los ingresos y urgencias en período epidémico con respecto al período no epidémico.Métodos: Se utilizaron las declaraciones al sistema de información microbiológica, el conjunto mínimo básico de datos y el registro de urgencias. Se calcularon los casos esperados para 2006 a partir de un modelo elaborado previamente. Si los casos observados superaban el umbral superior del 95% de los esperados, la semana se consideró epidémica. Se compararon las características de los ingresos y urgencias en ambos períodos.Resultados: En 2006 se diagnosticaron un 42% menos de los casos esperados. La media de ingresos diarios fue superior en período epidémico (diferencia=1,49; p=0,01), y también fue mayor la duración media del ingreso.Conclusión: La actividad del servicio de pediatría se incrementó en período epidémico, por lo que es oportuna la implantación de actividades de vigilancia, programas de prevención y control frente a rotavirus en el ámbito hospitalario(AU)

Introduction: The aim of this study was to determine the weeks of high rotavirus circulation in Valladolid (Spain) and to compare the characteristics of hospitalizations and emergencies in epidemic and nonepidemic periods.Methods: The information sources consisted of the weekly notifications to the Microbiological Information System, the Minimum Data Set, and the Emergency Registry. Expected cases for 2006 were calculated using a previously developed model. Weeks with observed cases over the upper limit of the 95% confidence interval for expected cases were considered epidemic periods. Hospitalization and emergencies in epidemic and nonepidemic periods were compared.Results: The number of cases in 2006 was 42% less than the expected number. The mean number of daily admissions was higher in epidemic periods (d=1.49; p=0.01) and the length of admissions was longer.Conclusion: The activity of the paediatric service increased during the epidemic period. Consequently, implementation of surveillance activities and prevention and control programs for rotavirus in hospitals would seem advisable(AU)

[Opinion and Participation in the Regional Early Breast Cancer Detection Program in 2007 on the part of family physicians from a health district in the Autonomous Community of Madrid, Spain]. / Opinión y participación de los médicos de familia de la Comunidad de Madrid en el Programa Regional de Detección Precoz de Cáncer de Mama en 2007.

BACKGROUND: Mammogram screening is the most effective method for the early detection of breast cancer. The objective of this study is to evaluate the degree of knowledge, the opinion and the participation in the early breast cancer detection program on the part of the family physicians of the Autonomous Community of Madrid. METHODS: The population studied was comprised of family physicians from Madrid Health District Seven. An anonymous, self-administered questionnaire comprised of 30 questions grouped into physicians characteristics and opinion concerning the early breast cancer detection programs. RESULTS: A total of 46% of the physicians replied. A total of 94% of the physicians believed that it is their duty to inform their patients concerning preventive activities, including breast cancer screening, and 95% believed their advice to be useful for convincing women to have a mammogram. A total of 72% believed information to be lacking on this program. During the time when mammograms are being taken at their centres, 24% of the physicians surveyed always or almost always ask the women if they have any doubts or would like further information, 43% having set up appointments for them and 95% advising them to have a mammogram taken. CONCLUSIONS: The family physicians have a good opinion of the early breast cancer detection program and feel their advice to be effective for improving the participation in the program. They report lack of information and inform women about the program to only a small degree.

Opinión y participación de los médicos de familia de la Comunidad de Madrid en el programa regional de detección precoz de cáncer de mama en 2007 / Opinion and participation in the regional early breast cancer detection program in 2007 on the part of family physicians from a health district in the Autonomous Community of Madrid, Spain

Fundamento: La mamografía de cribado es el método más efectivo para la detección precoz de cáncer de mama. El objetivo de nuestro estudio es valorar el grado de conocimiento, opinión y participación de los médicos de familia de la Comunidad de Madrid en el programa de detección precoz de cáncer de mama. Métodos: La población de estudio fueron los médicos de familia del Area 7 de Madrid. Se diseñó un cuestionario anónimo autoadministrado, con 30 preguntas, agrupadas en características del médico, y opinión sobre los programas de detección precoz de cáncer de mama. Resultados: Se obtuvo un respuesta del 46%. El 94% de los médicos creen que es función suya informar a sus pacientes acerca de las actividades preventivas, incluidas el cribado de cáncer de mama, y el 95% creen que su consejo es útil para convencer a las mujeres a que se realicen una mamografía. El 72% cree que le falta información sobre el programa. Durante el periodo de realización de mamografías en su centro, el 24% pregunta siempre o casi siempre a las mujeres si tienen dudas o quieren más información, el 43% si les ha llegado la citación y el 95% les aconsejan que se realicen la mamografía. Conclusiones: Los médicos de familia tienen buena opinión del programa de detección precoz de cáncer de mama, y creen en la efectividad de su consejo para mejorar la participación en él. Refieren falta de información, y en pocas ocasiones informan a la mujer sobre el programa (AU)

Background: Mammogram screening is the most effective method for the early detection of breast cancer. The objective of this study is to evaluate the degree of knowledge, the opinion and the participation in the early breast cancer detection program on the part of the family physicians of the Autonomous Community of Madrid. Methods: The population studied was comprised of family physicians from Madrid Health District Seven. An anonymous, self-administered questionnaire comprised of 30 questions grouped into physician’s characteristics and opinion concerning the early breast cancer detection programs. Results: A total of 46% of the physicians replied. A total of 94% of the physicians believed that it is their duty to inform their patients concerning preventive activities, including breast cancer screening, and 95% believed their advice to be useful for convincing women to have a mammogram. A total of 72% believed information to be lacking on this program. During the time when mammograms are being taken at their centres, 24% of the physicians surveyed always or almost always ask the women if they have any doubts or would like further information, 43% having set up appointments for them and 95% advising them to have a mammogram taken. Conclusions: The family physicians have a good opinion of the early breast cancer detection program and feel their advice to be effective for improving the participation in the program. They report lack of information and inform women about the program to only a small degree (AU)

[Trend and seasonal variations of Campylobacter gastroenteritis in Valladolid, Spain. A five-year series, 2000-2004]. / Tendencia y variaciones estacionales de las gastroenteritis por Campylobacter en Valladolid. Serie de cinco años: 2000-2004.

BACKGROUND: Campylobacter is one of the main enteric pathogens, nevertheless many aspects of its epidemiology still are not well known. This study aims to analyze the trend and seasonal pattern in Valladolid. METHODS: A time series analysis was developed using an additive model. The information sources were the reports to the Microbiological Information System from the main hospitals in Valladolid. Patients who showed a positive coproculture to Campylobacter spp. in the period 2000-2004 were considered cases. Trend, seasonal coefficients, incidence rates by age, sex and year of notification and incidence rate ratios were calculated. RESULTS: A decreasing trend in reported cases was observed. A significant seasonal coefficient was obtained in the 6th four-week period (c=12,854, p = 0.023). The incidence rate was higher among those under five years of age and among males, rising up to 1841.9 cases (95% CI: 1797.2-1889.6) and 99.7 cases (95% CI: 96.9-102.4) per 100,000 inhabitants-year respectively. CONCLUSIONS: Campylobacter infections occurs to a greater extent in late springtime, affecting mainly children. It is necessary to delve deeper into the knowledge of the epidemiology of this microorganism at the local level with a multidisciplinary approach, taking both microbiological and epidemiological aspects into account.