Background
Every year, an estimated one million children and young adolescents become ill with tuberculosis, and around 226,000 of those children die. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular ...World Health Organization (WHO)‐recommended rapid diagnostic test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. We previously published a Cochrane Review 'Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for tuberculosis disease and rifampicin resistance in children'. The current review updates evidence on the diagnostic accuracy of Xpert Ultra in children presumed to have tuberculosis disease. Parts of this review update informed the 2022 WHO updated guidance on management of tuberculosis in children and adolescents.
Objectives
To assess the diagnostic accuracy of Xpert Ultra for detecting: pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and rifampicin resistance, in children with presumed tuberculosis.
Secondary objectives
To investigate potential sources of heterogeneity in accuracy estimates. For detection of tuberculosis, we considered age, comorbidity (HIV, severe pneumonia, and severe malnutrition), and specimen type as potential sources.
To summarize the frequency of Xpert Ultra trace results.
Search methods
We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, three other databases, and three trial registers without language restrictions to 9 March 2021.
Selection criteria
Cross‐sectional and cohort studies and randomized trials that evaluated Xpert Ultra in HIV‐positive and HIV‐negative children under 15 years of age. We included ongoing studies that helped us address the review objectives. We included studies evaluating sputum, gastric, stool, or nasopharyngeal specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), and fine needle aspirate or surgical biopsy tissue (lymph node tuberculosis). For detecting tuberculosis, reference standards were microbiological (culture) or composite reference standard; for stool, we also included Xpert Ultra performed on a routine respiratory specimen. For detecting rifampicin resistance, reference standards were drug susceptibility testing or MTBDRplus.
Data collection and analysis
Two review authors independently extracted data and, using QUADAS‐2, assessed methodological quality judging risk of bias separately for each target condition and reference standard. For each target condition, we used the bivariate model to estimate summary sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We summarized the frequency of Xpert Ultra trace results; trace represents detection of a very low quantity of Mycobacterium tuberculosis DNA. We assessed certainty of evidence using GRADE.
Main results
We identified 14 studies (11 new studies since the previous review). For detection of pulmonary tuberculosis, 335 data sets (25,937 participants) were available for analysis. We did not identify any studies that evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis. Three studies evaluated Xpert Ultra for detection of rifampicin resistance. Ten studies (71%) took place in countries with a high tuberculosis burden based on WHO classification. Overall, risk of bias was low.
Detection of pulmonary tuberculosis
Sputum, 5 studies
Xpert Ultra summary sensitivity verified by culture was 75.3% (95% CI 64.3 to 83.8; 127 participants; high‐certainty evidence), and specificity was 97.1% (95% CI 94.7 to 98.5; 1054 participants; high‐certainty evidence).
Gastric aspirate, 7 studies
Xpert Ultra summary sensitivity verified by culture was 70.4% (95% CI 53.9 to 82.9; 120 participants; moderate‐certainty evidence), and specificity was 94.1% (95% CI 84.8 to 97.8; 870 participants; moderate‐certainty evidence).
Stool, 6 studies
Xpert Ultra summary sensitivity verified by culture was 56.1% (95% CI 39.1 to 71.7; 200 participants; moderate‐certainty evidence), and specificity was 98.0% (95% CI 93.3 to 99.4; 1232 participants; high certainty‐evidence).
Nasopharyngeal aspirate, 4 studies
Xpert Ultra summary sensitivity verified by culture was 43.7% (95% CI 26.7 to 62.2; 46 participants; very low‐certainty evidence), and specificity was 97.5% (95% CI 93.6 to 99.0; 489 participants; high‐certainty evidence).
Xpert Ultra sensitivity was lower against a composite than a culture reference standard for all specimen types other than nasopharyngeal aspirate, while specificity was similar against both reference standards.
Interpretation of results
In theory, for a population of 1000 children:
• where 100 have pulmonary tuberculosis in sputum (by culture):
‐ 101 would be Xpert Ultra‐positive, and of these, 26 (26%) would not have pulmonary tuberculosis (false positive); and ‐ 899 would be Xpert Ultra‐negative, and of these, 25 (3%) would have tuberculosis (false negative).
• where 100 have pulmonary tuberculosis in gastric aspirate (by culture):
‐ 123 would be Xpert Ultra‐positive, and of these, 53 (43%) would not have pulmonary tuberculosis (false positive); and ‐ 877 would be Xpert Ultra‐negative, and of these, 30 (3%) would have tuberculosis (false negative).
• where 100 have pulmonary tuberculosis in stool (by culture):
‐ 74 would be Xpert Ultra‐positive, and of these, 18 (24%) would not have pulmonary tuberculosis (false positive); and ‐ 926 would be Xpert Ultra‐negative, and of these, 44 (5%) would have tuberculosis (false negative).
• where 100 have pulmonary tuberculosis in nasopharyngeal aspirate (by culture):
‐ 66 would be Xpert Ultra‐positive, and of these, 22 (33%) would not have pulmonary tuberculosis (false positive); and ‐ 934 would be Xpert Ultra‐negative, and of these, 56 (6%) would have tuberculosis (false negative).
Detection of rifampicin resistance
Xpert Ultra sensitivity was 100% (3 studies, 3 participants; very low‐certainty evidence), and specificity range was 97% to 100% (3 studies, 128 participants; low‐certainty evidence).
Trace results
Xpert Ultra trace results, regarded as positive in children by WHO standards, were common. Xpert Ultra specificity remained high in children, despite the frequency of trace results.
Authors' conclusions
We found Xpert Ultra sensitivity to vary by specimen type, with sputum having the highest sensitivity, followed by gastric aspirate and stool. Nasopharyngeal aspirate had the lowest sensitivity. Xpert Ultra specificity was high against both microbiological and composite reference standards. However, the evidence base is still limited, and findings may be imprecise and vary by study setting. Although we found Xpert Ultra accurate for detection of rifampicin resistance, results were based on a very small number of studies that included only three children with rifampicin resistance. Therefore, findings should be interpreted with caution. Our findings provide support for the use of Xpert Ultra as an initial rapid molecular diagnostic in children being evaluated for tuberculosis.
This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:
Primary objectives
To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for a) PTB ...in children presumed to have tuberculosis; b) lymph node tuberculosis in children presumed to have tuberculosis; c) tuberculous meningitis in children presumed to have tuberculosis; and d) rifampicin resistance in children presumed to have tuberculosis.
For tuberculosis detection, the role of the index tests would be a replacement for standard practice.
For rifampicin resistance detection, the role of the index tests would be an initial replacement test for culture‐based drug susceptibility testing.
As the SARS-CoV-2 outbreak rapidly spread to pandemic proportions, the global tuberculosis (TB) and HIV care communities voiced increasing concerns. Although an estimated 58 million lives were saved ...through TB diagnosis and treatment between 2000 and 2018, the current SARS-CoV-2 pandemic threatens to reverse these gains by overwhelming the healthcare system, disrupting patient access to care, and spurring reallocation of resources from TB and HIV services. Furthermore, in already stressed settings with high burdens of TB and HIV infection, the risk and impact of triple infection with TB, HIV, and SARS-CoV-2 will likely be greatest. Here, Kay et al. discuss two papers on the association between COVID-19 and clinical outcomes in patients with HIV and TB coinfection.
Pregnant women are at high risk from influenza due to disproportionate morbidity, mortality, and adverse pregnancy outcomes following infection. As such, they are classified as a high-priority group ...for vaccination. However, changes in the maternal immune system required to accommodate the allogeneic fetus may alter the immunogenicity of influenza vaccines. A large number of studies have evaluated the safety of the influenza vaccine. Here, we will review available studies on the immunogenicity and efficacy of the influenza vaccine during pregnancy, focusing on both humoral and cellular immunity.
Abstract
Background
The prevention of tuberculosis (TB) in child contacts of TB cases and people living with human immunodeficiency virus (HIV) is a public health priority, but global access to TB ...preventive therapy (TPT) remains low. In 2019, we implemented Vikela Ekhaya, a novel community-based TB contact management program in Eswatini designed to reduce barriers to accessing TPT.
Methods
Vikela Ekhaya offered differentiated TB and HIV testing for household contacts of TB cases by using mobile contact management teams to screen contacts, assess their TPT eligibility, and initiate and monitor TPT adherence in participants’ homes.
Results
In total, 945 contacts from 244 households were screened for TB symptoms; 72 (8%) contacts reported TB symptoms, and 5 contacts (0.5%) were diagnosed with prevalent TB. A total of 322 of 330 (98%) eligible asymptomatic household contacts initiated TPT. Of 322 contacts initiating TPT, 248 children initiated 3 months of isoniazid and rifampicin and 74 children and adults living with HIV initiated 6 months of isoniazid; 298 (93%) completed TPT. In clustered logistic regression analyses, unknown HIV status (adjusted odds ratio aOR 5.7, P = .023), positive HIV status (aOR 21.1, P = .001), urban setting (aOR 5.6, P = .006), and low income (aOR 5.9, P = .001) predicted loss from the cascade of care among TPT-eligible contacts.
Conclusion
Vikela Ekhaya demonstrated that community-based TB household contact management is a feasible, acceptable, and successful strategy for TB screening and TPT delivery. The results of this study support the development of novel, differentiated, community-based interventions for TB prevention and control.
Vikela Ekhaya offered differentiated tuberculosis and human immunodeficiency virus testing for 945 household contacts of 244 tuberculosis cases, using mobile contact management teams to screen contacts, and initiating and monitoring tuberculosis preventive therapy (TPT) adherence for 322 contacts in their homes. The program achieved TPT initiation rates of 98% and completion rates of 93% using community-based service delivery.
HIV-infected children and adolescents are at increased risk for tuberculosis (TB). Antiretroviral therapy (ART) reduces TB risk in HIV-infected adults, but its effectiveness in HIV-infected children ...and adolescents is unknown. We analyzed data from 7 integrated pediatric HIV/TB centers in 6 countries in sub-Saharan Africa. We used a Bayesian mixed-effect model to assess association between ART and TB prevalence and used adaptive lasso regression to analyze risk factors for adverse TB outcomes. The study period encompassed 57,525 patient-years and 1,160 TB cases (2,017 cases/100,000 patient-years). Every 10% increase in ART uptake resulted in a 2.33% reduction in TB prevalence. Favorable TB outcomes were associated with increased time in care and early ART initiation, whereas severe immunosuppression was associated with death. These findings support integrated HIV/TB services for HIV-infected children and adults and demonstrate the association of ART uptake with decreased TB incidence in high HIV/TB settings.
Pregnant women are particularly susceptible to complications of influenza A virus infection, which may result from pregnancy-induced changes in the function of immune cells, including natural killer ...(NK) cells. To better understand NK cell function during pregnancy, we assessed the ability of the two main subsets of NK cells, CD56
, and CD56
NK cells, to respond to influenza-virus infected cells and tumor cells. During pregnancy, CD56
and CD56
NK cells displayed enhanced functional responses to both infected and tumor cells, with increased expression of degranulation markers and elevated frequency of NK cells producing IFN-γ. To better understand the mechanisms driving this enhanced function, we profiled CD56
and CD56
NK cells from pregnant and non-pregnant women using mass cytometry. NK cells from pregnant women displayed significantly increased expression of several functional and activation markers such as CD38 on both subsets and NKp46 on CD56
NK cells. NK cells also displayed diminished expression of the chemokine receptor CXCR3 during pregnancy. Overall, these data demonstrate that functional and phenotypic shifts occur in NK cells during pregnancy that can influence the magnitude of the immune response to both infections and tumors.
Interferon-gamma release assays are increasingly used in children to establish evidence of tuberculosis (TB) infection and to assist in the diagnosis of TB disease. The QuantiFERON-TB Gold In-Tube ...assay is being phased out in favor of a next-generation test, the QuantiFERON-TB Gold Plus (QFT-Plus) assay. The QFT-Plus assay is designed with two antigen tubes to differentially stimulate CD4
and CD8
T cells. The performance of this assay has been documented extensively in adults but has not yet been evaluated in children. Here, we compare the performance of the two assays in a cohort of 46 children exposed to TB and 12 children diagnosed with TB disease in Eswatini. The tests demonstrated excellent concordance in both TB disease (100% agreement, Cohen's kappa = 1) and TB infection (96% agreement, Cohen's kappa = 0.91). Most of the children with household exposure tested negative for TB infection by both tests, indicating the ongoing need for new tests for TB infection that can be easily implemented in TB high-burden settings at minimal cost.
Preventing the progression of a drug-resistant tuberculosis (DR-TB) infection to disease is an important pillar of the DR-TB elimination strategy. International guidelines have recently proposed ...fluoroquinolones for tuberculosis preventive therapy (TPT) in DR-TB contacts, although the available evidence is low quality. The pooled data from small observational studies suggest that a fluoroquinolone-based TPT is safe, effective and cost-effective as a preventive treatment in DR-TB contacts. Three clinical trials are currently ongoing to generate higher quality evidence on the efficacy of levofloxacin and delamanid as a DR-TB preventive therapy. Additional evidence is also needed, regarding TPT treatment in fluoroquinolone-resistant-TB contacts, patient and health care worker perceptions on DR-TB preventive therapy for contacts, and the service delivery models to increase DR-TPT access. This state-of-the-art review presents the current literature on TPT for contacts of DR-TB cases, focusing on the available evidence and international guidelines.
Pregnancy-induced alterations in immunity may contribute to the increased morbidity associated with influenza A virus infection during pregnancy. We characterized the immune response of monocytes and ...plasmacytoid dendritic cells (pDCs) to influenza A virus infection in 21 pregnant and 21 nonpregnant women. In pregnant women, monocytes and pDCs exhibit an exaggerated proinflammatory immune response to 2 strains of influenza A virus, compared with nonpregnant women, characterized by increased expression of major histocompatibility complex class II (approximately 2.0-fold), CD69 (approximately 2.2-fold), interferon γ-induced protein 10 (approximately 2.0-fold), and macrophage inflammatory protein 1β (approximately 1.5-fold). This enhanced innate inflammatory response during pregnancy could contribute to pulmonary inflammation following influenza A virus infection.
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