Why being an expert – despite xpert –remains crucial for children in high TB burden settings

Bacha, Jason; Ngo, Katherine; Clowes, Petra; Draper, Heather R.; Ntinginya, Elias N.; DiNardo, Andrew; Mangu, Chacha; Sabi, Issa; Mtafya, Bariki; Mandalakas, Anna M.

doi:10.1186/s12879-017-2236-9

Cited by 28 publications

(17 citation statements)

References 22 publications

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“…All children were tested for mycobacteria in sputum, gastric or nasogastric lavage fluid but we did not obtain positive culture results. This is largely in accordance with previous studies [17] and confirmed the paucibacillary nature of childhood TB. In addition mycobacterial culture analyses were hampered by insufficient sample volumes gained from the majority of young children included in this study ( …”

Section: Study Population and Methodssupporting

confidence: 93%

Alternative Quantiferon cytokines for diagnosis of children with active tuberculosis and HIV co-infection in Ghana

Lundtoft

Awuah

Nausch

et al. 2017

Med Microbiol Immunol

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IFN-γ release assays (IGRAs) often present false-negative or indeterminate results in children with tuberculosis. HIV co-infection may contribute to decreased sensitivity of IGRAs by impairing T-cell IFN-γ expression. Measurement of alternative cytokines in QuantiFERON (QFT) supernatants can circumvent the IFN-γ-dependency and may improve QFT sensitivity. We aimed to identify additional cytokines from QFT supernatants for detection of Mycobacterium tuberculosis infection in children with tuberculosis and HIV co-infection from Ghana. Concentrations of 18 cytokines in QFT supernatants from children (0-16 years) with tuberculosis concomitantly infected with HIV (n = 25) or without HIV (n = 24) from Ghana were measured using cytometric bead array (CBA). 29% of the children showed positive IFN-γ test results, and five cytokines, i.e., IL-6, IL-21, TNF-α, IL-1α and IP-10, detected M. tuberculosis infection with comparable or, for IL-6, with significantly higher sensitivity (59%). Increased age and HIV co-infection were associated with decreased cytokine induction, and especially IL-21 and IP-10 were less prevalent in HIV co-infected children with tuberculosis. Combined cytokine analyses increased proportions of positive tests, and a four-cytokine subset (i.e., IL-6, IL-21, IFN-γ, IL-1α) predicted 78% of the children with tuberculosis correctly. Combined evaluation of IFN-γ and alternative cytokines improved IGRA-sensitivity in children with tuberculosis.

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Section: Study Population and Methodssupporting

confidence: 93%

Alternative Quantiferon cytokines for diagnosis of children with active tuberculosis and HIV co-infection in Ghana

Lundtoft

Awuah

Nausch

et al. 2017

Med Microbiol Immunol

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“…Low utilisation of Xpert® has been illustrated in other low income, high TB burden countries both in adults and children [ 47 – 49 ]. From surveys of implementation in high TB burden countries including Kenya, reasons associated with low utilisation included operational issues like power outages and poor specimen referral; doubts about impact to TB morbidity and mortality; preference to trust clinical acumen; low sensitivity especially in children; challenges in getting good specimens and false negatives; and lack of awareness amongst health care workers and patients [ 45 , 48 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Variability in distribution and use of tuberculosis diagnostic tests in Kenya: a cross-sectional survey

et al. 2018

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BackgroundGlobally, 40% of all tuberculosis (TB) cases, 65% paediatric cases and 75% multi-drug resistant TB (MDR-TB) cases are missed due to underreporting and/or under diagnosis. A recent Kenyan TB prevalence survey found that a significant number of TB cases are being missed here. Understanding spatial distribution and patterns of use of TB diagnostic tests as per the guidelines could potentially help improve TB case detection by identifying diagnostic gaps.MethodsWe used 2015 Kenya National TB programme data to map TB case notification rates (CNR) in different counties, linked with their capacity to perform diagnostic tests (chest x-rays, smear microscopy, Xpert MTB/RIF®, culture and line probe assay). We then ran hierarchical regression models for adults and children to specifically establish determinants of use of Xpert® (as per Kenyan guidelines) with county and facility as random effects.ResultsIn 2015, 82,313 TB cases were notified and 7.8% were children. The median CNR/100,000 amongst 0-14yr olds was 37.2 (IQR 20.6, 41.0) and 267.4 (IQR 202.6, 338.1) for ≥15yr olds respectively. 4.8% of child TB cases and 12.2% of adult TB cases had an Xpert® test done, with gaps in guideline adherence. There were 2,072 microscopy sites (mean microscopy density 4.46/100,000); 129 Xpert® sites (mean 0.31/100,000); two TB culture laboratories and 304 chest X-ray facilities (mean 0.74/100,000) with variability in spatial distribution across the 47 counties. Retreatment cases (i.e. failures, relapses/recurrences, defaulters) had the highest odds of getting an Xpert® test compared to new/transfer-in patients (AOR 7.81, 95% CI 7.33-8.33). Children had reduced odds of getting an Xpert® (AOR 0.41, CI 0.36-0.47). HIV-positive individuals had nearly twice the odds of getting an Xpert® test (AOR 1.82, CI 1.73-1.92). Private sector and higher-level hospitals had a tendency towards lower odds of use of Xpert®.ConclusionsWe noted under-use and gaps in guideline adherence for Xpert® especially in children. The under-use despite considerable investment undermines cost-effectiveness of Xpert®. Further research is needed to develop strategies enhancing use of diagnostics, including innovations to improve access (e.g. specimen referral) and overcoming local barriers to adoption of guidelines and technologies.Electronic supplementary materialThe online version of this article (10.1186/s12879-018-3237-z) contains supplementary material, which is available to authorized users.

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“…Even in the era of the GeneXpert and Xpert Ultra [ 9 , 10 ], challenges remain for TB diagnosis in children, which highlights the fact that better diagnostics for children might have to be based on host immune responses rather than pathogen detection. However, none of the currently available immune-diagnostic tests, including the tuberculin skin test (TST) and interferon (IFN)-γ release assays (IGRA), can distinguish between latent Mycobacterium tuberculosis (M.tb) infection (LTBI) and TB disease, or more importantly distinguish between TB disease and other respiratory infections 11 , 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

A three-marker protein biosignature distinguishes tuberculosis from other respiratory diseases in Gambian children

et al. 2020

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Background Our study aimed to identify a host cytokine biosignature that could distinguish childhood tuberculosis (TB) from other respiratory diseases (OD). Methods Cytokine responses in prospectively recruited children with symptoms suggestive of TB were measured in whole blood assay supernatants, harvested after overnight incubation, using a Luminex platform. We used logistic regression models with Least Absolute Shrinkage and Selection Operator (LASSO) penalty to identify the optimal biosignature associated with confirmed TB disease in the training set. We subsequently assessed its performance in the test set. Findings Of the 431 children included in the study, 44 had bacteriologically confirmed TB, 60 had clinically diagnosed TB while 327 had OD. All children were HIV-negative. Application of LASSO regression models to the training set ( n = 260) resulted in the combination of IL-1ra, IL-7 and IP-10 from unstimulated samples as the optimally discriminant cytokine biosignature associated with bacteriologically confirmed TB. In the test set ( n = 171), this biosignature distinguished children diagnosed with TB disease, irrespective of microbiological confirmation, from OD with area under the receiver operator characteristic curve (AUC) of 0•74 (95% CI: 0•67, 0•81), and demonstrated sensitivity and specificity of 72•2% (95% CI: 60•4, 82•1%) and 75•0% (95% CI: 64•9, 83•4%) respectively, with its performance independent of their age group and their age- and sex-adjusted nutritional status. Interpretation This novel biosignature of childhood TB derived from unstimulated supernatants is promising. Independent validation with further optimisation will improve its performance and translational potential. Funding Steinberg Fellowship (McGill University); Grand Challenges Canada; MRC Program Grant.

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Why being an expert – despite xpert –remains crucial for children in high TB burden settings

Cited by 28 publications

References 22 publications

Alternative Quantiferon cytokines for diagnosis of children with active tuberculosis and HIV co-infection in Ghana

Alternative Quantiferon cytokines for diagnosis of children with active tuberculosis and HIV co-infection in Ghana

Variability in distribution and use of tuberculosis diagnostic tests in Kenya: a cross-sectional survey

A three-marker protein biosignature distinguishes tuberculosis from other respiratory diseases in Gambian children

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