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Objective: Our cross-sectional study aimed at evaluating the diagnostic performance of Focused Assessment with Sonography for HIV-associated tuberculosis (FASH) to detect extrapulmonary tuberculosis in extremely resource-limited settings, with visceral leishmaniasis as a differential diagnosis with overlapping sonographic feature., Design: Cross-sectional study., Setting: Voluntary Counselling and Testing Centre (VCT) of Yirol Hospital, South Sudan., Participants: From May to November 2017, 252 HIV-positive patients out of 624 newly admitted to VCT Centre were registered for antiretroviral treatment. According to the number of trained doctors available to practise ultrasound (US) scan, a sample of 100 patients were screened using the FASH protocol., Interventions: Following a full clinical examination, each patient was scanned with a portable US scanner in six different positions for pleural, pericardial, ascitic effusion, abdominal lymphadenopathy and hepatic/splenic microabscesses, according to the FASH protocol. A k39 antigen test for visceral leishmaniasis was also performed on patients with lymphadenopathy and/or splenomegaly. All demographic, clinical and HIV data, as well as FASH results and therapy adjustments, were recorded following the examination., Results: The FASH protocol allowed the detection of pathological US findings suggestive of tuberculosis in 27 out of the 100 patients tested. Overall, FASH results supported tuberculosis treatment indication for 16 of 21 patients, with the treatment being based exclusively on FASH findings in half of them (8 patients). The group of FASH-positive patients had a significantly higher proportion of patients with CD4 count below 0.2 x10 9 /L (n=22, 81%) as compared with FASH-negative patients (n=35, 48%) (p=0.003). Moreover, 48% (n=13) of FASH-positive patients had CD4 below 100 cells/mm 3 . All patients tested had a negative result on k39 antigen test., Conclusion: FASH was found to be a relevant diagnostic tool to detect signs of tuberculosis. Further research is needed to better define a patient profile suitable for investigation and also considering diagnostic accuracy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Extrapulmonary tuberculosis (EPTB) accounts for a significant proportion of tuberculosis cases worldwide. Nevertheless, the diagnosis is often delayed or even missed due to insidious clinical presentation and poor performance of diagnostic tests. Culture, the classical gold standard for tuberculosis, suffers from increased technical and logistical constraints in EPTB cases. In this review the authors outline current diagnostic options for the main forms of EPTB. The authors also discuss the opportunities and challenges linked in particular to microbiological diagnostics and to the attempts to find a new gold standard test for EPTB. Finally, new biomarkers and tests currently under evaluation are hopefully on the way to introduce significant improvements in EPTB diagnosis, for which clinical suspicion will nevertheless be essential.

Several studies showed that assessing levels of specific circulating microRNAs (miRNAs) is a non-invasive, rapid, and accurate method for diagnosing diseases or detecting alterations in physiological conditions. We aimed to identify a serum miRNA signature to be used for the diagnosis of tuberculosis (TB). To account for variations due to the genetic makeup, we enrolled adults from two study settings in Europe and Africa. The following categories of subjects were considered: healthy (H), active pulmonary TB (PTB), active pulmonary TB, HIV co-infected (PTB/HIV), latent TB infection (LTBI), other pulmonary infections (OPI), and active extra-pulmonary TB (EPTB). Sera from 10 subjects of the same category were pooled and, after total RNA extraction, screened for miRNA levels by TaqMan low-density arrays. After identification of "relevant miRNAs", we refined the serum miRNA signature discriminating between H and PTB on individual subjects. Signatures were analyzed for their diagnostic performances using a multivariate logistic model and a Relevance Vector Machine (RVM) model. A leave-one-out-cross-validation (LOOCV) approach was adopted for assessing how both models could perform in practice. The analysis on pooled specimens identified selected miRNAs as discriminatory for the categories analyzed. On individual serum samples, we showed that 15 miRNAs serve as signature for H and PTB categories with a diagnostic accuracy of 82% (CI 70.2-90.0), and 77% (CI 64.2-85.9) in a RVM and a logistic classification model, respectively. Considering the different ethnicity, by selecting the specific signature for the European group (10 miRNAs) the diagnostic accuracy increased up to 83% (CI 68.1-92.1), and 81% (65.0-90.3), respectively. The African-specific signature (12 miRNAs) increased the diagnostic accuracy up to 95% (CI 76.4-99.1), and 100% (83.9-100.0), respectively. Serum miRNA signatures represent an interesting source of biomarkers for TB disease with the potential to discriminate between PTB and LTBI, but also among the other categories.

Despite the improvements in the global fight against tuberculosis (TB), critical points still remain and fuel the epidemic. Even today, only 30% of the estimate number of people suffering from TB worldwide are correctly diagnosed, and lower proportions of cases are diagnosed in high-TB-burden, low-resource settings. Current TB diagnostics are still suboptimal in their performance for childhood TB, smear-negative TB, extrapulmonary TB, HIV-TB and drug-resistant TB. Furthermore, there is no gold standard test for the identification of latent TB infection status. Improving diagnosis is therefore a strategic goal in TB research, and the pipeline of diagnostic tools is rapidly growing: new ways of performing "old" tests (e.g. sputum smear microscopy) and completely innovative tools (e.g. new technologies for molecular diagnosis) are under investigation or have already been endorsed by WHO. Some of the structural limits of current TB diagnostics are likely to be overcome by such new tools, but research is still needed. Finally, the roll-out of new technologies and the development of newer ones will necessarily have to take into account the diagnostic needs of each context they are directed to (point-of-need testing approach), together with the logistic, economic and technical constraints present in the majority of high-TB-burden settings.