Background
Every year, at least one million children become ill with tuberculosis and around 200,000 children die. Xpert MTB/RIF and Xpert Ultra are World Health Organization (WHO)‐recommended rapid ...molecular tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with signs and symptoms of tuberculosis, at lower health system levels. To inform updated WHO guidelines on molecular assays, we performed a systematic review on the diagnostic accuracy of these tests in children presumed to have active tuberculosis.
Objectives
Primary objectives
• To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for (a) pulmonary tuberculosis in children presumed to have tuberculosis; (b) tuberculous meningitis in children presumed to have tuberculosis; (c) lymph node tuberculosis in children presumed to have tuberculosis; and (d) rifampicin resistance in children presumed to have tuberculosis
‐ For tuberculosis detection, index tests were used as the initial test, replacing standard practice (i.e. smear microscopy or culture)
‐ For detection of rifampicin resistance, index tests replaced culture‐based drug susceptibility testing as the initial test
Secondary objectives
• To compare the accuracy of Xpert MTB/RIF and Xpert Ultra for each of the four target conditions
• To investigate potential sources of heterogeneity in accuracy estimates
‐ For tuberculosis detection, we considered age, disease severity, smear‐test status, HIV status, clinical setting, specimen type, high tuberculosis burden, and high tuberculosis/HIV burden
‐ For detection of rifampicin resistance, we considered multi‐drug‐resistant tuberculosis burden
• To compare multiple Xpert MTB/RIF or Xpert Ultra results (repeated testing) with the initial Xpert MTB/RIF or Xpert Ultra result
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry up to 29 April 2019, without language restrictions.
Selection criteria
Randomized trials, cross‐sectional trials, and cohort studies evaluating Xpert MTB/RIF or Xpert Ultra in HIV‐positive and HIV‐negative children younger than 15 years. Reference standards comprised culture or a composite reference standard for tuberculosis and drug susceptibility testing or MTBDRplus (molecular assay for detection of Mycobacterium tuberculosis and drug resistance) for rifampicin resistance. We included studies evaluating sputum, gastric aspirate, stool, nasopharyngeal or bronchial lavage specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), fine needle aspirates, or surgical biopsy tissue (lymph node tuberculosis).
Data collection and analysis
Two review authors independently extracted data and assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy ‐ Revised (QUADAS‐2). For each target condition, we used the bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We assessed certainty of evidence using the GRADE approach.
Main results
For pulmonary tuberculosis, 299 data sets (68,544 participants) were available for analysis; for tuberculous meningitis, 10 data sets (423 participants) were available; for lymph node tuberculosis, 10 data sets (318 participants) were available; and for rifampicin resistance, 14 data sets (326 participants) were available. Thirty‐nine studies (80%) took place in countries with high tuberculosis burden. Risk of bias was low except for the reference standard domain, for which risk of bias was unclear because many studies collected only one specimen for culture.
Detection of pulmonary tuberculosis
For sputum specimens, Xpert MTB/RIF pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 64.6% (55.3% to 72.9%) (23 studies, 493 participants; moderate‐certainty evidence) and 99.0% (98.1% to 99.5%) (23 studies, 6119 participants; moderate‐certainty evidence). For other specimen types (nasopharyngeal aspirate, 4 studies; gastric aspirate, 14 studies; stool, 11 studies), Xpert MTB/RIF pooled sensitivity ranged between 45.7% and 73.0%, and pooled specificity ranged between 98.1% and 99.6%.
For sputum specimens, Xpert Ultra pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 72.8% (64.7% to 79.6%) (3 studies, 136 participants; low‐certainty evidence) and 97.5% (95.8% to 98.5%) (3 studies, 551 participants; high‐certainty evidence). For nasopharyngeal specimens, Xpert Ultra sensitivity (95% CI) and specificity (95% CI) were 45.7% (28.9% to 63.3%) and 97.5% (93.7% to 99.3%) (1 study, 195 participants).
For all specimen types, Xpert MTB/RIF and Xpert Ultra sensitivity were lower against a composite reference standard than against culture.
Detection of tuberculous meningitis
For cerebrospinal fluid, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 54.0% (95% CI 27.8% to 78.2%) (6 studies, 28 participants; very low‐certainty evidence) and 93.8% (95% CI 84.5% to 97.6%) (6 studies, 213 participants; low‐certainty evidence).
Detection of lymph node tuberculosis
For lymph node aspirates or biopsies, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 90.4% (95% CI 55.7% to 98.6%) (6 studies, 68 participants; very low‐certainty evidence) and 89.8% (95% CI 71.5% to 96.8%) (6 studies, 142 participants; low‐certainty evidence).
Detection of rifampicin resistance
Xpert MTB/RIF pooled sensitivity and specificity were 90.0% (67.6% to 97.5%) (6 studies, 20 participants; low‐certainty evidence) and 98.3% (87.7% to 99.8%) (6 studies, 203 participants; moderate‐certainty evidence).
Authors' conclusions
We found Xpert MTB/RIF sensitivity to vary by specimen type, with gastric aspirate specimens having the highest sensitivity followed by sputum and stool, and nasopharyngeal specimens the lowest; specificity in all specimens was > 98%. Compared with Xpert MTB/RIF, Xpert Ultra sensitivity in sputum was higher and specificity slightly lower. Xpert MTB/RIF was accurate for detection of rifampicin resistance. Xpert MTB/RIF was sensitive for diagnosing lymph node tuberculosis. For children with presumed tuberculous meningitis, treatment decisions should be based on the entirety of clinical information and treatment should not be withheld based solely on an Xpert MTB/RIF result. The small numbers of studies and participants, particularly for Xpert Ultra, limits our confidence in the precision of these estimates.
This study identified factors associated with adherence to a 6-month isoniazid preventive therapy (IPT) course among adolescents and children living with HIV. Forty adolescents living with HIV and 48 ...primary caregivers of children living with HIV completed a Likert-based survey to measure respondent opinions regarding access to care, quality of care, preferred regimens, perceived stigma, and confidence in self-efficacy. Sociodemographic data were collected and adherence measured as the average of pill counts obtained while on IPT. The rates of suboptimal adherence (< 95% adherent) were 22.5% among adolescents and 37.5% among the children of primary caregivers. Univariate logistic regression was used to model the change in the odds of suboptimal adherence. Independent factors associated with suboptimal adherence among adolescents included age, education level, the cost of coming to clinic, stigma from community members, and two variables relating to self-efficacy. Among primary caregivers, child age, concerns about stigma, and location preference for meeting a community-health worker were associated with suboptimal adherence. To determine whether these combined factors contributed different information to the prediction of suboptimal adherence, a risk score containing these predictors was constructed for each group. The risk score had an AUC of 0.87 (95% CI: 0.76, 0.99) among adolescents and an AUC of 0.76 (95% CI: 0.62, 0.90), among primary caregivers suggesting that these variables may have complementary predictive utility. The heterogeneous scope and associations of these variables in different populations suggests that interventions aiming to increase optimal adherence will need to be tailored to specific populations and multifaceted in nature. Ideally interventions should address both long-established barriers to adherence such as cost of transportation to attend clinic and more nuanced psychosocial barriers such as perceived community stigma and confidence in self-efficacy.
The present study explored what effect manufacturing has on the antioxidant properties of teas coming from a single cultivar but processed differently to give a white, two black (Orthodox and CTC) ...and two green (low-caffeine and non-decaffeinated) teas. Total phenol (TPC), flavonoids (TFC), theaflavins, individual catechins content, and chelating activity were also investigated. Using the ABTS, ORAC and LDL assays the following ‘antioxidant profile’ was obtained: green≥low-caffeine green>white≥black Orthodox>black CTC, with statistically significant correlation between ORAC and LDL assays (r2=0.444, p=0.0067), whereas TPC and TFC significantly correlate with the ABTS one (r2=0.871, p=0.000 and r2=0.438, p=0.007, respectively). Metal chelating activity, which was lowest in the green teas, does not correlate with antioxidant activity but appears to be influenced by theaflavins content. The results contribute to better understand how the manufacturing process influences the antioxidant activity of tea when variables (geographical region, environmental conditions, cultivar type, plucking techniques) are kept to a minimum. Secondly, we show that novel African green, white and black Orthodox teas, made from tea varieties typically used in black CTC tea production, may have potential health benefits comparable with commonly consumed teas.
► Antioxidant activity (AA) of tea from same cultivar but processed differently. ► When tea processing is the only variable, AA is highest in green tea. ► AA correlates with total phenol, flavonoid and catechins content. ► Metal-chelating activity correlates with total theaflavin content. ► Novel African green, white and black orthodox teas have potential health benefits.
In a human immunodeficiency virus (HIV) clinic for children and their families in Eswatini, we sought to understand the use of antibiotics and identify specific areas for improvement. We performed a ...retrospective patient chart review as part of a quality improvement (QI) initiative to assess antimicrobial use before and after implementation of a standardized antimicrobial guide. For each prescribing period, 100 random patient encounters were selected for review if the indication for antibiotics, duration, and dose were consistent with World Health Organization (WHO) guidelines. Two physicians reviewed each encounter using a structured abstraction tool, with a third resolving discrepancies. Results were analyzed using a chi-square test of proportions and a structured survey was performed to assess perceptions of the guide. After the implementation of an antimicrobial guide, there was a significant decrease in the proportion of clinic visits with an antibiotic prescribed (p < 0.001). Incorrect indication for antimicrobial use decreased from 20.4% in the initial period to 10.31% and 10.2% but did not reach significance (p = .0621) in the subsequent periods after implementation. Incorrect dose/duration decreased from 10.47% in the initial period to 7.37% and 3.1% in the subsequent periods, but this was also was not significant (p = 0.139). All prescribers who completed the survey felt that it positively impacted their prescribing. Our study found that an antimicrobial guide reduced and improved the prescription of antimicrobials, demonstrating practical solutions can have a lasting impact on prescribing in low resource settings.
Pregnant women experience increased morbidity and mortality after influenza infection, for reasons that are not understood. Although some data suggest that natural killer (NK)- and T-cell responses ...are suppressed during pregnancy, influenza-specific responses have not been previously evaluated. Thus, we analyzed the responses of women that were pregnant ( n = 21) versus those that were not ( n = 29) immediately before inactivated influenza vaccination (IIV), 7 d after vaccination, and 6 wk postpartum. Expression of CD107a (a marker of cytolysis) and production of IFN-γ and macrophage inflammatory protein (MIP) 1β were assessed by flow cytometry. Pregnant women had a significantly increased percentage of NK cells producing a MIP-1β response to pH1N1 virus compared with nonpregnant women pre-IIV median, 6.66 vs. 0.90% ( P = 0.0149) and 7 d post-IIV median, 11.23 vs. 2.81% ( P = 0.004), indicating a heightened chemokine response in pregnant women that was further enhanced by the vaccination. Pregnant women also exhibited significantly increased T-cell production of MIP-1β and polyfunctionality in NK and T cells to pH1N1 virus pre- and post-IIV. NK- and T-cell polyfunctionality was also enhanced in pregnant women in response to the H3N2 viral strain. In contrast, pregnant women had significantly reduced NK- and T-cell responses to phorbol 12-myristate 13-acetate and ionomycin. This type of stimulation led to the conclusion that NK- and T-cell responses during pregnancy are suppressed, but clearly this conclusion is not correct relative to the more biologically relevant assays described here. Robust cellular immune responses to influenza during pregnancy could drive pulmonary inflammation, explaining increased morbidity and mortality.
Significance Pregnant women are subject to increased morbidity and mortality after influenza-virus infection. Pregnancy-induced suppression of the cellular immune system to promote fetal tolerance has been suggested as a potential mechanism. Here, we report that, whereas pregnant women indeed have decreased natural killer (NK)- and T-cell functional responses after nonspecific stimulation with phorbol 12-myristate 13-acetate and ionomycin, they have significantly increased NK- and T-cell responses to influenza virus compared with nonpregnant women. Intriguingly, these differences were present prior to influenza vaccination and were further enhanced after vaccination. Collectively, our data suggest a model in which an enhanced inflammatory response to influenza during pregnancy results in additional pathology in pregnant women, providing a potential explanation for their disproportionate morbidity and mortality.
Abstract
Background
Antiretroviral therapy (ART) regimens that contain dolutegravir (DTG) have been associated with increases in body mass index (BMI) in adults. However, this relationship has not ...been well described in adolescents.
Methods
In a retrospective observational cohort of 460 virally suppressed (<200 copies/mL) adolescents living with human immunodeficiency virus at a clinical site in Eswatini, body mass index (BMI) measurements were analyzed between 1 year prior to the transition to DTG and up to 1 year after DTG transition. Random-effects linear spline models were used to describe the rate of change in BMI before and after the transition to DTG.
Results
In adolescents, BMI increased at a rate of 0.3 kg/m2 per year before DTG transition and increased to a rate of 1.2 kg/m2 per year after DTG transition. Sex of the adolescent modified the relationship between DTG and rate of BMI change: BMI rate of change after DTG transition was increased by 1.1 kg/m2 in females and 0.6 kg/m2 per year in males.
Conclusions
Transition to DTG in virally suppressed adolescents (aged 10–19 years) is associated with an increase in the rate of BMI change. Female adolescents may experience a larger change than males. Further investigation is required to elucidate the mechanism that underlies these observations and to assess how DTG impacts BMI in adolescents following longer durations of treatment.
Investigation of household contacts exposed to infectious tuberculosis (TB) is widely recommended by international guidelines to identify secondary cases of TB and limit spread. There is little data ...to guide the use of contact investigations outside of the household, despite strong evidence that most TB infections occur outside of the home in TB high burden settings. In older adolescents, the majority of infections are estimated to occur in school. Therefore, as part of a project to increase active case finding in Swaziland, we performed school contact investigations following the identification of a student with infectious TB.
The Butimba Project identified 7 adolescent TB index cases (age 10-20) with microbiologically confirmed disease attending 6 different schools between June 2014 and March 2015. In addition to household contact investigations, Butimba Project staff worked with the Swaziland School Health Programme (SHP) to perform school contact investigations. At 6 school TB screening events, between May and October 2015, selected students underwent voluntary TB screening and those with positive symptom screens provided sputum for TB testing.
Among 2015 student contacts tested, 177 (9%) screened positive for TB symptoms, 132 (75%) produced a sputum sample, of which zero tested positive for TB. Household contact investigations of the same index cases yielded 40 contacts; 24 (60%) screened positive for symptoms; 19 produced a sputum sample, of which one case was confirmed positive for TB. The odds ratio of developing TB following household vs. school contact exposure was significantly lower (OR 0.0, 95% CI 0.0 to 0.18, P = 0.02) after exposure in school.
School-based contact investigations require further research to establish best practices in TB high burden settings. In this case, a symptom-based screening approach did not identify additional cases of tuberculosis. In comparison, household contact investigations yielded a higher percentage of contacts with positive TB screens and an additional tuberculosis case.
Background
Globally, children under 15 years represent approximately 12% of new tuberculosis cases, but 16% of the estimated 1.4 million deaths. This higher share of mortality highlights the urgent ...need to develop strategies to improve case detection in this age group and identify children without tuberculosis disease who should be considered for tuberculosis preventive treatment. One such strategy is systematic screening for tuberculosis in high‐risk groups.
Objectives
To estimate the sensitivity and specificity of the presence of one or more tuberculosis symptoms, or symptom combinations; chest radiography (CXR); Xpert MTB/RIF; Xpert Ultra; and combinations of these as screening tests for detecting active pulmonary childhood tuberculosis in the following groups.
– Tuberculosis contacts, including household contacts, school contacts, and other close contacts of a person with infectious tuberculosis.
– Children living with HIV.
– Children with pneumonia.
– Other risk groups (e.g. children with a history of previous tuberculosis, malnourished children).
– Children in the general population in high tuberculosis burden settings.
Search methods
We searched six databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, on 14 February 2020 without language restrictions and contacted researchers in the field.
Selection criteria
Cross‐sectional and cohort studies where at least 75% of children were aged under 15 years. Studies were eligible if conducted for screening rather than diagnosing tuberculosis. Reference standards were microbiological (MRS) and composite reference standard (CRS), which may incorporate symptoms and CXR.
Data collection and analysis
Two review authors independently extracted data and assessed study quality using QUADAS‐2. We consolidated symptom screens across included studies into groups that used similar combinations of symptoms as follows: one or more of cough, fever, or poor weight gain and one or more of cough, fever, or decreased playfulness. For combination of symptoms, a positive screen was the presence of one or more than one symptom.
We used a bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs) and performed analyses separately by reference standard. We assessed certainty of evidence using GRADE.
Main results
Nineteen studies assessed the following screens: one symptom (15 studies, 10,097 participants); combinations of symptoms (12 studies, 29,889 participants); CXR (10 studies, 7146 participants); and Xpert MTB/RIF (2 studies, 787 participants). Several studies assessed more than one screening test. No studies assessed Xpert Ultra. For 16 studies (84%), risk of bias for the reference standard domain was unclear owing to concern about incorporation bias. Across other quality domains, risk of bias was generally low.
Symptom screen (verified by CRS)
One or more of cough, fever, or poor weight gain in tuberculosis contacts (4 studies, tuberculosis prevalence 2% to 13%): pooled sensitivity was 89% (95% CI 52% to 98%; 113 participants; low‐certainty evidence) and pooled specificity was 69% (95% CI 51% to 83%; 2582 participants; low‐certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 339 would be screen‐positive, of whom 294 (87%) would not have pulmonary tuberculosis (false positives); 661 would be screen‐negative, of whom five (1%) would have pulmonary tuberculosis (false negatives).
One or more of cough, fever, or decreased playfulness in children aged under five years, inpatient or outpatient (3 studies, tuberculosis prevalence 3% to 13%): sensitivity ranged from 64% to 76% (106 participants; moderate‐certainty evidence) and specificity from 37% to 77% (2339 participants; low‐certainty evidence). Of 1000 children where 50 have pulmonary tuberculosis, 251 to 636 would be screen‐positive, of whom 219 to 598 (87% to 94%) would not have pulmonary tuberculosis; 364 to 749 would be screen‐negative, of whom 12 to 18 (2% to 3%) would have pulmonary tuberculosis.
One or more of cough, fever, poor weight gain, or tuberculosis close contact (World Health Organization four‐symptom screen) in children living with HIV, outpatient (2 studies, tuberculosis prevalence 3% and 8%): pooled sensitivity was 61% (95% CI 58% to 64%; 1219 screens; moderate‐certainty evidence) and pooled specificity was 94% (95% CI 86% to 98%; 201,916 screens; low‐certainty evidence). Of 1000 symptom screens where 50 of the screens are on children with pulmonary tuberculosis, 88 would be screen‐positive, of which 57 (65%) would be on children who do not have pulmonary tuberculosis; 912 would be screen‐negative, of which 19 (2%) would be on children who have pulmonary tuberculosis.
CXR (verified by CRS)
CXR with any abnormality in tuberculosis contacts (8 studies, tuberculosis prevalence 2% to 25%): pooled sensitivity was 87% (95% CI 75% to 93%; 232 participants; low‐certainty evidence) and pooled specificity was 99% (95% CI 68% to 100%; 3281 participants; low‐certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 63 would be screen‐positive, of whom 19 (30%) would not have pulmonary tuberculosis; 937 would be screen‐negative, of whom 6 (1%) would have pulmonary tuberculosis.
Xpert MTB/RIF (verified by MRS)
Xpert MTB/RIF, inpatient or outpatient (2 studies, tuberculosis prevalence 1% and 4%): sensitivity was 43% and 100% (16 participants; very low‐certainty evidence) and specificity was 99% and 100% (771 participants; moderate‐certainty evidence). Of 1000 children, where 50 have pulmonary tuberculosis, 31 to 69 would be Xpert MTB/RIF‐positive, of whom 9 to 19 (28% to 29%) would not have pulmonary tuberculosis; 931 to 969 would be Xpert MTB/RIF‐negative, of whom 0 to 28 (0% to 3%) would have tuberculosis.
Studies often assessed more symptoms than those included in the index test and symptom definitions varied. These differences complicated data aggregation and may have influenced accuracy estimates. Both symptoms and CXR formed part of the CRS (incorporation bias), which may have led to overestimation of sensitivity and specificity.
Authors' conclusions
We found that in children who are tuberculosis contacts or living with HIV, screening tests using symptoms or CXR may be useful, but our review is limited by design issues with the index test and incorporation bias in the reference standard.
For Xpert MTB/RIF, we found insufficient evidence regarding screening accuracy.
Prospective evaluations of screening tests for tuberculosis in children will help clarify their use. In the meantime, screening strategies need to be pragmatic to address the persistent gaps in prevention and case detection that exist in resource‐limited settings.
Mass cytometry is a novel platform for high-dimensional phenotypic and functional analysis of single cells. This system uses elemental metal isotopes conjugated to monoclonal antibodies to evaluate ...up to 42 parameters simultaneously on individual cells with minimal overlap between channels. The platform can be customized for analysis of both phenotypic and functional markers. Here, we will describe methods to stain, collect, and analyze intracellular functional markers and surface phenotypic markers on natural killer cells.
The identification and screening of children at high risk of tuberculosis is essential to the control and prevention of child tuberculosis (TB). BUTIMBA, an active case finding and household ...contact-tracing project implemented between 2013 and 2015 in Eswatini, evaluated 5,413 contacts of 1,568 index cases, of whom 82 (1.5%) were diagnosed with TB disease. We conducted univariate and multivariate clustered logistic regression analyses of risk factors for any TB diagnosis among child household contacts of TB cases. Children younger than 5 years and children with positive HIV status were more likely to have TB than children aged 5-14 years and children with negative HIV status, respectively (adjusted odds ratio aOR: 2.2,
< 0.001; aOR: 5.0,
< 0.001). Children with one or more TB symptoms were more likely to be diagnosed with TB based on clinical criteria, but less likely to have bacteriologically confirmed TB, highlighting subjectivity in determination of child TB.
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