Probable Tuberculosis Research Articles

High Prevalence of Tuberculosis Infection and Disease in Child Household Contacts of Adults With Rifampin-resistant Tuberculosis.

Household contact (HHC) investigation is an important strategy to identify individuals with tuberculosis (TB) exposure, infection and disease, including those who may benefit from tuberculosis preventive therapy (TPT). Data in children exposed to rifampin-resistant TB are limited. In preparation for and to inform the feasibility of an interventional trial, HHC of adults with pulmonary rifampin-resistant TB from high TB-burden countries were evaluated in a cross-sectional study. Using interferon-gamma release assay and study-specific and 2015 international consensus definitions of intrathoracic TB in children, we evaluated the prevalence and predictors of TB infection and disease in child (<15 years) HHCs. Of 303 child HHCs, median age (range) 7 years (0-14), 57% [95% confidence interval (CI): 50%-64%] had a positive interferon-gamma release assay result (TB infected). TB infection was associated with the index case smoking (P = 0.034), being the parent or sleeping in the same room (P = 0.002) and the child HHC being age ≥5 years and having attended school (P = 0.013). Four had study-defined confirmed TB and 9 had probable TB, a prevalence of 4.3% (95% CI: 2.6%-7.1%). Using the international consensus definitions, 4 had confirmed TB and 49 had unconfirmed TB, a prevalence of 17.2% (95% CI: 12.9%-22.4%). Twenty (7%) children had received TPT. The prevalence of TB infection and disease was high in child HHC exposed to rifampin-resistant TB. Few children had routinely received TPT. High-quality evidence is needed to inform strong recommendations for and access to TPT in children exposed to TB resistant to rifampin.

Enteropathogen spectrum and effect on antimycobacterial pharmacokinetics among children with tuberculosis in rural Tanzania: a prospective cohort study

SummaryBackgroundEnteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively affect antimycobacterial pharmacokinetics, particularly among malnourished children. We sought to quantify enteropathogen burden among children initiating tuberculosis treatment in rural Tanzania and determine the effect of enteropathogen burden on serum antimycobacterial pharmacokinetics.MethodsWe performed a prospective cohort study at one site in rural Tanzania as an exploratory substudy of a large multicountry cohort study. We included children younger than 15 years of age with confirmed or probable tuberculosis undergoing treatment with first-line tuberculosis therapy; children were excluded from the study if they were unable to undergo sample collection. Participants were consecutively recruited from the inpatient paediatric wards or the outpatient tuberculosis clinic at Haydom Lutheran Hospital, Tanzania. The main outcome was to quantify symptomatic enteropathogen burden and the effect on serum antimycobacterial pharmacokinetics. We quantified enteropathogen burden (defined as the sum of distinct enteropathogens detected in stool) using a multipathogen PCR capable of simultaneous detection of 37 bacterial, viral, and parasitic species or species groups from stool collected within 72 h of treatment initiation. Comprehensive clinical assessment, including presence of gastrointestinal symptoms, was performed at baseline, and serum was collected approximately 2 weeks after treatment initiation at steady state and throughout the dosing interval with concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol measured by liquid chromatography with a tandem mass spectrometry assay to quantify peak (Cmax) and total area under the concentration curve (AUC0–24), as determined by non-compartmental analysis. Enteropathogen burden was compared with pharmacokinetic measurements using bivariable and multivariable linear regression.Findings58 children were assessed for eligibilty and enrolled between June 25, 2016, and Feb 6, 2018; 44 had complete stool testing and serum pharmacokinetic data, and they were included in the analyses. 20 (45%) were female, and 24 (55%) were male. 37 (84%) had moderate or severe malnutrition. A mean of 2·1 (SD 1·3) enteropathogens were detected per participant. Target peak concentrations of rifampicin were reached in eight (18%) of 44 participants, isoniazid in 24 (54%) of 44 participants, pyrazinamide in 28 (74%) of 38 participants, and ethambutol in six (15%) of 39 participants. Compared with controlled comparisons, each summative additional bacterial enteropathogen detected was associated with a 40% lower rifampicin Cmax (95% CI −62 to −5) and a 36% lower ethambutol Cmax (−52 to −14), while viral pathogens were associated with a 51% lower isoniazid Cmax (−75 to −7). The combination of gastrointestinal symptoms and detection of an additional enteropathogen was associated with a 27% reduction in rifampicin AUC0–24 (95% CI −47 to −1).InterpretationTanzanian children undergoing tuberculosis treatment rarely attained pharmacokinetic targets; enteropathogen carriage was common and enteropathogen burden was associated with significant reductions in the concentrations of some antimycobacterial drugs. Further research should explore mechanistic relationships of individual pathogens and antimycobacterial pharmacokinetics in larger cohorts, or determine if screening for and treating enteropathogens at tuberculosis treatment initiation improves pharmacokinetic target attainment.FundingNational Institute of Allergy and Infectious Diseases, National Institutes of Health.

Diagnostic Accuracy of Urine Lipoarabinomannan Testing in Early Morning Urine versus Spot Urine for Diagnosis of Tuberculosis among People with HIV.

ABSTRACTThe Fujifilm SILVAMP TB LAM (FujiLAM) assay offers improved sensitivity compared to Determine TB LAM Ag (AlereLAM) for detecting tuberculosis (TB) among people with HIV. Here, we examined the diagnostic value of FujiLAM testing on early morning urine versus spot urine and the added value of a two-sample strategy. We assessed the diagnostic accuracy of FujiLAM on cryopreserved urine samples collected and stored as part of a prospective cohort of adults with HIV presenting for antiretroviral treatment in Ghana. We compared FujiLAM sensitivity and specificity in spontaneously voided urine samples collected at inclusion (spot urine) versus in the first voided early morning urine (morning urine) and for a one (spot urine) versus two samples (spot and morning urine) strategy. Diagnostic accuracy was determined against both microbiological (using sputum culture and Xpert MTB/RIF testing of sputum and urine to confirm TB) and composite reference standards (including microbiologically confirmed and probable TB cases). Paired urine samples of spot and morning urine were available for 389 patients. Patients had a median CD4 cell count of 176 cells/μL (interquartile range [IQR], 52 to 361). Forty-three (11.0%) had confirmed TB, and 19 (4.9%) had probable TB. Overall agreement for spot versus morning urine test results was 94.6% (kappa, 0.81). Compared to a microbiological reference standard, the FujiLAM sensitivity (95% confidence interval [CI]) was 67.4% (51.5 to 80.9) for spot and 69.8% (53.9 to 82.8) for morning urine, an absolute difference (95% CI) of 2.4% (−10.2 to 14.8). Specificity was 90.2% (86.5 to 93.1) versus 89.0% (85.2 to 92.1) for spot and morning urine, respectively, a difference of 1.2% (−3.7 to 1.4). A two-sample strategy increased FujiLAM sensitivity from 67.4% (51.5 to 80.9) to 74.4% (58.8 to 86.5), a difference of 7.0% (−3.0 to 16.9), while specificity decreased from 90.2% (86.5 to 93.1) to 87.3% (83.3 to 90.6), a difference of −2.9% (−4.9 to −0.8). This study indicates that FujiLAM testing performs equivalently on spot and early morning urine samples. Sensitivity could be increased with a two-sample strategy but at the risk of lower specificity. These data can inform future guidelines and clinical practice.IMPORTANCE This study indicates that FujiLAM testing performs equivalently on spot and early morning urine samples for detecting tuberculosis among people with HIV. Sensitivity could be increased with a two-sample strategy but at the risk of lower specificity. These data can inform future guidelines and clinical practice around FujiLAM.

Performance of Xpert Ultra nasopharyngeal swab for identification of tuberculosis deaths in northern Tanzania

ObjectiveNumerous tuberculosis (TB) deaths remain undetected in low-resource endemic settings. With autopsy-confirmed tuberculosis as our standard, we assessed the diagnostic performance of Xpert MTB/RIF Ultra (Ultra; Cepheid) on nasopharyngeal specimens collected postmortem. MethodsFrom October 2016 through May 2019, we enrolled pediatric and adult medical deaths to a prospective autopsy study at two referral hospitals in northern Tanzania with next-of-kin authorization. We swabbed the posterior nasopharynx prior to autopsy and tested the samples later by Ultra. At autopsy we collected lung, liver, and, when possible, cerebrospinal fluid for mycobacterial culture and histopathology. Confirmed tuberculosis was defined as Mycobacterium tuberculosis complex recovery by culture with consistent tissue histopathology findings; decedents with only histopathology findings, including acid-fast staining or immunohistochemistry, were defined as probable tuberculosis. ResultsOf 205 decedents, 78 (38.0%) were female and median (range) age was 45 (0,96) years. Twenty-seven (13.2%) were found to have tuberculosis at autopsy, 22 (81.5%) confirmed and 5 (18.5%) probable. Ultra detected M. tuberculosis complex from the nasopharynx in 21 (77.8%) of 27 TB cases (sensitivity 70.4% [95% confidence interval {CI} 49.8–86.2%], specificity 98.9% [95% CI 96.0–99.9%]). Among confirmed TB, the sensitivity increased to 81.8% (95% CI 59.7–94.8%). Tuberculosis was not included as a death certificate diagnosis in 14 (66.7%) of the 21 MTBc detections by Ultra. DiscussionNasopharyngeal Ultra was highly specific for identifying in-hospital tuberculosis deaths, including unsuspected tuberculosis deaths. This approach may improve tuberculosis death enumeration in high-burden countries.

Congenital tuberculosis presenting with erythema nodosum: a case report

Erythema nodosum is an entity with a relatively low incidence of 1 to 5 per 100,000 live births. The condition is relatively uncommon in prepubertal children and exceptionally rare before 2 years of age. In the paediatric age group, both sexes are equally affected. Although uncommon in children, it remains the most frequent form of panniculitis in paediatrics for which the diagnosis is almost always clinical. The most common cause in children is streptococcal pharyngitis.The association of erythema nodosum with tuberculosis is well known in endemic areas and must always be excluded. All children with erythema nodosum should be stratified by risk for tuberculosis exposure. Congenital tuberculosis is an unusual and severe clinical presentation of tuberculosis infection. It is rare, even where tuberculosis is endemic. Timely administration of standard antitubercular treatment results in a good outcome. We report a two-month-old male infant who presented with fever, lethargy, dyspnea, and refusal to feed and whose mother was diagnosed as probable multidrug-resistant tuberculosis. Our patient emphasizes the importance of maternal history, typical skin lesions, and histopathological study in order to approach a definitive diagnosis and institute timely administration of antitubercular drugs.

Tuberculosis in Children in a Pediatric Hospital in Mexico.

Tuberculosis (TB) remains a global problem and a diagnostic challenge, especially in pediatrics. The aim of this study was to describe the clinical, microbiological, radiological, and histopathological data of TB in children. A 7-year retrospective and descriptive cohort study that included 127 patients under 18 years of age with diagnosis of active TB was conducted from 2011 to 2018 in a pediatric hospital. Tuberculosis was microbiologically confirmed using Ziehl-Neelsen (ZN) staining, culture or polymerase chain reaction (PCR) in a total of 94 (74%) cases. Thirty-three cases were defined as probable TB based on tuberculin skin test result and epidemiological evaluation. The TB forms found were lymph node (39.3%), bone (15.7%), lung (13.6%), and meningeal TB (8.6%). The most common symptoms were fever (48.8%) and adenopathy (45.6%). History of contact was established in 34.6%. Positive ZN staining (sensitivity 30%) and culture (sensitivity 37%) were found in 29% and 37.7% of subjects, respectively. About 64.5% depicted abnormal chest X-ray. Xpert MTB/RIF® (PCR) was positive in 9.4% and biopsy was compatible in 52.7% of these samples. It is fundamental to have laboratory and epidemiological evaluation that support the diagnosis of the disease in children and thus, define its management; since, in most cases, early microbiologic confirmation is lacking.

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.

Burden of TB during COVID-19 pandemic-single center experience.

To the Editor, COVID-19 pandemic has impacted tuberculosis (TB) diagnosis, surveillance and management due to lock down, hesitancy in visiting hospitals due to fear of contracting SARS-COV-2, healthcare workforce shortage due to over-helming cases and lab burdened with testing for SARS-COV-2.[1] We looked at the burden of TB during COVID-19 pandemic in our institution and specific risk factors for TB during this period. A retrospective observational study by electronic medical record review was done in a 750 bedded quaternary centre in Kerala, South India, between January 2020–2022. Number of cases reported through NIKSHAY, the web enabled patient management system for TB control under the National Tuberculosis Elimination Programme (NTEP), during this period were noted and compared with previous years’ hospital and national data. Clinical and radiological features, associated with COVID-19 infection and comorbidities were looked at. During the study period 293 cases of TB were newly diagnosed of which 117 were diagnosed in 2020 and 176 in 2021. The trend in cases notified revealed that there was >50% drop in cases during 2020 as compared to 2018 and 2019 [Figure 1]. The nadir in case numbers was between March and June 2020 which was similar to national data and was during the period of lockdown in the country.[2,3] The cases gradually increased during later part of 2020 and in 2021 [Figure 2]. Majority were men (62%); 6.14% belonged to paediatric age group. Extrapulmonary TB (EPTB) was noted in 63%. The common comorbidities noted were diabetes mellitus (64%), chronic kidney disease (28%) and systemic hypertension (28%). Fifteen patients (5.12%) had TB diagnosed either concurrently (1%) or within 4 weeks (4.09%) of COVID-19 infection. Twelve of these cases were microbiologically confirmed TB; 3 were probable TB of which 2 cases were diagnosed as pleural TB based on the pleural fluid analysis and 1 was diagnosed as lymph node TB by histopathology. Among the 15 patients, one half had pulmonary TB; among the EPTB, lymph node TB (28.3%) was the commonest. Among those with TB and recent COVID-19 infection, 72% had received steroids.Figure 1: Monthly data of newly detected TB cases in numbers over the yearsFigure 2: TB cases repoted to Nikshay before and during COVID pandemicTo summarize, the number of TB cases reported during COVID-19 pandemic was low and least during lockdown period and is similar to national data, suggesting that delay in approaching healthcare could be a reason. Majority of patients who had TB post COVID-19 had history of steroid use for COVID-19 infection suggesting that steroids could be a risk factor for opportunistic infections like TB. This is of importance as India is a TB endemic country. Steroid use for COVID 19 should be as per guidelines and those exposed to steroids and other immune suppression should be closely followed up for opportunistic infections such as TB. Enhancing TB surveillance by integrating TB and COVID-19 diagnosis by bi-directional testing as recommended by the Ministry of Health and Family Welfare in India is the need of the hour for early diagnosis of TB during pandemic.[4] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Tuberculosis Diagnosis in HIV-Infected Children: Comparison of the 2012 and 2015 Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease.

There is no gold standard for tuberculosis diagnosis in children. Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children were proposed by international experts in 2012 and updated in 2015. We aimed to compare the 2012 and 2015 Clinical Case Definitions in HIV-infected children with suspected tuberculosis. We enrolled HIV-infected children with suspected tuberculosis in Burkina Faso, Cambodia, Cameroon, and Vietnam (ANRS [Agence Nationale de Recherches sur le SIDA et les hépatites virales] 12229 PAANTHER [Pediatric Asian African Network for Tuberculosis and HIV Research] 01 Study). We classified children using the 2012 and 2015 Case Definitions considering as tuberculosis cases those with confirmed tuberculosis and those with probable and unconfirmed tuberculosis in the 2012 and the 2015 classifications, respectively. We assessed agreement between both classifications. Of 438 children enrolled, 197 (45.0%) children were classified as tuberculosis (45 confirmed, 152 probable) using the 2012 Case Definition and 251 (57.3%) were classified as tuberculosis (55 confirmed, 196 unconfirmed) using the 2015 classification. Inter-classification agreement for tuberculosis diagnosis was 364/438, 83.1%, with a kappa statistic of 0.667 (95% confidence interval 0.598-0.736). Of 152 children with probable tuberculosis (2012), 142 (93.4%) were considered as tuberculosis by the 2015 version and 10 (6.6%) as unlikely tuberculosis including 9 with spontaneous clinical improvement. Of 132 possible tuberculosis (2012), 58 (43.9%) were reclassified as tuberculosis (2015). Agreement between the 2 versions of the Case Definition was substantial but more children were considered as tuberculosis using the 2015 version. Spontaneous symptom resolution reinforces both confidence in the "unlikely" category as being children without tuberculosis and the importance of the clinician's treatment decision in the study.

Gut Microbiome in Probable Intestinal Tuberculosis and Changes following Anti-Tuberculosis Treatment.

PurposeInformation on the gut microbiome in patients with intestinal tuberculosis (ITB) and changes therein following anti-tuberculosis treatment (ATT) is lacking. We aimed to elucidate differences in stool microbiome between ITB patients and controls and to evaluate stool microbiome changes after ATT.Materials and MethodsEleven patients with probable ITB underwent ATT for 6 months, with stool samples collected at 0, 2, and 6 months. We performed next-generation sequencing of 16S rRNA genes in stool bacteria and compared the gut microbiome.ResultsInitially, the relative abundance of Verrucomicrobia was higher (5.0% vs. <1%) and that of Proteobacteria was lower (<1% vs. 6.6%) in ITB patients than in controls. Higher numbers of butyrate-producing bacteria (Blautia and Roseburia) were noted in ITB patients. The alpha-diversity of stool microbiome of ITB patients was lower than that in controls (p=0.045). There was a significant difference in beta-diversity between the groups (p=0.001). At 6 months, the proportion of Verrucomicrobia decreased to <1%, while the proportion of Proteobacteria remained at <1%.ConclusionThere were no significant differences in alpha- and beta-diversity in the stool microbiome at 0, 2, and 6 months after ATT. The stool microbiome composition of probable ITB patients was different from that of controls, and 6 months of ATT did not significantly affect it.

Disseminated lymph node tuberculosis after splenectomy: an unusual case report in an adolescent

BackgroundSplenectomized patients are at an increased risk for overwhelming post-splenectomy infections typically with encapsulated bacteria. The clinical association between splenectomy and lymph-node tuberculosis is unclear.Case presentationWe describe a rare case of disseminated tuberculous lymphadenitis in an 18-year-old woman with history of splenectomy because of hereditary sherocytosis. She was admitted with enlargement of bilateral-cervical and left-axillary lymph nodes and fever. A diagnosis of probable tuberculosis was made based on the findings of fine-needle aspiration. Histology showed granulomas and extensive caseous necrosis, with the site of puncture located at an enlarged lymph node on the right side. The diagnosis was confirmed via nucleic-acid amplification tests following excisional biopsy of the left axillary lymph node. Disseminated tuberculous lymphadenitis was localized in the bilateral neck, right lung hilum, left sub-axillary region, and mediastinum, as detected from contrast-enhanced computed tomography of the neck.ConclusionsMycobacterium tuberculosis infection should be considered in children and adolescents with extensive enlargement of lymph nodes after splenectomy.

A case report of probable ocular tuberculosis following biologics

Biological drugs, especially anti-TNF-α agents, have revolutionized the treatment of chronic immune-inflammatory diseases, however complications include reactivation of tuberculosis and increased incidence of other infections. We report a 28-year-old male, on biological agents for HLA B27 positive spondyloarthropathy, inflammatory bowel disease and psoriasis, who presented with occlusive retinal perivasculitis. Following a thorough clinical examination and ocular and systemic investigation, a diagnosis of probable ocular tuberculosis (POTB) with tubercular retinal vasculitis (TRV) was made. Biologics were temporarily withdrawn and anti-tubercular therapy (ATT) initiated with good response. Patients on biologics need close monitoring, for ocular and systemic infections especially TB.

Utility of plasma cell-free DNA detection using homobifunctional imidoesters using a microfluidic system for diagnosing active tuberculosis

Background It is difficult to diagnose tuberculosis (TB), particularly sputum-scarce pulmonary TB and extrapulmonary TB, using conventional diagnostic tests. Since these cases require additional invasive procedures to obtain appropriate specimens, new non-invasive diagnostic tests are needed. Plasma cell-free DNA (cfDNA) detection has gained interest as a novel diagnostic test for TB as it is convenient and less invasive. Therefore, we investigated the performance of enriched cfDNA for diagnosing pulmonary TB and extrapulmonary TB. Methods All patients suspected to have TB, who consented to the use of blood for detecting cfDNA, were prospectively enrolled from January 2019 to June 2020. We categorised the patients as confirmed, probable, possible TB, and not-TB. We compared the performance of cfDNA with those of conventional diagnostic tests. Results Among the 96 patients enrolled, 40 (41.7%) had TB, including 34 with confirmed TB and six probable TB, and 41 (42.7%) did not have TB. Acid-fast bacilli microscopy, Xpert MTB/RIF, and mycobacterial culture results were positive in 12 (31.6%), 22 (61.1%), and 25 (65.8%) patients, respectively. The sensitivity and specificity of cfDNA were 80.0% and 78.1%, respectively. While the sensitivity and specificity of cfDNA were similar to those of interferon-gamma releasing assay (IGRA) (sensitivity 80.6% and specificity 71.4%), the combined sensitivity and specificity of the two assays were 94.4% and 64.3%, respectively, which can be used to rule out TB. Conclusions Plasma cfDNA assay seems to be a useful adjunct to the current tests for diagnosing TB, especially when used in combination with IGRA for ruling out TB. Abbreviations TB tuberculosis cfDNA cell-free DNA PCR polymerase chain reaction AFB acid-fast bacilli IGRA interferon-gamma releasing assay CT computed tomography HIV human immunodeficiency virus

An outbreak of pulmonary tuberculosis and a follow-up investigation of latent tuberculosis in a high school in an eastern city in China, 2016-2019.

In October 2016, a senior high school student was diagnosed with sputum-smear positive [SS(+)] pulmonary tuberculosis (TB). We conducted an investigation of an outbreak in the school, including among students and teachers diagnosed with latent TB, who we followed until July 2019. We defined latent TB infection (LTBI) as a tuberculin skin test (TST) induration of 15mm or larger; probable TB as a chest radiograph indicative of TB plus productive cough/hemoptysis for at least 2 weeks, or TST induration of 15mm or larger; and confirmed TB as two or more positive sputum smears or one positive sputum smear plus a chest radiograph indicative of TB or culture positive with M. tuberculosis. We conducted mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing based on 24 loci in the isolates. Between October 2016 and July 2019, we identified 52 cases, including nine probable, six confirmed, and 37 LTBI cases. The index case-student had attended school continuously despite having TB symptoms for almost three months before being diagnosed with TB. We obtained three isolates from classmates of the index case in 2016; all had identical MIRU-VNTR alleles with the index case. The LTBI rate was lower among students (7.41%, 30/405) than among teachers (26.92%, 7/26) (rate ratio [RR] = 0.28, 95% confidential interval [CI]: 0.13-0.57). Among the 17 students who had latent TB and refused prophylaxis in October 2016, 23.53% (4/17) became probable/confirmed cases by July 2019. None of the six teachers who also refused prophylaxis became probable or confirmed cases. Of the 176 students who were TST(-) in October 2016, 1.70% (3/176) became probable/confirmed cases, and among the 20 teachers who were TST(-), 1 became a probable case. Delayed diagnosis of TB in the index patient may have contributed to the start of this outbreak; lack of post-exposure chemoprophylaxis facilitated spread of the outbreak. Post-exposure prophylaxis is strongly recommended for all TST-positive students; TST-negative students exposed to an SS(+) case should be followed up regularly so that prophylaxis can be started if LTBI is detected.

Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a prospective, multicentre cohort study

SummaryBackgroundBlood transcriptomic signatures for diagnosis of tuberculosis have shown promise in case-control studies, but none have been prospectively designed or validated in adults presenting with the full clinical spectrum of suspected tuberculosis, including extrapulmonary tuberculosis and common differential diagnoses that clinically resemble tuberculosis. We aimed to evaluate the diagnostic accuracy of transcriptomic signatures in patients presenting with clinically suspected tuberculosis in routine practice.MethodsThe Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years) suspected of having tuberculosis in the routine clinical inpatient and outpatient setting were recruited at ten National Health Service hospitals in England for IDEA and were included in VANTDET if they provided consent for genomic analysis. Patients had whole blood taken for microarray analysis to measure abundance of transcripts and were followed up for 6–12 months to determine final diagnoses on the basis of predefined diagnostic criteria. The diagnostic accuracy of six signatures derived from the cohort and three previously published transcriptomic signatures with potentially high diagnostic performance were assessed by calculating area under the receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.FindingsBetween Nov 25, 2011, and Dec 31, 2013, 1162 participants were enrolled. 628 participants (aged ≥16 years) were included in the analysis, of whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with highest performance for identifying all active tuberculosis gave an AUC-ROC of 0·87 (95% CI 0·81–0·92), sensitivity of 77% (66–87), and specificity of 84% (74–91). The best-performing published signature gave an AUC-ROC of 0·83 (0·80–0·86), sensitivity of 78% (73–83), and specificity of 76% (70–80). For detecting highly probable tuberculosis, the best novel signature yielded results of 0·86 (0·71–0·95), 77% (56–94%), and 77% (57–95%). None of the relevant cohort-derived or previously published signatures achieved the WHO-defined targets of paired sensitivity and specificity for a non-sputum-based diagnostic test.InterpretationIn a clinically representative cohort in routine practice in a low-incidence setting, transcriptomic signatures did not have adequate accuracy for diagnosis of tuberculosis, including in patients with highly probable tuberculosis where the unmet need is greatest. These findings suggest that transcriptomic signatures have little clinical utility for diagnostic assessment of suspected tuberculosis.FundingNational Institute for Health Research.

Septic Arthritis of the Hip in Lome (Togo)

Objectives: To determine the epidemiological, clinical, and bacteriological characteristics of septic arthritis of the hip (SAH) among patients hospitalized in the departments of Rheumatology in Lomé. Patients and Methods: This was a multicentre, descriptive study, conducted over a 16-year period, from January 2004 to December 2020 on patients’ records at the three departments of Rheumatology in Lomé. We included in this study only patients with complete laboratory and radiological data. Patients who underwent hip replacement surgery and those with arthritis of the hip due to all inflammatory arthropathies were excluded. The diagnosis of SAH was based on clinical, radiological and bacteriological features. In the absence of bacteriological confirmation, the presumptive etiological diagnosis was based on epidemiological data, contacting with a person with tuberculosis, the presence of high-grade fever, the mode of presentation of the symptoms, the patient’s general appearance, and the result of the tuberculin skin test. The data was collected using Epi info 7.0 and statistical analysis was performed using STATA/IC 11.0. Results: Out of 3776 patients hospitalized in the three departments over the study period, 705 (18.67%) were diagnosed with septic arthritis of which 70 (9.92%) patients with SAH. The 70 patients with SAH were 44 (62.86%) females, and 26 (37.14%) males, with a sex ratio of 1.7 F/M. The mean age of the patients was 42.43 ± 19.37 years (range: 5 years and 80 years) and the mean duration of symptoms was 6.57 ± 8.85 months (range: 2 days and 48 months). The pain was inflammatory in nature in 46 (65.71%) and mechanical in nature in 24 (34.29%) patients. The onset of the disease was progressive in 50 (71.43%) patients and sudden in 20 (28.57%) patients. The locations of the pain were: groin only 25 (35.71%), greater trochanter only 15 (21.43%), groin and lower back 14 (20%), and groin and greater trochanter 9 (12.86%). Sixty-four patients (91.43%) were limping and only six (08.57%) were crippled. Weight loss was noted in 38 (54.29%) patients. A risk factor was identified in 63 (90.00%) patients; they were chronic alcohol abuse 24 (34.29%), poor hygiene 17 (24.29%), sickle cell disease 13 (18.57%), HIV infection five (7.14%), and diabetes four (05.71%). Radiologic features suggestive of SAH were seen on plain radiograph and computed tomography in 55 (78.57%) and 15 (21.43%) patients, respectively. The SAH was unilateral (48 right hip and 20 left hip) in 68 (97.14%) patients and bilateral in two (02.86%) patients. The diagnosis of SAH was probable tuberculosis in 46 (65.71%) patients and probable pyogenic bacteria in 24 (34.29%) patients. The outcome was favourable in 68 (97.14%) patients and two (02.86%) patients died. Conclusion: The hip remains a relatively rare localization of infectious pathologies. Most cases of SAH are due to tuberculosis.

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.

Detection of genital tuberculosis among women with infertility using best clinical practices in India: An implementation study

BackgroundDiagnosis of genital tuberculosis (TB) as a cause of infertility still remains a diagnostic dilemma for clinicians, as no standard guidelines exist. The recently proposed best practices for genital TB diagnosis have not been evaluated yet in India. ObjectivesTo implement best practices to diagnose and treat likely genital TB as a cause of infertility. MethodsBetween April 2016 and June 2018, consenting women seen at a tertiary hospital infertility clinic were assessed by thorough TB related clinical history, ultrasonography, tuberculin skin test (TST), and ESR. Those with suspected genital TB underwent laparohysteroscopy. Clinical and laboratory characteristics were compared between likely (microbiologically confirmed or probable TB) and unlikely (possible and no genital TB) genital TB. Fertility outcome was assessed among women initiated on anti-TB treatment (ATT). ResultsOf 185 women seeking infertility care, likely genital TB was identified among 29 (15.7%) women, with 6 (21%) confirmed and 23 (79%) probable genital TB. Compared to unlikely genital TB cases, the likely genital TB group were found to have past history of TB (p < 0.001); positive TST (p = 0.002) and elevated ESR (p = 0.001). Among the likely genital TB group, all 6 confirmed genital TB were started on ATT and 2 (33.3%) conceived. Of 5 probable genital TB started on ATT, 3 (60%) conceived. ConclusionApproximately 1/6th of women seeking infertility care met the criteria for likely genital TB. Conception among over-half of treated probable genital TB cases provides preliminary evidence that best clinical practices can be utilized, but needs further confirmatory studies.

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.

Loop-mediated isothermal amplification (LAMP) in the respiratory specimens for the diagnosis of pediatric pulmonary tuberculosis: A pilot study

BackgroundLoop-mediated isothermal amplification (LAMP) assay is a novel molecular diagnostic technique that can be used for the diagnosis of tuberculosis (TB). It is most suited for developing countries as it is rapid, inexpensive, highly sensitive, requiring minimal infrastructure, training and manpower. Studies in pediatric TB are lacking. We evaluated LAMP in the diagnosis of pediatric pulmonary TB. MethodologyThis was a cross-sectional analytical study conducted at a tertiary care teaching hospital in North India from July 2014 to June 2015 involving 60 children with suspected pulmonary TB. Respiratory specimens (sputum, gastric lavage, bronchoalveolar lavage and/or endotracheal aspirates) were collected and subjected to BACTEC MGIT 960 culture, IS6110 PCR, and LAMP assay targeting IS6110 gene of Mycobacterium tuberculosis. ResultsThirty seven children had confirmed and probable TB according to the composite reference standard (CRS). Among all the 3 tests used for diagnosis of Pulmonary TB, LAMP had highest sensitivity (37.8%) followed by PCR (27%), and culture (21.6%) when compared against the predefined CRS. Culture had maximum specificity of 100%; and PCR, and LAMP had specificity of 95–96%. The sensitivity, specificity, PPV, and NPV of LAMP against culture as reference standard were 75%, 72.4%, 42.9%, and 91.3% respectively. Similarly sensitivity, specificity, PPV, and NPV of PCR against culture as reference standard were 75%, 86.2%, 60%, and 86.2% respectively. On combining LAMP with culture, sensitivity increased to 45.7% (7.8% increase, p = 0.04). ConclusionWe noted that LAMP had highest sensitivity when compared to culture and PCR and comparable specificity.