Pooling sputum testing to diagnose tuberculosis using xpert MTB/RIF and xpert ultra: a cost-effectiveness analysis.

BACKGROUND: The World Health Organization (WHO) recommends the diagnosis of tuberculosis (TB) using molecular tests, such as Xpert MTB/RIF (MTB/RIF) or Xpert Ultra (Ultra). These tests are expensive and resource-consuming, and cost-effective approaches are needed for greater coverage. METHODS: We evaluated the cost-effectiveness of pooling sputum samples for TB testing by using a fixed amount of 1,000 MTB/RIF or Ultra cartridges. We used the number of people with TB detected as the indicator for cost-effectiveness. Cost-minimization analysis was conducted from the healthcare system perspective and included the costs to the healthcare system using pooled and individual testing. RESULTS: There was no significant difference in the overall performance of the pooled testing using MTB/RIF or Ultra (sensitivity, 93.9% vs. 97.6%, specificity 98% vs. 97%, p-value > 0.1 for both). The mean unit cost across all studies to test one person was 34.10 international dollars for the individual testing and 21.95 international dollars for the pooled testing, resulting in a savings of 12.15 international dollars per test performed (35.6% decrease). The mean unit cost per bacteriologically confirmed TB case was 249.64 international dollars for the individual testing and 162.44 international dollars for the pooled testing (34.9% decrease). Cost-minimization analysis indicates savings are directly associated with the proportion of samples that are positive. If the TB prevalence is ≥ 30%, pooled testing is not cost-effective. CONCLUSION: Pooled sputum testing can be a cost-effective strategy for diagnosis of TB, resulting in significant resource savings. This approach could increase testing capacity and affordability in resource-limited settings and support increased testing towards achievement of WHO End TB strategy.

Systematic Review of Pooling Sputum as an Efficient Method for Xpert MTB/RIF Tuberculosis Testing during the COVID-19 Pandemic.

GeneXpert-based testing with Xpert MTB/RIF or Ultra assays is essential for tuberculosis diagnosis. However, testing may be affected by cartridge and staff shortages. More efficient testing strategies could help, especially during the coronavirus disease pandemic. We searched the literature to systematically review whether GeneXpert-based testing of pooled sputum samples achieves sensitivity and specificity similar to testing individual samples; this method could potentially save time and preserve the limited supply of cartridges. From 6 publications, we found 2-sample pools using Xpert MTB/RIF had 87.5% and 96.0% sensitivity (average sensitivity 94%; 95% CI 89.0%-98.0%) (2 studies). Four-sample pools averaged 91% sensitivity with Xpert MTB/RIF (2 studies) and 98% with Ultra (2 studies); combining >4 samples resulted in lower sensitivity. Two studies reported that pooling achieved 99%-100% specificity and 27%-31% in cartridge savings. Our results show that pooling may improve efficiency of GeneXpert-based testing.

IgG Seroconversion and Pathophysiology in Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

Saliva Alternative to Upper Respiratory Swabs for SARS-CoV-2 Diagnosis.

PCR of upper respiratory specimens is the diagnostic standard for severe acute respiratory syndrome coronavirus 2 infection. However, saliva sampling is an easy alternative to nasal and throat swabbing. We found similar viral loads in saliva samples and in nasal and throat swab samples from 110 patients with coronavirus disease.

Clinical characteristics and risk factors of patients with severe COVID-19 in Jiangsu province, China: a retrospective multicentre cohort study.

BACKGROUND: Coronavirus Disease-2019 (COVID-19) pandemic has become a major health event that endangers people health throughout China and the world. Understanding the factors associated with COVID-19 disease severity could support the early identification of patients with high risk for disease progression, inform prevention and control activities, and potentially reduce mortality. This study aims to describe the characteristics of patients with COVID-19 and factors associated with severe or critically ill presentation in Jiangsu province, China. METHODS: Multicentre retrospective cohort study of all individuals with confirmed Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections diagnosed at 24 COVID-19-designated hospitals in Jiangsu province between the 10th January and 15th March 2020. Demographic, clinical, laboratory, and radiological data were collected at hospital admission and data on disease severity were collected during follow-up. Patients were categorised as asymptomatic/mild/moderate, and severe/critically ill according to the worst level of COVID-19 recorded during hospitalisation. RESULTS: A total of 625 patients, 64 (10.2%) were severe/critically ill and 561 (89.8%) were asymptomatic/mild/moderate. All patients were discharged and no patients died. Patients with severe/critically ill COVID-19 were more likely to be older, to be single onset (i.e. not belong to a cluster of cases in a family/community, etc.), to have a medical history of hypertension and diabetes; had higher temperature, faster respiratory rates, lower peripheral capillary oxygen saturation (SpO2), and higher computer tomography (CT) image quadrant scores and pulmonary opacity percentage; had increased C-reactive protein, fibrinogen, and D-dimer on admission; and had lower white blood cells, lymphocyte, and platelet counts and albumin on admission than asymptomatic/mild/moderate cases. Multivariable regression showed that odds of being a severe/critically ill case were associated with age (year) (OR 1.06, 95%CI 1.03-1.09), lymphocyte count (109/L) (OR 0.25, 95%CI 0.08-0.74), and pulmonary opacity in CT (per 5%) on admission (OR 1.31, 95%CI 1.15-1.51). CONCLUSIONS: Severe or critically ill patients with COVID-19 is about one-tenths of patients in Jiangsu. Age, lymphocyte count, and pulmonary opacity in CT on admission were associated with risk of severe or critically ill COVID-19.

Prolonged Fecal Shedding of SARS-CoV-2 in Pediatric Patients: A Quantitative Evidence Synthesis.

The aim of the study was to investigate differences in viral shedding in respiratory and fecal samples from children with novel coronavirus disease 19. We searched PubMed, SCOPUS, Embase, and Web of Science databases to identify pediatric studies comparing the pattern of fecal and respiratory shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA. Summary estimates were calculated using random-effects models. Four studies reporting data from 36 children were included. A higher proportion of children had viral shedding in stools after 14 days of symptoms onset compared to respiratory samples (risk ratio = 3.2, 95% confidence interval 1.2-8.9, I2 = 51%). Viral RNA shedding was longer in fecal samples with a mean difference of approximately 9 days (mean difference = 8.6, 95% confidence interval 1.7-15.4, I2 = 77%) compared with respiratory samples. SARS-CoV-2 shedding seems to be present in feces for a longer time than in the respiratory tract of children. Although fecal SARS-CoV-2 presence in feces do not confirm its transmissibility, the high and fast spread of the novel coronavirus disease 19 worldwide indicate other transmission routes are also plausible.

Yield of household contact investigation of patients with pulmonary tuberculosis in southern Ethiopia.

BACKGROUND: Household Contacts (HHCs) of patients with pulmonary tuberculosis (PTB) have a higher risk of developing TB. Contact investigation is recommended to reach this group and identify undiagnosed cases. In this study, we have determined the yield of contact investigation among HHCs of patients with smear-positive PTB, and estimated TB burden. METHODS: We conducted retrospective record review for the occurrence of TB among HHCs of Index PTB+ cases treated between November 2010 and April 2013 in 12 public health facilities in Boricha district. HHCs were followed up monthly and revisited between March and June 2015. Information on additional TB cases diagnosed and treated among HHCs were documented. HHCs who were diagnosed as having TB after the index cases were diagnosed and treated were considered as 'incident cases'. Presumptive TB case was defined as those having cough for ≥2 weeks or enlarged lymph node. Diagnosis of TB among HHCs were made using smear-microscopy and/or X-rays, and clinically for Extra-pulmonary TB (EPTB). RESULTS: One thousand five hundred and seventeenth HHCs of 344 index cases were visited and screened for TB and followed up for a median of 37 months. 77 (5.1% - 72 with PTB and 5 with EPTB) HHCs developed TB during 4713 person-years of follow-up with an estimated incidence of 1634 (95% CI: 1370-2043) per 100,000 person-years follow-up which is much higher than the estimated TB incidence for the general population in Ethiopia of 210/100,000. Half (41/77) of incident TB cases were diagnosed within the first year of diagnosis of the index cases and 88% (68/77) were adults (Hazard Ratio: 4.03; 95% CI: 2.00-8.12). CONCLUSION: HHCs of index PTB+ cases have high risk of developing active TB. Long term follow-up of HHCs could help improve TB case finding depending on country contexts. Further studies on effectiveness and feasibility of the approach and integration in routine settings are needed.

Interventions to increase tuberculosis case detection at primary healthcare or community-level services.

BACKGROUND: Pulmonary tuberculosis is usually diagnosed when symptomatic individuals seek care at healthcare facilities, and healthcare workers have a minimal role in promoting the health-seeking behaviour. However, some policy specialists believe the healthcare system could be more active in tuberculosis diagnosis to increase tuberculosis case detection. OBJECTIVES: To evaluate the effectiveness of different strategies to increase tuberculosis case detection through improving access (geographical, financial, educational) to tuberculosis diagnosis at primary healthcare or community-level services. SEARCH METHODS: We searched the following databases for relevant studies up to 19 December 2016: the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library, Issue 12, 2016; MEDLINE; Embase; Science Citation Index Expanded, Social Sciences Citation Index; BIOSIS Previews; and Scopus. We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and the metaRegister of Controlled Trials (mRCT) for ongoing trials. SELECTION CRITERIA: Randomized and non-randomized controlled studies comparing any intervention that aims to improve access to a tuberculosis diagnosis, with no intervention or an alternative intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and risk of bias, and extracted data. We compared interventions using risk ratios (RR) and 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included nine cluster-randomized trials, one individual randomized trial, and seven non-randomized controlled studies. Nine studies were conducted in sub-Saharan Africa (Ethiopia, Nigeria, South Africa, Zambia, and Zimbabwe), six in Asia (Bangladesh, Cambodia, India, Nepal, and Pakistan), and two in South America (Brazil and Colombia); which are all high tuberculosis prevalence areas.Tuberculosis outreach screening, using house-to-house visits, sometimes combined with printed information about going to clinic, may increase tuberculosis case detection (RR 1.24, 95% CI 0.86 to 1.79; 4 trials, 6,458,591 participants in 297 clusters, low-certainty evidence); and probably increases case detection in areas with tuberculosis prevalence of 5% or more (RR 1.52, 95% CI 1.10 to 2.09; 3 trials, 155,918 participants, moderate-certainty evidence; prespecified stratified analysis). These interventions may lower the early default (prior to starting treatment) or default during treatment (RR 0.67, 95% CI 0.47 to 0.96; 3 trials, 849 participants, low-certainty evidence). However, this intervention may have may have little or no effect on treatment success (RR 1.07, 95% CI 1.00 to 1.15; 3 trials, 849 participants, low-certainty evidence), and we do not know if there is an effect on treatment failure or mortality. One study investigated long-term prevalence in the community, but with no clear effect due to imprecision and differences in care between the two groups (RR 1.14, 95% CI 0.65 to 2.00; 1 trial, 556,836 participants, very low-certainty evidence).Four studies examined health promotion activities to encourage people to attend for screening, including mass media strategies and more locally organized activities. There was some increase, but this could have been related to temporal trends, with no corresponding increase in case notifications, and no evidence of an effect on long-term tuberculosis prevalence. Two studies examined the effects of two to six nurse practitioner educational sessions in tuberculosis diagnosis, with no clear effect on tuberculosis cases detected. One trial compared mobile clinics every five days with house-to-house screening every six months, and showed an increase in tuberculosis cases.There was also insufficient evidence to determine if sustained improvements in case detection impact on long-term tuberculosis prevalence; this was evaluated in one study, which indicated little or no effect after four years of either contact tracing, extensive health promotion activities, or both (RR 1.31, 95% CI 0.75 to 2.30; 1 study, 405,788 participants in 12 clusters, very low-certainty evidence). AUTHORS' CONCLUSIONS: The available evidence demonstrates that when used in appropriate settings, active case-finding approaches may result in increase in tuberculosis case detection in the short term. The effect of active case finding on treatment outcome needs to be further evaluated in sufficiently powered studies.

Human Immunodeficiency Virus and Risk of Type 2 Diabetes in a Large Adult Cohort in Jos, Nigeria.

BACKGROUND: Human immunodeficiency virus (HIV) infection and the use of antiretroviral therapy (ART) may increase the risk of type 2 diabetes mellitus (T2DM). However, data from regions with a high burden of HIV/AIDS are limited. We determined the prevalence of T2DM at the time of presentation to a large HIV clinic in Nigeria, as well as the incidence of diabetes 12 months following ART initiation. METHODS: Data from patients enrolled for ART from 2011 to 2013 was analyzed, including 2632 patients on enrollment and 2452 reevaluated after 12 months of ART commencement. The presence of diabetes, and demographic, clinical, and biochemical data were retrieved from standardized databases. CD4(+), HIV RNA load, and hepatitis C virus status were noted. Bivariate and logistic regressions were used to identify risk factors for T2DM. RESULTS: Baseline T2DM prevalence was 2.3% (95% confidence interval, 1.8%-2.9%); age, but not body mass index (BMI), was a risk factor for diabetes. After 12 months of ART, an additional 5.3% had developed T2DM. Newly developed diabetes was not associated with age, but was associated with BMI. There were no significant associations between prevalent or incident diabetes and CD4(+), viral load, or type of ART. CONCLUSIONS: Diabetes is not uncommon in HIV-infected individuals at the time of presentation to HIV services. Patients initiating ART have a high risk of developing diabetes in the first year of ART. Excessive weight gain should be avoided, as incident diabetes was associated with a BMI ≥25.0 kg/m(2).

Co-infections with Chikungunya and Dengue Viruses, Guatemala, 2015.

We screened serum samples referred to the national reference laboratory in Guatemala that were positive for chikungunya or dengue viruses in June 2015. Co-infection with both viruses was detected by reverse transcription PCR in 46 (32%) of 144 samples. Specimens should be tested for both arboviruses to detect co-infections.

Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update.

Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspected of having intrathoracic tuberculosis. The changes proposed should enhance harmonized classification for intrathoracic tuberculosis disease in children across studies, resulting in greater comparability and the much-needed ability to pool study results.

A Blueprint to Address Research Gaps in the Development of Biomarkers for Pediatric Tuberculosis.

Childhood tuberculosis contributes significantly to the global tuberculosis disease burden but remains challenging to diagnose due to inadequate methods of pathogen detection in paucibacillary pediatric samples and lack of a child-specific host biomarker to identify disease. Accurately diagnosing tuberculosis in children is required to improve case detection, surveillance, healthcare delivery, and effective advocacy. In May 2014, the National Institutes of Health convened a workshop including researchers in the field to delineate priorities to address this research gap. This blueprint describes the consensus from the workshop, identifies critical research steps to advance this field, and aims to catalyze efforts toward harmonization and collaboration in this area.

Testing Pooled Sputum with Xpert MTB/RIF for Diagnosis of Pulmonary Tuberculosis To Increase Affordability in Low-Income Countries.

Tuberculosis (TB) is a global public health problem, with the highest burden occurring in low-income countries. In these countries, the use of more sensitive diagnostics, such as Xpert MTB/RIF (Xpert), is still limited by costs. A cost-saving strategy to diagnose other diseases is to pool samples from various individuals and test them with single tests. The samples in positive pool samples are then retested individually to identify the patients with the disease. We assessed a pooled testing strategy to optimize the affordability of Xpert for the diagnosis of TB. Adults with presumptive TB attending hospitals or identified by canvassing of households in Abuja, Nigeria, were asked to provide sputum for individual and pooled (4 per pool) testing. The agreement of the results of testing of individual and pooled samples and costs were assessed. A total of 738 individuals submitted samples, with 115 (16%) being Mycobacterium tuberculosis positive. Valid Xpert results for individual and pooled samples were available for 718 specimens. Of these, testing of pooled samples detected 109 (96%) of 114 individual M. tuberculosis-positive samples, with the overall agreement being 99%. Xpert semiquantitative M. tuberculosis levels had a positive correlation with the smear grades, and the individual sample-positive/pooled sample-negative results were likely due to the M. tuberculosis concentration being below the detection limit. The strategy reduced cartridge costs by 31%. Savings were higher with samples from individuals recruited in the community, where the proportion of positive specimens was low. The results of testing of pooled samples had a high level of agreement with the results of testing of individual samples, and use of the pooled testing strategy reduced costs and has the potential to increase the affordability of Xpert in countries with limited resources.

Tuberculosis case detection in Nigeria, the unfinished agenda.

OBJECTIVE: Underdetection of TB is a major problem in sub-Saharan Africa. WHO recommends countries should have at least 1 laboratory per 100,000 population. However, this recommendation is not evidence based. METHODS: We analysed surveillance data of the Nigerian National TB Control Programme (2008-2012) to describe TB case detection rates, their geographical distribution and their association with the density of diagnostic laboratories and HIV prevalence. RESULTS: The median CDR was 17.7 (range 4.7-75.8%) in 2008, increasing to 28.6% (range 10.6-72.4%) in 2012 (P < 0.01). The CDR2012 was associated with the 2008 baseline; however, states with CDR2008 < 30% had larger increases than states with CDR2008 > 30. There were 990 laboratories in 2008 and 1453 in 2012 (46.7% increase, range by state -3% to +118). The state CDR2012 could be predicted by the laboratory density (P < 0.001), but was not associated with HIV prevalence or the proportion of smear-positive cases. CDR2012 and laboratory density were correlated among states having < and > than 1 laboratory per 100,000 population. CONCLUSION: There are large variations in laboratory density and CDR across the Nigerian states. The CDR is associated with the laboratory density. A much larger number of diagnostic centres are needed. It is likely that a laboratory density above the recommended WHO guideline would result in even higher case detection, and this ratio should be considered a minimum threshold.

Patient and community experiences of tuberculosis diagnosis and care within a community-based intervention in Ethiopia: a qualitative study.

BACKGROUND: The Ethiopian TB control programme relies on passive case finding of TB cases. The predominantly rural-based population in Ethiopia has limited access to health facilities creating barriers to TB services. An intervention package aimed to bring TB diagnosis and treatment services closer to communities has been implemented through partnership with health extension workers (HEWs). They undertook advocacy, communication and social mobilization (ACSM) activities, identified symptomatic individuals, collected sputum, prepared smears and fixed slides at community level. Field supervisors supported HEWs by delivering smeared slides to the laboratory, feeding back results to the HEWs and following up smear-negative cases. Patients diagnosed with TB initiated treatment in the community, they were supported by supervisors and HEWs through the local health post. Case notification increased from 64 to 127/100,000 population/year. METHODS: This qualitative study assessed community members' treatment seeking behaviour and their perceptions of the intervention. In-depth interviews (n=36) were undertaken with participants in six districts. Participants were clients of the community-based intervention, currently on TB treatment or those screened negative for TB. Transcripts were translated to English and a thematic analytical framework was developed guided by the different steps symptomatic individuals take within the intervention package. Coding was done and queries run using NVivo software. RESULTS: Prior to the intervention many patients with chronic cough did not access TB services. Participants described difficulties they faced in accessing district level health facilities that required travel outside their communities. Giving sputum samples and receiving results from within their home communities was appreciated by all participants. The intervention had a high level of acceptability; particularly clear benefits emerged for poor women and men and those too weak to travel. Some participants appeared to prefer a diagnosis of TB, this is likely because receiving a negative smear microscopy result brought further uncertainty and necessitated seeking further investigation. CONCLUSIONS: There is evidence rural populations with high levels of poverty, and in particular women, are at high risk of unmet health needs and undiagnosed TB. Embedding TB services within communities was an acceptable approach for vulnerable groups experiencing poor access to health facilities. In the Ethiopian context this approach can facilitate early diagnosis and improve treatment outcomes.

Exploring providers' perspectives of a community based TB approach in Southern Ethiopia: implication for community based approaches.

BACKGROUND: There is increasing interest in the role of close-to-community providers in supporting universal health coverage, but questions remain about the best approaches to supporting and motivating these providers, and the optimal package they can deliver indifferent contexts and support required. We report on the experiences of different health providers involved in a community based intervention to support access to tuberculosis diagnosis and treatment in Southern Ethiopia. METHODS: The aim of the study is to explore the experiences of health providers in delivering a community-based tuberculosis package in southern Ethiopia and to draw lessons for community-based programmes. A qualitative methodology was used. Methods included in-depth interviews (IDIs, n= 37) with all health provider groups: Community health promoters (CHPs), health extension workers (HEWs), district supervisors and laboratory technicians were undertaken to obtain a detailed understanding of the experiences of providers in the community based tuberculosis package. These were complemented with cadre specific focus group discussions (n= 3). We used the framework approach for qualitative analysis. RESULTS: The key theme that emerged was the positive impact the community-based intervention had on vulnerable groups' access to diagnosis, care and treatment for tuberculosis. Providers found the positive feedback from, and visible impact on, communities very motivating. Other themes related to motivation and performance included supervision and support; learning new skills; team problem solving/ addressing challenges and incentives. Against the backdrop of the Ethiopian Health Extension Programme (HEP), HEWs were successfully able to take on new tasks (collecting sputum and preparing smears) with additional training and appropriate support from supervisors, laboratory technicians and CHPs. CONCLUSION: All categories of providers were motivated by the high visible impact of the community-based intervention on poor and vulnerable communities and households. HEWs role in the community-based intervention was supported and facilitated through the structures and processes established within the community-based intervention and the broader nation-wide Health Extension Programme. Within community based approaches there is need to develop context embedded strategies to support, sustain and motivate this critical cadre who play a pivotal role in linking health systems and rural communities.

Reduction in Rotavirus Disease and Sustained Predominance of G2P[4] Rotavirus Strain following Introduction of Rotavirus Vaccine in Recife, Brazil.

Rotavirus vaccination was introduced in Brazil in March 2006. We describe the distribution of rotavirus genotypes in children with acute gastroenteritis in a hospital in Recife, Brazil, during pre- and post-vaccination periods. There was a 43.8% reduction in the proportion of diarrhea episodes due to rotavirus. Nevertheless, we observed a sustained predominance of G2P[4] as the main genotype identified in the post-vaccination period.

Use of tuberculin skin test, IFN-γ release assays and IFN-γ-induced protein-10 to identify children with TB infection.

Current tests of tuberculosis (TB) infection (tuberculin skin test (TST), interferon (IFN)-γ-release assays (IGRAs) and IFN-γ-induced protein (IP)-10) have limitations and their value when used consecutively to identify infected children has not been explored. This study describes TST, IGRA and IP-10 responses in children in contact with adults with TB, the agreement of the tests and whether using multiple tests indentifies more infected children. 330 children (aged 1-15 yrs) in contact with adults with pulmonary TB and 156 controls were studied in Ethiopia. Children exposed to adults with high bacilli grades in sputum were more likely to have positive TST, IFN-γ and IP-10 than controls. The agreement of positive tests was directly associated with the sputum bacilli grades (p<0.001 for all). The agreement of negative tests was higher in control children. The consecutive use of the tests increased the number of children classified as having at least one positive test. Using three tests increases the number of children classified as infected. This increase is associated with the bacilli load of the adults. Using only one test may underestimate the proportion of infected children, but the interpretation of the data is difficult due to the lack of reference standards.

Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel.

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.