Definite Tuberculosis Research Articles

Combination of exhaled breath condensate samples with lipoarabinomannan point of care assay for pulmonary tuberculosis (TB) diagnosis: protocol for a diagnostic accuracy study

IntroductionThe WHO estimates a gap of about 30% between the incident (10.6 million) and notified (7.5 million) cases of tuberculosis (TB). Combined with the growing recognition in prevalence surveys of...

Discovering novel biomarkers for diagnosis and treatment monitoring of active pulmonary tuberculosis by ion metabolism analysis

Tuberculosis (TB) is a highly lethal infectious disease that poses a global threat. Timely and accurate biomarker for TB diagnosis and treatment monitoring remains a pressing need. Ions, the crucial trace element for humans, may be potential targets for TB diagnosis and the forecasting of TB development. To explore the potential of ions as biomarkers, we measured and compared the levels of various ions in whole blood and plasma samples from healthy control (HC), pulmonary TB patients (TB), cured pulmonary TB patients (RxTB), and other non-TB pneumonia patients (PN) by using ultra-high performance liquid chromatography-tandem mass spectrometry. Our study demonstrated that Cu (AUC = 0.670), Pb (AUC = 0.660), and Zn (AUC = 0.701) in whole blood exhibited promising diagnostic performance for TB. Then we used a neural network (NNET) for TB prediction, the AUC values used to differentiate definite TB from HC or PN in plasma were 0.867 and 0.864, respectively. The AUC values used to differentiate definite TB from HC or PN in whole blood were 0.818 and 0.660, respectively. Our correlation analysis showed that Zn (r= 0.356, p=0.001) and Cu (r= 0.361, p=0.0004) in plasma are most closely related to disease severity. Additionally, six ions (Cu, Sb, V, Mn, Fe, Sr) in plasma and whole blood were altered following anti-TB therapy. These results showed that ions could be diagnostic biomarkers for TB. Furthermore, the level of particular ions can forecast the degree of lung damage and the success of the TB treatment. In conclusion, this study highlights the possibility of using ions from blood samples to enable rapid tuberculosis diagnosis.

Pooled sputum testing by Xpert® MTB/RIF Ultra for active tuberculosis case finding among high-risk groups in a low-incidence area: a prospective study

Background Early detection and treatment of tuberculosis (TB) are of great importance to stop its spread. However, optimising the active case findingstrategy is critical to improving its feasibility in regions where TB is epidemic. Method The different pooled ratios between TB-positive and TB-negative sputum specimens were evaluated and a pooling ratio of 5:1 was used for the active case finding screening by Xpert MTB/RIF Ultra among high-risk groups in Beijing. Results The sensitivity of pooling ratio at 5:1 was 97.5% (39/40). Between October 2022 and March 2023, among 17,681 participants, 1729 metthe active case finding criteria and were screened by 350 5:1 sputum pools by Xpert MTB/RIF Ultra. Four pools (1.1%) tested positive and were further confirmed as definite active TB cases. In our study population with high TB incidence (231/100,000), the cost for detection of individual patients was reduced by 77.4% at a 5:1 pooling ratio. Conclusions pooled sputum testing at a suitable ratio using Xpert MTB/RIF Ultra provides a rapid, efficient, and cost-effective method for active TB case finding among high-risk groups in a low-incidence area.

Diagnostic accuracy of Lipoarabinomannan detection by lateral flow assay in pleural tuberculosis

BackgroundLipoarabinomannan (LAM) antigen serves as an attractive biomarker to diagnose Tuberculosis (TB). Given the limitations of current diagnostic modalities for Pleural TB, current study evaluated LAM’s potential to serve as a point-of-care test to diagnose pleural TB.MethodsA cross sectional, diagnostic accuracy study was conducted during February to November 2021 in a tertiary care hospital in India. LAM antigen detection was performed on pleural fluid as well as early morning urine specimen of suspected pleural TB patients by “Alere/ Abott Determine TB LAM” lateral flow assay (LAM-LFA). The results were compared to microbiological reference standards/MRS (Mycobacterial culture or NAAT) and Composite reference standards/CRS (MRS plus Clinico-radiological diagnosis).ResultsA total of 170 subjects were included in the analysis, including 26 with Definite TB, 22 with Probable TB, and 122 with No TB. Compared to MRS and CRS, the sensitivity (61.54% & 45.83%) and positive predictive value (PPV) (57.14 & 78.57%) of Pleural LAM-LFA testing were found to be suboptimal, whereas the specificity (91.67% & 95.08%) and negative predictive value (NPV) (92.96% & 81.69%) of the assay were found to be good. Urinary LAM-LFA performed even worse than pleural LAM-LFA, except for its higher specificity against MRS and CRS (97.2% and 98.3%, respectively). Specificity and PPV of pleural LAM detection increased to 100% when analysed in a subgroup of patients with elevated ADA levels (receiver operating curve analysis-derived cut off value > 40 IU/ml).ConclusionDetection of LAM antigen by LFA directly from pleural fluid was found to be a useful test to predict absence of the disease if the test is negative rather than using as a POCT for diagnosis.

Accuracy of the InnowaveDX MTB/RIF test for detection of Mycobacterium tuberculosis and rifampicin resistance: a prospective multicentre study

ABSTRACT Early and accurate diagnosis of tuberculosis (TB) is necessary to initiate proper therapy for the benefit of the patients and to prevent disease transmission in the community. In this study, we developed the InnowaveDX MTB/RIF (InnowaveDX) to detect Mycobacterium tuberculosis (MTB) and rifampicin resistance simultaneously. A prospective multicentre study was conducted to evaluate the diagnostic performance of InnowaveDX for the detection MTB in sputum samples as compared with Xpert and culture. The calculated limit of detection (LOD) for InnowaveDX was 9.6 CFU/ml for TB detection and 374.9 CFU/ml for RIF susceptibility. None of the other bacteria tested produced signals that fulfilled the positive TB criteria, demonstrating a species-specificity of InnowaveDX. Then 951 individuals were enrolled at 7 hospitals, of which 607 were definite TB cases with positive culture and/or Xpert results, including 354 smear-positive and 253 smear-negative cases. InnowaveDX sensitivity was 92.7% versus bacteriologically TB standard. Further follow-up revealed that 61 (91.0%) out of 67 false-positive patients with no bacteriological evidence met the criteria of clinically diagnosed TB. Among 125 RIF-resistant TB patients diagnosed by Xpert, 108 cases were correctly identified by InnowaveDX, yielding a sensitivity of 86.4%. Additionally, the proportion of very low bacterial load in the discordant susceptibility group was significantly higher than in the concordant susceptibility group (P = 0.029). To conclude, we have developed a novel molecular diagnostic with promising detection capabilities of TB and RIF susceptibility. In addition, the discordant RIF susceptibility results between InnowaveDX and Xpert are more frequently observed in samples with very low bacterial load.

Use of Pleural Fluid Digital PCR Analysis to Improve the Diagnosis of Pleural Tuberculosis.

The diagnosis of pleural tuberculosis (TB) remains difficult due to the paucity of Mycobacterium tuberculosis in pleural fluid (PF). This study aimed to improve pleural TB diagnosis using highly sensitive digital PCR (dPCR) technique. A total of 310 patients with evidence of PF were consecutively enrolled, 183 of whom suffered from pleural TB and 127 from non-TB. PF samples were prospectively collected and total DNA was extracted. The copy numbers of M. tuberculosis insertion sequence (IS) 6110 and IS1081 in DNA were quantified using dPCR. The overall area under the curve of IS6110-dPCR was greater than that of IS1081-dPCR (0.85 versus 0.79). PF IS6110 OR IS1081-dPCR (according to their cut-off values, "positive" was defined as either of them was positive, while "negative" was defined as both of them were negative) had higher sensitivity and equal specificity compared with single target-dPCR. The sensitivity of PF IS6110 OR IS1081-dPCR for total, definite, and probable pleural TB was 59.0% (95% CI = 51.5% to 66.2%), 72.8% (95% CI = 62.6% to 81.6%), and 45.1% (95% CI = 34.6% to 55.8%), respectively. Its specificity was 100% (95% CI = 97.1% to 100.0%). PF IS6110 OR IS1081-dPCR showed a higher sensitivity than smear microscopy (57.4% versus 7.1%), mycobacterial culture (55.3% versus 31.8%), and Xpert MTB/RIF (57.6% versus 23.0%). Long antituberculosis treatment time (>1 month) was found to be associated with negative dPCR results in pleural TB patients. This study indicates that PF IS6110 OR IS1081-dPCR is an accurate molecular assay, which is more sensitive than routine etiological tests and has the potential to enhance the definite diagnosis of pleural TB. IMPORTANCE Pleural TB is one of the most frequent causes of pleural effusion, especially in areas with high burden of TB. Due to the paucibacillary nature of the disease, the diagnostic sensitivities of all available bacteriological and molecular tests remain poor. There is an urgent need to develop new efficient methods. Digital PCR (dPCR) is the third generation of PCR that enables the exact quantification of trace nucleic acids in samples. This study evaluates the diagnostic performance of pleural fluid (PF) dPCR analysis for pleural TB, and shows that PF IS6110 OR IS1081-dPCR has a higher sensitivity than routine etiological tests such as smear microscopy, mycobacterial culture, and Xpert MTB/RIF. This work provides a new choice for improving the definite diagnosis of pleural TB.

Rifapentine and isoniazid for prevention of tuberculosis in people with diabetes (PROTID): protocol for a randomised controlled trial

BackgroundDiabetes mellitus (DM) increases the risk of tuberculosis (TB) and will hamper global TB control due to the dramatic rise in type 2 DM in TB-endemic settings. In this trial, we will examine the efficacy and safety of TB preventive therapy against the development of TB disease in people with DM who have latent TB infection (LTBI), with a 12-week course of rifapentine and isoniazid (3HP).MethodsThe ‘Prevention of tuberculosis in diabetes mellitus’ (PROTID) consortium will randomise 3000 HIV-negative eligible adults with DM and LTBI, as evidenced by a positive tuberculin skin test or interferon gamma release assay, to 12 weeks of 3HP or placebo. Participants will be recruited through screening adult patients attending DM clinics at referral hospitals in Tanzania and Uganda. Patients with previous TB disease or treatment with a rifamycin medication or isoniazid (INH) in the previous 2 years will be excluded. The primary outcome is the occurrence of definite or probable TB disease; secondary outcome measures include adverse events, all-cause mortality and treatment completion. The primary efficacy analysis will be intention-to-treat; per-protocol analyses will also be carried out. We will estimate the ratio of TB incidence rates in intervention and control groups, adjusting for the study site using Poisson regression. Results will be reported as efficacy estimates (1-rate ratio). Cumulative incidence rates allowing for death as a competing risk will also be reported. Approximately 1000 LTBI-negative, HIV-negative participants will be enrolled consecutively into a parallel cohort study to compare the incidence of TB in people with DM who are LTBI negative vs positive. A number of sub-studies will be conducted among others to examine the prevalence of LTBI and active TB, estimate the population impact and cost-effectiveness of LTBI treatment in people living with DM in these African countries and address gaps in the prevention and therapeutic management of combined TB-DM.DiscussionPROTID is anticipated to generate key evidence to guide decisions over the use of TB preventive treatment among people with DM as an important target group for better global TB control.Trial registrationClinicalTrials.govNCT04600167. Registered on 23 October 2020

Diagnostic Performance of a Novel CXCL10 mRNA Release Assay for Mycobacterium tuberculosis Infection

One-fourth of the world’s population has been infected with Mycobacterium tuberculosis (M.tb). Although interferon-gamma release assays (IGRAs) have been shown to be valid methods for identifying M.tb infection and auxiliary methods for diagnosis of active tuberculosis (TB), lower sensitivity and higher indeterminate rate were often detected among immunosuppressed patients. IP-10 was an alternative biomarker due to the higher expression level after M.tb antigen stimulation, but whether CXCL10 mRNA (the gene that transcribes for the IP-10 protein) can be used as a target for M.tb infection diagnosis was limited. Therefore, we aimed to evaluate the performance of a novel M.tb-specific CXCL10 mRNA release assay in diagnosis of M.tb infection. Suspected TB patients and healthy controls were prospectively recruited between March 2018 and November 2019 from three hospitals in China. CXCL10 mRNA release assay and traditional interferon-gamma release assay (T-SPOT.TB) were simultaneously performed on peripheral blood. Of the 1,479 participants enrolled in the study, 352 patients with definite TB and 153 healthy controls were analyzed. CXCL10 mRNA release assay provided a sensitivity of 93.9% (95% CI = 90.8–96.2%) and a specificity of 98.0% (95% CI = 94.3–99.6%) in the diagnosis of M.tb infection, respectively, while T-SPOT.TB gave a sensitivity of 94.5% (95% CI = 91.5–96.6%) and a specificity of 100% (95% CI = 97.6–100.0%) in the diagnosis of M.tb infection, respectively. The diagnostic performance of CXCL10 mRNA release assay was consistent with T-SPOT.TB, with a total coincidence rate of 95.0% (95% CI = 93.0–96.9%) and a Cohen’s kappa value of 0.89 (0.84–0.93, p < 0.001). However, among TB patients with HIV co-infection (n = 14), CXCL10 mRNA release assay presented significantly higher positive rate [92.9% (66.1–99.8%) vs. 61.5% (31.6–86.1%), p = 0.029] than those of T-SPOT.TB. These results suggested that M.tb-specific CXCL10 mRNA was a novel and useful target in the diagnosis of M.tb infection.

Diagnostic value of bronchoscopy in sputum-negative pulmonary tuberculosis patients and its correlation with clinicoradiological features.

CONTEXT:Tuberculosis (TB) remains endemic in Saudi Arabia. Little local data have been reported on bronchoscopic evaluation of sputum-negative pulmonary TB patients, which poses a significant diagnostic and therapeutic challenge.AIMS:To determine the diagnostic value of bronchoscopy and bronchoalveolar lavage (BAL) and its correlation with clinical and radiological features in sputum-negative, culture-confirmed pulmonary TB patients.METHODS:We performed a retrospective analysis of patients with definite or probable pulmonary TB with overall negative (smear and/or polymerase chain reaction [PCR]) or scanty sputum that had undergone bronchoscopy with BAL over a period of 5 years. Patients’ symptoms, radiological features, lung lobe lavaged, BAL acid-fast bacilli (AFB) stain, Mycobacterium TB (MTB)-PCR, and mycobacterial cultures were analyzed. Mycobacterial cultures (either sputum or BAL) were used as a reference standard.RESULTS:Out of 154 patients, 49 (32%) were overall sputum negative and underwent a diagnostic bronchoscopy. Dry cough and fever were the most common symptoms. Uncontrolled diabetes mellitus was the most frequent comorbidity identified in 15 (31%) patients. Fifty-nine percent of the patients had diffuse lung infiltrates, with consolidation being the most common abnormality (41%), followed by cavitation (39%). Right upper lobe was the most frequent lung lobe lavaged (31%), while transbronchial lung biopsies (TBLB) were obtained in 21 (43%). BAL mycobacterial culture and MTB PCR were positive in 35 (71%) and 23 (47%) patients, respectively. Combined BAL MTB PCR and TBLB provided rapid diagnosis in 28 (57%) patients.CONCLUSIONS:An overall diagnostic yield of 90% was achieved with combined use of BAL MTB PCR, culture, and histopathology. Upper lobe lavage and presence of cavities on chest imaging had a higher diagnostic yield.

Combined IFN-\u03b3 and IL-2 release assay for detect active pulmonary tuberculosis: a prospective multicentre diagnostic study in China

BackgroundWe performed a prospective multicentre diagnostic study to evaluate the combined interferon-γ (IFN-γ) and interleukin-2 (IL-2) release assay for detect active pulmonary tuberculosis (TB) in China.MethodsAdult patients presenting symptoms suggestive of pulmonary TB were consecutively enrolled in three TB-specialized hospitals. Sputum specimens and blood sample and were collected from each participant at enrolment. The levels of Mycobacterium tuberculosis (MTB)-specific antigen-stimulated IFN-γ and IL-2 were determined using enzyme-linked immunosorbent assay (ELISA).ResultsBetween July 2017 and December 2018, a total of 3245 patients with symptoms suggestive of pulmonary TB were included in final analysis. Of 3245 patients, 2536 were diagnosed as active TB, consisting of 1092 definite TB and 1444 clinically diagnosed TB. The overall sensitivity and specificity of IFN-γ were 83.8% and 81.5%, respectively. In addition, compared with IFN-γ, the specificity of IL-2 increased to 94.3%, while the sensitivity decreased to 72.6%. In addition, the highest sensitivity was achieved with parallel combination of IFN-γ/IL-2, with a sensitivity of 87.9%, and its overall specificity was 79.8%. The sensitivity of series combination test was 68.5%. Notably, the sensitivity of series combination test in definite TB (72.1%) was significantly higher than that in clinically diagnosed TB (65.8%).ConclusionIn conclusion, we develop a new immunological method that can differentiate between active TB and other pulmonary diseases. Our data demonstrates that the various IFN-γ/IL-2 combinations provides promising alternatives for diagnosing active TB cases in different settings. Additionally, the diagnostic accuracy of series combination correlates with severity of disease in our cohort.

Factors associated with negative pleural adenosine deaminase results in the diagnosis of childhood pleural tuberculosis

BackgroundUntil now, the influential factors associated with pleural adenosine deaminase (ADA) activity among children remain unclear. This retrospective study was therefore conducted aiming to investigate the factors associated with negative pleural ADA results in the diagnosis of childhood pleural tuberculosis (TB).MethodsBetween January 2006 and December 2019, children patients with definite or possible pleural TB were recruited for potential analysis. Then, patients were stratified into two categories: negative pleural ADA results group (experimental group, ≤40 U/L) and positive pleural ADA results group (control group, > 40 U/L). Univariate and multivariate logistic regression analyses were performed to estimate risk factors for negative pleural ADA results.ResultsA total of 84 patients with pleural TB were recruited and subsequently classified as experimental (n = 17) and control groups (n = 67). Multivariate analysis (Hosmer–Lemeshow goodness-of-fit test: χ2 = 1.881, df = 6, P = 0.930) revealed that variables, such as chest pain (age-adjusted OR = 0.0510, 95% CI: 0.004, 0.583), pleural total protein (≤45.3 g/L, age-adjusted OR = 27.7, 95% CI: 2.5, 307.7), pleural lactate dehydrogenase (LDH, ≤505 U/L, age-adjusted OR = 59.9, 95% CI: 4.2, 857.2) and blood urea nitrogen (≤3.2 mmol/L, age-adjusted OR = 32.0, 95% CI: 2.4, 426.9), were associated with negative pleural ADA results when diagnosing childhood pleural TB.ConclusionOur findings demonstrated that chest pain, pleural total protein, pleural LDH, and blood urea nitrogen were associated with a negative pleural ADA result for the diagnosis of pleural TB among children. When interpreting pleural ADA levels in children with these characteristics, a careful clinical assessment is required for the pleural TB diagnosis.

Treatment delay in childhood pleural tuberculosis and associated factors

BackgroundDelay in diagnosis and treatment worsens the disease and clinical outcomes, which further enhances the transmission of tuberculosis (TB) in the community. Therefore, this study aims to assess treatment delay and its associated factors among childhood pleural TB patients in China.MethodsBetween January 2006 and December 2019, consecutive patients aged ≤15 years with definite or possible pleural TB were included for analysis. Treatment delay duration was defined as the time interval from the onset of symptoms to treatment initiation and was stratified into two categories: < 30 days, ≥30 days (median delay day is 30 days). The electronic medical records of children were reviewed to obtain demographic characteristics, clinical characteristics, laboratory examinations, and radiographic findings. Univariate and multivariate logistic regressions were used to explore the factors associated with treatment delay in patients.ResultsA total of 154 children with pleural TB were included, with a mean age of 12.4 ± 3.3 years. The median treatment delay was 30 days (interquartile range, 10–60 days) and 51.3% (n = 79) of patients underwent a treatment delay. Multivariate analysis revealed that heart rate (≤92 beats/min, age-adjusted OR = 2.503, 95% CI: 1.215, 5.155) and coefficient of variation of red cell distribution width (RDW-CV, ≥12.9%, age-adjusted OR = 4.705, 95% CI: 2.048, 10.811) were significant risk factors for treatment delays in childhood pleural TB.ConclusionOur findings suggested that a significant treatment delay occurs among children with pleural TB in China. Patients with a low heart rate or a high RDW-CV experienced delays in the initiation of anti-TB therapy. Therefore, well awareness of the associations between clinical characteristics and treatment delay may improve the management of children with pleural TB and enable us to develop preventive strategies to reduce the treatment delay.

Evaluation of Xpert MTB/RIF Ultra Assay for Diagnosis of Childhood Tuberculosis: a Multicenter Accuracy Study.

A multicenter study was performed to evaluate the value of testing gastric aspirate (GA) with Xpert MTB/RIF Ultra assay (Ultra) for childhood tuberculosis (TB) detection in China. In total, 129 children with active TB and 173 children without TB were enrolled. The sensitivity of Ultra in bacteriologically confirmed TB and probable TB cases was 87.5% (42/48) and 44.4% (36/81), respectively. The specificity of Ultra was high (99.4%, 172/173). When Ultra, culture, and acid-fast bacilli outcomes were integrated as a composite reference standard, the percentage of children with definite TB increased from 37.2% (48/129) to 67.4% (87/129). The sensitivity of Ultra is 80.0% (40/50) in children aged <4 years, which is significantly higher than that in older children (48.1%, 38/79) (P < 0.001). Ultra conducted using GA samples can provide faster results, allowing an early and accurate TB diagnosis, especially in younger children with difficulty producing sputum.

Ultrasound in managing extrapulmonary tuberculosis: a randomized controlled two-center study

BackgroundPatients with clinically suspected tuberculosis are often treated empirically, as diagnosis - especially of extrapulmonary tuberculosis - remains challenging. This leads to an overtreatment of tuberculosis and to underdiagnosis of possible differential diagnoses.MethodsThis open-label, parallel-group, superiority randomized controlled trial is done in a rural and an urban center in Tanzania. HIV-positive and -negative adults (≥18 years) with clinically suspected extrapulmonary tuberculosis are randomized in a 1:1 ratio to an intervention- or control group, stratified by center and HIV status. The intervention consists of a management algorithm including extended focused assessment of sonography for HIV and tuberculosis (eFASH) in combination with chest X-ray and microbiological tests. Treatment with anti-tuberculosis drugs is started, if eFASH is positive, chest X-ray suggests tuberculosis, or a microbiological result is positive for tuberculosis. Patients in the control group are managed according national guidelines. Treatment is started if microbiology is positive or empirically according to the treating physician. The primary outcome is the proportion of correctly managed patients at 6 months (i.e patients who were treated with anti-tuberculosis treatment and had definite or probable tuberculosis, and patients who were not treated with anti-tuberculosis treatment and did not have tuberculosis). Secondary outcomes are the proportion of symptom-free patients at two and 6 months, and time to death. The sample size is 650 patients.DiscussionThis study will determine, whether ultrasound in combination with other tests can increase the proportion of correctly managed patients with clinically suspected extrapulmonary tuberculosis, thus reducing overtreatment with anti-tuberculosis drugs.Trial registrationPACTR, Registration number: PACTR201712002829221, registered December 1st 2017.

Tuberculosis burden in stage 5 chronic kidney disease patients undergoing dialysis therapy at Livingstone Hospital, Port Elizabeth, South Africa.

Tuberculosis (TB) is currently the leading cause of death from a single infectious agent worldwide. Patients who receive dialysis are particularly vulnerable to TB infection owing to immune dysfunction. Nonetheless, there is a paucity of incidence data on dialysis patients infected with TB in high-burden countries, such as South Africa (SA). To determine the incidence of TB in prevalent chronic kidney disease stage 5 (CKD-5D) patients on dialysis at a single centre in Eastern Cape Province, SA, and to identify the risk factors associated with TB infection. We conducted a retrospective cohort study of all consenting CKD-5D patients between April 2010 and March 2014 at Livingstone Hospital Renal Unit, Port Elizabeth, the Eastern Cape. TB was defined as definite or probable according to World Health Organization (WHO) criteria, and the cohort was split into those who developed TB (TB+) and those who did not (TB-). One hundred and eleven patients were enrolled - predominantly black Africans (73%) and women (53%); the mean age (standard deviation (SD)) was 42 (9.8) years. The prevalence of HIV infection was 11%, all patients were receiving antiretroviral treatment and all had suppressed viral loads. Sixty-eight patients were on haemodialysis and 43 on peritoneal dialysis. Nineteen patients were diagnosed with 20 episodes of TB; 14 cases were pulmonary TB and 6 cases extrapulmonary TB. Of the patients with TB, 2 were HIV-infected, 7 (35%) were definite TB cases and 13 (65%) were probable cases. The calculated incidence rate was 4 505/100 000 patient years. Only informal housing (30% in TB+ v. 12% in TB-; p=0.042) and a history of hospitalisation (90% v. 76%, respectively; p=0.042) were significantly associated with a diagnosis of TB. Dialysis patients in the Eastern Cape region of SA are at extremely high risk of acquiring TB, with an incidence rate 4.1 times that of the local population and &gt;5 times that of the general SA population. Only informal housing and a history of hospitalisation were identified as positive risk factors for TB in this young population with a low HIV prevalence. Isoniazid prophylaxis in this high-risk group might be of benefit, but further studies are required to inform such treatment.

Standardized Urine-Based Tuberculosis (TB) Screening With TB-Lipoarabinomannan and Xpert MTB/RIF Ultra in Ugandan Adults With Advanced Human Immunodeficiency Virus Disease and Suspected Meningitis.

BackgroundDiagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults.MethodsWe prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018–2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing.ResultsWe enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13–102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%–30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83–2.49; P = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13–28.5; P = .04).ConclusionsIn hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation.

Evaluation of QuantiFERON tuberculosis Gold In-Tube assay for diagnosis of active tuberculosis in children.

Tuberculin skin test (TST) is still used in diagnostic algorithms of childhood tuberculosis (TB). QuantiFERON TB Gold In-Tube assay (QFT-GIT) is an alternative test to TST based on the detection of interferon-gamma release upon in vitro induction of peripheral mononuclear cells by TB antigens. In this study, we aimed to determine the diagnostic value and performance of QFT-GIT for active childhood TB. This retrospective study was conducted between January 2005 and December 2011 in three referral hospitals in Turkey with 124 children who were diagnosed with definite active TB. Sensitivity values of TST and QFT-GIT were determined by accepting the microbiological confirmation as the gold standard of diagnosis of TB. In our study, sensitivity of QFT-GIT and TST was found to be 65 and 66% respectively. However, combined usage of QFT-GIT and TST was found to be more sensitive (85%) than TST or QFT-GIT alone (P < 0.0001). Although negative results of QFT-GIT or TST did not exclude the diagnosis of active TB in children, their positivity supported the diagnosis. Specificity could not be measured as only microbiologically confirmed cases of Mycobacterium tuberculosis disease were enrolled in the study. Although sensitivities of TST and QFT-GIT are too low to exclude active TB, their positivity supports diagnosis of active TB in children concomitant with signs and symptoms. QFT-GIT and TST should be used together to enhance diagnostic sensitivity and could help exclude a diagnosis of TB if the pretest probability is low.

1374. Diagnostic Utility of Whole Body Positron Emission Tomography-Computerized Tomography (PET-CT) in Patients with Suspected Central Nervous System Tuberculosis: A Retrospective, Descriptive Study

BackgroundThere is difficulty in diagnosing central nervous system (CNS) tuberculosis (TB) in the early stages because features mimic viral and pyogenic meningitis. There is a need to determine alternate methods to diagnose CNS TB. Whole-body PET-CT, used mainly in oncology, has shown promise in the detection of tuberculosis and monitoring response to anti-tuberculous therapy. Utility in CNS TB is unexplored.MethodsRetrospective, cohort, single-center study. Patients were included if they fulfilled the following criteria: (1) Probable/possible tuberculous meningitis as per the Lancet Consensus Score; (2) undergone whole-body PET-CT with 18-fluorodeoxyglucose and intravenous contrast; (3) less than one week of anti-tuberculous therapy at the time of PET-CT; (4) clinical response to antituberculous treatment and steroids; (5) no other etiological agent identified.ResultsWe identified 9 patients that fulfilled the above criteria. 5 of these patients were immunosuppressed (4 had advanced AIDS, one patient was on immunosuppressive therapy). We found that 86.4% of patients (7 out of 9) had radiological features suggestive of probable active TB outside the CNS (Figure 1). Of these 7 patients, 5 patients had definite TB (defined as positive Ziehl–Neelsen stain or Gene Xpert MTB/RIF assay or culture for tubercle bacilli) outside the CNS while 2 had histopathological evidence of TB (granulomatous inflammation) (Figure 2). All strains of TB were rifampin sensitive. The sites of isolation of tuberculosis were (Figure 3). (a) Abdominal lymph node in 2 patients (40%); (b) cervical lymph node in 2 patients (40%); (c) sputum in 1 patient (20%). In patients with evidence of disease outside the CNS, the average maximum standardized uptake value (SUV Max) in diverse anatomical locations was 5.75 (range 1.9–11.2). The most frequent manifestation PET-CT manifestation suggestive of TB outside the CNS in decreasing order of frequency was cervical lymphadenopathy (in 55.5% of patients), pleural and pulmonary parenchymal involvement (44.4% in each), followed by mediastinal nodes and abdominal lymph nodes in 33.3% (Figure 4).ConclusionPET-CT is a valuable tool in treatment-naive (less than 1 week of anti-tuberculous therapy) patients with suspected CNS tuberculosis. A large proportion of patients have evidence of TB outside the CNS. Disclosures All authors: No reported disclosures.

Prednisolone dose during treatment of tuberculosis might be a risk factor for mortality in patients with systemic lupus erythematosus: a hospital-based cohort study.

Patients with systemic lupus erythematosus (SLE) are at high risk of tuberculosis (TB) because of their immunocompromised status and the use of immunosuppressive drugs. In endemic regions, TB complicates the diagnosis and treatment of SLE, but the risk factors of mortality in these patients have not been investigated. In this study, we reviewed medical records during 2006-2016. Patients who fulfilled the 1997 American College of Rheumatology SLE criteria and presented with definite TB were enrolled. The primary outcome was mortality during TB treatment. There were 5388 SLE patients screened, and 30 patients were enrolled. Seven patients died during follow-up. Compared with the survival group, patients in the mortality group had significantly more central nervous system involvement of TB, higher Systemic Lupus Erythematosus Disease Activity Index-2000 scores and more cyclophosphamide use before TB, and higher prednisolone dose before and during TB treatment. Cox regression showed that prednisolone dose during TB treatment was an independent risk factor for mortality (per 10 mg/day increase, hazard ratio (HR) 1.61, p = .019). For SLE patients, prednisolone dose during TB treatment is an independent risk factor for mortality. Keeping prednisolone dose at less than 25 mg per day during TB treatment might be a reasonable strategy in these patients.

Xpert MTB/Rif Ultra for the Diagnosis of HIV-Associated Tuberculous Meningitis: A Prospective Validation

Introduction: Tuberculous meningitis accounts for 1-5% of tuberculosis (TB) cases. Diagnostic delay contributes to poor outcomes. We evaluated the performance of the new Xpert MTB/Rif Ultra (Ultra) for TB meningitis diagnosis. Methods: In a prospective diagnostic accuracy study, we tested the cerebrospinal fluid (CSF) of adults presenting with sub-acute meningitis to Mulago and Mbarara Hospitals, Uganda. We centrifuged the CSF, resuspended the cell pellet in 2mL CSF and tested 0.5ml aliquots with Ultra, Xpert, and mycobacterial growth indicator tube (MGIT) culture. We quantified diagnostic performance against 1) the uniform case definition of probable or definite TB meningitis and 2) a composite microbiological reference standard. Findings: From November 2016 to January 2019, we screened 466 adults with suspected meningitis and tested 204 for TB meningitis. Uniform clinical case definition classified 51 participants as probable/definite TB meningitis. Against this uniform case definition, Ultra had 76% sensitivity (39/51) compared with Xpert 56% (25/45; P=0·001) or culture 61% (27/44; P=0·02). Against the composite reference standard, Ultra had sensitivity of 93% (39/42), higher than Xpert at 66% (25/38; p=0·006) or culture at 72% (27/37; p=0·09). Ultra detected nine TB meningitis cases missed by Xpert and culture. In multivariate analysis, decreasing CSF glucose was a predictor of definite TB meningitis (P=0.001). Interpretation: Ultra detects TB meningitis with higher sensitivity than Xpert and culture in this HIV-positive population. However, with a negative predictive value of 93% Ultra cannot be used as a 'rule out' test. Clinical judgement and novel highly sensitive point of care tests are still required. Funding Statement: This research was made possible through support from the National Institute of Neurologic Disorders and Stroke (R01NS086312), the Fogarty International Center (K01TW010268, K43TW010718), and National Institute of Allergy and Infectious Diseases (T32AI055433). Declaration of Interests: FVC is supported through a Wellcome Trust Clinical PhD Fellowship (Grant no. 210772/Z/18/Z). FVC is an honorary fellow of the Makerere University – Uganda Virus Research Institute Centre of Excellence for Infection and Immunity Research and Training (MUII-plus). MUII-plus is supported through the DELTAS Africa Initiative (Grant no. 107743). The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS), Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (Grant no. 107743) and the UK Government. The MRC/UVRI and LSHTM Uganda Research Unit is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. All other authors have nothing to disclose. Ethics Approval Statement: Institutional review board and Uganda National Council of Science and Technology approvals were obtained and informed consent was obtained from participants or their surrogate (in patients with altered mental status). The study was conducted in line with the Standards for Reporting Diagnostic Accuracy Studies.