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RationaleIn 2016, a new interferon-gamma release assay (IGRA) was introduced, QuantiFERON-TB Gold Plus (QFT-Plus), claimed to have improved sensitivity in active tuberculosis (TB).ObjectivesThis study aimed to determine the performance of QFT-Plus, compared with previous generation IGRAs and the tuberculin skin test (TST), in children with TB in Europe.MethodsMulticentre, ambispective cohort study within the Paediatric Tuberculosis Network European Trials Group (ptbnet), a dedicated paediatric TB research network comprising >300 members, capturing TB cases Measurements and main results1001 TB cases from 16 countries were included (mean age (IQR) 5.6 (2.4–12.1) years). QFT-Plus was performed in 358, QFT Gold in-Tube (QFT-GIT) in 600, T-SPOT.TBin 58 and TST in 636 cases. The overall test sensitivities were: QFT-Plus 83.8% (95% CI 80.2% to 87.8%), QFT-GIT 85.5% (95% CI 82.7% to 88.3%), T-SPOT.TB77.6% (95% CI 66.9% to 88.3%) and TST (cut-off ≥10 mm) 83.3% (95% CI 83.3% to 86.2%). There was a trend for tests to have lower sensitivity in patients with miliary and/or central nervous system (CNS) TB (73.1%, 70.9%, 63.6% and 43.5%, respectively), and in immunocompromised patients (75.0%, 59.6%, 45.5% and 59.1%, respectively).ConclusionsThe results indicate that the latest generation IGRA assay, QFT-Plus, does not perform better than previous generation IGRAs or the TST in children with TB disease. Overall, tests performed worse in CNS and miliary TB, and in immunocompromised children. None of the tests evaluated had sufficiently high sensitivity to be used as a rule-out test in children with suspected TB.

Endogenous reactivation and exogenous reinfection are two possible causes of recurrent tuberculosis (TB). However, in some cases, precise cause determination can be challenging. In this study, we used whole genome sequencing to determine pairwise SNV distances and detect differing SNVs in initial and subsequent isolates for recurrent TB cases when the first and second episodes were caused by Mycobacterium tuberculosis (Mtb) strains with an identical spoligotype pattern. In total, 104 Mtb isolates from 36 recurrent TB and 16 single TB episode patients were included in the study. Most isolate pairs belonged to the SIT1 (n=21), SIT42 (n=9), SIT53 (n=9), and SIT254 (n=7) spoligotypes, and in 27 cases, resistance to at least one anti-TB drug was found in either isolate. Drug susceptibility was more common in the recurrent TB patient cohort, and longitudinal single TB episode isolates were more prone to be drug-resistant (p=0.03), while the association between patient cohort and spoligotype was not statistically significant (p=0.07). The pairwise SNV-distance between the longitudinal single TB episode isolates was small (0-7 SNVs). Among the recurrent TB isolates, based on the high SNV-distance (38–273 SNVs), six reinfection cases (16.7%) were identified. This distance was small (Mtb strain. No statistically significant difference in the time interval between specimen collection in the reactivation and reinfection Mtb sample groups (p=0.13) or an association between recurrence cause and drug resistance status (p=0.62) or spoligotype (p=0.79) could be detected. The mycobacterial median mutation rate of longitudinal single TB episodes and possible reactivation isolate pairs (n=37) was 0.12 SNVs/genome/year (IQR 0-0.39), and in 18 cases (48.6%), it was equal to zero. No statistically significant differences in mutation rate were found between recurrent TB and longitudinal single TB episode isolates (p=0.087), drug-susceptible and resistant isolates (p=0.37) or isolates of Beijing and other genotype families (p=0.33). Furthermore, four cases of fluoroquinolone resistance development through the acquired SNVs in the gyrA gene were identified. To conclude, this study highlighted the complexity of recurrent episode cause determination and showed the usefulness of differing SNV identification in both Mtb isolates in such cases. Expected drug susceptibility was the only discriminative factor for recurrent TB episode-causing mycobacterial strains, while no differences between reactivation and reinfection sample groups could be identified.

Children had better treatment outcomes and lower mortality rates than adults., Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (

Background Urogenital tuberculosis (TB) is rare in children and usually develops due to reactivation of the foci in the genitourinary tract after the latency period following initial infection. Urogenital TB in children has no pathognomonic clinical features that can result in overlooking or misdiagnosing this clinical entity. Here, we report important findings regarding the pathogenesis and transmission of TB by using genotyping and whole-genome sequencing (WGS) in a study of renal TB case in a child. Case presentation A 13-year-old boy was admitted to the hospital because of high fever, severe dry cough, flank pain and painful urination. Abdominal ultrasonography and CT revealed an 8 mm calculus in the kidney, and clinical findings were initially interpreted as nephrolithiasis. Nevertheless, due to the atypical clinical presentation of kidney stone disease, additional investigations for possible TB were performed. The QuantiFERON®-TB Gold Plus test was positive, and the Mantoux test resulted in 15 mm of induration, confirming infection with Mycobacterium tuberculosis (Mtb). Chest X-ray was normal. Chest CT revealed calcified intrathoracic lymph nodes. The urine sample tested positive for acid-fast bacilli, and Mtb cultures were obtained from urine and bronchial aspirate samples, resulting in a final diagnosis of intrathoracic lymph node and renal TB. Contact investigation revealed that the child’s father was diagnosed with TB when the child was 1 year old. Genotyping and WGS analysis of Mtb isolates of the child and his father confirmed the epidemiological link and pointed to the latency of infection in the child. Conclusions This case report confirmed the development of active TB from calcified lesions in adolescent after 12 years of exposure, demonstrated the absence of microevolutionary changes in the Mtb genome during the period of latency, and proved the importance of appropriate evaluation and management to prevent the progression of TB infection to active TB disease. The use of WGS provided the ultimate resolution for the detection of TB transmission and reactivation events.

Background An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. Methods and findings To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged, In a systematic review and meta-analysis conducted to inform World Health Organization guidelines, Elizabeth Harausz and colleagues investigate different treatment regimens and outcomes for children with multidrug-resistant tuberculosis., Author summary Why was this study done? Treatment for multidrug-resistant tuberculosis (MDR TB) affects 32,000 children per year, requires longer treatment with much more toxic medications than drug-susceptible tuberculosis. Unfortunately, little is know about the optimal treatment for children with MDR TB. This study reviewed treatment and outcome data from children around the world in order to better understand the management of MDR-TB in children. This study also sought to understand the risk factors for poor treatment outcomes in children with MDR-TB. This study informed the World Health Organization guidelines on treatment of MDR-TB in children. What did the researchers do and find? We performed a systematic review and individual patient data meta-analysis on clinical characteristics and treatment outcomes on 975 children from across 18 countries. Children were analyzed in two separate groups, those with bacteriologically confirmed MDR-TB and those who were clinically diagnosed with MDR-TB. We found that, in general, children do well when treated with the second-line MDR-TB medications (78% overall had successful treatment outcomes), despite the fact that there was a high burden of severe disease. Malnutrition and not being treated for HIV (if the child was HIV-positive) during TB treatment significantly increased the risk of poor outcomes. Second-line injectable agents and high-dose isoniazid were associated with treatment success. However, a high proportion of children with non-severe disease who received no second-line injectable agents still did well; therefore, children with non-severe disease may be able to be spared from these toxic medications. What do these findings mean? Consideration should be given to using high-dose isoniazid in treatment regimens, and if children have non-severe disease, the possibility of excluding second-line injectable agents from the treatment regimen should be considered. HIV treatment should be started as soon as is possible, and malnutrition should be aggressively treated.

During last decades an incidence of chronic inflammatory diseases is on the rise in the world. There is an increasing need for drugs, including TNFα inhibitors, to help patients suffering from these diseases. However risk of TB infection and disease increases in patients receiving TNF α therapy. In Latvia there are national guidelines implemented, determining screening for TB infection and disease before initiation and during therapy with TNFα therapy. Aim: To evaluate the conformity of actions by health care providers with national guidelines. Material and methods: Retrospective descriptive cross-sectional study. The data was collected through questionnaires, sent out to all 40 TB/pneumonologists in Latvia. They contain information from patient records of those that were diagnosed with LTBI and/or active TB before or during TNFα therapy, for the period of time from 01.01.2014 to 30.09.2015. Data from questionnaires was abstratcted by coding using binary numbers and letters in the computer program Microsoft Excel. Results: Active TB developed in 4 (3%) out of 136 patients receiving TNFα treatment. TB contact history was identified in 2 of 30 patients diagnosed with LTBI. PPD test was performed in 67 (49%) and IGRA test in 104 (77%) of TNFα treatment candidates, respectively. Majority of latently infected patients (97%) had received preventive treatment with isoniazid, however only 4 (13%) of 30 patients received recomended 9 months therapy. Conclusion: The overall conformity with national guidelines was good. Mostly both tests were not performed due to the logistic difficulties. Improvement of algorythm should be discussed.

OBJECTIVE To perform a comprehensive analysis of case detection, diagnosis and treatment of tuberculosis (TB) in children and adolescents in Latvia, and to evaluate the utility of the current approach. DESIGN A retrospective study of all Latvian children and adolescents diagnosed with TB from 1 January 2011 to 31 December 2014. RESULTS Of 3081 patients diagnosed with TB during 2011-2014, 250 (8%) were aged

Setting: Drug-resistant tuberculosis (TB) is an important public health problem in Latvia. Objective: To document trends, characteristics and treatment outcomes of registered patients with multi-drug-resistant (MDR-) and extensively drug-resistant (XDR-) TB in Latvia from 2000 to 2010. Design: A retrospective national cohort study. Results: Of 1779 patients, 1646 (92%) had MDR- and 133 (8%) XDR-TB. Over 11 years, the proportion of XDR-TB among MDR-TB patients increased from 2% to 18%. Compared to MDR-TB patients, those with XDR-TB were significantly more likely to have failed MDR-TB treatment (OR 8.4, 95%CI 4.3–16.2), have human immunodeficiency virus infection (OR 3.2, 95%CI 1.8–5.7), be illegal drug users (OR 5.7, 95%CI 2.6–11.6) or have had contact with MDR-TB patients (OR 1.9, 95%CI 1.3–2.8). Cure rates for XDR-TB were 50%. Compared with MDR-TB patients, those with XDR-TB had a higher risk of treatment failure (29% vs. 8%, respectively, P < 0.001). Unfavourable treatment outcomes were significantly associated with being male; having smear-positive disease; pulmonary cavities; failure, default or relapse after previous MDR-TB treatment; and a history of incarceration. Conclusion: More MDR-TB in Latvia is now also XDR-TB. This study identified several risk factors for XDR-TB and, for unfavourable treatment outcomes, highlighting the importance of early diagnosis and appropriate management of MDR-/XDR-TB.

Using of T-Spot.TB and Mantoux tests in diagnosis of M. tuberculosis infection in BCG vaccinated children aged five and younger Infection with M. tuberculosis (MT) is difficult to diagnose in young BCG (Bacillus Calmette-Guérin) vaccinated children using Mantoux test alone, as a positive test result may be due to infection with MT and previous BCG vaccination. We aimed to test the T-SPOT. TB test for BCG-vaccinated children aged five and younger in two groups — with or without contact with an active tuberculosis (ATB) patient. Prospectively a study group of 121 children (having contact with ATB patient) and a control group of 64 children (without known contact with ATB patient) were examined using Mantoux and T-SPOT. TB tests. The T-SPOT. TB test was positive in 66 (54.5%) study group children and in 2 (3.1%) control group children (P < 0.01). Induration in the Mantoux test ≥ 10 mm was observed in 62 (91.0%) of 68 T-SPOT. TB positive children, and 34 (29.1%) of 117 T-SPOT. TB negative children (P < 0.01). In the group with a negative T-SPOT. TB result boosting of the Mantoux test was observed in 21 (66%) of 32 children who had received repeated Mantoux testing before being included in the study. According to the results, the application of the T-SPOT. TB test is reasonable for primary contact children evaluation and follow-up contact children for whom primary tests did not confirm infection with MT.

Mutations causing resistance to aminoglycosides, such as kanamycin (KAN), amikacin (AMK), and streptomycin, are not completely understood. In this study, polymorphisms of aminoglycoside resistance influencing genes such as rrs, eis, rpsL, and gidB in 41 drug-resistant and 17 pan-sensitive Mycobacterium tuberculosis clinical isolates in Latvia were analyzed. Mutation A1400G in rrs gene was detected in 92% isolates with high resistance level to KAN and diverse MIC level to AMK. Mutations in promoter region of eis were detected in 80% isolates with low-level MIC of KAN. The association of K43R mutation in rpsL gene, a mutation in the rrs gene at position 513, and various polymorphisms in gidB gene with distinct genetic lineages of M. tuberculosis was observed. The results of this study suggest that association of different controversial mutations of M. tuberculosis genes to the drug resistance phenotype should be done in respect to genetic lineages.