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Rapid, cost-effective, and sensitive diagnostic assays are essential for global tuberculosis (TB) control, especially in high TB burden, resource-limited settings. The current study was designed to evaluate diagnostic accuracy of Truenat MTB-Rif Dx (MolBio) in children less than 18 years of age, with symptoms suggestive of TB. Gastric aspirate, induced sputum, and broncho-alveolar lavage samples were subjected simultaneously to AFB-smear, GeneXpert MTB/RIF, liquid culture (MGIT-960) and Truenat MTB-Rif Dx. The index-test results were evaluated against microbiological reference standards (MRS). Truenat MTB-Rif Dx had a sensitivity of 57.1%, specificity of 92% against MRS. The sensitivity and specificity of the Truenat MTB-RIF Dx compared with liquid culture was 58.7% and 87.5% while GeneXpert MTB/RIF was 56% and 91.4%. The performance of both GeneXpert MTB/RIF and Truenat MTB-Rif Dx are comparable. Result of our study demonstrates that Truenat MTB-Rif can aid in early and efficient diagnosis of TB in children.

Newer molecular diagnostics have brought paradigm shift in early diagnosis of tuberculosis [TB]. WHO recommended use of GeneXpert MTB/RIF [Xpert] for Extra-pulmonary [EP] TB; critics have since questioned its efficiency. The present study was designed to assess the performance of GeneXpert in 761 extra-pulmonary and 384 pulmonary specimens from patients clinically suspected of TB and compare with Phenotypic, Genotypic and Composite reference standards [CRS]. Comparison of GeneXpert results to CRS, demonstrated sensitivity of 100% and 90.68%, specificity of 100% and 99.62% for pulmonary and extra-pulmonary samples. On comparison with culture, sensitivity for Rifampicin [Rif] resistance detection was 87.5% and 81.82% respectively, while specificity was 100% for both pulmonary and extra-pulmonary TB. On comparison to sequencing of rpoB gene [Rif resistance determining region, RRDR], sensitivity was respectively 93.33% and 90% while specificity was 100% in both pulmonary and extra-pulmonary TB. GeneXpert assay missed 533CCG mutation in one sputum and dual mutation [517 & 519] in one pus sample, detected by sequencing. Sequencing picked dual mutation [529, 530] in a sputum sample sensitive to Rif, demonstrating, not all RRDR mutations lead to resistance. Current study reports observations in a patient care setting in a high burden region, from a large collection of pulmonary and extra-pulmonary samples and puts to rest questions regarding sensitivity, specificity, detection of infrequent mutations and mutations responsible for low-level Rif resistance by GeneXpert. Improvements in the assay could offer further improvement in sensitivity of detection in different patient samples; nevertheless it may be difficult to improve sensitivity of Rif resistance detection if only one gene is targeted. Assay specificity was high both for TB detection and Rif resistance detection. Despite a few misses, the assay offers major boost to early diagnosis of TB and MDR-TB, in difficult to diagnose pauci-bacillary TB.

Extra-pulmonary TB (EPTB) is difficult to diagnose due to paucibacillary nature of disease. Current study evaluated accuracy of Truenat MTB and MTB-Rif Dx (TN), for detection of  Mycobacterium tuberculosis  and resistance to rifampicin. Samples were collected from 2103 treatment naive adults with presumptive EPTB, and tested by smear microscopy, liquid culture (LC) (MGIT-960) and GeneXpert MTB/RIF (GX) (Microbiological Reference Standards, MRS). TN results were compared to MRS and Composite Reference Standards (CRS, Microbiology, histopathology, radiology, clinical features prompting decision to treat, response to treatment). CRS grouped patients into 551 confirmed, 1096 unconfirmed, and 409 as unlikely TB. TN sensitivity and specificity was 73.7% and 90.4% against GX. Against LC, Overall sensitivity of GX was 67.6%, while that of TN was 62.3%. Highest sensitivity by TN was observed in pus samples (89%) and highest specificity (92%) in CSF samples, similar to GX. TN sensitivity was better in fluid and biopsy samples and slightly inferior for lymph node aspirates compared to GX. TN sensitivity for RIF resistance detection was slightly superior to GX. TN and GX results were further compared to Clinical Reference Standards. TN detected 170 TB patients initiated on treatment missed by GX, while GX detected 113 such patients missed by TN. Of 124 samples with RIF resistance discordance between GX and TN, GX reported 103/124 as sensitive, 3/124 as indeterminate and 18 as resistant (13/18 samples had low/very low DNA load) while TN reported RIF resistance indeterminate in 103/111 low/very low DNA load samples. Due to paucibacillary nature of EPTB samples, culture yield was poor and phenotypic drug susceptibility testing failed to resolve the discordance. The study establishes TN at par with GX and can be utilized for quick and accurate diagnosis of EPTB.

Mixed/polyclonal infections due to different genotypes are reported in Tuberculosis. The current study was designed to understand the fate of mixed infections during the course of treatment and follow-up and its role in disease pathogenesis. Sputum samples were collected on 0,1,2,3,6,12 and 24 months from 157 treatment-naïve patients, cultures subjected to Drug-Susceptibility-testing (MGIT 960), spoligotyping, MIRU-VNTR and SNP genotyping. All isolated colonies on thin layer agar (7H11) were subjected to spoligotyping. One thirty three baseline cultures were positive (133/157, 84.7%), 43(32.3%) had mixture of genotypes. Twenty-four of these patients (55.8%) showed change in genotype while six showed different drug-susceptibility patterns while on treatment. Twenty-three (53.5%) patients with polyclonal infections showed resistance to at least one drug compared to 10/90 (11.1%) monoclonal infections (P<0.0001). Eight patients had recurrent TB, two with a new genotype and two with altered phenotypic DST. The coexistence of different genotypes and change of genotypes during the same disease episode, while on treatment, confirms constancy of polyclonal infections. The composition of the mixture of genotypes and the relative predominance may be missed by culture due to its limit of detection. Polyclonal infections in TB could be a rule rather than exception and challenges the age-old dogma of reactivation/reinfection.

IntroductionUniversal coverage of vaccines alone cannot be relied upon to protect at-risk populations in lower- and middle-income countries against the impact of the coronavirus disease 2019 (COVID-19) pandemic and newer variants. Live vaccines, including Bacillus Calmette–Guérin (BCG), are being studied for their effectiveness in reducing the incidence and severity of COVID-19 infection.MethodsIn this multi-centre quadruple-blind, parallel assignment randomised control trial, 495 high-risk group adults (aged 18–60 years) were randomised into BCG and placebo arms and followed up for 9 months from the date of vaccination. The primary outcome was the difference in the incidence of COVID-19 infection at the end of 9 months. Secondary outcomes included the difference in the incidence of severe COVID-19 infections, hospitalisation rates, intensive care unit stay, oxygen requirement and mortality at the end of 9 months. The primary analysis was done on an intention-to-treat basis, while safety analysis was done per protocol.ResultsThere was no significant difference in the incidence rates of cartridge-based nucleic acid amplification test (CB-NAAT) positive COVID-19 infection [odds ratio (OR) 1.08, 95% confidence interval (CI) 0.54–2.14] in the two groups, but the BCG arm showed a statistically significant decrease in clinically diagnosed (symptomatic) probable COVID-19 infections (OR 0.38, 95% CI 0.20–0.72). Compared with the BCG arm, significantly more patients developed severe COVID-19 pneumonia (CB-NAAT positive) and required hospitalisation and oxygen in the placebo arm (six versus none; p = 0.03). One patient belonging to the placebo arm required intensive care unit (ICU) stay and died. BCG had a protective efficacy of 62% (95% CI 28–80%) for likely symptomatic COVID-19 infection.ConclusionsBCG is protective in reducing the incidence of acute respiratory illness (probable symptomatic COVID-19 infection) and severity of the disease, including hospitalisation, in patients belonging to the high-risk group of COVID-19 infection, and the antibody response persists for quite a long time. A multi-centre study with a larger sample size will help to confirm the findings in this study.Clinical Trials RegistryClinical Trials Registry India (CTRI/2020/07/026668).Plain Language SummaryThe Bacillus Calmette–Guérin (BCG) vaccine has been studied previously in several settings, including reducing childhood mortalities due to viral infections and induction of trained immunity and reducing upper respiratory tract infections and pneumonia in older adults. This multi-centre trial has tried to evaluate the efficacy of BCG revaccination in reducing the incidence and severity of COVID-19 infections in adults between 18 and 60 years of age belonging to the high-risk group owing to the presence of comorbidities including diabetes, chronic kidney disease, chronic liver disease and chronic lung diseases. A single dose of BCG vaccine produced significantly high titres of BCG antibodies lasting for six months. While there was no significant reduction in the incidence of COVID-19 infection, there was an 8.4% reduction in the incidence of symptomatic COVID-19 disease at the end of 9 months of follow-up. In addition, there were significantly fewer severe COVID-19 infections requiring hospital stay and oxygen support. However, the overall numbers of severe COVID-19 infections were low. Thus, the study shows that BCG can protect against symptomatic and severe COVID-19 disease. However, it might not reduce the incidence of new infections. The study results are significant for low- and middle-income countries without adequate coverage of primary doses of COVID-19 vaccination, let alone the booster doses. Future studies should evaluate the BCG vaccine’s efficacy as a booster compared with routine COVID-19 vaccine boosters.

Abstract Background and Objective: Female genital tuberculosis (FGTB) is an important type of extrapulmonary tuberculosis (TB) associated with morbidity especially infertility in developing countries. Laparoscopy may be difficult and hazardous in FGTB. The aim of the study was to observe the difficulties and complications of laparoscopy in FGTB cases. Materials and Methods: It was a prospective study over 12 years' period on 412 cases of diagnostic laparoscopy performed on FGTB cases with infertility. All patients underwent history taking and clinical examination and endometrial sampling for acid-fast bacilli (AFB) microscopy, culture, polymerase chain reaction (PCR), gene Xpert (last 212 cases) and histopathological evidence of epithelioid granuloma. Another 412 cases of diagnostic laparoscopy in the absence of FGTB performed during same time were taken as controls from the pool of non-TB cases. Various difficulties and complications were noted in both groups and statistical analysis was done. Results: Mean age, parity, body mass index and duration of infertility were 26.8 versus 25.4 years, 0.32 versus 0.28, 23.15 versus 25.28 Kg/m2 and 4.15 versus 5.12 years, respectively. Primary and secondary infertility was seen in 78.6% and 20.38% of cases in the study group and 74.75% and 25.24% in the control group, respectively. Endometrial biopsy showed AFB microscopy in 5.3%, culture in 6.3%, epithelioid granuloma in 15.77% and on peritoneal biopsy granuloma in 6.55%, positive PCR in 368 (89.32%) and positive gene Xpert in 38 out of 212 (17.92%, out of last 212 cases). Definite findings of FGTB were seen in 171 (41.50%) cases. Probable findings of FGTB were seen in 241 (58.49%) cases. Various complications were difficulty in the creation of pneumoperitoneum or insertion of trocar and cannula in 16.74% and 13.10% of cases as compared to 1.94% and 1.69% in the control group. Excessive bleeding was seen in 5.09% versus 0.97% cases, respectively. Various injuries observed were bowel injury in 1.69% versus 0.24% cases (small bowel in 1.21% vs. 0.24%, large bowel in 0.48% vs. 0.1%), while bladder injury was seen in 0.97% versus 0.24% cases, subacute intestinal obstruction was seen in 5.8% versus 0.72% cases respectively while flare up of TB was seen in 5.09% versus 0% in cases and controls, respectively. Wound infection was seen in 8.48% versus 1.25% cases, respectively. Interpretation and Conclusion: FGTB is associated with increased complications and difficulties as compared to laparoscopy in other cases.

Background: Hysterosalpingography (HSG) is radiographic evaluation of uterine cavity and tubal patency. Aims: The aim of this study was to evaluate the safety and utilisation of HSG in female genital tuberculosis (FGTB) with infertility. Settings and Design: The study was conducted in a tertiary referral centre of North India. Materials and Methods: It was a prospective study on 87 cases of FGTB with infertility. Diagnosis of FGTB was made by composite reference standard using the presence of acid-fast bacilli on microscopy/culture or positive GeneXpert, positive polymerase chain reaction or epithelioid granuloma on endometrial biopsy or definitive or probable findings on laparoscopy or hysteroscopy. Statistical Analysis Used: Suitable statistical methods were used with STATA software version 12.0. Results: HSG findings were normal in 49 (56.32%) cases. There were filling defects in 14 (16.09%), short and shrunken cavity in 4 (4.49%), intrauterine synechiae in 14 (16.09%), T-shaped cavity in 3 (3.44%) and deformed uterine cavity in 5 (5.74%) cases. Fallopian tube findings were hydrosalpinx in 12 (13.79%) and 11 (12.64%) cases, beading of tube in 4 (4.59%) and 2 (2.29%) cases, pipestem appearance in 2 (2.29%) cases each and Maltese cross appearance in 3 (3.44%) and 2 (2.29%) cases, respectively. Tubal blockage was seen in 69 (79.31%) and 67 (77.01%) cases being cornual block in 28 (32.18%) and 26 (29.88%) cases, mid-tubal block in 16 (18.39%) and 15 (17.24%) cases, multiple blocks in 10 (11.49%) and 12 (13.79%) cases and fimbrial block in 15 (17.24%) and 14 (16.09%) cases. None of the cases had flare-up of the disease after HSG in the current study. Conclusion: HSG is a useful modality in FGTB with infertility.

Tuberculous meningitis (TBM) is the most common form of neurotuberculosis and the fifth most common form of extrapulmonary TB. Early diagnosis and prompt treatment are the cornerstones of effective disease management. The accurate diagnosis of TBM poses a challenge due to an extensive differential diagnosis, low bacterial load and paucity of cerebrospinal fluid (CSF) especially in children. We describe the utility of ELISA and qPCR for the detection of Mycobacterium tuberculosis (M. tb) proteins (GlcB, HspX, MPT51, Ag85B and PstS1) and DNA for the rapid diagnosis of TBM. CSF filtrates (n = 532) derived from children were classified as 'Definite' TBM (M. tb culture positive, n = 29), 'Probable and Possible' TBM (n = 165) and 'Not-TBM' including other cases of meningitis or neurological disorders (n = 338). ROC curves were generated from ELISA and qPCR data of 'Definite' TBM and Non-Tuberculous infectious meningitis (NTIM) samples and cut-off values were derived to provide ≥ 95% specificity. devR qPCR, GlcB, HspX and PstS1 ELISAs showed 100% (88;100) sensitivity and 96-97% specificity in 'Definite' TBM samples. The application of these cut-offs to 'Probable and Possible' TBM groups yielded excellent sensitivity (98%, 94;99) and specificity (98%, 96;99) for qPCR and for GlcB, HspX and MPT51 antigen ELISAs (sensitivity 92-95% and specificity 93-96%). A test combination of qPCR with GlcB and HspX ELISAs accurately detected all TBM samples at a specificity of ~90%. Logistic regression analysis indicated that these tests significantly added value to the currently used algorithms for TBM diagnosis. The detection of M. tb GlcB/HspX antigens/devR DNA in CSF is likely to improve the utility of existing algorithms for TBM diagnosis and also hasten the speed of diagnosis.

India with a major burden of multidrug-resistant tuberculosis (MDR-TB) does not have national level data on this hazardous disease. Since 2006, emergence of extensively drug-resistant TB (XDR-TB) is considered a serious threat to global TB control. This study highlights the demographic and clinical risk factors associated with XDR-TB in Delhi. The study was conducted during April 2007 to May 2010. Six hundred eleven MDR-TB suspects were enrolled from four tertiary care hospitals, treating TB patients in Delhi and the demographic details recorded. Sputum samples were cultured using rapid, automated liquid culture system (MGIT 960). Drug susceptibility testing (DST) for Rifampicin (RIF) and Isoniazid (INH) was performed for all positive M. tuberculosis (M.tb) cultures. All MDR-TB isolates were tested for sensitivity to second-line drugs [Amikacin (AMK), Capreomycin (CAP), Ofloxacin (OFX), Ethionamide (ETA)]. Of 611, 483 patients were infected with MDR M. tuberculosis (M.tb) strains. Eighteen MDR-TB isolates (3.7%) were XDR M.tb strains. Family history of TB (p 0.045), socioeconomic status (p 0.013), concomitant illness (p 0.001) and previous intake of 2(nd) line injectable drugs (p 0.001) were significantly associated with occurrence of XDR-TB. Only two of the patients enrolled were HIV seropositive, but had a negative culture for M. tuberculosis. 56/483 isolates were pre-XDR M. tuberculosis, though the occurrence of pre-XDR-TB did not show any significant demographical associations. The actual incidence and prevalence rate of XDR-TB in India is not available, although some scattered data is available. This study raises a concern about existence of XDR-TB in India, though small, signaling a need to strengthen the TB control program for early diagnosis of both tuberculosis and drug resistance in order to break the chains of transmission.

Introduction: India witnessed the catastrophic second wave of COVID-19 during the summer months of 2021. Many patients with non-resolution of symptoms admitted to dedicated COVID-19 treatment centers required prolonged inpatient care which led to the unavailability of beds for other COVID-19 patients. The objective of this study was to determine the duration of SARS-CoV-2 positivity in moderate and severe COVID-19 patients requiring long-term pulmonary care as well as to find out the association between different variables with the persistence of the virus. Methodology: A retrospective chart review of clinical and laboratory data of patients with moderate and severe COVID-19 between 1st April 2021 and 15th July 2021 admitted for more than 28 days and requiring long-term pulmonary care was carried out at National Cancer Institute, AIIMS, India. SARS-CoV-2 RNA was detected with real-time reverse transcriptase-polymerase chain reaction-based tests. Data from all consecutively included patients satisfying the selection criteria were presented temporally and analyzed by Fisher’s exact test (p < 0.05). Results: All 51 patients tested positive for SARS-CoV-2 RNA at the 5th week of initial laboratory confirmation of COVID-19. The majority of the patients (38; 74.5%) remained positive for viral RNA till the 6th week and the median duration of viral positivity was 45 days. The clinical presentation of SARI at admission was significantly higher among patients with viral persistence till the 6th week (p < 0.05). Conclusions: The median duration of the viral positivity was 45 days and SARI at admission was significantly associated with viral persistence till the 6th week.