Need for caution when interpreting Xpert® MTB/RIF results for rifampin resistance among children.

BACKGROUND: Recommended by the World Health Organization as an initial diagnostic test for TB in children, Xpert® MTB/RIF is widely implemented in many countries, including Kenya.METHODS: Three hundred HIV-positive and negative children (<5 years) were enrolled in Kisumu County, Kenya, from October 2013 to August 2015. Multiple specimen types were collected from each child and tested using Xpert, liquid culture, and phenotypic drug susceptibility testing (DST). Samples positive for rifampin (RIF) resistance on Xpert were tested using line-probe assay and sequencing.RESULTS: Of 32 children with bacteriologically confirmed TB, 27 had positive Xpert results. Of these, 3/27 (11%, 95% CI 4-28) had RIF resistance detected on Xpert, but not by phenotypic DST, line-probe assay, or sequencing. For these three children, five Xpert tests showed RIF resistance; all five tests had semi-quantitative "very low" results and delay or absence of probe D signal, whereas no Xpert results with higher semi-quantitative results showed RIF resistance. All three children responded well to standard TB treatment.CONCLUSIONS: False RIF resistance may be detected in pediatric specimens. Further study is needed to determine if false RIF resistance is associated with low bacterial load.

Detection of Apparent Cell-free M. tuberculosis DNA from Plasma.

New diagnostics are needed to improve clinicians' ability to detect tuberculosis (TB) disease in key populations such as children and persons living with HIV and to rapidly detect drug resistance. Circulating cell-free DNA (ccfDNA) in plasma is a diagnostic target in new obstetric and oncologic applications, but its utility for diagnosing TB is not known. Here we show that Mycobacterium tuberculosis complex DNA can be detected in plasma of persons with sputum smear-positive TB, even in the absence of mycobacteremia. Among 40 participants with bacteriologically-confirmed smear-positive TB disease who had plasma tested by quantitative PCR (qPCR), 18/40 (45%) had a positive result on at least one triplicate reaction. Our results suggest that plasma DNA may be a useful target for improving clinicians' ability to diagnose TB. We anticipate these findings to be the starting point for optimized methods of TB ccfDNA testing and sequence-based diagnostic applications such as molecular detection of drug resistance.

The disconnect between a national tuberculosis drug resistance survey and treatment outcomes: a lost opportunity.

We linked results from the Fourth Botswana National Drug Resistance Survey (DRS), 2007-2008, to patient records from the national Electronic Tuberculosis Registry to determine treatment outcomes. Of 915 new patients, 651 (71%) had treatment data available. Completion or cure was achieved for 10/15 (67%, 95%CI 42-85) with isoniazid monoresistance, (6/16, 38%, 95%CI 18-61) with multidrug resistance, while 73% (391/537, 95%CI 69-76) were susceptible to first-line drugs. The analysis was limited because of unavailable treatment records and undocumented outcomes. Prospective analyses following DRSs should be considered to ensure adequate outcome data.

Using tuberculosis patient characteristics to predict future cases with matching genotype results.

SETTING: United States. BACKGROUND: It is unknown whether tuberculosis (TB) case or patient characteristics can predict the likelihood of future related TB cases. OBJECTIVE: To estimate the likelihood for future related cases, i.e., cases with matching TB genotypes within the same county diagnosed within the 2 years following the year of reporting of each included case. DESIGN: We considered all TB cases with genotyping results reported in the United States during 2004-2010. Predictive scores were calculated based on patient characteristics by dividing the number of patients who were not the last case in a county-level TB genotype cluster by the total number of patients. RESULTS: Overall, there was a 30.8% chance that a future related case would be detected during the 2 years following the report year of any given case. Future related cases were detected in 34.7% of instances following the diagnosis of smear-positive cases, 51.9% of instances following the diagnosis of a homeless patient and 45.2% of instances following the diagnosis of a patient who reported substance abuse. Predictive scores ranged by race (White 13.9%, Native Hawaiian 43.8%) and age group (⩾65 years 13.1%, 0-4 years 43%), and were higher for US-born patients. CONCLUSIONS: Behavioral and sociodemographic factors can help predict the likelihood of future related cases and can be used to prioritize contact investigations.

Contexte : Etats-Unis.Cadre : On ne sait pas si les caractéristiques d'un cas de tuberculose (TB) ou du patient permettent de prévoir la probabilité de contamination dans l'avenir.Objectif : Estimer la probabilité de cas présentant un génotype similaire dans le même conté et dans une période de 2 ans suivant le cas index.Schéma : Nous avons étudié tous les cas de TB avec génotypage déclarés aux Etats-Unis entre 2004 et 2010. Les scores prédictifs ont été calculés en fonction des caractéristiques du patient en divisant le nombre de patients qui n'étaient pas le dernier cas d'un groupement de génotypes au niveau d'un conté par le nombre total de patients.Résultats : Le risque global de nouveau cas lié à un autre cas était de 30,8% pendant les 2 années suivant l'année de déclaration de tout nouveau cas. Ces contaminations ont été détectées dans 34,7% des circonstances après diagnostic d'un cas à frottis positif, 51,9%, après diagnostic d'un patient sans domicile fixe et 45,2%, après diagnostic d'un patient toxicomane. Les scores prédictifs variaient en fonction de l'ethnie (Blancs 13,9% ; Amérindiens/Hawaïens 43,8%), l'âge (>65 ans 13,1% ; 0­4 ans 43%) et étaient plus élevé chez les patients nés aux Etats-Unis.Conclusion: Les facteurs comportementaux et socio-démographiques peuvent contribuer à prévoir la probabilité d'infection de cas dans le futur et peuvent servir à prioriser les recherches de sujets contacts.

Marco de referencia: En los Estados Unidos de América se desconoce si las características clínicas de un caso de tuberculosis (TB) o las características del paciente permiten pronosticar la probabilidad de aparición de futuros casos de TB relacionados.Objectivo: Evaluar la probabilidad de aparición en el futuro de casos relacionados ­ es decir, casos con genotipos equivalentes, diagnosticados en el mismo condado, durante los 2 primeros años después del año de notificación de cada caso incluido.Métodos: Se consideraron en el estudio todos los casos de TB notificados en los Estados Unidos que contaban con resultados de genotipificación entre el 2004 y el 2010. Se calcularon las puntuaciones pronósticas en función de las características del paciente, al dividir el número de pacientes que no fueron el último caso de un conglomerado genotípico de TB a escala del condado, por el número total de pacientes.Resultados: En general, se observó una probabilidad de 30,8% de aparición de un caso relacionado, durante los 2 años que siguieron al año de notificación de cualquier caso dado. Se observaron casos relacionados en el 34,7% de las veces después del diagnóstico de casos con baciloscopia positiva; el 51,9% de las veces después del diagnóstico de una persona sin domicilio; y en el 45,2% de las veces tras el diagnóstico de un paciente que refería consumo de drogas. Las puntuaciones pronósticas oscilaron, con respecto a la etnia, entre 13,9% en la etnia blanca y 43,8% en los nativos de Hawái); con respecto al grupo de edad, entre 13,1% a partir de los 65 años y 43% en el grupo entre 0 años y 4 años; y el índice pronóstico fue más alto en los pacientes nacidos en los Estados Unidos.Conclusión: Los factores comportamentales y sociodemográficos contribuyen a predecir la probabilidad de aparición de casos futuros relacionados con un caso de TB y se pueden utilizar con el propósito de priorizar las investigaciones de contactos.

Association between Mycobacterium tuberculosis lineage and time to sputum culture conversion.

SETTING: Mycobacterium tuberculosis comprises four principal genetic lineages: one evolutionarily ancestral (Indo-Oceanic) and three modern. Whether response to tuberculosis (TB) treatment differs among the lineages is unknown. OBJECTIVE: To examine the association between M. tuberculosis lineage and time to sputum culture conversion in response to standard first-line drug therapy. DESIGN: We conducted an exploratory retrospective cohort analysis of time to sputum culture conversion among pulmonary tuberculosis (PTB) cases reported in the United States from 2004 to 2007. RESULTS: The analysis included 13,170 PTB cases with no documented resistance to first-line drugs who received a standard four-drug treatment regimen. Among cases with baseline positive sputum smear results, relative to cases with Euro-American lineage, cases with Indo-Oceanic lineage had higher adjusted hazards of sputum culture conversion (aHR 1.32, 95%CI 1.20-1.45), whereas cases with East-African-Indian or East-Asian lineage did not differ (aHR 1.05, 95%CI 0.88-1.25 and aHR 0.99, 95%CI 0.91-1.07, respectively). Among cases with baseline negative sputum smear results, time to sputum culture conversion did not differ by lineage. CONCLUSION: Although these results are exploratory, they suggest that the eradication of viable bacteria may occur sooner among cases with Indo-Oceanic lineage than among those with one of the three modern lineages. Prospective studies of time to sputum culture conversion by lineage are required.

Evaluation of integrated registers for tuberculosis and HIV surveillance in children, Ethiopia, 2007-2009.

In 2008, Ethiopia implemented tuberculosis (TB) treatment registers that included columns for recording human immunodeficiency virus (HIV) test results (integrated registers) to replace the previous system of separate TB and HIV registers (pre-integration registers). We compared the proportion of children with documented HIV rapid test results at eight hospitals before and after adopting the integrated registers. HIV status was more consistently documented in the integrated registers; however, HIV status for infants aged <18 months could not be assessed, as the registers did not capture results from polymerase chain reaction-based testing. Recording procedures should be revised to document age-appropriate HIV diagnostic results and ensure referral for appropriate care.